Geriatric

Neurology
edited by
anil k. nair | marwan n. sabbagh
Geriatric Neurology
I dedicate this book to my patients and mentors. This book would not be
possible without my grandfather who carried me on his shoulders daily to an
elementary school miles away and my very supportive family.

AKN

I dedicate this work to my mother and father, who nurtured my unquenchable

thirst for knowledge.
MNS
Geriatric
Neurology
EDI T ED BY

ANIL K. NA IR MD
Director, Clinic for Cognitive Disorders
and Alzheimer’s Disease Center
Chief of Neurology, Quincy Medical Center
Quincy, MA, USA

MARWAN N. SABBAGH MD, FAAN

Director, Banner Sun Health Research Institute
Research Professor of Neurology
University of Arizona College of Medicine – Phoenix
Sun City, AZ, USA
This edition first published 2014
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Library of Congress Cataloging-in-Publication Data

Geriatric neurology (Nair)
Geriatric neurology/edited by Anil K. Nair and Marwan N. Sabbagh.
1 online resource.
Includes bibliographical references and index.
Description based on print version record and CIP data provided by publisher; resource not viewed.
ISBN 978-1-118-73064-5 (ePub) – ISBN 978-1-118-73065-2 (Adobe PDF) – ISBN 978-1-118-73068-3 (cloth)
I. Nair, Anil (Anil Kadoor), 1970- editor of compilation. II. Sabbagh, Marwan Noel, editor of
compilation. III. Title.
[DNLM: 1. Nervous System Diseases. 2. Aged. 3. Aging–physiology. 4. Nervous System
Physiological Phenomena. WL 140]
RC451.4.A5
618.97’68–dc23
2013038615
A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print
may not be available in electronic books.

Cover images: top row - copyright Wiley; bottom - courtesy of Anil K. Nair
Cover design by Andy Meaden

Set in 9.25/12 pt Palatino by Aptara Inc., New Delhi, India

1 2014
 Contents
About the Editors, vii
List of Contributors, viii
Preface, xii
Acknowledgments, xiii
Part 1 The Aging Brain in Neurology, 1
1 The Biology of Aging: Implications for Diseases
of Aging and Health Care in the Twenty-First
Century, 3
Douglas F. Watt
2 Functional Changes Associated with the Aging
Nervous System, 38
Julie A. Schneider and Chunhui Yang
Part 2 Assessment of the Geriatric Neurology
Patient, 69
3 Approach to the Geriatric Neurology Patient: The
Neurologic Examination, 71
Marwan N. Sabbagh and Anil K. Nair
4 Assessment of Cognitive Status in Geriatric
Neurology, 85
4.1 Mental Status Examination in the Geriatric
Neurology Patient, 87
Papan Thaipisuttikul and James E. Galvin
4.2 Neuropsychology in Geriatric Neurology, 98
Donald J. Connor and Marc A. Norman
5 Cognitive Reserve and the Aging Brain, 118
Adrienne M. Tucker and Yaakov Stern
6 Gait Disorders in the Graying Population, 126
Joe Verghese and Jessica Zwerling
7 Imaging of the Geriatric Brain, 136
7.1 Structural Neuroimaging in Degenerative
Dementias, 138
Liana G. Apostolova
7.2 Functional Imaging in Dementia, 146
Adam S. Fleisher and Alexander Drzezga
7.3 Amyloid Imaging, 162
Anil K. Nair and Marwan N. Sabbagh
8 Clinical Laboratory Investigations in Geriatric
Neurology, 170
Geoffrey S. Baird and Thomas J. Montine
Part 3 Neurologic Conditions in the
Elderly, 181
9 Cognitive Impairment and the Dementias, 183
9.1 Mild Cognitive Impairment, 187
Ranjan Duara, Miriam Jocelyn Rodriguez, and
David A. Loewenstein
9.2 Alzheimer’s Disease, 200
Martin R. Farlow
9.3 Dementia with Lewy Bodies, 208
Clive Ballard
9.4 Vascular Cognitive Impairment, 224
Helena C. Chui and Freddi Segal-Gidan
9.5 Frontotemporal Dementia, 239
David Perry and Howard Rosen
9.6 Primary Progressive Aphasia, 251
Maya L. Henry, Stephen M. Wilson,
and Steven Z. Rapcsak
9.7 Prion Diseases, 267
Michael D. Geschwind and Katherine Wong
9.8 Normal Pressure Hydrocephalus, 281
Norman R. Relkin
10 Depression in the Elderly: Interactions with
Aging, Stress, Chronic Pain, Inflammation, and
Neurodegenerative Disorders, 287
Douglas F. Watt
11 Cerebrovascular Diseases in Geriatrics, 302
Patrick Lyden, Khalil Amir and Ilana Tidus
v
vi Contents
12 Movement Disorders, 313
12.1 Parkinson’s Disease, 315
Robert Fekete and Joseph Jankovic
12.2 Essential Tremor and Other Tremor
Disorders, 325
Holly Shill
12.3 Progressive Supranuclear Palsy, 333
Virgilio Gerald H. Evidente
12.4 Corticobasal Degeneration, 344
Katrina Gwinn
13 Sleep Disorders, 347
Sanford Auerbach
14 Autonomic Dysfunction and Syncope, 358
Rohit R. Das
15 Geriatric Epilepsy, 370
David V. Lardizabal
16 Vertigo and Dizziness in the Elderly, 379
Terry D. Fife and Salih Demirhan
17 Disorders of the Special Senses in the Elderly, 396
Douglas J. Lanska
18 Nervous System Infections, 460
Ronald Ellis, David Croteau, and Suzi Hong
19 Delirium, 478
Alan Lerner, Stefani Parrisbalogun, and Joseph Locala
20 Headache in the Elderly, 486
Brian McGeeney
21 Neuromuscular Disorders, 494
Heber Varela and Clifton Gooch
Part 4 Therapeutics for the Geriatric
Neurology Patient, 519
22 Neurosurgical Care of the Geriatric Patient, 521
David Fusco, Rasha Germain, and Peter Nakaji
23 Treatment of Dementia, 556
Color plate section appears between pages 50 and 51
23.1 Evidence-Based Pharmacologic Treatment of
Dementia, 557
Jasmeet Singh, Marwan N. Sabbagh, and
Anil K. Nair
23.2 Immunotherapy for Alzheimer’s Disease, 574
Michael Grundman, Gene G. Kinney, Eric Yuen,
and Ronald Black
24 Geriatric Psychopharmacology, 586
Sandra A. Jacobson
25 Nonpharmacologic Treatment of Behavioral
Problems in Persons with Dementia, 615
Gary A. Martin and John Ranseen
26 Expressive Art Therapies in Geriatric
Neurology, 630
Daniel C. Potts, Bruce L. Miller, Carol A. Prickett,
Andrea M. Cevasco, and Angel C. Duncan
Part 5 Important Management Issues Beyond
Therapeutics in the Geriatric Neurology
Patient, 645
27 Dietary Factors in Geriatric Neurology, 647
Yian Gu and Nikolaos Scarmeas
28 Exercising the Brain: Nonpharmacologic
Interventions for Cognitive Decline Associated
with Aging and Dementia, 669
Brenna A. Cholerton, Jeannine Skinner, and
Laura D. Baker
29 Driving Impairment in Older Adults, 682
Anne D. Halli-Tierney and Brian R. Ott
30 Elder Abuse and Mistreatment, 699
Elliott Schulman, Ashley Roque, and Anna Hohler
31 Advocacy in Geriatric Neurology, 707
Glenn Finney and Anil K. Nair
Index, 713
 About the Editors
Anil K. Nair, MD, is the director of TheAlzCenter.org
and chief of neurology at Quincy Medical Center. He is
also the site director for clinical trials in neurology. He
completed his fellowship from Mayo Clinic, Rochester,
MN, and his neurology residency at the Cleveland Clinic
and Temple University after graduation from JIPMER,
Pondicherry, India. His interest area is early and preclin-
ical detection, prevention, and treatment of Alzheimer’s
dementia, and other neurocognitive disorders and
dementias.
Dr. Nair oversees the clinical and research facil-
ity called TheAlzCenter.org (The Alzheimer’s Center)
serving the south shore of Boston. The center aims to
advance the field of geriatric neurology and reduce the
costs of debilitating diseases such as Alzheimer’s dis-
ease and other related dementias. In addition to provid-
ing preventive, diagnostic, and therapeutic services to
patients with neurodegenerative and related diseases,
Dr. Nair runs clinical trials in multiple indications, pri-
marily in Alzheimer’s disease. He is dedicated to pro-
viding healthcare and referral services of the highest
quality and is committed to building partnerships that
increase the independence and quality of life for patients
with dementia.
Dr. Nair is also an investigator for the stroke and mem-
ory project at the Framingham Heart Study, which aims
to identify the risk factors involved in such diseases as
Alzheimer’s disease and related dementias.
Marwan N. Sabbagh, MD, FAAN, is a board-certified
neurologist and geriatric neurologist. As the director of
the Banner Sun Health Research Institute, Dr. Sabbagh has
dedicated his entire career to finding a cure for Alzheimer’s
and other age-related neurodegenerative diseases.
Dr. Sabbagh is a leading investigator for many promi-
nent national Alzheimer’s prevention and treatment tri-
als. He is senior editor for Journal of Alzheimer’s Disease,
BMC Neurology, and Clinical Neurology News, and has
authored and coauthored more than 200 medical and sci-
entific chapters, reviews, original research articles, and
abstracts on Alzheimer’s research. Dr. Sabbagh has also
authored The Alzheimer’s Answer—the book’s foreword
was written by Justice Sandra Day O’Connor—and edited
Palliative Care for Advanced Alzheimer’s and Dementia:
Guidelines and Standards for Evidence Based Care and coau-
thored The Alzheimer's Prevention Cookbook: Recipes to Boost
Brain Health (RandomHouse/TenSpeed, 2012).
Dr. Sabbagh is research professor in the Department of
Neurology, University of Arizona College of Medicine–
Phoenix. He is also an adjunct professor at Midwestern
University and Arizona State University. He earned his
undergraduate degree from the University of California
Berkeley and his medical degree from the University of
Arizona in Tucson. He received his internship at the Ban-
ner Good Samaritan Regional Medical Center in Phoenix,
AZ, and his residency training in neurology at Baylor
College of Medicine in Houston, TX. He completed his
fellowship in geriatric neurology and dementia at the
UCSD School of Medicine.
vii
 List of Contributors

Khalil Amir MD Helena C. Chui MD

Department of Neurology Department of Neurology
Cedars-Sinai Medical Centre Keck School of Medicine
Los Angeles, CA, USA University of Southern California
Los Angeles, CA, USA
Liana G. Apostolova MD, MS
Department of Neurology Donald J. Connor PhD, PhD
David Geffen School of Medicine Independent Practice
University of California Consultant in Clinical Trials
Los Angeles, CA, USA San Diego, CA, USA

Sanford Auerbach MD David Croteau MD

Departments of Neurology Department of Neurosciences and
Psychiatry and Behavioral Neurosciences HIV Neurobehavioral Research Center
Boston University School of Medicine University of California
Boston, MA, USA San Diego, CA, USA

Geoffrey S. Baird MD Rohit R. Das MD, MPH

Departments of Laboratory Medicine and Pathology Indiana University School of Medicine
University of Washington Indianapolis, IN, USA
Seattle, WA, USA
Salih Demirhan MD
Laura D. Baker PhD Marmara University School of Medicine
Department of Medicine - Geriatrics Istanbul, Turkey
Wake Forest School of Medicine
Winston-Salem, NC, USA Alexander Drzezga MD
Department of Nuclear Medicine
Clive Ballard MBChB MMedSci MRCPsych MD University Hospital of Cologne
Wolfson Centre for Age-Related Diseases Cologne, Germany
King’s College London
London, UK Ranjan Duara MD, FAAN
Wien Center for Alzheimer's Disease and
Ronald Black MD Memory Disorders Mount Sinai Medical Center
Chief Medical Officer Miami Beach;
Probiodrug AG Department of Neurology
Halle, Germany Herbert Wertheim College of Medicine
Florida International University, Miami
Andrea M. Cevasco PhD, MT-BC and University of Florida College of Medicine
School of Music University of Florida
College of Arts and Sciences Gainesville, FL, USA
University of Alabama
Tuscaloosa, AL, USA Angel C. Duncan MA-MFT, ATR
Cognitive Dynamics Foundation
Brenna A. Cholerton PhD Neuropsychiatric Research Center of
Department of Psychiatry and Behavioral Science Southwest Florida
University of Washington School of Medicine Albertus Magnus College
and Geriatric Research, Education, and Clinical Center American Art Therapy Association
Veterans Affairs Puget Sound Health Care System Fort Myers, FL, USA
Seattle, WA, USA

viii
 List of Contributors ix

Ronald Ellis MD, PhD Clifton Gooch MD, FAAN

Department of Neurosciences and Department of Neurology
HIV Neurobehavioral Research Center University of South Florida College of Medicine
University of California Tampa, FL, USA
San Diego, CA, USA
Michael Grundman MD, MPH
Virgilio Gerald H. Evidente MD President, Global R&D Partners, LLC
Movement Disorders Center of Arizona San Diego, CA, USA
Ironwood Square Drive
Scottsdale, AZ, USA Yian Gu PhD
Taub Institute for Research on Alzheimer’s Disease and
Martin R. Farlow MD the Aging Brain
Department of Neurology Columbia University Medical Center
Indiana University New York, NY, USA
Indianapolis, IN, USA
Katrina Gwinn MD
Robert Fekete MD National Institute of Neurological Disorders and Stroke
Department of Neurology National Institutes of Health
New York Medical College Bethesda, MD, USA
Valhalla, NY, USA
Anne D. Halli-Tierney MD
Terry D. Fife MD, FAAN Warren Alpert Medical School of Brown University
Barrow Neurological Institute Rhode Island Hospital
and Department of Neurology Providence, RI, USA
University of Arizona College of Medicine
Phoenix, AZ, USA Maya L. Henry PhD
Department of Communication Sciences and Disorders
Glenn Finney MD University of Texas at Austin and Memory
Department of Neurology and Aging Center
McKnight Brain Institute Department of Neurology
Gainesville, FL, USA University of California
San Francisco, CA, USA
Adam S. Fleisher MD, MAS
Banner Alzheimer's Institute Anna Hohler MD
Department of Neurosciences Department of Neurology
University of California Boston University School of Medicine
San Diego, CA, USA Boston, MA, USA

David Fusco MD Suzi Hong PhD

Division of Neurological Surgery Department of Psychiatry
Barrow Neurological Institute School of Medicine
St. Joseph’s Hospital and Medical Center University of California
Phoenix, AZ, USA San Diego, CA, USA

James E. Galvin MD, MPH Sandra A. Jacobson MD

Department of Neurology University of Arizona College of Medicine-Phoenix
and Department of Psychiatry Banner Sun Health Research Institute and
New York University Langone Medical Center Cleo Roberts Center for Clinical Research
New York, NY, USA Sun City, AZ, USA

Rasha Germain MD Joseph Jankovic MD

Division of Neurological Surgery
Barrow Neurological Institute
St. Joseph’s Hospital and Medical Center
Phoenix, AZ, USA
Michael D. Geschwind
Memory and Aging Center
Department of Neurology
University of California
San Francisco, CA, USA
Parkinson’s Disease Center and Movement
Disorders Clinic
Department of Neurology
Baylor College of Medicine
Houston, TX, USA
MD, PhD
Gene G. Kinney PhD
Chief Scientific Officer
Prothena Biosciences, Inc.
South San Francisco, CA, USA
x List of Contributors

Douglas J. Lanska MD, MS, MSPH, FAAN Marc A. Norman PhD, ABPP
Neurology Service Department of Psychiatry
Veterans Affairs Medical Center University of California
Great Lakes Health Care System San Diego, CA, USA
Tomah, WI, USA
Brian R. Ott MD
David V. Lardizabal MD Warren Alpert Medical School of Brown University
Epilepsy Program and Intraoperative Monitoring and The Alzheimer’s Disease and Memory Disorders Center
University of Missouri Rhode Island Hospital
Columbia, MO, USA Providence, RI, USA

Alan Lerner MD Stefani Parrisbalogun MD

Department of Neurology Rawson-Neal Psychiatric Hospital
Case Western Reserve University School of Medicine Las Vegas, NV, USA
Cleveland, OH, USA
David Perry MD
Joseph Locala MD Memory and Aging Center
Department of Psychiatry Department of Neurology
Case Western Reserve University School of Medicine School of Medicine
Cleveland, OH, USA University of California
San Francisco, USA
David A. Loewenstein PhD, ABPP
Department of Psychiatry and Behavioral Sciences Daniel C. Potts MD
Miller School of Medicine Cognitive Dynamics Foundation
University of Miami Veterans Affairs Medical Center
Miami, FL, USA The University of Alabama
Tuscaloosa, AL, USA
Patrick Lyden MD
Department of Neurology Carol A. Prickett PhD, MT-BC
Cedars-Sinai Medical Center School of Music
Los Angeles, CA, USA College of Arts and Sciences
University of Alabama
Gary A. Martin PhD Tuscaloosa, AL, USA
Integrated Geriatric Behavioral Health Associates
Scottsdale, AZ, USA John Ranseen PhD
Department of Psychiatry
Brian McGeeney MD University of Kentucky College of Medicine
Department of Neurology Lexington, KY, USA
Boston University School of Medicine
Boston, MA, USA Steven Z. Rapcsak MD
Department of Neurology
Bruce L. Miller MD University of Arizona
Memory and Aging Center Neurology Section
University of California Southern Arizona VA Health Care System
San Francisco, CA, USA Tucson, AZ, USA

Thomas J. Montine MD Norman R. Relkin MD, PhD

Departments of Pathology and Neurological Surgery Memory Disorders Program
University of Washington Department of Neurology
Seattle, WA, USA and Brain Mind Research Institute
Weill Cornell Medical College
Anil K. Nair MD New York, NY, USA
Clinic for Cognitive Disorders and Alzheimer’s Disease Center
Quincy Medical Center Miriam Joscelyn Rodriguez PhD
Quincy, MA, USA Wien Center for Alzheimer's Disease and Memory Disorders
Mount Sinai Medical Center
Peter Nakaji MD Miami Beach, FL, USA
Division of Neurological Surgery
Barrow Neurological Institute Ashley Roque MD
St. Joseph’s Hospital and Medical Center Boston University School of Medicine
Phoenix, AZ, USA Boston, MA, USA
 List of Contributors xi

Howard Rosen MD Papan Thaipisuttikul MD

Memory and Aging Center Department of Neurology
Department of Neurology and Department of Psychiatry
School of Medicine New York University Langone Medical Center
University of California New York, NY, USA
San Francisco, CA, USA
Ilana Tidus BSc
Marwan N. Sabbagh MD, FAAN Department of Neurology
Banner Sun Health Research Institute Cedars-Sinai Medical Centre
Sun City, AZ, USA Los Angeles, CA, USA

Nikolaos Scarmeas MD, MSc

Adrienne M. Tucker PhD
Cognitive Science Center Amsterdam
Taub Institute, Sergievsky Center
University of Amsterdam
Department of Neurology
Amsterdam, The Netherlands
Columbia University
New York, NY, USA
and Department of Social Medicine, Heber Varela MD
Department of Neurology
Psychiatry and Neurology
University of South Florida College of Medicine
National and Kapodistrian University of Athens
Tampa, FL, USA
Athens, Greece

Joe Verghese MD
Julie A. Schneider MD, MS
Department of Neurology and Medicine
Rush Alzheimer’s Disease Center
Albert Einstein College of Medicine
Department of Pathology and Department of
Bronx, NY, USA
Neurological Sciences
Rush University Medical Center
Douglas F. Watt PhD
Chicago, IL, USA
Department of Neuropsychology
Cambridge City Hospital, Harvard Medical School and
Elliott Schulman MD Alzheimer’s Disease Center/Clinic for Cognitive Disorders
Lankenau Institute for Medical Research Quincy Medical Center
Lankenau Medical Center Quincy, MA, USA
Wynnewood, PA, USA
Stephen M. Wilson PhD
Freddi Segal-Gidan PA, PhD Department of Speech
Department of Neurology Language and Hearing Sciences
Keck School of Medicine University of Arizona
University of Southern California Tucson, AZ, USA
Los Angeles, CA, USA
Katherine Wong BA
Holly Shill MD Memory and Aging Center
Banner Sun Health Research Institute Department of Neurology
Sun City, AZ, USA University of California
San Francisco, CA, USA
Jasmeet Singh MD, MPHA
Alzheimer’s Disease Center Chunhui Yang MD, PhD

Quincy Medical Center Rush Alzheimer’s Disease Center

Quincy, MA, USA and Department of Pathology
Rush University Medical Center
Chicago, IL, USA
Jeannine Skinner PhD
Department of Neurology
Eric Yuen MD
Vanderbilt School of Medicine
Clinical Development
Nashville, TN
Janssen Alzheimer Immunotherapy Research & Development
South San Francisco, CA, USA
Yaakov Stern PhD
Cognitive Neuroscience Division Jessica Zwerling MD
Department of Neurology Columbia Department of Neurology
University Medical Center Albert Einstein College of Medicine
New York, NY, USA Bronx, NY, USA
 Preface
As scientific knowledge about the nervous system and
neurological diseases explodes at an exponential rate, the
ability to master all aspects of neurology becomes increas-
ingly difficult. Because of this, neurology as a profession
is fragmenting much the same way that internal medicine
has, with many subspecialties of neurology emerging and
establishing themselves as board-recognized subspecial-
ties by the American Academy of Neurology and the
United Council of Neurological Subspecialties (UCNS).
Currently recognized subspecialties of the UCNS include
autonomic disorders, behavioral neurology and neuro-
psychiatry, clinical neuromuscular disease, headache
medicine, neural repair and rehabilitation, neurocritical
care, neuroimaging, and neuro-oncology. Other recog-
nized subspecialties include epilepsy, stroke, and move-
ment disorders.
For the past several years, the American Academy of
Neurology’s Geriatric Neurology section has been advo-
cating strongly for the creation of a boarded, recognized
subspecialty in geriatric neurology. This recommendation
was approved by the AAN and adopted by the UCNS.
Subsequently, the UCNS drafted a course outline for
examination purposes, convened an examining commit-
tee that drafted the exam questions, and has since proc-
tored three exam sessions. This book mirrors the new
board subspecialty of geriatric neurology within the larger
field of neurology. This project is written as a textbook for
an emerging field of neurology and provides evidence-
based scientific review of the current thinking in the field.
The content will be clearly articulated and summarized.
Geriatric neurology is the field of neurology dedi-
cated to age-related neurological diseases, including
xii
degenerative diseases (Alzheimer’s disease, Parkinson’s
disease, amyotrophic lateral sclerosis), gait and balance
disorders, neuropathies, stroke, and sleep disturbances.
Geriatric neurology is emerging as a subspecialty of neu-
rology. This emergence reflects the growing understand-
ing that geriatric patients have different neurological
conditions that require different diagnostic evaluations
and ultimately different features. Geriatric neurology is
not adult neurology redux. The field has similarities to
geriatrics and the approach to the geriatric patient is, by
definition, different. As such, clinical syndromes can have
features in common with younger patients but the etio-
logies are frequently different. Additionally, many neuro-
degenerative diseases are prevalent in the aged but less so
in general neurology.
This handbook is the summation of the field at pres-
ent. It follows the UCNS examination outline to an
extent in terms of topics covered. It covers all topics ger-
mane to geriatric neurology from disease-specific, neu-
roanatomical, diagnostic, and therapeutic perspectives.
The good news is that we have made tremendous strides
in understanding and managing the complications and
challenges of diseases that are encompassed within geri-
atric neurology. We now understand the neurological
changes that occur with age and the mechanisms that
contribute to changes. We hope it will enhance practice
skills and knowledge base for practitioners, residents,
and students.
Anil K. Nair
Marwan N. Sabbagh
 Acknowledgments

This work would not exist without the exhaustive efforts Wiley for their feedback, responsiveness, patience, and
of our contributors, who are the venerable authorities in support.
their respective fields. We would also like to thank our Finally, we would like to thank our spouses and chil-
assistants who were tireless and patient throughout— dren who endured our many late nights staying up writ-
Bonnie Tigner, Myste Havens, Deborah Nadler, Nicole ing and editing.
Chan, Roshni Patel, Sheela Chandrashekar, Ardriane
Hancock, Krystal Kan, and Vishakadutta Kumara- Anil K. Nair
swamy. We would like to thank the publishing team at Marwan N. Sabbagh

xiii
Part 1
The Aging Brain in Neurology
 Chapter 1
The Biology of Aging: Implications for
Diseases of Aging and Health Care in the
Twenty-First Century
Douglas F. Watt
Department of Neuropsychology Cambridge City Hospital, Harvard Medical School, and Alzheimer’s Center/Clinic for
Cognitive Disorders, Quincy Medical Center, Quincy, MA, USA

Summary
• Aging demographics, increasing penetration of diseases of aging, and the heightening expense of high technology
health-care interventions are creating exploding costs that are becoming economically unsustainable.
• Evolutionary theory suggests that aging is the fading out of adaptation once reproductive competence is achieved, and
reflects the lack of selection for a sustained post-reproductive adaptation.
• If extrinsic mortality is high in the natural environment, selection effects are less likely to promote organism
maintenance for extended periods. Alternatively, aging is simply change of the organism over time, and is primarily
under the control of the hypothalamic pituitary gonadotropin axis. Although traditionally viewed as opposing theories,
these may be simply different perspectives on the same process.
• Cellular and molecular theories attribute aging to a genetically modulated process, a consequence of “wear-and-tear”, or
a combination of both types of processes.
• Aging is probably a complex and recursive network of many changes.
• Molecular and cellular models of aging include: nuclear and mitochondrial and even ribosomal DNA damage, including
genomic instability, loss of epigenetic regulation, and mitochrondrial DNA deletion.
• Oxidative stress (OS) and associated mitochondrial dysfunction and decline
• Inflammation which is progressively disinhibited (‘inflammaging’)
• Glycation
• Declining autophagy
• Dysregulation of apoptosis
• Sarcopenia
• Cellular senescence
• Calorie or dietary restriction (CR/DR) has been shown to have positive effects in most but not all species on longevity
and aging.
• A network of interacting molecular pathways has been implicated in CR physiology. Sirtuins, a class of transcription
factors, are thought to play an important role in cell signaling and aging, in concert with mTOR, AMPK, PGC-1a, and
insulin signaling pathways.
• The target of rapamycin (TOR) signaling network influences growth, proliferation, and lifespan. Rapamycin, an
immunosuppressive macrolide, inhibits mammalian target of rapamycin (mTOR) and has been shown to increase lifespan.
• CR mimetics are substances that potentially mimic the molecular effects and physiology of CR. Resveratrol is the most
well known CR mimetic but only extends lifespan in obese animals.
• Genetic manipulation of growth hormone, IGF-1, and insulin signaling pathways may mimic CR effects.
• Lifestyle factors such as sleep, diet, exercise, and social support may affect a shared set of cellular and molecular
pathways.
• Exercise: elicits an acute anti-inflammatory response and inhibits production of proinflammatory cytokines.
Protective against disease associated with low grade systemic inflammation.
• Obesity: abdominal fat may contribute to the disinhibition of inflammation.
• Polyphenols, often regarded as antioxidants, affect cell physiology and cell signaling in a wide variety of ways that are
probably far more critical to their effects in mammalian physiology beyond any putative free radical scavenging.
• Healthy lifestyle practices match those of ancestral hunter gatherers (HGs), suggesting that diseases of aging may be
potentated by a mismatch between our genes and the modern environment.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

3
4 The Aging Brain in Neurology

Do not go gentle into that good night,

Old age should burn and rave at close of day;
Rage, rage against the dying of the light.
Dylan Thomas

Aging is arguably the most familiar

yet least-well understood aspect of human biology.
Murgatroyd, Wu, Bockmuhl, and Spengler (2009)

Old age is no place for sissies.

Bette Davis

Dedication: To my Dad, Richard F. Watt, who believed that the best scholarship and the best social values would
eventually reveal each other.

Introduction may exist due to the likely contribution of tribal elders to

Aging, now the focus of a rapidly expanding, if still
immature, biological science, remains one of the most
fundamental yet mysterious aspects of biology. The sci-
ence of aging has explored the cellular and molecular
basis of aging largely in three target organisms with fully
sequenced genomes and short lifespans (yeast, round-
worms, and fruit flies), as well as an increasing number
of in vivo studies in mammalian animal models. Evidence
argues that multiple pathways modulating aging in these
three target organisms are well conserved in mammals,
primates, and humans, although perhaps with additional
modifications. The science of aging has made progress in
describing and analyzing several critical phenotypes or
components of aging, including sarcopenia, glycation,
inflammation and oxidative stress (OS), endocrine dys-
crasia, apoptosis, telomere loss and cellular senescence,
genomic damage and instability, mitochondrial dysfunc-
tion and decline, and increasing junk protein and declin-
ing autophagy (removal of damaged or “junk” proteins).
Although the relationships among these various aspects
of aging remain incompletely mapped, evidence increas-
ingly indicates that they are deeply interactive, perhaps
reflecting the many linked “faces” or facets of aging.
Increasing evidence links most, if not all, of these pro-
cesses to the major diseases of aging and most neurode-
generative disorders.
Evolutionary perspectives argue that aging must be a
process against which natural selection operates mini-
mally, in a postreproductive animal. In other words, basic
selection processes ensure that enough members of the
species (absent predation or other accidental death) sur-
vive to a period of maximum reproductive competence
(otherwise, a species would not exist), but selection does
not and indeed cannot ensure longevity much past a peak
reproductive period. Aging is the result of this relative absence
of selection for an extended postreproductive adaptation. In this
sense, evolution “does not care too much about aging”,
although partial exceptions to this principle in humans
an extended “group fitness,” possibly helping to explain
why humans are longer lived than almost all other mam-
mals. Such evolutionary perspectives also suggest that
aging (and its deceleration) is likely to be highly polygen-
etic and not easily radically modified, arguing strongly
against any wild optimism about improvements to maxi-
mum human lifespan beyond its documented maxima
(about 120 years). Current thinking also suggests that
aging clearly reflects an “antagonistic pleiotropy”—genes
beneficial to and even critically necessary for growth and
reproduction “backfire” in older animals and contribute
to aging, in part through “unexpected” interactions.
However, aging research has extensively probed highly
conserved protective effects associated with dietary or
calorie restriction (DR/CR), the gold standard in terms
of a basic environmental manipulation that slows aging
in virtually every species in which it has been closely
studied, from yeast to mammals. CR/DR functions as a
global metabolic “reprogramming” for most organisms,
reflecting a shift of biological priorities from growth and
reproduction toward stasis and conservation. CR physiol-
ogy was presumably selected by allowing organisms to
survive in times of nutrient shortage and then resume the
critical business of growth and procreation when again in
environments more supportive of fecundity. CR extends
lifespan and reduces penetration of the diseases of aging
significantly, if not dramatically, in almost every species
in which it has been studied, but does not appear to be a
viable health-care strategy for the vast majority of individ-
uals (due to the intrinsic stresses of chronic hunger). CR
mimetics (substances offering at least some of the physiol-
ogy of CR without the stress of chronic hunger) may offer
some or many of the benefits of CR, protective effects of
enormous relevance to Western societies as they undergo
progressive demographic shifts in the direction of a larger
percentage of elderly citizens than at any point in human
history, with an impending tsunami of diseases of aging.
However, clinical and long-term data on CR mimetics is
badly lacking beyond animal models, where they show
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
impressive protective effects. CR mimetics are currently
being studied in multiple diseases of aging, including
cancer, heart disease, Alzheimer’s disease (AD), diabetes,
and several others.
Last but not least, accumulating evidence also indicates
that Western lifestyles and an associated pandemic of
obesity, reflecting a radical departure from our evolution-
ary environment, will expose us to increased penetration
by the diseases of aging, despite (or perhaps because of)
increasing life expectancy. These multifactorial lifestyle
changes (poorer sleep, little exercise, complex dietary
shifts, increased social isolation) may increase many of
the phenotypes or components of aging, including OS,
inflammation, glycation, insulin resistance, telomere
loss, disordered cell cycling and aberrant growth signals,
increased junk proteins, and DNA damage. Fundamental
shifts in health-care strategy and priorities will be needed
in the coming decades, away from high-technology inter-
ventions aimed at an advanced disease of aging (often
one at which little real prevention was ever aimed) and
toward a reprioritizing of meaningful prevention via
substantive lifestyle modifications. Such a shift in health-
care priorities is likely to be politically contentious, but
the current (and unsustainable) escalation of health-care
spending will eventually force basic changes in both
health-care policy and clinical practice. The science of
aging may eventually heuristically integrate much of our
currently fragmented approach to the diseases of aging
and thus merits much more attention and review not only
in medical school curriculums, but also in basic biomedi-
cal research initiatives.
Aging and mortality
All complex organisms age and eventually die1, with
highly variable limits to their typical lifespans, a variabil-
ity still poorly understood. The outer biological limit to
the human lifespan is generally thought to be approxi-
mately 120 years. The oldest carefully verified human
known was Jeanne Calment of France (1875–1997), who
died at age 122 years, 164 days (Robine and Allard, 1995).
As far as we know, we are the only species with a vivid
awareness of and preoccupation with our own mortal-
ity (and perhaps, at other times, an equally great denial).
Cultures from the earliest recorded history have been pre-
occupied with themes of dying and immortality, along
with whether it would be possible to escape death or find
a true “fountain of youth.” Wishes for and even expec-
tations of immortality are a powerful driver in many
1Only in organisms in which there is no real distinction between
soma and germ line (such as hydra and most bacteria) is aging
absent.
5
organized religions and spiritual traditions. Yet despite
such perennial and fundamental human wishes, no way
of truly preventing aging or achieving any version of bio-
logical immortality has ever been achieved in human his-
tory. Aging and our eventual demise from it both seem
as unavoidable as the next sunrise. Benjamin Franklin is
credited with the famous quote, “The only thing certain
in life are death and taxes.” More humorous perspectives
on these existential challenges include George Bernard
Shaw’s lament that youth was a wonderful thing and a
shame that it had to be wasted on the young. When I was
too young to fully appreciate the humor, my own father,
who passed away during the writing of this chapter at the
age of 93, offered, “Aging is vastly overrated, but most of
the time, it beats the alternative.” But ultimately, aging is
no joking matter, exposing humans to slow and inevitable
degradation of virtually every organ system, progressive
disability, and eventual outright physiological failure of
one sort or another, with inevitably fatal consequences.
Yet if we did not age and die, humans and their progeny
would quickly overrun the planet and totally exhaust
its ecology and resources, causing mass extinctions not
only for many other species, but potentially for our own
as well. Thus, any true “fountain of youth” for humans
might prove to be a seductive but ultimately deadly
Faustian bargain. Yet who does not want more life, par-
ticularly if in decent health and with preserved functional
capacities? Such primordial motivation and longing was
surely captured in Dylan Thomas’s haunting poem “Do
Not Go Gentle into That Good Night,” tapping universal
sentiments in the face of aging and mortality.
In this context, one might ask why a chapter on the
biology of aging appears in a textbook of geriatric neurol-
ogy. Trivially, the obvious answer is that aging has every-
thing to do with all things geriatric. However, less trivi-
ally and less obviously, one might argue that an under-
standing of the basic biology of aging could function as
a “touchstone” or integrative “hub” around which much
of the science of geriatric neurology might eventually be
organized. Central questions here could include: What is
aging? What drives the progressive deterioration of the
human organism over time? Why does it lead to what
have been called the “diseases of aging?” These diseases
would include not just classic neurodegenerative disor-
ders (most paradigmatically, AD, but also Parkinson’s
disease (PD), frontotemporal dementias, and motor neu-
ron diseases—all core clinical concerns for geriatric neu-
rologists, neuropsychologists, and psychiatrists), but also
coronary artery and cerebrovascular disease, other forms
of age-related vascular disease, diabetes, cancers, macu-
lar degeneration and glaucoma, arthritis, failing immu-
nocompetence, and perhaps many, if not most, forms of
end-stage organ disease.
Additional central questions potentially addressed by
the science of aging include the following: what can we
6 The Aging Brain in Neurology
do about slowing aging and extending the lifespan or,
for that matter, protecting ourselves from the diseases of
aging? Exactly how does aging lead to the various dis-
eases of aging, and what determines which disease of
aging an individual gets? Does someone truly die just
from “old age,” or do we die of a disease of aging? What
are the core biological processes responsible for aging?
Are these a few biological processes or many dozens?
What are the potential relationships (interactions) among
various core processes implicated in aging? What is the
relationship between aging in the brain and aging of the
body in general? Can the brain be differentially protected
from aging and age-related diseases? Would a slowing of
aging itself potentially delimit the penetration by the dis-
eases of aging in some or even all individuals? How radi-
cally? Is it possible to substantially slow aging, or perhaps
even to arrest it? Even more radically, could aging ever be
substantially reversed? Many of these questions do not
have well-validated scientific answers yet. Most of these
questions could be considered central biological ques-
tions for all the health-care disciplines and also questions
around which there is now a rich and emerging, if still
fundamentally young and incomplete, science of aging.
Implications of an aging demographic
in Western societies for priorities in
health care: prevention versus high-
technology medicine
Unfortunately, very little of an emerging science of aging
has trickled down into the health-care system and into
the awareness of most health-care professionals, where
a largely fragmented approach to the diseases of aging
predominates theory, clinical research, and treatment. In
addition, almost none of it seems to inform the way our
health-care system currently works. Substantive preven-
tion in relationship to the diseases of aging (let alone any
concerted focus on potentially slowing aging) garners
little substantive attention or meaningful share of fiscal
resources; instead high-technology intervention, often
aimed at an advanced disease of aging (at which little, if
any, prevention was typically ever aimed), consumes an
enormous fraction of medical resources and costs (Conrad,
2009). Recent estimates are that no more than 5% of health
care is spent on prevention, broadly defined, whereas
75–85% is spent on an established illness, typically a dis-
ease of aging (Centers for Disease Control and Prevention
(CDC), 2010). In 2010, at least $55 billion was spent on the
last 2 months of life, and an enormous fraction of total
medical costs was spent on end-of-life care (Social Security
Advisory Board (SSAB), 2009), often with little evidence
that this considerable expenditure improves the qual-
ity of life (and may even cause it to deteriorate, in some
instances). If one were to extrapolate our current (average)
end-of-life care costs to the baby boomers (a demographic
of roughly 60 million people), this could potentially yield
a total price tag of about $6 trillion for end-of-life care
for the baby boomer generation. Obviously, these trends
are unsustainable, but there is little evidence of progress
toward addressing, let alone reversing, them.
The emerging and expanding science of the biology of
aging, as a vigorous area of scientific inquiry, takes place at a
time when the demographics of Western societies are tilting
toward an increasingly high percentage of elderly citizens.
At the beginning of the twentieth century, when life expec-
tancy was about 47 years in the United States, until today,
there has been a roughly 30-year increase in life expectation
at birth (Minino et al., 2002). Roughly 25 years of this 30-year
gain in lifespan can be attributed to one primary factor: less-
ening the impact from early mortality due to infectious dis-
eases in children and young adults, in the context of better
hygiene and the creation of effective antibiotics and vaccines
(CDC, 1999). This has yielded a situation in which many
Western societies are now for the first time in human his-
tory facing the prospect of having more people over the age
of 60 than under the age of 15. Although currently roughly
13% of the United States is over the age of 65, within the next
20 years, this percentage is expected to increase by more
than half again, to roughly 20%. By the end of the century,
a whole one-third of the world’s population will be over the
age of 60 (Lutz et al., 2008). These demographic shifts will
centrally include a huge increase in the very old in the com-
ing four decades. In 2010, more than an estimated 5.5 million
Americans were 85 years or older; by the year 2050, that num-
ber is expected to almost quadruple to 19 million. Currently,
the number of centenarians in this country (Americans 100
years and older) is estimated at roughly 80,000, but by 2050,
there will be more than 500,000 Americans aged 100 years
or older. This is unprecedented in human history. However,
these significant increases in lifespan have not been accom-
panied by concomitant increases in “healthspan,” or in our
ability to substantially prevent (or successfully treat and
delimit) the disabling illnesses of later life, the major diseases
of aging (centrally including diabetes, cardiovascular dis-
ease, stroke, AD, and cancers), which remain largely refrac-
tory to amelioration. Some evidence (summarized later in
this chapter) argues that these diseases may be largely of
Western civilization (primarily due to modern lifestyles) and
relatively rare in elders from hunter gatherer (HG) societies,
compared to Western societies, even when the younger mor-
tality of HGs is taken into account (Eaton et al., 1988 a,b).
The impact of these large demographic shifts and the
associated increased penetration of diseases of aging on
health-care economics, combined with the increasing
costs of technology-driven health-care interventions, is
quietly anticipated to be fiscally catastrophic, involving a
steady annual escalation of health-care costs to unsustain-
able levels (US Government Accountability Office, 2007;
Conrad, 2009). The impact on health-care economics of an
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
aging demographic, combined with an increasing empha-
sis on high technology, is increasingly penetrant and,
frankly, worrisome, particularly in terms of its impact on
health-care economics in this country. In 2010, health-care
expenditures in the United States were approximately
18% of the gross domestic product (GDP), almost twice
as much, in terms of percentage of GDP, as in any other
Western society. Even just within the next several years,
at a current rate of increase of between 4% and 8% a year
(rates of increase moderated more by the recent recession
than by changing practice), by 2018–2019, roughly 20%
($1 in every $5) of the US GDP could be spent on health-
care expenses, an unprecedented fraction of our national
wealth and resources. The health-care expense as a pro-
portion of GDP is projected (without substantive changes
in practice trends or chronic illnesses) to rise to 28% in
2030 (more than $1 in every $4) and to 34% by 2040 (more
than $1 in every $3; Council of Economic Advisers (CEA),
2009). These are frightening statistics, suggesting that the
current rate of escalation in health-care expenditures is
totally unsustainable. However, the demographic shifts
toward an aging population are only one contributing fac-
tor in these accelerating expenditures and are paired with
the escalating cost of first-line drugs and high-technology
interventions and the high overhead associated with the
burgeoning health-care and health-insurance bureaucracy
itself (CEA, 2009). Evidence suggests that as much as three-
quarters of the increasing costs are due to factors other than
an aging demographic (CEA, 2009). Despite these enormous
and escalating financial outlays in health care, the overall
health may be actually declining in the United States, as
measured by several indices. Currently, the United States
rank around 50th in life expectancy, while other indices,
such as infant mortality, are also worrisome and rank 46th,
behind all of Western Europe and Canada (CIA Factbook).
Reflecting the major disease of aging with special rele-
vance for this textbook, costs for AD in 2010 were roughly
$170 billion in the United States alone (not counting an
additional roughly $140 billion in unpaid caretaker costs,
suggesting a real cost of over $300 billion in 2010 alone)
(Alzheimer’s Association, 2010).
These total costs of AD (assuming that current costs
continue and no cure or highly effective treatment is
found) are expected to potentially reach $2 trillion per
year in the United States alone by 2050, with 65 million
expected to suffer from the disease in 20 years worldwide,
at a cost of many trillions of dollars (Olshansky et al.,
2006). As the baby boomers enter the decades of greatest
risk for cancers, heart disease, stroke, arthritis, AD, macu-
lar degeneration, and other diseases of aging, evidence
indicates that the health-care system (as it is currently
structured) will eventually undergo a slowly progressive
but fundamental collapse in the context of these unsus-
tainable cost escalations. Meaningful strategic options to
prevent this fiscal implosion have not yet been developed.
7
In addition to its financial impact on health-care eco-
nomics, aging in the Western societies is anticipated to
have a more generalized and severely deleterious impact
on Western economies, as an increasing percentage of
retired elderly severely strain basic social safety net and
entitlement programs such as Medicare and Social Security,
deteriorate tax and revenue margins, and stretch virtually
every societal resource (McKinsey Global Institute, 2008).
In this context, scientific work on the biology of aging, par-
ticularly if it might reduce or substantially delay penetra-
tion by the diseases of aging into an aging population and
extend “healthspan” (as distinct from lifespan), appears
vitally relevant, if not badly needed. Despite these consid-
erations, the funding of research into all aspects of aging and
age-related disease garners only 11% of the $31 billion NIH
budget (Freudenheim 2010), and research into CR, our
only well-replicated lifestyle intervention to slow aging
and reduce diseases of aging, garners less than 1/100th of
1% of all biomedical research monies (Guarente, 2003).
Historical and basic evolutionary
perspectives on aging
Aging appears somehow woven into the very fabric of life
itself; a still controversial question is whether this is acci-
dental (in a sense, evolution did not worry much about
aging, as postreproductive deterioration in a complex bio-
logical system is inevitable) or whether aging is selected
(as nearly immortal organisms would destroy their envi-
ronment and thus render themselves extinct). These may
not be mutually exclusive perspectives. Aging is difficult
to define and has no single pathognomonic biomarker,
but to paraphrase a famous quote about obscenity, “You’ll
know it when you see it.” Aging can be defined operation-
ally as a progressive and time-dependent “loss of fitness”
that begins to manifest itself after the organism attains its
maximum reproductive competence (Vijg, 2009) but aging
could also be seen as simply the change of the organism
over time (Bowen and Atwood, 2004). Although this
seems to conflate development with aging, it has other
theoretical advantages (see discussion of endocrine dys-
crasia). Aging consists of a composite of characteristic
and often readily recognizable phenotypic changes and
can be defined statistically as a point at which normal or
expectable development shows an increasing probability
of death from all-cause mortality (excepting traumatic
injury, starvation, poisoning, or other accidental death)
with increasing chronological age of the organism. Intrin-
sic to aging is that its characteristic phenotypic changes
are progressive and affect virtually every aspect of physi-
ology and every organ of the body, from the skin, to car-
diac and muscle tissues, to the brain. Ontologically, aging
may reflect “entropy’s revenge,” as fundamental aspects
of life organization become increasingly disorganized,
8 The Aging Brain in Neurology
presumably due to a complex composite of processes
(Hayflick, 2007). Modern biological thought holds it axi-
omatic that purposeful genetic programs drive all bio-
logical processes occurring from the beginning of life to
reproductive maturity. However, after reproductive com-
petence is attained, current thinking is still divided on the
question of whether aging is a continuation of some col-
lection of genetic programs or whether it is the result of
the accumulation of random, irreparable losses in cellular
organization. Again, these may not be mutually exclusive.
References to aging abound in the earliest human cul-
tures’ writings and records, suggesting that humans have
been keenly aware of aging for millennia. The Bible refers
to aging and death as “the wages of sin,” at best, a colorful
metaphor and, of course, totally scientifically inadequate.
However, a modern biology of aging suggests that the
metaphor of aging as a “wage” is both appropriate and
heuristic: aging may readily reflect the “wages” of growth,
metabolism, and reproduction (excess junk proteins, OS,
glycation of proteins, and damage to both mitochondrial
and nuclear DNA) and also to the “wages” of organism
defense and repair (also known as inflammation).
Additionally, one must accept evolutionary principles
as fundamental here and grounding any discussion of
biological phenomenon, suggesting that aging must, in a
direct sense, reflect a relative absence of selection against aging
itself. However, what this might mean is not clear. Initial
evolutionary theories of aging hypothesized that aging
was “programmed” to limit the population size (immortal
organisms would destroy their environment and render
themselves quickly extinct) and/or to accelerate an adap-
tive turnover of generations, thereby possibly enhancing
adaptation to shifting environments. However, this argu-
ment has modest evidence for it, at best, as senescence
typically contributes minimally to mortality in the wild
(Kirkwood and Austad, 2000). Instead, mortality in wild
populations (as opposed to that seen in protected popula-
tions) is mostly due to extrinsic factors, such as infection,
predation, and starvation, and occurs mainly in younger
animals (Charlesworth, 1994). As a general rule, many, if
not most, wild animals simply do not live long enough to
grow old, again due to these extrinsic factors and not to
aging. In this sense, natural selection has a limited opportunity
to exert any direct influence over the processes of aging. Even in
species in which aging and senescence do make some con-
tribution to mortality in the wild (for example, in larger
mammals and some birds), any hypothetical “aging gene”
would be clearly deleterious; thus, it is highly unlikely
that it would be selected (Kirkwood and Austad, 2000).
Indeed, the relative rarity of aged animals in the wild is
an important clue about how fundamental evolutionary
processes relate to aging. With extrinsic factors being the
primary causes of mortality, there is invariably a progres-
sive weakening in the force of selection with increasing
age (Kirkwood and Austad, 2000). By the time an animal
in the wild reaches an age at which the percentage of a
given population surviving has declined to very low lev-
els, the force of selection is likely far too weakened (if not
almost nonexistent, given the low probability of reproduc-
tive success in an aged animal) to effectively weed out the
accumulation of genes with “late-acting” deleterious (in
other words, pro-aging) effects. This constitutes a “selec-
tion gap” that allows any alleles with late deleterious (pro-
aging) effects to accumulate over many generations, with
little or no intrinsic “countermechanism” (referred to as
the mutation accumulation theory of aging). A prediction
emerging from this theory is that because the negative
alleles are basically unselected mutations, there might be
considerable heterogeneity in their distribution within a
population of individuals. There is some evidence both
for and against this (Kirkwood and Austad, 2000).
A substantial modification of this basic idea is found
in the notion of aging as “antagonistic pleiotropy”
(Williams, 1957), that evolution would favor genes that
have good effects early in development (for example,
genes promoting growth and fecundity) even if these
genes had clearly bad effects at later stages of life. A criti-
cal and heuristic modification of this basic idea has been
provided by Bowen and Atwood (2004), who suggest
that alterations in the hypothalamic–pituitary–gonadal
(HPG) axis, characterized by increasing gonadotropins
and declining sex steroids create aging and by implication
its diseases, a process which is “paradoxically” under the
control of the very same hormonal systems that regulate
growth and reproduction (see Section “Endocrine Dys-
crasia”). In this sense, a small but reproductively signifi-
cant benefit early in life derived from particular genes or
alleles would easily outweigh (in terms of selection effect)
later deleterious effects, even if those later effects guar-
anteed eventual senescence and death, especially if those
genes promote growth and reproduction. Aging is thus
not the “wages of sin” but the wages of growth, repro-
duction, and metabolism. Of course, this suggests that
aging expresses intrinsic trade-offs, a theme also echoed
in the widely quoted “disposable soma” theory of aging
(Kirkwood, 1977) which suggests a balance of allocation
of metabolic resources between somatic maintenance
and reproduction. Effective maintenance of the organism
is required only for as long as it might typically survive
in the wild. For example, because roughly 90% of wild
mice die in their first year of life, biological programming
for metabolically expensive body maintenance programs
beyond this age benefits only 10% of the total population,
at most (Phelan and Austad, 1989). Given that a primary
cause for early mortality in wild mice is excessive cold
(Berry and Bronson, 1992), the disposable soma theory
suggests that mice would not benefit from developing
body maintenance and repair programs that would slow
aging nearly as much as investing metabolic resources
into thermogenesis and thermoregulatory mechanisms.
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
Thus, longevity may be determined in large part by the
level of “extrinsic” mortality in the natural environmental
niche (Kirkwood and Austad, 2000). If this level is high
(life expectancy thus is quite short), there is little chance
that the force of selection would create a high level of
protracted and successful somatic maintenance; the
more critical issue is making sure that organisms either
reproduce quickly before extrinsic mortality takes its
toll or have high fecundity and reproduction rates to
ensure that early mortality for many members of a spe-
cies does not eliminate reproduction for all members of
a species (rendering them extinct). On the other hand, if
“extrinsic” mortality is relatively low over long periods of
time, selection effects might well direct greater resources
toward building and maintaining a more durable organ-
ism, by modulating genes that might otherwise contrib-
ute to rapid aging. If this set of assumptions is correct, one
would predict that, in organisms in relatively safe envi-
ronments (those with low extrinsic mortality), aging will
evolve to be more retarded, while it would be predicted
to be more rapid in hazardous environments (slowed
aging in these environments would make little difference
to procreative success and species survival)—and these
predictions are generally well supported (Kirkwood and
Austad, 2000). Additionally, evolutionary developments
that reduce extrinsic mortality (for example, wings or
other adaptations to reduce vulnerability to predation,
highly protective armor (such as shells), or large brains
(enabling transition from prey species to top preda-
tor status) are linked to increased longevity (as seen in
birds, turtles, and humans), although mechanisms for
this increased longevity are still debated and remain to
be conclusively outlined (see Bowen and Atwood, 2004).
However, disposable soma theory has been criticized
(Blagosklonny, 2010b) as failing to account for many
aspects of aging, most particularly the greater longevity
of women and the role of specific genetic pathways (such
as mammalian target of rapamycin (mTOR),–see later sec-
tions on mTOR) that may heavily modulate aging. Aging
is increasingly thought to be not preprogrammed, but
more likely the result of a relative absence of selection for
“perfect” maintenance of the organism, past the period of
reproductive competence. Another way of putting this is
that aging is simply the “fading out of adaptation,” after
achieving the age of reproductive success and moving
into the postreproductive age (Rose, 2009). In other words,
there is no basis for evolution to have selected against
aging and for much better body maintenance, as these
issues would escape selection, unless there was a specific
selection pressure toward this. An example of a basic selec-
tion pressure that could reduce aging significantly might
be progressively delayed reproduction (procreating at slightly
later and later ages), which has been shown in animal
models to result in significant enhancement of longevity,
in complete concert with basic evolutionary principles
9
(Teotônio et al., 2009). In animal models of aging, this is
referred to as “experimental evolution” (Bennett, 2003).
Intriguingly, experimental work with delayed reproduc-
tion has successfully developed longer lived species (for
example, long-lived Drosophila, or fruit flies), but with the
cost of depression of early life fecundity, suggesting again
intrinsic trade-offs between slowed aging and growth and
reproduction (Sgrò and Partridge, 1999). However, there
is expert opinion (Johnson, Sinclair, and Guarente, 1999)
that there could well be selection to slow the pace of aging,
as such organisms could potentially have a more pro-
tracted period of reproductive fitness, conferring an adap-
tive advantage. Slower aging also appears intrinsically
related to later age of reproductive fitness (Bowen and
Atwood, 2004). Additionally, in hominid lines, evolution-
ary perspectives indicate that the existence of tribal elders,
with greater accumulated wisdom and experience, would
have improved evolutionary fitness for their tribal groups,
despite being largely past a reproductive age, suggesting
another potential selection mechanism driving “antiag-
ing” (“group fitness” or “inclusive fitness” in highly social
species such as hominids; Carey, 2003).
Basic cellular and molecular theories of aging probably
come in two fundamental forms: (1) aging as a genetically
modulated process (under the control of discrete genes
and molecular pathways—but not “preprogrammed”); (2)
aging as an “error” or stochastic or “wear-and-tear” pro-
cess (the best known of these being the oxidative damage/
stress theory). Neither “pure” type of theory is fully able
to explain all aspects of aging, suggesting that aging is
“quasiprogrammed” (Blagosklonny, 2009) and perhaps
related to both growth programs (which are continued
past the period of peak reproductive competence, as an
example of antagonistic pleiotropy) and stochastic cellu-
lar damage/wear and tear aspects (such as emerging from
disinhibited inflammation). CR, as the only conserved
antiaging physiology yet discovered (see the later sections
on CR and CR mimetics) may impact both of these (reduc-
ing growth programs and also attenuating factors such as
OS and inflammation that may drive stochastic damage).
Again, one has to assume that these issues do not contra-
dict or replace a basic evolutionary perspective (in which
aging reflects a relative absence of selection against wear
and tear, stochastic damage, or failure of inhibition of
many genes/pathways that might accelerate or drive age-
related decline). Kirkwood and Austad (2000) summarize
these considerations for an evolutionary genetics of aging
as three basic predictions (p. 236).
1 Specific genes selected to promote ageing are unlikely
to exist.
2 Aging is not programmed but results largely from ac-
cumulation of somatic damage, owing to limited invest-
ments in maintenance and repair. Longevity is thus regu-
lated by genes controlling levels of activities such as DNA
repair and antioxidant defense.
10 The Aging Brain in Neurology
3 In addition, there may be adverse gene actions at older
ages arising either from purely deleterious genes that es-
cape the force of natural selection or from pleiotropic genes
that trade benefit at an early age against harm at older ages.
Thus, aging could reflect the species-variable interac-
tions and intrinsic “tug-of-war” between deleterious and
degrading changes (and the declining influence of selec-
tion/adaptation in a postreproductive animal), with many
of these pro-aging factors intrinsic to growth, reproduction,
metabolism, inflammation, and other aspects of physiol-
ogy (“antagonistic pleiotropy”), versus various (and pre-
sumably selected) counterbalanced repair, protection, and
maintenance programs. Of course, if aging itself potentially
deteriorates those counterbalanced cellular repair and main-
tenance programs, this suggests that aging is a losing tug-
of-war between forces of cellular protection and forces of
cellular degradation, and that (as the tug-of-war metaphor
suggests), as one side loses, it may lose at an accelerating
rate. There is indeed some evidence, although it is hardly
conclusive, that aging may actually accelerate (Guarente,
2003). Few elderly would find this possibility surprising.
Cellular and molecular aspects of aging that might map
onto these various considerations about the evolutionary
basis for aging suggest a dizzying composite of pheno-
typic changes, including changes in mitochondrial, nuclear,
and ribosomal DNA; subsequent genomic and chromatin
changes and instability; increasing levels of OS (including
pleiotropic and differential expression of OS on membranes
and lipids, proteins, and nucleic acids, particularly mito-
chondrial); increasing systemic inflammation (“inflammag-
ing”), paradoxically concomitant with declining immuno-
competence; increasing glycation of proteins (and increasing
amounts of advanced glycation end products (AGEs), which
potentiate inflammation); increasing cellular senescence and
loss of telomeres; dysregulation of apoptosis (programmed
cell death is over- or under-recruited); and increasing junk
proteins, combined with impaired protein turnover and
declining removal of damaged (and glycated) proteins
(declining “autophagy”). Last but certainly not least, even
our stem cells age and reach senescence, preventing rejuve-
nation of many organ systems and structures. A clear sense
of what are leading versus trailing edges in this process (in
other words, clearly distinguished “causes” vs “effects”)
are still unclear and biology is clearly a place where causes
become effects and effects become causes. However, there is
evidence for each of these various aspects of cellular change
as direct contributors to all the manifestations of aging, includ-
ing evidence linking virtually all of these processes (“phenotypes of
aging”) to all the diseases of aging. Like many aspects of biolog-
ical regulation, and indeed life itself, recursive interactions
among these various processes may be essential; in other
words, the many mechanisms of aging may be highly inter-
active, suggesting that there cannot be a single pathway into
aging (see the discussion of the network of molecular path-
ways in CR effects), and that instead aging probably reflects a
complex and recursive network of (still incompletely understood)
changes. This is consistent with the severe limitations of all
“linear causality” models in biological systems, where cau-
sality is intrinsically more recursive, circular, and multifacto-
rial (Freeman, 2000). As critical examples of this principle of
reciprocal interaction, inflammation and OS are increasingly
linked and seen as mutually reinforcing (Jesmin et al., 2010),
OS is thought to drive DNA damage (both mitochondrial
and nuclear), glycation promotes inflammation, and declin-
ing removal of junk (including glycated) proteins may be
related to increased OS (Kurz, Terman, and Brunk, 2007) and
mitochondrial decline, while senescence promotes inflam-
mation, as does endocrine decline, as does increasing junk
protein while chronic inflammation and OS contribute to
senescence. All of these phenotypes may thus be interlinked
aspects of declining biological organization and increasing
entropy, as basic phenotypes of aging with positive feedback
loops between these phenotypes; new interactions seem to
be emerging regularly in research into aging and its dis-
eases. Such interaction may explain how processes involved
in a modest departure from an ideal youthful physiology
gives rise to a process that, over time, deterministically kills
the organism without exception. Aging in other words may
emerge from a deadly ‘recursion matrix’ of these interactive
phenotypes. This is consistent with overwhelming evidence
that nothing in biology truly emerges from single factors,
but from the concerted crosstalk and feedback between mul-
tiple partners. At the same time, several molecular pathways
(such as mTOR, and many molecular and cell-signaling
pathways with which mTOR interacts) may be particularly
critical to aging and the modulation of age-related change.
At the end of this chapter, we also summarize evidence that
lifestyle factors modulate risk for diseases of aging (and per-
haps aging itself), possibly accelerating or retarding it at least
to some degree. We also examine the difference between the
current Western technological environment and our original
evolutionary environment, in terms of the impact that mul-
tiple lifestyle variables may have on the cellular mechanisms
and the physiology of aging and the diseases of aging.
Basic molecular and cellular
perspectives on aging: phenotypes of
aging
Although popular conceptions of the molecular basis of
aging center around reactive oxygen species (ROS), hard
evidence for this as the prime driver of aging is actually
very mixed, and increasing evidence argues against it,
as least as the central process driving aging. However,
OS may interact with many of the other phenotypes of
aging, particularly inflammation, as well as disinhibited
growth factors/programs, suggesting that a softer form
of OS theory (that ROS may contribute to aging) may still
be valid.
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
Oxidative stress and associated mitochondrial
perspectives
A basic assumption about aging is that it must have a funda-
mental cellular basis, and cellular and molecular perspectives
on aging have dominated the scientific landscape of aging
research and theory. The oldest and most widely quoted
molecular theory about aging was provided by Harman,
1956, who postulated that oxidizing “free radicals” dam-
aged and degraded cells over time, causing aging. Harman’s
early work on radiation with experimental animals demon-
strated that aging had important similarities to the afteref-
fects of massive exposure to radiation, particularly cancer,
inflammation, apoptosis, and other tissue changes not dis-
similar to classic phenotypes of aging in older animals and
humans. Harman’s hypothesis emerged from his familiar-
ity with work on radiation exposure and early findings that
large doses of ionizing radiation generated enormous quan-
tities of free radicals. Harman subsequently published what
may be the first dietary antioxidant study (1957), studying
the effects of dietary 2-mercaptoethylamine, the most potent
radioprotective compound known at the time, and demon-
strating a modest 20% increase in average lifespan, although
the mechanism of action of this compound is still debated.
In 1972, Harman published an important extension to the
free radical theory, suggesting that the mitochondria were
the primary source for OS, as well as the primary site for
oxidative damage, and that the mitochondria therefore rep-
resented a kind of “biological clock” that he argued deter-
mined maximum lifespan. He concluded that his inability to
extend maximum lifespan with dietary supplements must
derive from the fact that most exogenous antioxidants do
not get into the mitochondria. He hypothesized that OS in
the mitochondria (vs its endogenous antioxidant defenses)
set an outer limit on a given species longevity. Some work
has suggested that OS is mostly generated by mitochondrial
complex 1 (Mozaffari et al., 2011).
This led to a second “vicious circle hypothesis” about OS
in relation to the mitochondria: that OS caused deterioration
in mitochondrial antioxidant defense systems and mito-
chondrial function in general, leading to more OS and, in
turn, driving more damage and increasing age-related dete-
rioration. Although this is clearly the most widely quoted
and accepted molecular theory of aging, particularly in the
popular media and product advertising, the most compre-
hensive and wide-ranging review of this theory to date (Van
Remmen, Lustgarten, and Muller, 2011) concludes that hard
support for it is actually quite mixed. Therefore, the authors
conclude that this theory remains unproven (but also not
clearly falsified either), at least in the original “hard” form
of the hypothesis (that OS in the mitochondria was the
driver of aging. It has also been known for some time that
OS markers increase with aging, although debate still rages
about how much of this is cause or effect of aging (Sohal
and Weindruch, 1996). There are many data points both for
and against the oxidative-stress-in-the-mitochondria theory
11
of aging, which might readily lead even the advanced stu-
dent of aging to a sense of confusion and frustration. On the
other hand, a softer form of the hypothesis—that OS in the
mitochondria may significantly contribute to aging—may be bet-
ter supported, particularly in view of the interaction between ROS
and other molecular pathways that clearly have been shown to con-
tribute to aging, and to the diseases of aging, such as inflammatory
signaling, and growth signaling (see Blagosklonny, 2008) (see
Section “Mammalian target of rapamycin”).
Much experimental work to test the basic hypothesis has
focused on genetic manipulations of antioxidant enzyme
systems in short-lived species. Support for the hypothesis
can be drawn from the results of knockouts of superox-
ide dismutase (SOD) 2 (Perez et al., 2009) and glutathione
peroxidase 4 (Ran et al., 2007), both of which show lethal
effects. Other primary data points in favor of the hypoth-
esis emerge from work correlating species longevity with
lowered rates of mitochondrial DNA mutation (Sanz et al.,
2006) and with other experimental manipulations of OS and
mitochondrial function (Hagen et al., 1999). Additionally,
longer lived rodents (white-footed mouse (Peromyscus leuco-
pus)) exhibit lower levels of ROS (superoxide and hydrogen
peroxide), compared to the shorter lived house mouse (Mus
musculus), and show higher cellular concentrations of some
antioxidant enzymes (catalase and glutathione peroxidase)
and lowered markers for protein oxidative damage (Sohal
et al., 1993). Schriner et al. (2005) generated transgenic mice
that overexpressed human catalase localized to peroxisome,
nucleus, or mitochondria (MCAT). Median and maximum
lifespans were maximally increased (averages of 5 months
and 5.5 months, respectively) in the MCAT group. Cardiac
pathology and cataract development were both delayed,
markers for oxidative damage were reduced, peroxide pro-
duction was attenuated, and mitochondrial DNA deletions
(perhaps the most serious form of mitochondrial damage)
were also reduced. These results offer strong support for the
free radical theory of aging and also argue that the mito-
chondria are indeed the most biologically relevant source of
these free radicals. In general, there is also broad, although
occasionally inconsistent, correlation among OS in the mito-
chondria, rates of mitochondrial DNA damage, and longev-
ity (Sanz et al., 2006;Barja and Herrero, 2000).
However, there is equally compelling data against this
classic hypothesis. The naked mole rat (NMR) demonstrates
an unusual phenotype of significantly delayed aging and
the longest lifespan of any rodent (about 30 years), five times
the expected lifespan based on body size, and exceptional
cancer resistance, despite elevated markers for OS and short
telomeres (Buffenstein et al., 2011). Additionally, the lack
of a significant lifespan decrease or accelerated aging phe-
notypes in SOD 2−/+ mice (missing one copy of the gene),
despite evidence for increased OS (Mansouri et al., 2006),
and increased mitochondrial DNA damage (Osterod et al.,
2001) are data points against this classic theory. Further com-
plicating the picture is the evidence that although oxidation
12 The Aging Brain in Neurology
of mitochondrial DNA is elevated in SOD 2−/+ mice, mito-
chondrial DNA deletions (thought to reflect the most serious
form of mitochondrial DNA damage) are not increased (Lin
et al., 2001). This suggests that this particular partial knock-
out model may not adequately probe the question of the
relationship between mitochondrial OS and longevity.
Other animal models demonstrate that increased expres-
sion of the major antioxidant enzymes involved in protec-
tion from mitochondrial OS, including upregulation of
the two isoforms of SOD (MnSOD and Cu/ZnSOD) and
catalase, individually or in various combinations, does not
extend maximum lifespan in mouse models (see Van Rem-
men, Lustgarten, and Muller, 2011 for detailed review).
Mice with genetically reduced individual components
of the antioxidant defense system have also been exten-
sively studied, including knockouts of two isoforms of
SOD (MnSOD and Cu/ZnSOD), glutathione peroxidases
(Gpx-1, Gpx-2, and Gpx-4), catalase, thioredoxin, and per-
oxiredoxin. Complete ablation of individual components
of antioxidant defense can often be embryonically lethal
(specifically, homozygous knockout of thioredoxin 2, glu-
tathione peroxidase 4, or MnSOD), but simply a loss of
one allele (generating about 50% loss in activity) in hetero-
zygous knockout mouse models (SOD1+/−, SOD2+/−, and
Gpx4+/−) does not result in reduced lifespan (Van Remmen,
Lustgarten, and Muller, 2011). Lastly, recent work shows
that combining a heterozygous knockout of MnSOD and
homozygous glutathione peroxidase 1 knockout clearly
results in increased OS, indexed through several clas-
sic markers (both protein carbonyls and oxidized nucleic
acids), but not in a decrease in lifespan (Zhang et al., 2009).
At face value, such negative results might suggest that
the “hard” form of the mitochondrial OS hypothesis (OS
is the primary driver of aging and mortality) is not well
supported. However, some very recent work argues that
antioxidant defense in the mitochondria involves factors
beyond these classic antioxidant enzyme systems and
requires activation of one of the seven sirtuins (SIRT3),
which promotes acetylation of antioxidant enzymes, sig-
nificantly enhancing their effectiveness. Hafner et al. (2010)
show that SIRT3-/- knockout mice show accelerated aging
phenotypes, including classical mitochondrial swelling.
Although earlier work on OS and CR emphasized the role
of SIRT1 and its homologs (Sinclair, 2005), recent work
has demonstrated that SIRT3 appears essential for CR-
mediated reduction in OS (Qiu et al., 2010), as homony-
mous knockout of SIRT3 prevents the expected reduction
of OS during CR. SIRT3 reduces OS by increasing activity
of SOD2 through deacetylation (Tao et al., 2010; Qiu et al.,
2010). In addition to regulating SOD2, SIRT3 reduces OS
by modulating the activity of isocitrate dehydrogenase 2
(IDH2), a mitochondrial enzyme generating nicotinamide
adenine dinucleotide phosphate (part of antioxidant
defense in the MITO; Someya et al., 2010). Thus, there may
be many players in the defense against OS in the MITO,
arguing that a comprehensive test of the OS hypothesis of
aging may be challenging to design and that single or even
combined manipulations of antioxidant enzyme systems
may be insufficient to fully probe Harman’s original and
provocative idea. In general, however, there is increasing
skepticism that the OS emerging from mitochondrial respi-
ration is the driver of aging or any version of a sole “prime
mover” in aging organisms. Additionally, many of the
data points supporting a classic OS hypothesis can poten-
tially be reinterpreted in light of evidence that ROS are a
secondary driver for mTOR (Blagosklonny, 2008) (see Sec-
tion “Mammalian target of rapamycin”); antioxidant inter-
ventions may therefore reduce overall drive or activation
of mTOR (which may slow aging). Additionally, cellular
senescence, another fundamental phenotype of aging, may
be hinged to DNA damage detection (Chen et al., 2007),
damage caused by ROS, suggesting that ROS concepts
have to be seen not as operating in etiological isolation, but
more as interactive with other phenotypes of aging.
A major practical challenge to test the basic hypoth-
eses of OS perspectives on aging and also explore thera-
peutic implications of this idea has been the question of
how to deliver antioxidants into the mitochondria (as
the primary cellular nexus for OS vs antioxidant protec-
tion). Most organic compounds conventionally regarded
as antioxidants (particularly the so-called “antioxidant”
vitamins A, E, and C) do not get into the mitochondria
in meaningful quantities, nor do others common in the
diet, such as many polyphenols. Work by Skulachev et al.
(2009) however, suggests that one can design molecules
that do materially affect OS (SkQs, in this case, comprising
plastoquinone, an antioxidant moiety, and a penetrating
cation and a decane/pentane link). In vitro work indeed
confirms that SkQ1 accumulates almost exclusively in
mitochondria. In several species of varying phylogenetic
complexity (the fungus Podospora anserina, the crusta-
cean Ceriodaphnia affinis, Drosophila, and mice), SkQ1 pro-
longed lifespan, especially at the early and middle stages
of aging. In mammals, SkQs inhibited development of
age-related diseases and involutional markers (cataracts,
retinopathy, glaucoma, balding, canities, osteoporosis,
involution of the thymus, hypothermia, torpor, peroxida-
tion of lipids and proteins). SkQ1 manifested “a strong
therapeutic action on some already pronounced retinopa-
thies, in particular, congenital retinal dysplasia.” With
eye drops containing 250 nM SkQ1, vision was restored
to 67 of 89 animals (dogs, cats, and horses) that became
blind because of a retinopathy. Moreover, SkQ1 pretreat-
ment of rats significantly decreased hydrogen peroxide
or ischemia-induced arrhythmia of the heart, reducing
the damaged area in myocardial infarction or stroke and
preventing the death of animals from kidney ischemia.
In p53 (−/−) knockout mice, 5 nmol/kg/day of SkQ1
decreased ROS levels in spleen and inhibited lympho-
mas. Thus, such “designer antioxidants” show promise
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
in slowing aging and in both preventing and potentially
treating diseases of aging. Intriguingly, of the many com-
mon dietary supplements regarded as “antioxidant” (see
Section “Polyphenols”), only melatonin has evidence for
consistent mitochondrial localization (Srinivasan et al.,
2011), with some evidence suggesting that it may function
as a significant mitochondrial protectant and regulator of
MITO bioenergetic function.
Intriguingly, and underlining the intrinsic connections
among the many biological phenotypes of aging, in recent
years, the OS theory of aging has forged increasing con-
nections to disinhibited inflammation and inflammatory
signaling, with many positive feedback loops between
the two processes, such that neatly separating these two
processes is difficult (see Section “Inflammation”). Recent
work on gene interactions (Jesmin et al., 2010) suggests
that OS is perhaps the critical common denominator
underpinning the intimate associations between obesity,
type II diabetes, and hypertension, and that obesity itself
may increase OS (Fernàndez-Sànchez et al., 2011). Evi-
dence also indicates that cancers and AD are hinged to OS,
suggesting that the long-term reduction of OS in aging
may have significant health benefits and may offer protec-
tion against many diseases of aging, even if the hard form
of the OS hypothesis (that ROS are the driver of aging)
is unsupported. Further evidence for critical interactions
among these various phenotypes of aging is suggested in
the landmark study by Sahin et al. (2011) which shows
that telomere dysfunction causes repression of mitochon-
drial biogenesis regulatory enzymes (PGC-1α/PGC-1β)
through activation of p53, leading to increased OS and
impaired mitochondrial biogenesis and bioenergetic
function. Suggesting another dimension to these dynamic
relationships among phenotypes of aging, recent work
has suggested that telomere loss may be directly related
to lifetime inflammation and OS burden, and that rate of
telomere loss in leukocytes predicts cardiovascular mor-
tality in men (Epel et al., 2009).
Inflammation
Increasing evidence argues that aging centrally involves
changes in both innate and adaptive immunity (in the
direction of declining adaptive immunity and compen-
satory upregulation of innate immunity), combined
with increasing systemic inflammation, recently dubbed
“inflammaging” (Franceschi et al., 2007), even in the
absence of obvious pathological consequences or lesions.
While traditional perspectives on inflammation empha-
size acute and local inflammatory processes and the
classic cardinal signs of localized inflammation (rubor et
tumor cum calore et dolore—redness and swelling with heat
and pain) involving many “acute phase” proteins, recent
work on “inflammaging” emphasizes a different side of
inflammation that is more systemic, chronic, and often (at
least initially, if not over the long term) asymptomatic.
13
Of course, inflammation is also a highly adaptive and
selected process, central to both organism defense and tis-
sue repair; without it, we could not survive long at all, and
it operates at virtually all levels of biological organization,
from the small molecular level all the way to the level of
behavioral organization (see Chapter 21, “Depression in
the Elderly: Interactions with Aging, Stress, Chronic Pain,
Inflammation, and Neurodegenerative Disorders”). Yet it
is centrally implicated in many, if not virtually all, of the
major diseases of aging, particularly atherosclerosis (see
Section “Diseases of Aging with Relevance to Neurol-
ogy”), AD, PD, most cancers, arthritis, and type II diabe-
tes (see Finch, 2011 for a detailed review). This profoundly
Janus-faced nature of inflammation may be one of the
most striking examples of “antagonistic pleiotropy,” sug-
gesting that aging and its acceleration may be at least par-
tially one of the “wages” of successful organism defense
and tissue repair. From the perspective of aging and its
diseases, the immune system may be simultaneously a
best friend and a worst enemy.
Blood levels of proinflammatory cytokines (such as
C-reactive protein and interleukin-6) are now widely
understood to be primary risk factors for vascular disease
and predictors of mortality/morbidity in cardiovascular
events. Underlining intimate relationships between pro-
inflammatory and anti-inflammatory signaling, the adap-
tive up-regulation of IL-6 due to exercise appears critical
to the anti-inflammatory production of IL-10 (Walsh et al.,
2011) and IL-1ra while inhibiting production of a cardinal
proinflammatory cytokine, TNF- . IL-6 was suggested to
be a “myokine,” defined as a cytokine that is produced
and released by contracting skeletal muscle fibers; it is
responsible for the anti-inflammatory effects of exercise,
part of increasing evidence that systemic inflammatory
signaling and “tone” are highly plastic and perhaps highly
responsive to diet and lifestyle issues (see the last sections
on lifestyle and dietary factors.). Indeed, many if not most
important lifestyle variables appear to modulate systemic
inflammatory tone directly, including classic dietary fac-
tors such as fiber consumption (Galland, 2010), omega-3
intake (Mittal et al., 2010), and polyphenol intake (Zhou
et al., 2011); sleep quality versus sleep deprivation (Moti-
vala, 2011); aerobic exercise (Walsh et al., 2011); and even
social stress (social isolation vs social comfort; Slavich et
al., 2010). This suggests that Western lifestyles (sedentary
and with typical Western diet patterns) may be, in toto,
seriously proinflammatory and may significantly increase
the risk of the diseases of aging most related to chronic
and systemic inflammation (many cancers, cardiovascu-
lar disease, AD and PD, diabetes, and arthritis).
Glycation, advanced glycation end products,
and AGE receptors
Glycation of proteins is a fundamental mechanism in
aging and in the deterioration of both organ structure
14 The Aging Brain in Neurology
and function, and is probably neglected in many treat-
ments of aging relative to its importance (Semba et al.,
2010; Bengmark, 2007). Glycation appears implicated
in almost every disease of aging, and not simply diabe-
tes, with glycation as a primary contributing cause and
not simply as a secondary effect. Additionally, AGEs
interact with receptors (rAGE) to upregulate inflam-
mation, another primary factor in the biology of aging
(see Section “Inflammation”), potentially contributing
to another critical dimension of aging. The creation of
AGEs involves bonding two or more proteins, a pro-
cess known as “cross-linking,” typically by the creation
of sugar–protein bonds. While some AGEs are rela-
tively short lived and fluctuate in response to diet and
metabolic state, other AGEs are long lived and virtually
impossible for the body to break down. The creation and
accumulation of these AGEs, particularly in essential tis-
sues such as coronary arteries and the brain, can have
serious effects on function and constitute a major risk
factor for a disease of aging in those organs (Semba et al.,
2010). For example, areas of arterial glycation are much
more likely to eventually become regions of atheroscle-
rosis and plaque accumulation, while glycation of CNS
tissue is associated with increasing inflammation and
the classic plaque and tangle pathology of AD (Srikanth
et al., 2011; Lue et al., 2010), with AGEs a major facilitat-
ing cofactor in the creation of both amyloid oligomers
and tangles (Gella and Durany, 2009). On the other hand,
rAGE activation may also increase autophagy as a pro-
tective response, and may reduce apoptosis after oxida-
tive injury (Kang et al., 2011), suggesting yet another
layer of interactions between these phenotypes of aging
(see Sections “Autophagy” and “Apoptosis”).
Glycation of tendons and other connective tissue may
form important foundations for loss of flexibility in aging.
Obviously, diabetes provides a classic model for the accel-
eration of glycation and generates a more rapid accumu-
lation of AGEs, with hemoglobin A1C a direct measure
of glycation of hemoglobin molecules (an example of a
relatively short-lived form of glycation). rAGE receptors
are also implicated in AD as a channel for amyloid oligo-
mers to enter cells where the oligomers potentially wreak
havoc with multiple cellular compartments, particularly
mitochondria and lysosomes (LeFerla, 2008). Glycation
can be inhibited by AGE breakers, which includes the
amino acid l-carnosine, and also blocked by multiple
polyphenols particularly ellagic acid. Green tea extract
(Babu et al., 2008), curcumin (Pari and Murugan, 2007),
and many flavonoids (Urios et al., 2007) have shown at
least some antiglycation functionality, along with alpha
lipoic acid (Thirunavukkarasu et al., 2005). This suggests
that a diet high in polyphenols and relatively low in free
sugars might prevent or reduce long-term glycation of tis-
sues (although this is never been proven in a human clini-
cal assay to our knowledge).
Autophagy
Autophagy is an essential catabolic process through
which existing proteins and other cellular components
are degraded and recycled, supporting the adaptive
function of removal and potential repair of damaged,
dysfunctional, or even toxic proteins and cellular organ-
elles. This function is dependent on “autophagosomes”
(an intracytoplasmic vacuole containing elements of a
cell’s own cytoplasm), typically fused with lysosomes
to facilitate the digestion of target proteins by lysosomal
proteases. Autophagy, like glycation, is perhaps one of
the more neglected critical storylines in aging in many
popular treatments of the subject, and its importance in
aging appears central. Indeed, it appears that aging can
be slowed significantly by simply improving this criti-
cal process—or, alternatively, perhaps aging itself causes
degradation of this process (Madeo et al., 2010). Antiag-
ing effects from improved autophagy are robust (Petro-
vski and Das, 2010) and include lifespan extension. Severe
dysfunction in the various autophagy pathways (typi-
cally caused by mutations) can correspondingly gener-
ate severe progeroid pathology, affecting multiple organ
systems, including muscle, the liver, the immune system,
and the brain. Defects in autophagy have shown acceler-
ated aging phenotypes in classic yeast, worm, and fruit
fly model organisms (primary models for aging in terms
of unraveling its basic cellular and molecular mecha-
nisms). In mammals, autophagy appears essential to life
and survival, as genetic knock-out of proteins required
for the process is lethal, suggesting a basic role in homeo-
stasis and development. More limited knock-out of genes
involved in autophagy in mice results in accelerated aging
phenotypes. While the precise underlying mechanisms
driving autophagy-related pathology remain obscure, the
study of Finkel and colleagues (Wu et al., 2009) suggests
that mitochondrial dysfunction is likely a critical factor.
Underscoring important reciprocal relationships among
the many phenotypes of aging, recent work suggests that
disruption of autophagy may manifest itself physiologi-
cally in terms of mitochondrial dysfunction and increased
OS (Wu et al., 2009).
Growing evidence links declining autophagy to all
the neurodegenerative disorders, with their characteris-
tic protein aggregations (often ubiquitinated, suggesting
that they are being tagged for removal), although patho-
logical changes can result from excessive or disinhibited
as well as deficient autophagy (Cherra and Chu, 2008).
Experimental animals genetically defective in autoph-
agy develop neurodegeneration accompanied by ubiq-
uitinated protein aggregates, demonstrating that basic
autophagy function is essential for long-term neuronal
health. Additionally, both age- and disease-associated
(with AD) reductions in the autophagy regulatory protein
beclin 1 have been found in patient brain samples (Cherra
and Chu, 2008), while treatments that promote autophagy
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
have been shown to reduce levels of pathological proteins
in several in vivo and in vitro models of neurodegenera-
tion. Rapamycin, lithium, and several polyphenols have
been shown to enhance degradation and also possibly
reduce synthesis of proteins that may contribute to toxic
oligomer formation, as well as larger extracellular aggre-
gates of toxic protein seen in several neurodegenera-
tive diseases. Quercetin, several other polyphenols, and
vitamin D all appear to increase autophagy, suggesting
important but incompletely mapped roles for diet and
lifestyle in modulating this critical aging-related process
(Wang et al., 2010b; Wu et al., 2011). These considerations
suggest that many neurodegenerative disorders (which
are all primary proteinopathies) may have future effec-
tive treatments based at least in part on the improvement
of autophagy function.
Apoptosis
Apoptosis, originally thought to be a deleterious and
primarily negative process, now is appreciated to have a
critical role in adaptation and longevity. Apoptosis must
balance regulation of the potential benefits of eliminating
damaged cells against the pathogenic impact of more mal-
adaptive forms of cell death (such as progressive cell loss
in postmitotic tissues, a major mechanism driving atrophy
in neurodegenerative disorders and contributing to end-
stage organ disease in postmitotic tissues.). Thus, a deli-
cate balance must be struck, and dysfunction in the regu-
lation of programmed cell death can mean that, on one
hand, apoptosis potentially contributes to atrophy and a
senescent cell phenotype, while, on the other, its failure
potentially leads to neoplastic cell proliferation. Apoptosis
is thus an important cellular defense for maintaining both
genetic stability and physiological function. An intrigu-
ing question is whether centenarians may be more or less
prone to apoptosis and whether longevity may slightly
favor an excessive trimming of still possibly viable cells
over allowing an increased percentage of potentially
rogue cells to survive–or the reverse (Monti et al., 2000).
Additional data points underscoring the importance
of a finely tuned apoptosis equation include that cells
that avoid apoptosis, particularly proliferating vascular
smooth muscle cells, participate centrally in atherosclero-
sis. Cancer could be thought of as the paradigmatic failure
of apoptosis, and several lines of evidence suggest that cel-
lular senescence and apoptosis (both of which contribute
to aging) are primary defenses against cancer (Chen et al.,
2007). On the other hand, accelerated apoptosis in post-
mitotic tissues such as the brain clearly contributes to vir-
tually all neurodegenerative disorders. This suggests that
adaptive regulation of apoptosis and its tuning and modu-
lation may be highly protective in relation to the diseases
of aging and, conversely, that disregulated apoptosis may
contribute to both aging and the diseases of aging. Just as
future modulators of autophagy may be treatments for
15
neurodegenerative diseases, similar prospects may apply
for regulators of apoptosis, although promotion of cancers
and perhaps obesity also would be potential concerns.
However, promoting apoptosis in senescent cells could be
highly desirable and might slow aging significantly (see
discussion in later section on Cellular Senescence).
Sarcopenia
Sarcopenia, the loss of both muscle mass and function,
is a universal feature of aging that has a major impact
on individual health and quality of life, predisposing
people to falls and eventual frailty, also often neglected
in treatments of aging and its phenotypes. Although the
term sarcopenia was first coined in 1989, its etiology is still
incompletely understood and its precise definition is still
debated. It centrally includes losses in muscle fiber quan-
tity and quality, alpha-motor neurons, protein synthesis,
and several anabolic and sex hormones (Waters et al.,
2010). Other factors may include altered basal metabolic
rate, increased protein requirement, and chronic inflam-
mation and OS. These changes lead to decreased overall
physical functioning, increased frailty, falls risk, and, ulti-
mately, the loss of independent living.
Sarcopenia is a critical aging phenotype. All elderly
show evidence of it, particularly after the seventh decade,
with a roughly 40% decline in muscle mass by the age
of 80 (Evans, 1995). Mechanisms leading to this are mul-
tifactorial and include mitochondrial dysfunction and
decline, altered apoptotic and autophagic processes, and
even altered trace metal homeostasis (Marzetti et al.,
2009). Like virtually every other aspect of aging, CR miti-
gates this process in a variety of species studied, again via
pleiotropic effects of CR, including mitochondrial biogen-
esis, reduction of OS, and improved apoptotic regulation
and autophagic processing. To our knowledge, reduction
of sarcopenia has not been demonstrated in humans with
CR mimetics.
Cellular senescence
No discussion of aging would be complete and without at
least a basic review of cellular senescence, first discovered
by Hayflick in vitro (Hayflick, 1965). Evidence argues that
cellular senescence probably evolved as a defense against
cancer and as a response to DNA damage and genomic
instability (Chen et al., 2007), and has to be seen as sit-
ting, like apoptosis, as a critical adaptive checkpoint on all
cell cycling. In this important sense, the cell cycle, apop-
tosis, senescence and carcinogenesis have to be all seen
as intimately related biological processes. Although cel-
lular senescence is popularly understood mechanistically
as driven by a simple loss of telomeres, evidence argues
that like all other phenotypes of aging, its true deriva-
tion is complex and highly multifactorial, and addition-
ally, that loss of telomeres is not simply due to the total
number of replication events, as originally assumed by
16 The Aging Brain in Neurology
Hayflick. Instead, evidence suggest many factors, partic-
ularly those related to chronic OS, chronic inflammation
and even chronic emotional stress (perhaps as proxy for
inflammation but perhaps reflecting other effects in addi-
tion to this) determine the rate of telomere loss, suggest-
ing a critical role for lifestyle in protecting against loss of
telomeres (Falus et al., 2010). Specifically, recent work has
shown that cumulative inflammatory load, as indexed
by the combination of high levels of IL-6 and TNF-α, is
associated with increased odds for short telomere length
in leukocytes (O’Donovan et. al., 2011). Emotional regula-
tion may play an underappreciated role in protection of
telomeres, and consistent with this, lifestyle interventions
that reduce stress, such as mindfulness meditation, have
even been shown to enhance both telomerase (Jacobs
et al., 2011) and preserve telomeres (Epel et al., 2009).
Additionally, recent work makes a principled distinc-
tion between cellular quiescence (cell cycle arrest) and
cellular senescence (Blagosklonny, 2011), with the for-
mer reversible, and paradoxically, with activation of the
progrowth mTOR pathways increasing the likelihood of
senescence, while inhibition of TOR saves cells from this
biological “dead-end” and shifts them into quiescence.
Thus, cell signaling pathways involved in aging also have
a critical role as well, suggesting that conjoined activa-
tion of DNA-damage sensing systems such as p53 and
p21 (which orchestrate blocks on cell cycling) and growth
pathways simultaneously helps to select senescence.
Additionally, and perhaps critically important in many
clinical situations, senescent cells develop a large cell
morphology and become hypersecretory in a proinflam-
matory direction. This is part of the evidence that aging is
a kind of a dysregulated “hyper-functional” state, driven
in part by disinhibited growth signals (mTOR acting as
a central integrator of those signals). As Blagosklonny
states, “cellular functions are tissue-specific: contraction
for smooth muscle cells, secretion of lipoproteins for
hepatocytes, aggregation for platelets, oxidative burst
for neutrophils, bone resorption for osteoclasts and so
on. These hyperfunctions lead to age-related diseases,
such as atherosclerosis, hypertension, macular degen-
eration, increasing the probability of organismal death”
(Blagosklonny, 2011. p 95). Thus, as Blagosklonny notes,
senescence reflects a biological version of cells respond-
ing simultaneously to “pressing the gas pedal” (growth
drive) and “getting on the brakes” at the same time (cell
cycle blocks driven by DNA-damage sensing systems).
Additionally, senescence both promotes inflammation
and is promoted by it, further underscoring recursive
relationships between these phenotypes of aging, and
offering further evidence of the Janus-faced nature of
inflammation, as an example of antagonistic pleiotropy
(Blagosklonny, 2011; Figure 1.1).That removing senescent
cells slows aging in a progeroid mouse model demon-
strates that senescence is not simply an aging phenotype
(an effect or component of aging), but a driver of aging
itself (Baker et al., 2011). This is consistent with much
other evidence that most if not all the phenotypes of aging
reciprocally reinforce one another, consistent with a circular/
recursive causality model of biological causation.
Endocrine dyscrasia
It has been only in the last 10 years or so (since the semi-
nal paper of Bowen and Atwood, 2004) that evidence has
accumulated for a primary role in aging for changes in
the hormonal-reproductive (HPG) axis potentially char-
acterized as an “endocrine dyscrasia”. Although many
are aware of the more famous components of this dys-
crasia (age-related declines in classic sex steroids with
the decline in male testosterone more gradual but start-
ing earlier than the steep menopausal decline of estrogen
and progesterone in females), Bowen and Atwood have
argued persuasively that the less appreciated upregula-
tion of luteinizing hormone and follicle stimulating hor-
mone from the pituitary and the associated increase in
gonadotropin-releasing hormone (GnRH) from the hypo-
thalamus to the pituitary (along with associated down
regulation of inhibins and upregulation of activins—as
peripheral modulators of HPG axis function) may play
a central role in aging and its phenotypes. As Atwood
and Bowen (2011) summarize, this theory is a clear exten-
sion of basic antagonistic pleiotropy concepts of aging:
“hormones that regulate reproduction act in an antago-
nistic pleiotropic manner to control aging via cell cycle
signaling—promoting growth and development early in
life in order to achieve reproduction, but later in life, in a
futile attempt to maintain reproduction, become dysregu-
lated and drive senescence. Since reproduction is the most
important function of an organism from the perspective
of the survival of the species, if reproductive-cell cycle
signaling factors determine the rate of growth, determine
the rate of development, determine the rate of reproduc-
tion, and determine the rate of senescence, then by defini-
tion they determine the rate of aging and thus lifespan.”
(p.100). As support for the theory, HPG axis dysregulation
may be a primary factor in AD, with elevation of luteiniz-
ing hormone and FSH, and decline of sex steroids as etio-
logical, and as contributing to an exaggerated mitogenic
signal that promotes beta-amyloid pathways, hyperphos-
phorylation of tau, synaptic retraction, and drives dys-
functional neurons into the cell cycle and from there into
programmed cell death (Atwood et al., 2005; Casadesus
et al., 2006). Challenges to this novel and heuristic theory
of aging include relatively its undeveloped linkages to
classic mTOR and insulin signaling pathways, as well as
links to other classic aging phenotypes, such as mitochon-
drial decline, OS, and “inflammaging”. However, recent
updates (Atwood and Bowen, 2011) summarize data link-
ing evidence for endocrine dyscrasia with multiple dis-
eases of aging, suggesting that an endocrine dyscrasia
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century 17

(a) (b) UPS

dysfunction

Unknown DA
factors metabolism

DA neuron
Compensatory dysfunction
Stochastic
mechanisms
and death

Normal DA content (%)

interaction Normal aging
between
multiple factors
Oxidative and
Inflammation
nitrative stress
PD (accelerated DA loss)
Mitochondrial
damage

Threshold for PD

Accelerants
• Genetic predispositions
• Environmental toxins
Time (yrs) • Cellular predispositions
• Prenatal infections
• Unknown factors

Figure 1.1 Cell cycle factors related to aging based on the stochastic acceleration hypothesis of Collier, Kanaan & Kordower (2011). A revised
hypothesis of the relationship between aging and Parkinson’s disease (PD) as they affect the biology of midbrain dopamine (DA) neurons.
The hypothesis incorporates evidence that supports the involvement of common cellular mechanisms in dopamine neuron dysfunction
in ageing and degeneration in Parkinson’s disease. (a) The effects of these altered cellular mechanisms as they accumulate during normal
ageing result in Parkinsonian dopamine neuron dysfunction, either very late in life or not at all (shown by the light gray line). However,
when these same cellular mechanisms are accelerated by specific, individually determined factors, Parkinsonism emerges earlier in the
lifespan (shown by the dark gray line). (b) The hypothesis contends that the cellular mechanisms that threaten dopamine neuron function
are identical, but are not linked in an orderly cascade of cause and effect; instead, they can contribute to varying degrees and combine in
patient-specific patterns, thus fulfilling the definition of a stochastic interaction: incorporating elements of randomness with directionality
toward dopamine neuron dysfunction. Light gray double-ended arrows show cellular events in normal ageing. Thicker, dark gray double-
ended arrows show accelerated cellular events in PD. UPS, ubiquitin-proteasome system. Similar mechanisms are implicated in cancer
pathogenesis also. Source: Blagosklonny (2011). Reproduced with permission from US Administration on Aging.

may interdigitate with and generate reciprocal synergies
with many other core phenotypes of aging mentioned in
this chapter, particularly disinhibited particularly inflam-
mation via promotion of TNF-α (Clark and Atwood,
2011). Novel approaches to antiaging therapies from this
theory would centrally include efforts to normalize HPG
axis function, not just through classic supplementation of
sex steroids, but also intercepting other aspects of altered
cell signaling, particularly overactivation of activins and
an undersupply of inhibins, although these two latter
manipulations are currently unavailable and represent
highly appealing targets for future technologies.
The slowing of aging: dietary or calorie
restriction and lifestyle interventions
Calorie restriction: evolutionary and
animal models
Although the effects of CR on longevity were described
more than 115 years ago (Jones, 1884), and its protection
against the diseases of aging has been appreciated for
almost a century (Rous, 1914), only more recently have
we begin to unravel the molecular mechanisms by which
CR extends lifespan and protects the organism from age-
related change. CR functions as a kind of global meta-
bolic reprogramming for virtually all organisms, extends
lifespan, and reduces penetration of the diseases of aging
significantly, if not dramatically, in most species in which
it has been studied. Although the precise molecular path-
ways and cellular effects of CR are still being studied and
debated, in general, it is viewed as a selected and phy-
logenetically conserved trade-off between reproductive
fecundity and physiological conservation/preservation,
and consistent with ideas in the previous section, results
in a downregulation of the gonadotropic axis (Bowen and
Atwood, 2004). A basic speculation has been that some
version of a basic CR mechanism arose relatively early in
evolution, during common periods of nutrient shortfalls,
to allow organisms to trade off reproduction for conser-
vation (when major energy shortages would have made
reproductive efforts too metabolically costly), allowing
an adaptive shift back to growth and reproduction at a
time when nutritional supplies were more abundant.
18 The Aging Brain in Neurology

Recent work has confirmed that CR effects are conserved Glucose

virtually throughout the entire animal kingdom, starting Testosterone Amino acids
with organisms as primitive as yeast and extending into
insects and other invertebrates, lower vertebrates such as Insulin Fatty acids
fish, mammals (Fernandes et al., 1976), primates (Lane et IGF-1 TOR
al., 2001; Roth et al., 2001), and even humans (Rochon
et al., 2011), although long-term studies on CR effects in
humans are still lacking. (Short-term studies clearly dem- Growth Aging
onstrate that the basic physiology of CR is well conserved Hyperfunction Diseases of aging
in humans, but life extension—confirming that aging is
Life time
indeed slowed—has not yet been empirically confirmed.
Most researchers, however, anticipate that this will be Figure 1.2 A simple schematic for the molecular pathway of mTOR

eventually demonstrated.) as “antagonistic pleiotropy”–that, in some sense, aging is simply the

CR/DR lacks a precise quantitative definition but might
be considered to reflect a roughly 30% reduction in calo-
ries from eating freely until satiation (Richardson, 1985).
CR effects for many species might begin at around a 25%
to 30% reduction and extend to a 50% to 65% reduction, at
which point CR transitions into starvation, a process that
does not demonstrate any of the protective effects of CR
and actively destroys global health. CR also requires that
basic macro- and micronutrients be obtained (vitamins,
minerals, fatty acids, and at least some protein). CR/DR
is probably not a simple “homogeneous” issue, and can
include differential restriction of proteins, carbohydrates,
and fats, with these different forms of DR probably acti-
vating different cellular pathways involved in nutrient
sensing and, therefore, having somewhat different physi-
ological effects. However, protein and amino acid restric-
tion clearly appears to be the more critical component, as
protein restriction without CR elicits a significantly more
robust profile of CR effects (Simpson and Raubenheimer,
2009) than the reverse (CR but without protein restric-
tion; Kim et al., 2010a). Reasons for this may hinge on the
importance of protein restriction for downregulation of
mTOR, which is required for maximal CR benefits (see
Section “Mammalian target of rapamycin”).
Protein restriction may cause downregulation of
growth factors and growth hormones (particularly GH,
but also IGF), as well as provide downstream inhibi-
tion of TOR pathways (Figures 1.2, 1.3 and 1.4), improv-
ing autophagy and decreasing protein synthesis, among
other effects, and may be particularly protective in rela-
tion to carcinogenesis (Anisimov et al., 2010); CR with-
out protein restriction may not be nearly as protective in
relation to cancers (Baur et al., 2006). Carbohydrate and
glucose restriction, on the other hand, may more directly
modulate insulin pathways and their several downstream
targets. Intriguingly, evidence indicates that single amino
acid restriction (specifically limiting dietary methionine
or tryptophan) can yield CR effects (Caro et al., 2009),
with subsequent reduced ROS in the mitochondria, low-
ered insulin and blood sugar levels, improved insulin
sensitivity, and more (in other words, a CR physiology).
This suggests an intriguing and perhaps less burdensome
flip side of a protracted growth process that is not sufficiently turned
off after a peak reproductive period. Source: Blagosklonny (2009).
Reproduced with permission from US Administration on Aging.
option to classic CR approaches, without at least some
of the aversive effects of classic CR diets (foods high in
methionine include eggs, fish, soy, and many seeds, espe-
cially sesame seeds). CR without protein restriction, on the
other hand, may not produce lifespan extension, probably
because of a blunting of the CR protective effects against
carcinogenesis, as well as perhaps a more limited down-
regulation of IGF (and other growth factors) and lessened
overall inhibition of mTOR (Anisimov et al., 2010; see the
next sections on mTOR).
Insulin Calorie
restriction
IR S1/2
GF
PI-3K
LKB1
AMPK
TOR Metformin
S6K RAPA
Other
Environmental genetic
factors factors
Aging
Age-related
diseases
Figure 1.3 A simple schematic of some of the cellular pathways
implicated in calorie restriction, aging, and the slowing of aging.
Nutrients, growth factors (GF), and insulin activate the TOR
pathway, which is involved in aging and age-related diseases.
Other genetic factors and environmental factors (such as smoking,
sedentary lifestyles, and obesity) contribute to age-related
diseases. Several potential antiaging modalities (metformin, calorie
restriction, and rapamycin and several polyphenols particularly
resveratrol) all directly or indirectly (via impact on AMP kinase)
inhibit the TOR pathway. Source: Blagosklonny (2009, 2010a).
Reproduced with permission from US Administration on Aging.
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century 19

TOR activity AMPK activity Low P:C diet

Levels of glucose

Levels of glucose
High P:C diet

Levels of amino acids Levels of amino acids

Leptin; insulin/IGF; etc. Stress factors; sirtuins; etc

Nutrients
High aa:glu Low aa:glu
Insulin resistance; Insulin sensitivity;
autophagy and TOR AMPK autophagy and
repair inhibited repair promoted
Eat less Eat more

Anabolic responses Catabolic responses

Protein synthesis, lipogenesis, Cell cycle arrest, inhibition of
cell proliferation, growth, growth and reproduction,
reproduction lipolysis, proteolysis

Vicious cycle to obesity

Overeat on low %P diets
Live longer

Obesity and insulin resistance

Die early
Lipolysis, elevated FA, lean
muscle breakdown, enhanced
hepatic gluconeogenesis
Figure 1.4 A schematic summarizing the hypothesis
for how diet balance might affect lifespan via
Depleted muscle mass and aa
the TOR and AMPK signaling pathways. Source:
pool; reduced lean signal (IL-
Simpson and Raubenheimer (2009). Reproduced
15?); low aa:glu; high AMPK
with permission from US Administration on Aging.

Calorie restriction: genes and pathways
Many genes and molecular pathways are implicated in CR
effects, consistent with the previous discussion. Indeed,
many researchers and theorists at this point believe that
CR involves a whole family or network of interacting
molecular pathways. These would include insulin signal-
ing 1/2, IGF and other growth factors, PI3 kinase, AKT
(protein kinase B), forkhead transcription factors, PGC1- ,
AMP kinase, sirtuins, and mTOR (Figures 1.3 and 1.4). This
network of pathways argues against any version of a sin-
gle primary pathway being responsible for CR effects, and
suggests a highly pleiotropic phenotype, consistent with
other evidence that adaptive growth processes must be, by
necessity, sensitive to a host of signals (see Section Mam-
malian Target of Rapamycin). Thus CR as a protective
and antiaging intervention, probably operates through a
network of linked molecular pathways, where recursive
interactions and relationships may be incompletely under-
stood at present. Although a class of transcription factors
called sirtuins, particularly SIRT1, were initially conceptu-
alized as the critical regulators of CR effects (Sinclair, 2005),
recent work suggests that SIRT1 may operate on and influ-
ence some, but not all, of the CR network, while SIRT3
may also be critical as well. However, research suggests
that CR (if it includes significant protein restriction) down-
regulates mTOR while also upregulating AMPK (Baur,
2006), up-regulates several sirtuins (Sinclair 2005), pro-
motes mitochondrial biogenesis, and significantly reduces
inflammation (Figures 1.3 and 1.4). Effects from inhibition
of TOR are increasingly thought to be critical to mediating
lifespan extension and slowing the aging process with DR.
As a result, this TOR pathway has supplanted the sirtu-
ins as the most studied and most intriguing cell-signaling
group of pathways in aging (and antiaging) science. As
such, it merits a detailed overview.
Mammalian Target of Rapamycin
Target of rapamycin (TOR) belongs to a highly conserved
group of kinases from the PIKK (phosphatidylinositol)
family, increasingly conceptualized as core and essential
integrators of growth signaling. Knockout of mTOR is
consistently embryonically lethal across several species,
20 The Aging Brain in Neurology
suggesting a strong antagonistic pleiotropy affect for
this particular gene (Blagosklonny, 2010a). Rapamycin,
an immunosuppressive macrolide, was first discovered
as the product of a soil bacteria from Easter Island. It
directly and potently inhibits the activity of TOR (TOR
complex 1 (TORC1), but not until recently did we under-
stand that it also impacts TOR complex 2 (TORC2)).
TOR was first identified in yeast but subsequently has
been found to exist in all eukaryotic organisms. TORC1
(rapamycin sensitive) is thought to be the central element
of the TOR signaling network, monitoring and integrat-
ing a large set of intra- and extracellular processes and
controlling growth, proliferation, and lifespan with a
host of complex downstream effects (Kapahi et al., 2010).
TORC2 is also rapamycin sensitive, but contributes to the
full activation of AKT, an upstream and critical signaler
of TORC1; it also mediates spatial control of cell growth
by regulating the actin cytoskeleton (Hall, 2008) and
disruption of TORC2 by rapalogs appears to drive the
“paradoxical” insulin resistance seen in chronic admin-
istration (Lamming et al., 2012). TOR plays a highly con-
served and central role in coupling nutrient sensing to
growth signals, integrating signals from wnt-β-catenin
signaling pathway (growth factors involved in stem cell
differentiation and regulation), glucose and lipid avail-
ability (signaled by AMP kinase), protein and amino
acids deficiency or availability (growth resources), sig-
nals from multiple other growth factors and hormones,
and even oxygen availability and hypoxia signals to
dynamically determine the envelope of growth versus conser-
vation signaling in the cell. TORC1 is thus thought to act as
a growth “checkpoint” and signal integrator, determin-
ing whether the extra- and intra cellular milieu is favor-
able to growth and, if not, producing effects consistent
with a CR phenotype. TORC1 has many output targets,
altered in either CR or CR mimetic effects from rapamy-
cin, including messenger RNA translation (inhibited
in CR), autophagy (increased in CR), transcription and
ribosome biogenesis (inhibited in CR), proliferation and
growth (inhibited in CR), and several other key cellular
processes, including stress resistance (increased by CR);
for a fine technical review of TOR research, see Kapahi
et al. (2010). Inhibition of mTOR by rapamycin has been
shown experimentally to increase lifespan, even when
given to mice in late middle age (Harrison et al., 2009).
This finding suggests that rapamycin is a more powerful
CR mimetic than resveratrol, which has failed to extend
lifespan outside of obese animals (Baur et al., 2006; Miller
et al., 2011). On the basis of age at 90% mortality, rapamy-
cin led to increased lifespan of 14% for females and 9%
for males. Intriguingly, patterns of mortality and disease
in rapamycin-treated mice did not differ from those of
control mice, suggesting that treatment with rapamycin
globally delays aging and age-related disease in a non-
specific and fairly “even” fashion (Harrison et al., 2009),
arguing for at least some involvement of mTOR in virtu-
ally all age-related disease that might cause or contribute
to mortality (at least in mice). Inhibition of TOR’s major
downstream targets, such as S6K, a kinase involved in
ribosome biogenesis, appears to be important to the pro-
tective (antiaging) effects of TOR inhibition, and a knock-
out of this gene (S6K) also increases lifespan in mice
and, intriguingly, generates activation of AMP kinase;
this suggests dynamic relationships between mTOR
and AMP kinase (Selman et al., 2009) that are probably
incompletely mapped at this time (as two core primary
mediators of CR/DR effects).
Figure 1.4 (from Simpson and Raubenheimer, 2009) sche-
matically summarizes relationships between AMP kinase
and mTOR. These two kinases are increasingly viewed
as possibly integrating much of CR physiology, with an
upregulation of AMP kinase and a downregulation of
mTOR potentially orchestrating the entire range of CR
effects through their conjoint activity. These two kinases are
differentially involved in nutrient sensing, with TOR acti-
vated by high amino acid/glucose ratios (in other words,
plenty of amino acids and proteins to build new tissue, thus
releasing a “go” signal to anabolic processes and growth)
and AMP kinase activated by low amino acid/glucose
ratios. Thus, protein/carbohydrate dietary ratio may influ-
ence differential activation/inhibition of TOR and of AMP
kinase (and these two integrators of CR physiology are also
interactive, with AMP kinase inhibiting mTOR). These dif-
ferential nutrient-sensing systems may help explain why
CR without at least some protein restriction may not be
as effective as a general antiaging strategy (Blagosklonny,
2010a, 2010b), particularly in relation to the prevention of
cancers, because such a diet does not maximally down-
regulate mTOR. Additionally, Figure 1.4 may help explain
why resveratrol by itself (a primary activator of AMP
kinase, but not a primary or direct inhibitor of mTOR) does
not produce a lifespan extension in animal models (outside
of obesity) because it does not inhibit mTOR sufficiently.
Calorie-restriction mimetics
Given the intrinsically stressful and unpleasant nature
of basic CR approaches (for example, CR animals typi-
cally cannot be housed together because they are too
irritable and will fight), most believe that CR is simply
not a viable health-maintenance strategy for most people.
If anything, the recent pandemic of obesity has under-
lined that most individuals, when given ready access to
tasty and addicting high-calorie-density foods, are sim-
ply not going to restrict their calorie intake voluntarily,
regardless of the well-known and widely appreciated
negative consequences. This has led to increasing inter-
est in CR mimetics, defined as any substance that poten-
tially mimics the molecular effects and physiology of CR
(without the stress of making a person hungry much of
the time). There are probably many substances that cause
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
mild nausea, visceral upset, or other GI distress and that
subsequently inhibit food intake, but although these can
show CR effects in sustained administration in animal
models, they cannot be considered CR mimetics. Addi-
tionally, drugs that may directly modulate appetite (such
as Rimonabant, an endocannabinoid-1 receptor blocker)
might also show CR effects in sustained administration
by modulating consumption and hunger drive at central
levels, but they also cannot be considered true CR mimet-
ics. One emerging prediction might be that CR mimetics
will occupy an increasingly central role in primary pre-
vention in relation to the diseases of aging in the com-
ing decades, but an enormous amount of basic research
remains to be done before widespread implementation of
CR mimetics would be advisable or feasible; long-term
data in both preclinical and clinical populations also is
lacking (although data collection and trials of CR mimet-
ics are underway in relation to many diseases of aging).
There are actually a number of CR mimetics with accu-
mulating research supporting CR effects, but the most
famous of these is clearly resveratrol, a molecule that
has received enormous research attention in the last 15
years. In addition, metformin is a true CR mimetic (a
drug commonly used to treat type II diabetes and rarely
categorized in conventional medical literature as a CR
mimetic) and 2-deoxyglucose are CR mimetics (2-deoxy-
glucose was actually the first described CR mimetic and
interferes with glycolysis, preventing glucose utilization
by cells even when abundant glucose is available, but it
is cardiotoxic in chronic administration). Fisetin, derived
from Fustet shrubs, is a flavonoid polyphenol that has
also demonstrated CR mimetic effects. Rapamycin (as a
primary inhibitor of TOR) is also a potent CR mimetic; to
date, only rapamycin has demonstrated lifespan extension
when given to older mammals (many CR mimetics have
demonstrated lifespan extension in other target species,
such as yeast, fruit flies, fish, and worms). Other polyphe-
nols (a very large group of compounds found in fruits and
vegetables, totaling perhaps as many as 6000 substances)
may have mild CR effects, particularly quercetin, resve-
ratrol, and its first cousin, pterostilbene (Belinha et al.,
2007). However, single-polyphenol regimens, particularly
resveratrol, have not shown lifespan extension (Pear-
son et al., 2008)2, except in obese animals (protecting mice
from premature mortality and the undesirable physiology
of obesity (Baur et al., 2006) or cases in which resveratrol
was combined with every-other-day dieting (EOD) as a
2
Given that AMP kinase inhibits mTOR, resveratrol might have
some modest indirect effects on this critical pathway. Studies on
resveratrol reviewed in later sections (see the section on CR mimetics)
suggest that mTOR inhibition is likely to be modest, given the
absence of lifespan extension in mammalian animal models, outside
of obese animals, where its AMPK promotion may be protective and
promote similar aging trajectories to non-obese animals.
21
mild CR alternative (also demonstrated in a mouse model
in Pearson et al., 2008). Although resveratrol was initially
assumed to have its protective effects through SIRT1 acti-
vation, recent work has clarified that AMP kinase is prob-
ably the necessary and sufficient target for the protective
effects of resveratrol (Um et al., 2010). Recent work has
suggested that pterostilbene may be a more effective CR
mimetic, with better bioavailability than resveratrol, and
also a better activator of PPAR-α (Rimando et al., 2005),
with more beneficial effects on lipid profiles, while still
showing extraordinarily low toxicity (Ruiz et al., 2009).
Evidence suggest that resveratrol and its analogs, like
pterostilbene (along with metformin and quercetin, two
other CR mimetics), are probably only partial CR mimet-
ics; even moderately high-dose resveratrol (20–30 mg per
kilogram) does not appear to protect mice against late-
life cancers (particularly a form of virally induced lym-
phoma, a very common cause of death in aged laboratory
mice; Pearson et al., 2008) and does not extend lifespan
outside of obese animals. Intriguingly, a nutraceutical
combination of resveratrol and quercetin appeared to
provide better mimicking of CR physiology than resvera-
trol alone (Barger et al., 2008; although longevity was not
indexed specifically). This suggests that combinations of
partial CR agents may get us closer to mimicking a full CR
physiology than a single compound particularly a com-
bination of rapamycin and an AMPK modulator such as
resveratrol or metformin -- a logical combination that has
yet to be tested, and where AMPK modulation might help
reduce the insulin resistance seen on chronic administra-
tion of rapalogs (associated with its TORC2 disruption).
These considerations (Figure 1.4, by Simpson and
Raubenheimer 2009) suggest that a complete or ideal CR
mimetic might both activate AMP kinase and directly
inhibit mTOR (not simply indirectly through increased
AMPK activity), without toxicities or major side effects, a
design target that no single known compound at this time
yet achieves. Inhibition of mTOR (via rapamycin) has
shown promising protection against diseases of aging in
mammalian animal models (Stanfel et al., 2009). Perhaps
a combination of low-dose rapamycin and resveratrol or
pterostilbene might achieve the desirable targets of mTOR
inhibition and AMPK activation, and thus function as
a full CR/DR mimetic. To prove this in a mouse model,
one would have to show further protective benefits from
those achieved with rapamycin alone if resveratrol or
pterostilbene were added in late middle age. This intrigu-
ing hypothesis has never been probed or tested even in a
mammalian animal model. Full testing of these ideas in
humans appears even further away, underlining an enor-
mous gap between research promise and clinical reality
in this vital area of biological science. Given the potential
impact that a full, robust, and safe CR mimetic could have
on aging and the diseases of aging (particularly the poten-
tial extension of “healthspan”), there is remarkably little
22 The Aging Brain in Neurology
research into this area, relative to its potential biological
promise. Indeed, conventional medicine still sees CR/DR
and CR mimetics largely as biological “fringe” subjects,
instead of appreciating their potentially enormous pro-
tective functions and central and paradigmatic insights.
Large pharmaceutical firms have just recently begun to
pay more attention to this area of CR and its mimetics
(see the recent GSK acquisition of Sirtris, www.gsk.com/
media/pressreleases/2008/2008_us_pressrelease_10038
.htm).
Calorie-restriction variants and mutants
There are many ways to generate CR effects, beyond clas-
sic CR approaches. One of the most basic of these is sim-
ply intermittent fasting (which may not result in nearly as
much weight loss as full CR but still activates a CR physiol-
ogy), along with methionine restriction (as noted earlier). In
addition, there is manipulation of growth hormone (such as
growth hormone knockout) and IGF-1 and insulin signal-
ing manipulations (consistent with overwhelming evidence
that insulin-signaling pathways are primary targets for CR
effects; Figures 1.3 and 1.4). A dwarf mouse implement-
ing a growth hormone knockout shows a roughly 60% life
extension (and won a recent Methuselah prize; Bartke and
Brown-Borg, 2004). This animal showed reduced hepatic
synthesis of IGF-1, reduced secretion of insulin, increased
sensitivity to insulin actions, reduced plasma glucose,
reduced generation of ROS markers, upregulated anti-
oxidant defenses, increased resistance to OS, and reduced
oxidative damage, all quite consistent with CR physiol-
ogy. Probably many dozens of genes can be modified to
yield some variation of a CR physiology and at least some
increase in longevity (and therefore slowing of aging), con-
sistent with the evidence that CR/DR activates a complex
and highly interactive network of cell signaling and regula-
tory pathways (Yuan et al., 2011; Lorenz et al., 2009).
Lifestyle and dietary factors
There is increasing, if not collectively convincing, evi-
dence that core lifestyle factors such as exercise and diet
(as well as sleep quality and social stress vs social com-
fort) potentially influence many aspects of aging, thus
constituting a complex collection of negative and positive
risk factors for all the diseases of aging. This collection of
lifestyle variables are also presumably interactive with a
small group of known polymorphisms and a likely much
larger group of unmapped polymorphisms that collec-
tively may have a large effect on longevity (Yashin et al.,
2010) and risk for specific diseases of aging. Future map-
ping of those polymorphisms (and their likely complex
interactions with lifestyle variables) may allow much bet-
ter prediction of risk, and eventually allow for more effec-
tive and tailored early interventions, to reduce specific
risk for a particular disease of aging. As but a small exam-
ple of these issues, IL-10 endowment may affect risk for
AD. Although a good night’s sleep, a healthy and more
balanced diet, regular aerobic exercise, and social sup-
port are generally regarded as having nothing to do with
each other biologically, recent work in relationship to all
of these lifestyle factors suggests that they impact a broad
but fundamentally shared set of cellular and molecular
pathways. These shared effect pathways include mul-
tiple if not most aspects of cell signaling (internal cel-
lular regulation): regulation of cell cycling, regulation
of inflammatory, stress, defense and growth pathways,
including mTOR. Although our understanding of diet,
exercise versus sedentary lifestyle, sleep, and stress ver-
sus social comfort is still evolving, evidence suggests that
basic lifestyle factors either promote or inhibit inflamma-
tion, protect insulin sensitivity versus generating insulin
resistance, and create more OS versus protect against it,
while promoting (or inhibiting) autophagy, cellular senes-
cence, and apoptosis in aging, thus modulating virtually
every known phenotype of aging. Additionally and rarely
appreciated within traditional medicine, all the individual
components of so-called healthy lifestyle practices appear to
be part of our ancient evolutionary environment and reflect
HG lifestyle characteristics. This suggests the possibility
of a version of a “unified field theory” in relationship to
long-term health versus chronic disease, and that healthy
living may reduce complex and still poorly understood
“mismatches” between our genome and our current bio-
logical environment in Western societies. In general, such
ideas have little current visibility within conventional
medical circles (although a reprioritizing of prevention is
now being widely emphasized), but a nascent awareness
of these more global biological perspectives on health
versus chronic disease is slowly emerging, energized by
increasing research into lifestyle and its complex biologi-
cal impact.
Exercise
Regular aerobic exercise is widely recognized as an
essential component of a healthy lifestyle, yet fewer than
15% of individuals living in the United States engage
in adequate amounts of aerobic exercise; a majority of
people in the United States are almost completely sed-
entary (Roberts and Barnard, 2005). Sedentary lifestyles
are thought to contribute to risk for all diseases of aging,
particularly cardiovascular disease, metabolic syndrome,
and type II diabetes, especially when combined with a
Western diet. Exercise has an extremely complex biologi-
cal footprint, but among its many effects, exercise offers
protection against all-cause mortality, particularly against
atherosclerosis, DMII, and several but perhaps not all
cancers, notably colon and breast cancer. It also signifi-
cantly reduces frailty and sarcopenia. Regular exercise
appears specifically protective against diseases associated
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
with chronic low-grade systemic inflammation (Peterson
and Peterson, 2005), perhaps due the anti-inflammatory
response elicited by an acute bout of exercise, largely
mediated by muscle-derived IL-6. IL-6 stimulates produc-
tion of anti-inflammatory cytokines (such as IL-1ra and
IL-10) and inhibits subsequent (postexercise) production
of the key proinflammatory cytokine TNF-α. In addition,
IL-6 stimulates lipolysis and fat oxidation and metabo-
lism (see Peterson and Peterson, 2005 for a detailed
review). These anti-inflammatory effects also inhibit insu-
lin resistance, which is partly modulated by TNF-α and
by NFκ-B/AP-1, transcription factors centrally involved
in inflammatory signaling.
Exercise may also upregulate antioxidant defenses
(Kaliman et al., 2011), while OS actually initially increases
during a bout of exercise, with subsequent upregulation
of endogenous defenses (referred to as mitochondrial
hormesis or “mitohormesis”). Some work on the effects
of exercise calls into question the conventional wisdom
of blocking OS, as evidence suggests that this actually
impairs exercise benefit and even may prevent beneficial
effects of CR (Ristow and Schmeisser, 2011). Exercise may
also increase neurotrophins, improve stress resistance,
improve mood, increase emotional and stress resilience,
and enhance cognitive function and learning (Ratey, 2009),
and consistent with these effects, at least some preventa-
tive/protective effects against most neurodegenerative
disorders, particularly AD, have also been demonstrated.
Obesity
One of the most worrisome public health trends over the
last 20 years has been a steady and dramatic increase in
the prevalence of overweight and obese individuals. Cur-
rent statistics suggest that roughly one-third of the United
States is obese (with a body mass index (BMI), greater
than 30), with another one-third of the population over-
weight (BMI over 25 but less than 30; Wang et al., 2007).
Additionally some evidence suggests that the rate of
obesity is still increasing despite much attention to this
public health issue, and may reach 50% penetration in the
United States by 2025. Equally worrisome is the emerg-
ing evidence that the rates of obesity in the United States
are actually higher in children than in adults, perhaps
due to a highly undesirable combination of increasingly
sedentary gameplay (in which video games have largely
supplanted more physical activity), increasing fast food
consumption, and overconsumption of sugary bever-
ages. Obesity is increasingly appreciated as a risk factor
for virtually every disease of aging, beyond its popular
link to risk for cardiovascular disease. Obesity contributes
significantly to risk for hypertension, dyslipidemia, insu-
lin resistance and type II diabetes, multiple cancers, and
even AD. Evidence suggests that increased abdominal fat
(vs subcutaneous fat) is a more significant risk factor than
generalized obesity, and this relationship is potentiated,
23
curiously enough, in otherwise leaner subjects (Pischon et
al., 2008), as abdominal fat may have a particularly potent
effect on dysregulation of inflammation (Fontana et al.,
2007) via promotion of proinflammatory cytokines. Aging
itself decreases subcutaneous fat while increasing abdom-
inal fat, and simply reducing abdominal fat surgically has
a prolongevity effect in animal models. Increased visceral
fat is independently associated with all-cause mortality,
insulin resistance and diabetes, cardiovascular disease,
cerebrovascular disease, AD, and disability in the elderly
(Florido et al., 2011). Additionally, there is evidence for
intrinsic relationships between obesity and upregu-
lated inflammation (in part as compensatory and a way
of using more energy) and, on the other hand, CR and
reduced inflammation (Ye and Keller, 2010).
Polyphenols
Although conventionally regarded as “antioxidants”,
polyphenols are an enormous class of substances (con-
stituting perhaps as many as 6000 distinct compounds)
found in plants, principally fruits and vegetables, that
have enormously pleiotropic effects on human and
mammalian physiology. Some of these effects may be
more biologically significant than any direct “free radi-
cal scavenging” done by any polyphenol; they include
many effects on cell signaling, the regulation of growth
factors and apoptosis, the regulation of cell cycling, the
regulation of inflammation, the modulation of many (if
not most) cellular stress pathways, an impact on multiple
transcription factors (including those involved in energy
homeostasis), and (consistent with their conventional
designation) the management of OS (Virgili and Marino,
2008). Many of these effects on aspects of cell signaling
require much lower levels of polyphenol than any direct
free radical scavenging in serum or tissues. Indeed, from
this perspective, polyphenols look less like “antioxidants”
and more like complex cell physiology and cell signaling
modulators. However, it seems unlikely that such a desig-
nation will replace the catchy title of “antioxidant,” even
in the context of increasing evidence that such a title may
be fundamentally if not profoundly misleading. Many, if
not most, of the phenotypes of aging (OS, mitochondrial
dysfunction, inflammation, and declining autophagy,
among others) appear to be partially modulated by vari-
ous polyphenols. From this perspective, if our ancestors
consumed more plants than we do and did so over tens
of thousands of years (if not much longer), the relative
removal of polyphenols from the human diet (in those
eating minimal fruits and vegetables) would be pre-
dicted to have complex but potentially profound effects
on physiology and on the biological trajectories of aging.
Conversely, those eating a rich variety of plants may be
more protected against accelerated aging and the diseases
24 The Aging Brain in Neurology
of aging. Of these two predictions, the second has been
better studied, and is generally supported, while the first
has some evidence for it as well, but is not well elucidated.
Polyphenols consist of several classes of chemical sub-
stances, including nonflavonoid compounds (such as res-
veratrol, other stilbenes, and curcuminoids), and classic
flavonoids (consisting of two large classes, anthocyanins,
which are colorful and pigmented, and anthoxanthins,
which are colorless). Resveratrol and its first cousin,
pterostilbene, are both naturally occurring phytoalex-
ins produced by plants in response to fungal infection
(phytoalexins are all “plant defense” compounds). Of the
anthoxanthin family, quercetin is one of the best-known
and best-studied members, along with EGCG (a mem-
ber of the catechins family, with catechins constituting
a large group of polyphenols in tea and wine). Dietary
sources for polyphenols include many foods that have
been ancient components of the human diet for many
hundreds and even thousands of years: fruits and their
juices (typically containing both anthocyanins and antho-
xanthins), tea (catechins), coffee (chlorogenic, caffeic and
ferulic acids), red wine (anthocyanins, resveratrol, and
quercetin), vegetables (many anthoxanthins and antho-
cyanins), some cereals, chocolate (multiple flavonoids,
including catechins and proanthocyanidins), and various
legumes, particularly soy (isoflavones) and peanuts.
In this context, there are multiple challenges to any
emerging science that might explain the roles polyphe-
nols could play in health maintenance and the slowing of
at least some aspects of aging and/or age-related disease.
First, there are many thousands of different bioflavonoids
in toto, but only a handful with much in vivo research (res-
veratrol, curcumin, green tea extract, and quercetin are
perhaps best studied). Most of the studies of polyphe-
nols use in vitro approaches; although there are increas-
ing numbers of in vivo studies in animal models, very
few clinical studies have taken place in humans. As an
additional major challenge to potential therapeutic use,
virtually all bioflavonoids have relatively poor bioavail-
ability, which may be part of their extraordinarily non-
toxic biological footprint. Most polyphenols are rapidly
conjugated (typically sulfated and glucuronided), and
variably metabolized, often with an uncertain biological
status of their multiple metabolites. The proper study of
any polyphenol in potentially slowing or preventing any
disease of aging is methodologically challenging and also
expensive (long time frames are needed and it is difficult
to control for many other positive and negative lifestyle
risk factors). With all these scientific and methodologi-
cal challenges, there is little financial incentive to study
polyphenols in humans in relation to the diseases of
aging or aging itself, given the poor return on investment
with inexpensive agents that cannot be patented. This
collection of factors has generated the current situation,
where one finds much promising animal-model data for
multiple polyphenols in relation to a disease of aging, but
a dearth of good human clinical studies. This is chang-
ing slowly, and several polyphenols are in clinical trails
related to several diseases of aging.
One of the few completed studies of a polyphenol in
a human clinical population demonstrated that resvera-
trol is effective at higher doses in treating diabetes (Patel
et al., 2011). Clinical studies are underway related to can-
cer, AD, and heart disease. Curcumin is also being increas-
ingly studied for its anti-inflammatory, antiproliferative,
and antiaging effects. Curcuminoids are thought to affect
many dozens of cellular pathways and, like many poly-
phenols, block NF kappa-B, a transcription factor involved
in the regulation and activation of inflammatory responses
(Aggarwal, 2010). Curcumin is also one of several poly-
phenolic inhibitors of mTOR, a critical nutrient-sensing
and growth factor integrative pathway that is increasingly
implicated as a molecular target of CR; if inhibited, it may
slow aging and also inhibit or delay diseases of aging
(Beevers et al., 2009), but curcumin has notoriously poor
bioavailability and rapid metabolism (Bengmark, 2006).
Diseases of aging (with particular relevance
to neurology)
This list of diseases is truncated due to space consider-
ations, and does not include many important illnesses,
including motor neuron diseases, frontotemporal lobar
degenerative disorders, and various brain cancers.
Cardiovascular disease
Although “cardiovascular disease” technically refers
to any disease that affects the heart or blood vessels, the
term has become increasingly synonymous over the last 20
years with atherosclerosis. This disease of aging is directly
responsible for more deaths than any other in Western
societies, killing twice as many individuals as all cancers
combined and probably more than all the other diseases
of aging put together (Minino et al., 2006). Thus, it clearly
merits a summary review. Evidence argues that lifestyle
and cultural factors have to be considered as primary etio-
logical issues here. As Kones pointedly states “Americans
are under assault by a fierce epidemic of obesity, diabetes,
and cardiovascular disease, of their own doing. Latest data
indicate that 32% of children are overweight or obese, and
fewer than 17% exercise sufficiently. Over 68% of adults
are overweight, 35% are obese, nearly 40% fulfill criteria
for metabolic syndrome, 8–13% have diabetes, 34% have
hypertension, 36% have prehypertension, 29% have predi-
abetes, 15% of the population with either diabetes, hyper-
tension, or dyslipidemia are undiagnosed, 59% engage in
no vigorous activity, and fewer than 5% of the US popula-
tion qualifies for the American Heart Association (AHA)
definition of ideal cardiovascular health. Health, nutrition,
and exercise illiteracy is prevalent, while misinformation
and unrealistic expectations are the norm. Half of American
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
adults have at least one cardiovascular risk factor. Up to
65% do not have their conventional risk biomarkers under
control. Of those patients with multiple risk factors, fewer
than 10% have all of them adequately controlled. Even
when patients are treated according to evidence-based pro-
tocols, about 70% of cardiac events remain unaddressed.
Undertreatment is also common. Poor patient adherence,
probably well below 50%, adds further difficulty in reduc-
ing cardiovascular risk. Available data indicate that only a
modest fraction of the total cardiovascular risk burden in
the population is actually now being eliminated. A fresh
view of these issues, a change in current philosophy, lead-
ing to new and different, multimechanistic methods of pre-
vention may be needed. Adherence to published guidelines
will improve substantially outcomes in both primary and
secondary prevention. Primordial prevention, which does
not allow risk values to appear in a population, affords
more complete protection than subsequent partial reversal
of elevated risk factors or biomarkers” (Kones, 2011, p. 61).
Consistent with these statements, recent research dem-
onstrates that the underlying process of atherogenesis is a
complex and long-term process involving many players,
including endothelial cells, cytokines and immunoglobu-
lins, immune cells, growth factors, extracellular matrix
molecules, and lipids, but with a primary role for OS and
inflammation. Atherogenesis requires a cascade of pro-
cesses, starting with a maladaptive, sustained proinflam-
matory reaction to oxidized lipid deposition in the arterial
wall. The initiating event appears to be the deposition of
apoB-containing lipids, typically oxidized low-density
lipoproteins. Oxidation of these lipids dramatically
increases the likelihood that the deposition process will
irritate the vessel, promoting increased proinflammatory
cytokine release; this suggests that plasma redox balance
may be a critical variable (Maharjan et al., 2008). Hyperlip-
idemia is also associated with declining endothelial nitric
oxide synthase (eNOS) and increasing nitroxidative stress
in the endothelium (Heeba et al., 2009). These inflamma-
tory cascades lead to accumulation and swelling in arte-
rial structures, mostly from macrophage cells combined
with lipids (principally, oxidized low-density lipopro-
tein (LDL), VLDL, and other fatty acids), calcium (par-
ticularly in advanced lesions), and a certain amount of
fibrous connective tissue. Glycation of proteins (an intrin-
sic component or phenotype of aging), as well as foreign
antigens, can also promote these fundamental inflamma-
tory changes (Milioti et al., 2008), with regions of more
glycated tissue and AGEs promoting and accelerating the
formation of these plaque structures (Kim et al., 2010b).
These slowly developing structures (atheromatous
plaques) are found at least to some degree in most individu-
als in Western societies, and early asymptomatic stages of this
process are found in many young adults; however, they are
rare in HGs (Eaton et al., 1988 a,b). LDL is the most common
ApoB plasma lipoprotein, but ApoB-containing VLDL,
25
remnant VLDL (depleted of triglycerides), intermediate-
density lipoprotein (IDL), and LP(a) have also been shown
to be atherogenic, along with ApoB from chylomicron rem-
nants; this suggests that many forms of lipid contribute to
risk. These lesions actually begin in childhood and develop
slowly over many, many decades. The early stages of depo-
sition are called “fatty streaks,” but they are not composed
of adipose cells; instead, they consist of white cells, espe-
cially macrophages, that have taken up oxidized LDL. After
these cells accumulate large amounts of cytoplasmic mem-
branes (and high cholesterol content), they become “foam
cells.” When foam cells undergo apoptosis, the contents
are deposited into the surrounding tissue, attracting more
macrophages and inflammation, and causing a positive and
self-sustaining feedback loop. Upon activation by proin-
flammatory stimuli, macrophages and lymphocytes release
proinflammatory cytokines that stimulate the migration of
smooth muscle cells (SMCs) from the medium of the vessel
wall. SMCs then contribute to more foam cell and fibrous
cap formation, also under the influence of proinflamma-
tory cytokines (for example, IFN-γ and TNF-α secreted by
T helper cells, and IL-12 secreted by macrophages and foam
cells; Milioti et al., 2008). Eventually, foam cells die via apop-
tosis, dumping nondegradable cholesterol crystals that form
the lipid core of the plaque structure. Plaque structures can
be either stable or unstable, with vulnerable plaque tending
to be faster growing and with higher macrophage content,
suggesting that autoinflammatory processes not only con-
tribute to the early, more silent stage of the process, but also
drive the deadly late stages of the process well. Recent work
by Wang et al., 2011 suggests a potentially pivotal role by
immunoglobulins (IgE) as a critical player in the activation
of macrophages, and with high correlations between IgE
levels and degree of plaque instability.
Although popularly viewed as a disease of cholesterol
(a perspective that dominated the earlier conceptualiza-
tions of vascular disease in the 1960s and 1970s), increas-
ing scientific opinion favors atherosclerotic vascular
disease as a disease of inflammation and OS. Consistent
with this, increasing evidence shows that statins actu-
ally impact both inflammatory and OS issues (Heeba
et al., 2009), while promoting upregulation of heme
oxygenase (an important antioxidant defense enzyme).
Statins appear to inhibit vascular disease through pleio-
tropic mechanisms, including decreased synthesis of
LDL, increased removal of LDL (through hepatic LDL
receptors), upregulation of eNOS, increased tissue-type
plasminogen activator, and also inhibited endothelin 1,
a potent vasoconstrictor and mitogen. All of these pro-
mote improved endothelial function. Statins also reduce
free radical release, thus inhibiting LDL-C oxidation (Liao
and Laufs, 2005), while increasing endothelial progeni-
tor cells and reducing both the number and activity of
inflammatory cells and cytokines. They also may help
stabilize atherosclerotic plaques, reduce production of
26 The Aging Brain in Neurology
metalloproteinases, and inhibit platelet adhesion/aggre-
gation (Liao and Laufs, 2005).
Although it is extremely common in Western societies
(at least in some stage, even if clinically silent), extensive
vascular disease is virtually nonexistent in HG groups
(Eaton and Eaton, 2002). This suggests a primary role for
etiology in the Western lifestyle and diet (see later sec-
tions on diet and lifestyle variables), in which multiple,
if not virtually all, components of the Western diet and
lifestyle appear proinflammatory relative to HG lifestyles
(sedentary vs highly aerobically active, altered omega-6/
omega-3 ratios, poorer sleep, greater social isolation,
lower consumption of fiber, lower consumption of pro-
tective polyphenol phytochemicals, and high BMI vs low
BMI in HG groups).
In addition to atherosclerosis (which is clearly the larg-
est problem in pathological vascular aging in Western
cultures), there is also vascular aging independent of ath-
erogenesis. Increasing evidence implicates angiotensin II
(Ang II) signaling as central to this process (Wang, Khazan,
and Lakatta 2010). Arterial remodeling and decline in aging
(even without atherosclerosis) is increasingly thought to be
linked to Ang II signaling (Wang, Khazan, and Lakatta,
2010a). Components of Ang II signaling (including sev-
eral reactive oxygen species, multiple growth factors,
matrix metalloproteinases, chemokines, and nicotinamide
adenine dinucleotide phosphate-oxidase) are upregulated
within arterial walls in many species including humans,
during aging. In vivo studies suggest that elevation of Ang
II signaling drives accumulation of AGE (advanced gly-
cated end products, which are themselves proinflamma-
tory), increased collagen, disruption of elastin, and inva-
sive hypertrophy of both smooth muscle and endothelial
cells (Wang, Khazan, and Lakatta 2010a). Obvious clinical
implications are that attenuating Ang II signaling may sig-
nificantly retard this age-associated arterial remodeling,
suggesting important protective effects for ACE inhibitors
and ARB compounds. Intriguingly, multiple polyphenols,
including those in pomegranate juice (rich in tannins and
anthocyanins), appear to inhibit angiotensin signaling (per-
haps in part from nonspecific antioxidant effects, but also
from inhibition of angiotensin-converting enzyme activity)
and may also reduce blood pressure (Stowe, 2011). Ang II
also enhances ROS production by activating NAD(P)H oxi-
dase and uncoupling eNOS. Systemic inhibition of Ang II
thus may potentially have CR mimetic (antiaging) effects,
due to its central role in coordination of vascular aging, OS,
and impact on the mitochondria (de Cavanagh, et al., 2011).
These processes driving vascular aging and disease are
of obvious primary relevance to vascular dementias, as
well as to common findings of white matter erosion (typi-
cally referred to as white matter hyperintensities or white
matter ischemic change on MRI and CT scans), sometimes
appearing as a highly comorbid pathology with AD
(Brickman et al., 2009). Indeed, separating amyloid
angiopathy (a frequent vascular concomitant to AD) from
other forms of atherosclerosis is almost impossible within
clinical settings.
Alzheimer’s disease
As the disease of aging with perhaps the greatest relevance
to this textbook, there has been a paradigm shift over the
last 20 years away from the original assumption that AD
has nothing to do with aging. Of course, this could not pos-
sibly have been true, given the simple fact that AD roughly
doubles in incidence every 5 years after the age of 60–65
and that aging remains the greatest risk factor for nonfa-
milial sporadic AD. Recent research suggests that markers
for OS and mitochondrial decline (Pratico, 2010; Aliev et
al., 2010; Mancuso et al., 2007) are elevated even prior to
the appearance of extracellular amyloid deposition, which
takes place in the preclinical stages of the disease. Indeed,
multiple lines of evidence link AD to many, if not virtu-
ally all, of the phenotypes of aging, including inflamma-
tion (Masters and O’Neill, 2011), OS, accumulation and/or
clearance failure of characteristic pathogenic proteins (Bar-
nett and Brewer, 2011), and increasing deleterious synaptic
effects from those proteins and from associated inflamma-
tion (De Strooper, 2010; Mondragon-Rodriguez et al., 2010;
Palop and Mucke, 2010). Recent work has suggested that
pathogenic proteins (such as oligomeric amyloid) are not
being cleared out (Mawuenyega et al., 2010), underlining
an important role for declining autophagy in the etiology.
These considerations suggest that AD is indeed a highly
pleiotropic and complex disease with several stages in
which we may still not understand fully all the critical
factors, or exactly how they interact to create a cascade
with distinct stages, and with different processes and
interactions presumably critical at different stages. What
were originally adaptive mechanisms (such as inflamma-
tion, recruitment of amyloid pathways by various stresses
and neuroplasticity challenge, phosphorylation, apopto-
sis, cell cycling, and so on) may become pathogenic in
the context of chronic synergistic recruitment, biological
stress, and neuroplasticity challenge. This suggests an
image of AD in which a host of individually adaptive and
compensatory mechanisms jointly “conspire” to drive
the brain into a neurodegenerative process (Mondragon-
Rodriguez et al., 2010). Given that these interactions
among a host of individually adaptive processes occur
well past a reproductive period, they would escape vir-
tually any conceivable selection pressure or modification.
In this sense, the vulnerability to AD may reflect a “fault
line” in the human genome consistent with the evolution-
ary perspectives outlined earlier. Thus, AD itself may be
an expression of antagonistic pleiotropy in which genes
and molecular pathways that were adaptive during peri-
ods of youth and fecundity potentially backfire in aging,
particularly when synergistically recruited. Table 1.1
summarizes some, but not all, of the complex interactions
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century 27

Table 1.1 Factors contributing to a neurodegenerative mratrix in AD

Biomarker Produced by Producing Clinical/Other correlates

Beta amyloid plaque Aging, ↓ clearance, oxidative stress/ Inflammation (glial activation), Subtle regional atrophic changes.
(extracellular Aβ) inflammation APOE4, altered BBB function? oxidative stress, more Second biomarker appearing after
↑ gonadotropins (LH/FSH) and declining sex oligomers? OS/MITO decline
steroids?
Small aggregate amyloid β/γ secretases, inflammation, oxidative Synaptic loss and dysfunction, Synaptic loss (NMDA, AMPA), loss
(oligomeric Aβ) stress, ↓ clearance, endocrine dyscrasia? OS, inflammation of LTP, increased LTD
Plaque?
Inflammation (INFLAM) Amyloid fibrils and oligomers, ↓ ACh, ↑ rAGE Synaptic dysfunction, Contributes directly to cognitive
(↑ innate immunity) signaling, aging, OS, endocrine dyscrasia? apoptosis, declining dysfunction via multiple effects
neurotrophins, OS, ↑Aβ?
Central insulin resistance Inflammation (↑ NFk-b, AP-1, TNF-α, other ↓ Energy, HC damage, ↑ Promotes synaptic dysfunction
(in CNS) proinflammatory cytokines), chronic stress? kinases (→ neurofibrillary and loss; promotes amyloidosis
tangles?), declining autophagy?
Oxidative stress (OS), Declining control over OS in aging, Aβ Synaptic and neural loss, Appears before plaques/tangling;
MITO decline oligomers in MITO, metal ions, INFLAM, INFLAM, Aβ, increased membrane OS increases with
advanced glycation end products, junk tangling? aberrant cell cycling disease, but DNA OS markers
protein → apoptosis do not
Excitotoxicity and Ca++ Oligomers (Aβ) in MITO, and at Ca++ Synaptic dysfunction, Synaptic dysfunction, eventually
dysfunction channels, ↑ kynurenine (from increased apoptosis, esp. in HC/EC SL/NL
cytokines) regions
Neurotrophin and neuro- Oligomers (Aβ) → receptor internalization, ACh loss → ↑ Aβ, BDNF/ NGF Synaptic dysfunction, promotion of
transmitter depletion tau pathology → microtubule dysfunction, declines, aberrant cell cycling both SL and apoptosis
inflammation and apoptosis
Neurofibrillary tangling Oxidative stress (OS) → ↑ kinases (w/ Basal forebrain (ACh) loss, SL, Tracks atrophic change (SL/NL) and
and tau aggregates ↓ phosphatases), insulin resistance? apoptosis declining cognitive function closely.
Downstream effect of Aβ oligomers? Precursors (PHF) appear long
Aberrant cell cycling? before beta amyloid deposition
Atrophy HC/EC → lateral Multifactorial, with many factors listed Proceeds functional declines Major biomarker for degenerative
temporal → frontal/ contributing to synaptic loss and apoptosis (slightly) changes in clinical stages of AD
parietal
Cognitive loss, especially Synaptic loss early, SL plus NL later Declining fxn, compensatory Primary functional measure,
STM, then language and (apoptosis) neuroplasticity effort? necessary for diagnosis
executive function

Source: Adapted from Watt et al. (2012) with permission from Springer.
SL: synaptic loss, NL: neural loss (neuronal cell death), Aβ: beta-amyloid, BBB fx: Blood Brain Barrier Function, MITO: mitochondria, ACh:
acetylcholine, NGF: nerve growth factor, BDNF: Brain Derived Neurotrophic Factor, rAGE: receptors for advanced glycation end products (which
promote inflammation), HC: hippocampus, EC: entorhinal cortex, apoptosis: programmed cell death, NFk-b: Nuclear Factor Kappa B (transcription
factor involved in inflammatory signaling), AP-1: activator protein 1 (transcription factor involved in inflammatory signaling), Oligomers: several
molecules of beta amyloid stuck together, Kinases: enzymes promoting phosphorylation and tangling, NMDA/AMPA: subtypes of glutamate receptor,
LTP: long-term potentiation, LTD: long-term depression, lateral temporal: lateral temporal lobe, frontal/parietal: frontal and parietal convexity.

between putative etiological factors in AD, emphasizing
an image of the disease as highly multifactorial, but one
in which many primary phenotypes of aging (OS, disor-
dered cell cycling, inflammation, glycation, apoptosis,
mitochondrial decline, accumulation of junk proteins,
and declining autophagy) appear not only contributory,
but also highly interactive, arguing against any version of
a single factor etiology.
Parkinson’s disease
PD and its more aggressive and malignant close relative,
diffuse Lewy body disease (DLBD), are idiopathic neurode-
generative diseases characterized by intraneuronal accumu-
lation of Lewy bodies (aggregates of alpha-synuclein), par-
ticularly in substantia nigra (midbrain dopamine-producing
regions) in classical PD (and much more widely in DLBD).
It is marked by progressive loss of DA cell bodies, deafferen-
tation of basal ganglia, and dysfunction in direct and indi-
rect corticostriatal pathways. Subsequent primary symp-
toms include resting tremor, slowing of movement, rigidity
and gait difficulties, and eventual postural instability. There
is evidence of differential vulnerability to degeneration in
nigral regions, with “ventral tier” neurons more vulner-
able than “dorsal tier,” and with VTA neurons least effected
(Collier et al., 2011), despite the fact that these fields form a
continuous sheet of DA neurons. This differential vulner-
ability is viewed in recent work as multifactorial. In animal
models, it appears linked to several markers, including the
appearance of alpha-synuclein, ubiquitin (as a marker of
proteasome activation), lipofuscin (as a marker of lysosome
28 The Aging Brain in Neurology
activation), 3-nitrotyrosine (as a marker for nitroxidative
stress), dopamine transporter activation, and markers of
astrocyte and microglial activation (inflammation markers).
Dysfunctional mitochondria and activated microglial cells
are thought to be the primary intracellular source of reac-
tive oxygen species, and lysosome-mediated autophagy
is the primary cellular mechanism for removing defective
mitochondria. The progressive accumulation of lipofuscin
(conventionally regarded as “age pigment”) is thought to
reflect an index of mitochondrial damage and subsequent
lysosomal degradation of defective mitochondria (Terman
et al., 2006). Collier et al. (2011) argue that the etiology of
PD, while still uncertain, may reflect stochastic interactions
among inflammation, OS, declining autophagy, and accu-
mulations of pathogenic junk proteins, producing a “sto-
chastic acceleration hypothesis”. These kinds of basic mod-
els (although omitting inclusion of many other aging phe-
notypes such as glycation, endocrine change, and telomere
loss) (Figure 1.1) may provide a template for unraveling
the etiology of other neurodegenerative disorders, particu-
larly AD, but also the FTD family and some types of cancer,
where the connections to aging and aging phenotypes are
less clearly established. The high percentage of AD pathol-
ogy in patients with DLBD argues also for a fundamental
relationship between AD and PD that is still incompletely
mapped.
Aging processes and the brain:
cognitive changes in aging
Although enormous evidence suggests that aging in the brain
cannot be neatly separated from aging of the whole organ-
ism, at the same time, one has to consider that aging may
be differentially expressed across different organ systems,
and that the brain might be exposed differentially to aging
processes (and perhaps differentially protected as well),
including effects on the brain of pathological forms of aging,
as described in the discussions of AD and PD. Much work
suggests that a variety of neurocognitive functions decline
with aging, even in those without demonstrable neurologi-
cal disease (although the enormous difficulty in removing
preclinical AD completely from one’s aging cohort/control
group, plus the ubiquitous penetration of vascular disease in
Western societies raises serious questions about how many
studies purporting to show age-related cognitive change
may be measuring at least in part prodromal stages of neu-
rological decline from a major disease of aging). In any case,
robust evidence suggests that a host of neurocognitive pro-
cesses decline in aging, including episodic memory, work-
ing memory, spatial memory, processing speed, and even
implicit (skill) learning, along with various motor func-
tions, particularly motor speed and fine motor control (see
Yeoman et al., 2012 for overview). The precise neural bases
for these declines are still open to debate, and although initial
assumptions heavily emphasized age-related neuronal
loss, increasing evidence argues that these neurocognitive
declines are probably pleiotropic in origin, with synaptic loss
possibly more important than actual neuronal loss. This itself
also appears multifactorial, with roles for aminergic and neu-
rotrophin decline, and where increased CNS inflammation
might also play a role, but this has until recently been mini-
mally probed, both in clinical and preclinical approaches
(Cribbs et al., 2012). Loss of the smaller and highly plastic
thin dendritic spines (more than the “fat” mushroom spines
which appear more resistant to aging) appears to be one of
the best candidates for an ultrastructural basis to age-related
cognitive change, at least in relevant animal models (and
thin spines which are more NMDA receptor-dense also
appear more sensitive to deprivation of classic sex steroid
hormones) (Dumitriu et al., 2010). A physiological correlate
to cognitive declines in aging related to declarative (episodic)
memory appears to be the phenomenon of prolonged hyper-
polarization in aged hippocampal neurons, associated with
changes in NMDA, AMPA, calcium channels, and other ion
channels (Yeoman et al., 2012).
Departure from ancient evolutionary
environment: impact on aging processes
and promotion of diseases of aging
Enormous evidence indicates that Western societies involve
diets and lifestyles that are radically different from HG
lifestyles and diets and, indeed, radically different from
the original evolutionary environment in which the entire
hominid line evolved. This may produce an “evolution-
ary discordance” (Konner, 2001) that may have profound
effects on human health and a major influence on the bio-
logical trajectories of human aging. This notion of a radical
departure from an evolutionary environment and a subse-
quent mismatch between our genes and our environment
may provide a unifying context for connecting all increased
risk factors for all the diseases of aging: Humans in modern
technological societies are now living much longer (primar-
ily due to our successful control over predation, starvation,
and infection as primary causes of early mortality for chil-
dren and younger adults). Put differently, all of the so-called
healthy lifestyle practices that have been discovered piecemeal
through many empirical studies (such as a diet high in fruits and
vegetables, healthy omega-3/omega-6 ratios, high intake of fiber,
and regular exercise) all have as a unifying context that they are
components of our original long-term biological environment as
HGs (Eaton and Eaton, 2002). This suggests that healthy life-
style practices reduce or perhaps even virtually eliminate
chronic mismatches between a genome carved in a more
ancient HG environment and our current technological
environment. Unfortunately, adoption of these healthy life-
style practices is far from widespread in the United States or
in other Western societies, and it may be relatively restricted
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
to those better educated and those belonging to more fortu-
nate socioeconomic groups (Johannson et al., 1999).
The fundamental hominid diet for probably more than
two million years (preagriculture) was lean protein sources
(game and fish), supplemented by significant quantities of
fruits and vegetables (Cordain et al., 2005). Modern tech-
nological diets are higher in fat (particularly omega-6 fats)
and carbohydrates (largely from grains and other agricul-
tural products) and now contain significant transfats (which
did not exist in our original biological environment); they
also are frequently deficient in fiber and multiple protective
phytochemicals (polyphenols) and possibly low in other
several critical micronutrients, including choline and pho-
spolipids, multiple B vitamins, and several minerals (Eaton
et al., 2007). In addition, vitamin D deficiency is now quite
common (Holick, 2007), while this was probably very rare, if
not nonexistent, in ancient HG societies, in which skin color
seems to have evolved to match latitudes and to balance
vitamin D production with skin protection, given that both
modern sunscreens and indoor living were nonexistent.
The following tables summarize some of these funda-
mental differences between an ancient biological environ-
ment for humans and the current environment, including
Original Evolutionary Environment
1 Regular aerobic exercise (2-3+ hours per day)
2 9+ hours sleep (see #1)
3 Calorie limitations (intermittent CR)
4 High-phytochemical/polyphenol diets
5 Omega-6/omega-3 ratio 1:1 to 3:1 with modest intake of
overall fats
6 High intake of fiber (about 50-100 g per day)
7 Low sugar/carbs, except fruits/veggies
8 Intake of K+ > Na+ (K+ > 4 gm/d)
9 Pro-alkaline diet
10 Minimal to no glycated proteins
11 Intimate social groups/tribes
12 Early mortality: infection, starvation, predation, and
intraspecies violence: life expectancy 35-45 years
Biomarkers
Hunter Gatherers
1 BMI 21–24
2 Total cholesterol under 125
3 Blood pressure 100–110/70–75
4 VO2 max good to superior
5 Homocysteine low
6 Vitamin D about 50–100 ng/mL
7 Higher B vitamin/folate levels
8 High insulin sensitivity
9 Fasting plasma leptin 2–4ng/mL
10 Waist/height ratio <45
11 Physical activity >1000 kcal/d
29
work on biomarkers from studies of HG societies (Eaton
and Eaton, 1999; Eaton et al., 2007; Eaton et al., 1998a,b;
Cordain et al., 2005). This evidence for huge biological
environment shifts during a period of minimal genetic
change for humans (the last 10,000 years) suggests a
potential “unified field theory” for the diseases of aging
(and that diseases of aging are largely “diseases of civili-
zation”; Melnik et al., 2011). Ironically, humans have never
lived longer than they are living in modern technological
societies: The average life expectancy at birth within pre-
industrial HG societies was probably roughly 30–35 years
(Konner and Eaton, 2010). However, this significantly
extended lifespan in technological cultures is one in
which penetration by a major disease of aging (excepting
osteoarthritis, which is common in HG groups) appears
more likely, relative to the few elders who existed in HG
societies (Dunn, 1968; Konner and Eaton, 2010). Conclu-
sive data on this question is lacking, however, and recon-
struction of more ancient (Paleolithic) HG lifestyles and
biological state involves extrapolating from the relatively
few HG societies that survived into the twentieth century
(columns adapted from Eaton and Eaton, 1999; Eaton et
al., 2007; Eaton et al., 1998a,b; Cordain et al., 2005).
Modern Technological Environment
1 Minimal to no aerobic exercise (< 15 min/d)
2 7 hours or less of sleep (see #1)
3 Unlimited calories
4 Low phytochemical/polyphenol diets
5 Omega-6/Omega-3 ratio 10:1 to 20:1 with typically
higher intake of fats
6 Low intake of fiber (≤ 15 gm/d)
7 High sugar/carbs, not from fruits/veggies
8 Intake of Na+ > K+ (Na+ > 4 gm/d)
9 Pro-acidic diet
10 Common glycated protein (especially milk products)
11 Social isolation common
12 Death from an advanced disease of aging: life
expectancy 75-85 years
Current Technological Societies
1 About 30% BMI >30, about 30% BMI 25–30
2 Total cholesterol about 200 or higher
3 120/80 (normative), with hypertension common
4 VO2 max fair to poor (sedentary lifestyles)
5 Homocysteine significantly higher
6 Vitamin D deficiency common (10–30 ng/mL)
7 Common B12 and folate deficiencies
8 Variable degrees of insulin resistance
9 Fasting plasma leptin 4–8ng/mL
10 Waist/height ratio 52–56
11 Physical activity about 150–490 kcal/d for most
30 The Aging Brain in Neurology
Although conclusive data is still lacking, preliminary
evidence suggests that HG societies did not appear to have
nearly the incidence of cancer and heart disease (Eaton and
Eaton, 2002), diabetes (Eaton et al., 2002), or AD (Eaton
and Eaton, 1999) suffered by modern societies, even when
the relative rarity of elder members is taken into account
(Konner and Eaton, 2010). Consistent with these findings
and hypotheses, a paleolithic diet improved diabetic bio-
markers more than the highly touted Mediterranean diet
(Lindeberg et al., 2007) and improved BP and glucose toler-
ance, decreased insulin secretion, increased insulin sensi-
tivity, and improved lipid profiles, all without weight loss
in healthy sedentary humans (Frassetto et al., 2009). Addi-
tional evidence (summarized in Spreadbury, 2012) suggests
the provocative hypothesis that virtually all processed or
“acellular” carbohydrates—which tend to be high-density
carbohydrate foods—(ancient sources of carbohydrates in
fruits and vegetables were low density) contribute directly
to an inflammatory gastrointestinal microbiota which leads
directly to leptin resistance, disordering of fundamental
energy homeostasis through effects on multiple satiety
peptides, and promotion of obesity. Spreadbury further
argues that modern diets are truly distinct from ancient
diets not in relationship to either nutrient density or gly-
cemic index but only around carbohydrate density (Spread-
bury, 2012) due to acellular grain-based foods.
It is difficult to know precisely what the sum total or com-
posite effect of such global and pervasive shifts in our basic
biological environment might be, or what each factor may
contribute to the overall increasing burden of diseases of
aging in Western societies. However, the evidence favors the
hypothesis that these shifts are first of all individually del-
eterious. Therefore, collectively, they are likely to be highly
undesirable and potentially profound. Indeed, there may be
poorly mapped synergisms among these various factors in
promoting diseases of aging, as virtually every one of these
factors—the complex multifactorial dietary shifts, seden-
tary versus aerobic lifestyles, common obesity generated
by these two factors, vitamin D deficiency, low-grade sleep
deprivation, and increased social isolation and stress (vs the
intimate social groups of our ancestors)—all impact the regu-
lation and management of inflammation (as even psychosocial
isolation and social stress is a proinflammatory event). This
suggests that, collectively, Western lifestyles (when com-
pared to the lifestyles of our HG ancestors) may be hugely
proinflammatory. There is evidence that autoinflammation
involves increased OS (Finch, 2011), drives insulin resis-
tance, and is potentiated by glycation (Semba et al., 2010),
and increases cellular senescence. Such a global view of the
biological environment also suggests strongly that single-
component “fad diet” approaches, such as the elimination
of all fructose, sugar, or carbohydrates, are not likely to be
successful unless combined with a larger group of dietary
and lifestyle changes (although refined carbohydrate reduc-
tion as noted may help with reducing obesity, inflammation,
and pulsatile insulin over-production all of which may be
critical in the Western society burden of diseases of aging).
In any case, this analysis, which suggests a complex and
highly interactive composite of environmental shifts relative
to ancient HG environments that collectively are probably
biologically profound.
Many, if not most, of these lifestyle and dietary factors may
also deteriorate the endogenous management of OS (Kali-
man et al., 2011). Given that autoinflammation creates OS
for “bystander” tissues (Finch, 2011), these lifestyle variables
may impose a double burden: increasing OS while depriv-
ing us of several protective factors (found in our ancient
evolutionary diet and lifestyle) that might ameliorate or pro-
tect against OS. OS, modulated by both diet and exercise, is
also believed to be a primary factor in genetic damage and
genomic instability (Prado et al., 2010), leading potentially
into cancers and the acceleration of cellular senescence, as a
primary defense against cancer (Ogrunc and Fagagna 2011).
Cellular senescence in turn appears to be proinflammatory,
creating a so-called “senescence-associated secretory pheno-
type” (SASP) (Blagosklonny, 2011). Many of these dietary
and lifestyle factors also modulate the glycation of proteins
and the formation of AGEs (particularly diets low in fiber
and polyphenols and high in refined sugars/carbs), with
AGE products a primary regulator and inducer of inflam-
mation. Inflammation itself may promote insulin resistance
and, thus, glycation, suggesting many positive feedback
loops between these classic metabolic and age-related pro-
cesses. Common vitamin D, B12 and folate deficiencies
may contribute to declining autophagy, and also increasing
inflammation (Holick, 2007), promoting cognitive decline in
aging, increased homocysteine (as a marker and proxy for
OS and inflammation), and possibly increased AD (Tangney
et al., 2011). Many lifestyle factors also impinge on the cell
signaling related to endogenous defenses against OS, partic-
ularly exercise, polyphenol intake, inflammatory state, obe-
sity and excessive energy, and insulin resistance. Indeed, the
typical alterations in energy homeostasis in Western diets
and lifestyles, leading to an excess of energy (in turn, lead-
ing to obesity), are a primary activator of mTOR (mTOR, as
a pathway that integrates nutrient signaling and growth fac-
tors), increasingly implicated as a central factor in the regu-
lation and induction of aging (Blagosklonny, 2009, 2010a). In
addition, multiple polyphenols (modestly) and DR, particu-
larly protein restriction, inhibit mTOR. Collectively, these
considerations suggest that Western lifestyles may directly
impact the biology of the diseases of aging (and aging itself)
directly and powerfully in a multitude of undesirable ways.
Thus, although the central prolongevity triumph of Western
civilization and medicine, the prevention and treatment of
bacterial infection, has had a very positive impact on median
survival to old age, Western lifestyles may accelerate aging
and the diseases of aging in a multitude of other ways. Pre-
venting the diseases of aging therefore has to begin with an
appreciation for the central importance of lifestyle change,
 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century
back toward at least some approximation of our evolution-
ary environment.
What constitutes optimal prevention of
the diseases of aging?
In sum, this large constellation of globally altered lifestyle
variables impacts the fundamental biology of aging and
also modulates the underlying mechanisms directly driv-
ing all the diseases of aging. Jointly, these lifestyle factors,
interacting with our genome (containing many currently
unmapped polymorphisms that presumably directly mod-
ulate aging processes and the vulnerability to diseases of
aging variably across individuals), in concert with multi-
ple lifestyle behaviors, determine what aging trajectories
our systems enter as we get older. These basic interac-
tions between lifestyle (which we can map out) and many
polymorphisms in our genetic endowment (which we can
now map only minimally) determine how much our fun-
damental cellular repair mechanisms and defenses against
cellular damage and aging are supported and enhanced as
much as possible, versus overtaxed and overwhelmed. The
primary and multifactorial mechanisms of aging reviewed
in this chapter appear to lead invariably into the diseases
of aging, if given enough time and enough room to work.
Indeed, the sum total of presence or absence of all the diseases of
aging in an individual may be one of the best ways to globally
index aging itself (Blagosklonny, 2009). Challenges remain
in operationalizing such a definition, of course, given that
practical, cost-effective (and nonintrusive) metrics in rela-
tion to many of the diseases of aging are not yet clinically
available. Unfortunately, the conventional medical per-
spective on diseases of aging in this country is still largely
unaware of evidence that they may reflect common mecha-
nisms operating in different tissues and systems; instead,
conventional medicine mostly approaches each major dis-
ease of aging in a piecemeal and fragmented fashion. This
chapter argues strongly against that traditional approach.
Western lifestyles (consisting of a typical Western diet
pattern and a sedentary lifestyle with poor sleep and
increased social isolation) appear quite undesirable in terms
of aging of the brain and body, deteriorate capacities to deal
with various biological and social stresses, and remove us
from our proper and ancient evolutionary environment. We
have changed remarkably little genetically since our days
as HGs, but our lifestyles have changed dramatically. This
suggests that much of our current difficulties with health
are not due to some exotic collection of esoteric biological
derailments that can only be interpreted and treated by a
“medical–industrial complex” and understood by someone
with a doctoral degree; instead, they are due to a fundamen-
tal, if not profound, mismatch between our genes and our
environment (Stipp, 2011). This suggests that basic health
considerations should focus on approximating that ancient
31
biological environment as much as possible: regular aero-
bic exercise, large amounts of fruits and vegetables, not too
many calories, minimal processed food and other products
of “food technology” (particularly our highly addicting fast
food), a better omega-6/omega-3 ratio (typically very high
in most Western diets with significant omega-3 deficiency),
reduced social isolation, and improved sleep quality and
quantity. As noted earlier, all these common recommenda-
tions place us closer to our ancient evolutionary environ-
ment and reduce this fundamental and destructive discor-
dance between genes and environment in Western lifestyles.
At this point, there is no cure for virtually any disease
of aging (perhaps excepting some cancers), so meaningful
prevention needs to a genuine priority instead of an after-
thought in our health-care system. We must be willing to
spend money on prevention and to make lifestyle changes
a genuine cultural priority. It is also quite sobering to real-
ize that, even in the context of the best possible preventa-
tive efforts, all one can do is delay the onset of a major disease
of aging: Eventually, we will all succumb to one of these mani-
festations of aging. However, such delay in onset of a major
disease of aging can potentially increase healthspan (even
if major lifespan extension remains elusive) and substan-
tially decrease the burden of diseases of aging in old age,
along with their often punitive impact on quality of life
and personal and societal economics (see Chapter 21).
Prevention, in this context of the many considerations
reviewed in this chapter, thus has to mean much more than
“statins and beta-blockers” (controlling multiple conven-
tional risk biomarkers that clearly have some prognostic
value but may only minimally index our deceptive yet radi-
cal physiological departure from our ancestors). Instead, real
prevention must mean, for the large majority of individuals in
a culture and not simply for a fortunate few, reapproaching our
original evolutionary environment. In simplest terms, as a cul-
ture, these major lifestyle changes must mean that we exer-
cise and sleep significantly more, eat significantly less, and
eat more wisely (consuming more of the “paleolithic” foods
of our ancestors and less the questionable and addictive
products of food technology). In addition, we need to aim
more for quality of social connection than quantity of mate-
rial consumption, as quality and depth of social attachment
is emerging as one of the better predictors of long-term
health (Seeman and Crimmins, 2001; see Chapter 10).
Making these critical changes in priorities and approach,
both individually and in terms of the embedded high-tech
priorities of our health-care systems, is likely to be painful
in many ways, as well as profoundly politically contentious.
However, one cannot envision any viable long-term pre-
scription or big-picture view of biological health that does
not place these simple principles first. Additionally, this
view of health (that it emerges from the basic fit between
genes and environment) places health back into a proper
evolutionary perspective that is badly lacking in many
treatments of diseases of aging. There seems to be little
32 The Aging Brain in Neurology
sense in the current health-care environment that Darwin’s
central insights (about the match between genetic endow-
ment and environment determining adaptive success) has
any relevance to discussions of basic health or illness. Has
modern medicine abandoned Darwin? A central implicit
myth of the “medical–industrial complex” (implicit in the
sense that it is largely embedded in relentless advertising
and is never explicitly stated) may be that high-tech medi-
cine and first-line drugs are our best defense against the
chronic diseases of aging, a supposition for which there is
very little substantive evidence, and much counterevidence.
An additional option for the future may be the possibility
of a highly effective CR mimetic: perhaps a future version of
resveratrol or rapamycin, some combination of our current
(partial) CR mimetics, or perhaps even a completely new
and different compound yet to be discovered. It seems an
easy prediction that a truly safe and effective CR mimetic
(which, by definition, would give the physiology of CR
without the pain of chronic hunger) that could both slow
aging and substantively delay onset of all the diseases of
aging would be a compound that almost everyone would
readily consider taking and many if not virtually everyone
would find highly attractive. Indeed, if a patentable agent
were proven highly effective and safe, one could easily
predict that it would eventually become the best-selling
prescription medicine of all time. However, such consider-
ations (potential widespread use of CR mimetics) embed
a major conundrum, similar to that posed by the poten-
tial creation of an “exercise pill.” Would individuals with
the option to take a safe and effective CR mimetic still be
adequately motivated to modify problematic lifestyle hab-
its and move closer toward the original evolutionary envi-
ronment of humans, which we believe promotes long-term
health and healthy (or at least healthier) aging? One can
readily appreciate the temptation to continue eating prob-
lematic but tasty foods and remaining overweight and sed-
entary, if one’s anxiety about any potential disease of aging
could be significantly ameliorated by simply taking a pill.
Such a dilemma in many ways goes to the heart of dif-
ficult choices confronting modern technological Homo sapi-
ens in relation to both health care and, more fundamentally,
long-term health. Do we trust in our high technology first and
foremost? Do we place exclusive faith in our technological compe-
tencies, to the exclusion of trusting in biological relationships that
are (at least, in some sense) pretechnological? Or must we place
equal or even greater trust in our basic evolutionary heritage and
our embeddedness in a complex biological matrix and ecology, the
environment that carved our genome? Put in simplest terms, do
we think that health promotion is primarily a technological or a
lifestyle matter? Answers to these questions may determine
a great many things about our long-term health in the com-
ing century and our health-care system. Additionally, these
choices mirror much larger and even more difficult choices
about our basic relationship to a complex biological matrix
(the extended environment), which is clearly showing
the negative impact of human technologies. A tempting
hypothesis is that our disregard of the environment may be
intrinsically hinged to the overvaluation of technology and
the undervaluation of our biological “embeddedness” and
our fundamental evolutionary context; these considerations
were summarized in the previous sections regarding the
basic notion of an evolutionary discordance between our
genes and our current technological environment, diet, and
lifestyles. In simplest terms, overvaluing high-tech medi-
cine over “low-tech” lifestyle change may be a mistake we
are culturally primed to make in how we view health and
how we construct and finance our health-care systems.
Whatever answers we might construct to such ques-
tions, there seems little question that Western societies face
enormous challenges in a tsunami of age-related disease,
in an aging population, at a time when fundamentally
unhealthy lifestyles promoting those very same diseases
of aging are widespread within the United States and in
other Western societies. Health-care professionals of virtu-
ally all disciplinary persuasions need to take responsibility
for educating both patients and the general public about
these issues, as a critical part of reprioritizing genuinely
proactive and early prevention efforts and health mainte-
nance via lifestyle change over much later high-technology
interventions that are proving to be prohibitively costly
while at the same time yielding very uncertain if not mini-
mal benefits in relation to quality of life.
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 Chapter 2
Functional Changes Associated with the
Aging Nervous System
Julie A. Schneider1,2,3 and Chunhui Yang1,2
1
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
2
Department of Pathology, Rush University Medical Center, Chicago, IL, USA
3
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

Summary
• The aging brain undergoes complex changes with an increased vulnerability to distinct pathologies, particularly
degenerative and vascular.
• Age-related brain changes may include changes in volume, neuron size and number, white matter integrity, and
synapse/dendrites; however, may be difficult to distinguish effects of normal aging vs. disease.
• Amyloid plaques one of the hallmarks of Alzheimer’s disease (AD) are common in aging and may represent early AD.
• Neurofibrillary tangles (NFT) another hallmark of AD are seen in other conditions, and in the hippocampus in the
aging brain, where they may be related to memory loss separate from AD.
• Vascular diseases including atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, and infarcts are
exceedingly common in the brains of older persons.
• The most common causes of dementia in aging are AD, vascular, and Lewy body pathology. These pathologies are
often mixed in the brains of older persons.
• AD is characterized by the wide-spread accumulation of amyloid, neocortical neuritic plaques and extensive limbic
NFT (often extending to neocortex). A pathologic diagnosis of AD is found in some “normal” elders suggesting
subclinical disease.
• Dementia with Lewy bodies (DLB) is characterized by Lewy bodies in the substantia nigra, limbic structures and
neocortex. AD changes often coexist
• Vascular dementia is characterized by diffuse or strategically located infarcts or other vascular lesions (eg.
hemorrhages). Microinfarcts are also related to dementia.
• Frontotemporal Lobar degeneration (FTLD) with tau or ubiquitin (TDP) inclusions is increasingly recognized; FTLD
is the underlying pathology of Frontotemporal dementia but may also underlie dementias with more typical
presentations.
• Less common causes of dementia include Corticobasal degeneration (CBD), Progressive Supranuclear Palsy
(PSP), Creutzfeld-Jacob disease, Wernicke-Korsakoff syndrome (WKS) and other structural, metabolic, or infectious
conditions.
• Mild cognitive impairment (MCI) is characterized by the same common age-related pathologies, but often the pathology
is intermediate in severity. In some cases there is sufficient pathology for a pathologic diagnosis of AD.
• The presence of significant brain pathology in persons with MCI and dementia suggests that there are structural and
cognitive reserve mechanisms in aging.
• Movement disorders, particularly parkinsonism are very common in aging. Mild changes often don’t fit into a specific
disease category.
• Idiopathic Parkinson’s disease (bradykinesia, rigidity, tremor, and gait impairment) is characterized by loss of
dopaminergic neurons in the substantia nigra and Lewy bodies. Co-existing dementia is common and may be related
to concomitant AD changes or neocortical Lewy bodies (DLB)
• Multisystem atrophy, CBD and PSP are less common causes of parkinsonism.
• Amyotrophic Lateral Sclerosis is characterized by loss of upper and lower motor neurons and leads to progressive
weakness and may have accompanying dementia.
• Brain tumors, notably metastases, glioblastomas (malignant glial tumor), and meningiomas (benign growths attached to
the dura) are common in aging.
• Toxic metabolic encephalopathies may include changes related to systemic diseases such as liver or kidney disease, in
which astrocytes undergo Alzheimer type II changes. Excessive alcohol use may lead to thiamine deficiency and WKS.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

38
 Functional Changes Associated with the Aging Nervous System 39

• Older persons are more susceptible to infectious diseases including bacterial, viral and fungal meningitis,
cerebritis and encephalitis.
• Recent and past head trauma may cause problems in aging.
• Subdural hematomas are most commonly related to tearing of bridging veins from relatively minor head trauma and
falls.
• Chronic traumatic encephalopathy is related to repeated clinical or subclinical concussions and may be associated
with a degenerative dementia characterized by changes in memory, personality and behavior.

Introduction
It is widely recognized that the brain and other parts of
the nervous system undergo complex changes with age.
For example, loss of brain weight and volume, changes
in neurons and synapses, and oxidative, inflammatory,
and biochemical changes have all been described in the
aging brain. Moreover, the aging brain and nervous
system show an increased vulnerability to a variety of
distinct pathologies, particularly degenerative and vas-
cular. The relationship between what may be considered
“normal” age-related brain changes and disease has
been debated.
This chapter provides an overview of the neuropathol-
ogy of the aging brain, including “normal” aging, the
pathology of cognitive impairment and dementia, vascu-
lar disease, motor impairments, and other common geri-
atric brain conditions, such as toxic metabolic conditions,
neoplasms, infections, and traumatic injury that may
affect the elderly.
The aging brain
The differentiation between “normal” aging and disease
in the brain is complicated by multiple factors, including
changing historical perspectives on what constitutes nor-
mal cognition and motor function in aging, the presence
of slowly accumulating pathologies, and the concept of
neural reserve (that is, normal cognitive or motor func-
tion in spite of significant amounts of pathology). This
is to be considered on a background of changing tech-
niques, more sophisticated studies, and semantic argu-
ments about common changes versus disease. Although
concepts regarding normal versus disease will likely
continue to change, it remains valuable to discuss some
of the currently considered age-related neuropathologic
changes.
Brain size and neuronal loss
Numerous studies have investigated age-related
changes in brain weight, size, and neuron number.
Although studies have been conflicting, it remains
widely accepted that most of these brain parameters
decrease with advancing age. Most of the data from the
early part of the twentieth century were based on stud-
ies with variable clinical information, making conclu-
sions uncertain (Duckett, 2001). In general, studies of
normal aging have been hindered by the intrusion of
early disease states and the absence of detailed cog-
nitive testing proximate to death (Peters et al., 1998).
Recent pathologic studies using carefully selected con-
trols and/or sophisticated stereologic techniques have
shown that, on average, normal older subjects show
only slight changes in the overall weight (Tomlinson
and Blessed, 1968), cortical thickness (Mouton et al.,
1998), and neuronal number in the absence of dis-
eases (Tomlinson and Blessed, 1968; Terry and DeTe-
resa, 1987; Hof and Glannakopoulos, 1996; Mouton
et al., 1998; Peters et al., 1998; Duckett, 2001). Inher-
ent intersubject premorbid variability, especially for
neuron number, remains a concern in evaluating the
results of pathologic studies. Neuroimaging studies
can provide expanded data on size and also evaluate
longitudinal change. These studies suggest that ven-
tricular rather than cortical volume shows the larg-
est annual change (Resenick et al., 2000). Effects may
also be regional; neuroimaging studies show age-
related thinning of the prefrontal cortex (Fjell et al.,
2009), with lesser (Sullivan et al., 1995) or more vari-
able (Fjell et al., 2009) involvement of the entorhinal
and hippocampus in normal aging. Overall, neuronal
loss is probably small, estimated at likely no more than
10% (Peters et al., 1998). Importantly, although mor-
phologic changes may be slight, animal (Stemmelin
and Cassel, 2003) and neuroimaging (Resenick et al.,
2000) studies suggest that even small changes in the
structure may have functional consequences. Studies
on aging are now increasingly focused on cell-specific
and lamina-specific vulnerabilities (Peters et al., 1998),
regional modifications in synaptic remodeling (Terry et
al., 1991; Masliah et al., 2006) and dendritic complexity
(Scheibel, 1988; Richard and Taylor, 2010), white mat-
ter changes (Moody et al., 1995; Fernando et al., 2006;
Gunning-Dixon et al., 2009; Simpson et al., 2009; Mur-
ray et al., 2010), and other downstream or compen-
satory changes, such as neurogenesis (Willott, 1999;
Lowe et al., 2008; Pannese, 2011).
40 The Aging Brain in Neurology
White matter changes
Neuroimaging studies have shown that there is a greater
loss of volume in the cerebrum from white matter com-
pared to gray matter in aging (Resenick et al., 2000).
Moreover, these changes appear to preferentially affect
the prefrontal white matter (Gunning-Dixon et al., 2009).
This partly explains the increase in ventricular size often
seen in aging (Tomlinson and Blessed, 1968; Duckett,
2001). Neuropathologic studies also show age-related
white matter changes (Moody et al., 1995; Fernando
et al., 2006; Simpson et al., 2009), with changes in mul-
tiple functional pathways (Simpson et al., 2009) and a
possible relationship with chronic hypoperfusion (Fer-
nando et al., 2006). White matter changes may result in
cortical “disconnection” (Gunning-Dixon et al., 2009),
and executive function appears to be specifically vul-
nerable to these age-related white matter changes (Mur-
ray et al., 2010).
Synaptic and dendritic changes in aging
Synapses are among the most important structures for
neuronal communication. Synaptic loss during normal
aging has been studied extensively in the last couple of
decades. Quantitative studies using electron microscopy
have revealed significant losses of synapses with age in
laboratory animals and humans and have been estimated
at about 10% (Terry et al., 1991; Duckett, 2001; Masliah
et al., 2006; Pannese, 2011). However, neurons in older
brains appear to retain some capacity for synaptic and
dendritic plasticity and ability to form new synapses
in response to injury or environmental manipulations
(Pannese, 2011). These data are supported by studies
suggesting that cognitive activities and training may
improve function (Wilson and Mendes de Leon, 2002;
Treiber et al., 2011).
Dendrites (see Figure 2.1) account for 90% of the total
surface area of a neuron’s receptive area, with more than
90% of excitatory synapses connected by dendritic spines
(see Figure 2.2) and complexity that may vary by region
(Scheibel, 1988). Studies have reported a significant
Figure 2.1 Apical dendrite (arrow head) and cell body (arrow) of
pyramidal neuron, hippocampus CA1, mouse brain (Golgi stain).
(For a color version, see the color plate section.)
Figure 2.2 Dendritic spines, mouse brain, hippocampus CA1 (Golgi
stain). (For a color version, see the color plate section.)
age-related loss of dendrites, both shortening and fewer
dendritic branches, in the cerebral cortex (Masliah et al.,
2006). Large projection neurons have been shown to have
simplification (pruning) of the neuronal dendritic tree;
because these dendrites are located in layer I of the cere-
bral cortex, this loss may result in layer I cortical atrophy
(Lowe et al., 2008).
Alzheimer’s disease changes in
“normal aging”
Neurofibrillary tangles (NFTs) and amyloid beta (Aβ)
plaques are the pathologic hallmarks of Alzheimer’s
disease (AD; Section “Alzheimer’s disease”) and accu-
mulate in large number in persons with AD dementia.
Yet it is not uncommon to see NFT and plaques in small
numbers in the aging brain of persons without cogni-
tive impairment (Bennett et al., 2006). In some instances,
this may represent the earliest pathologic stage of AD.
Indeed, with notable exceptions such as chronic trau-
matic encephalopathy, Aβ plaques appear to be relatively
specific to the AD pathophysiologic process. In contrast,
NFTs are observed in a variety of other diseases and
are extremely common in the limbic regions of almost
all older persons. It has been suggested that NFT in the
mesial temporal lobe may be related to the memory loss
in AD and separately underlie age-related memory loss
(Jack et al., 2010).
Microscopic vascular pathology in the
aged brain
Vascular changes are extraordinarily common, with the
majority of older persons having some degree of ath-
erosclerosis, arteriosclerosis, or cerebral amyloid angi-
opathy (CAA) (Section “Cerebrovascular disease in the
elderly”). Atherosclerotic plaques commonly occur in
the intra and extracranial vessels of the Circle of Wil-
lis. Arteriolosclerosis (hyaline thickening of small ves-
sels) is particularly common in the white matter, basal
 Functional Changes Associated with the Aging Nervous System
ganglia, and thalamus. More severe forms are associ-
ated with hypertension and diabetes and are thought
to underlie the development of infarcts. Mild dilation
of perivascular Virchow–Robin spaces may occur with
or without small vessel disease. Small venules in the
periventricular white matter tend to show increased
deposition of collagen in the adventitia (Moody et al.,
1995), referred to as periventricular venous collageno-
sis. Mild forms of amyloid angiopathy are also common
even in the absence of AD (Arvanitakis et al., 2011a).
The role of each of these vascular changes, particularly
when mild or in the absence of infarction, is not clear,
although data suggest that severe vessel disease in the
absence of frank infarction is related to damage to the
brain and functional impairment (Arvanitakis et al.,
2011a; Buchman et al., 2011). Vascular disease is dis-
cussed in detail in Section “Cerebrovascular disease in
the elderly.”
Other changes
Age-associated macroscopic changes also include thick-
ening of the arachnoid and prominence of arachnoid
granulations. Microscopically, aged brains often show
an accumulation of lipofuscin in specific neuronal
populations and regional prominence of corpora amy-
lacea. Although not related to a specific disease state,
and often considered benign, the significance of these
changes has been debated. In addition, although more
numerous in disease, older brains may show granulo-
vacuolar degeneration and Hirano bodies primarily in
the hippocampal region. Other biochemical and cellular
changes, such as inflammatory shifts, oxidative stresses,
and glial pathology, may also be important in normal
aging and/or disease. For instance, microglia are nor-
mally inconspicuous in the young brain, but with aging,
microglia may show signs of activation (Jurgens and
Johnson, 2012), even in older persons with normal cog-
nition. This is particularly the case with expression of
class II major histocompatibility antigen (MHCII; see
Figure 2.3).
Neuropathology of mild cognitive
impairment and dementia
Mild cognitive impairment (MCI) and dementia are
clinical diagnoses based on history, cognitive testing,
neurologic examination, and supportive studies. It is
currently believed that there is a continuum of normal
cognitive aging, MCI, and dementia, and although each
has a characteristic clinical phenotype, it can be difficult
to distinguish normal aging from MCI and to distin-
guish MCI from dementia, especially at their intersec-
tions. The brain pathologies underlying normal cogni-
tive aging, MCI, and dementia also lie on a continuum
41
Figure 2.3 Activated cortical microglia in older person without
cognitive impairment; antibody to class II major histocompatibility
antigen (MHCII). (For a color version, see the color plate section.)
from no pathology to mild pathology and from mild
pathology to abundant pathology. The most common
pathologies associated with MCI and dementia are AD,
infarcts (with or without associated clinical stroke), and
Lewy body (LB) pathology. Although it has long been
recognized that AD pathology is the most common
pathology underlying dementia, we now know that
older persons with dementia most often have mixed
brain pathologies, most commonly AD pathology and
infarcts, followed by AD and LBs (MRC CFAS, 2001;
White et al., 2005; Schneider et al., 2007a; Sonnen et
al., 2007; O’Brien et al., 2009; Nelson and Abner, 2010).
Furthermore, it is recognized that older persons with-
out cognitive impairment may have many of the same
types and burdens of pathologies as in persons with
dementia, suggesting neural or cognitive reserve and
subclinical disease (Elkins et al., 2006; Rentz et al., 2010;
Tucker and Stern, 2011). This section focuses on the
neuropathology of AD, MCI, mixed dementias, vascu-
lar dementia (also known as vascular cognitive impair-
ment), and dementia with Lewy bodies (DLB). This
section also covers the expanding spectrum of the less
common frontotemporal lobar degenerations (FTLD)
and briefly reviews less common conditions associated
with age-related cognitive impairment, such as Wer-
nicke–Korsakoff syndrome (WKS) and Creutzfeldt–
Jakob disease (CJD). Cognitive impairment may also
occur as a result of other changes in the brain, includ-
ing infections, trauma, and neoplasms, which other
sections discuss.
Alzheimer’s disease
There are both macroscopic and microscopic changes that
occur in AD. These changes are evident prior to the clini-
cal diagnosis in majority of the patients.
42 The Aging Brain in Neurology
(a) (b)
Macroscopic appearance of AD
A decrease in brain weight is a usual but inconstant find-
ing. Cortical atrophy is typical but also variable and has
been shown to correlate with the level of cognition (Mou-
ton et al., 1998). The mesial temporal lobe structures,
including the temporal cortex, amygdala, entorhinal cor-
tex, and hippocampus, are most affected, with the tem-
poral horns of the lateral ventricles often being enlarged
(see Figure 2.4); frontal and parietal regions are also com-
monly affected. The occipital lobe and the motor cortex
are relatively spared (see Figure  2.4). The gross appear-
ance of the basal ganglia, thalamus, and hypothalamus is
usually unremarkable. The midbrain exhibits pallor of the
substantia nigra (SN) in about one-quarter to one-third of
AD cases. Pallor of the locus coeruleus in the rostral pons
is common in AD.
(a) (b)
Figure 2.4 Alzheimer’s disease brain showing
(a) narrowing of gyri and widened sulci, and
hippocampal atrophy with enlargement of
lateral ventricles, especially temporal horn
(b). (For a color version, see the color plate
section.)
Microscopic findings of Alzheimer’s disease:
neurofibrillary tangles and amyloid beta plaques
The two histologic hallmarks defining the pathology of
AD since the original description by Alois Alzheimer in
1906 are NFTs and the extracellular amyloid beta (Aβ)
deposits of senile plaques. NFTs are intraneuronal inclu-
sions that consist of abnormally phosphorylated tau pro-
tein aggregate as paired helical filaments. NFTs occupy
the cell body and extend into the apical dendrite. They
are not easily discerned on hematoxylin–eosin (H&E)
staining but are agyrophilic (that is, visualized by silver
impregnation methods, such as modified Bielschowsky
(see Figure  2.5), Gallyas, Campbell–Switzer, and Bodian
stains. In addition, specific immunohistochemical stain-
ing with antibodies to the abnormal tau protein sensitively
demonstrates NFT (see Figure 2.5). The morphology
Figure 2.5 Neurofibrillary tangles:
(a) hippocampus CA1 (modified
Bielschowsky stain); (b) frontal
cortex (immunohistochemistry
with antibodies to paired helical
filament). (For a color version, see
the color plate section.)
 Functional Changes Associated with the Aging Nervous System
Figure 2.6 Ghost tangles, hippocampus CA1 (modified
Bielschowsky silver stain). (For a color version, see the color plate
section.)
of NFTs varies with the nature of the neurons in which
they reside. Those in the cortex are usually flame shaped
or triangular, and those in the subcortical or brainstem
nuclei are typically globose. NFTs that survive after the
neurons have died are visualized as “extracellular ghost
tangles” and tend to be slightly larger and less densely
stained than typical NFT (see Figure 2.6). Braak and Braak
observed that the progression of NFT changes in older
persons follow a predictable pattern (Braak and Braak,
1991). They found a characteristic distribution and pro-
gression of NFTs in older persons, which comprised of six
stages, starting in the transentorhinal and entorhinal lay-
ers and progressing to the neocortex. The first two stages
involve NFTs in the entorhinal, transentorhinal, CA1, and
subiculum. In stages III and IV, increasing numbers of
NFTs accumulate in the limbic system, and in stages V
and VI, NFTs become abundant in neocortical areas. NFTs
generally occur in a predictable laminar distribution; in
the entorhinal cortex, NFTs are almost always present in
large projection neurons of layers II and IV, whereas lay-
ers III, V, and VI have relatively few tangles.
(a)
Figure 2.7 Neuritic plaque
pathology in AD. (a) Three
NPs in the neocortex on
H&E stain are difficult to
see. (b) The same NPs are
easily visualized on modified
Bielschowsky silver stain. (For
a color version, see the color
plate section.)
43
Senile plaques are the other hallmark of AD pathology
and consist of fibrillar amyloid material, composed of Aβ,
which shows a characteristic red–green birefringence in
Congo red-stained sections. Aβ is produced by the abnormal
proteolytic cleavage of amyloid precursor protein (APP), a
membrane protein that, when normally cleaved by alpha
secretase, secretes nonamyloidogenic fragments. Abnormal
cleavage with beta secretase and gamma secretase results
in the production of Aβ peptide that is 39–43 amino acids
in length; the insoluble form is deposited as Aβ40 or Aβ42.
Other proteins, such as interleukins, apoE, and components
of the complement system, also deposit in plaques (Thal
et al., 2006). AD is pathologically characterized by at least
two plaque types, neuritic plaques (NP) and diffuse plaques
(DP). NP is the type of plaque critical for neuropathologic
diagnosis of AD (Mirra et al., 1991) and is characterized by
thickened neurites; these plaques often have a dense central
core of amyloid surrounded by a less compact peripheral
halo of amyloid. Plaques may be difficult to visualize on rou-
tine H&E stains but are easily seen on silver stain (see Fig-
ure 2.7) or with antibodies to the Aβ protein (see Figure 2.8).
The dense core and peripheral halo are often separated by a
clear zone that contains glial cells and dystrophic neuronal
processes that often show abnormally phosphorylated tau
protein (Thal et al., 2000). NP may be associated with reac-
tive astrocytes, and microglial cells may be seen within the
dense central core (Thal et al., 2000). Immunostaining with
antibodies to specific forms of Aβ typically shows that the
dense center core is enriched in Aβ40, while the periphery
has predominantly Aβ42 (Thal et al., 2000). NPs are promi-
nent in the amygdala and hippocampal subicular complex
and are present in association cortices in AD; similar to
NFTs; however, they are less common in primary motor and
visual cortices. DPs are also common in AD and consist of
deposits of amyloid without thickened or PHF-containing
neurites. Some plaques, especially DPs, have a perivascular
orientation, usually in association with amyloid angiopathy
(see Figure 2.8). Morphologic characteristics and protein and
cellular components of senile plaques permit differentiation
of plaque types (Thal et al., 2000).
(b)
44 The Aging Brain in Neurology
(a) (b)
(c) (d)
Similar to the stages of NFT as described by Braak,
the progression of senile plaque pathology has also been
described (Thal et al., 2000; Thal et al., 2006). In the first
phase, DPs deposit in the neocortex. In the second phase,
Aβ plaques deposit in allocortical areas, such as the
entorhinal region, and in the subiculum/CA1 region of
hippocampus. In the third phase, the basal ganglia, the
thalamus, and the hypothalamus become involved, fol-
lowed in the fourth phase with the involvement of the
midbrain and the medulla oblongata. Finally, in the fifth
phase, senile plaques develop in the pons and the cere-
bellum. Deposition of Aβ amyloid in the leptomeningeal
and cortical small arteries and arterioles occurs in most
individuals with AD, but it also occurs in “normal” aging
(Arvanitakis et al., 2011a). When severe, CAA is associ-
ated with lobar hemorrhages, perivascular scarring, and
less commonly infarcts. CAA is preferentially deposited
in the small vessels of the occipital cortex and meninges;
thus, CAA should be considered in the presence of poste-
rior lobar hemorrhages (see Figure 2.8).
Criteria for the pathologic diagnosis of AD
Significant progress has been made in identifying clini-
cal biomarkers for the diagnosis of AD, yet a definitive
diagnosis of AD still requires pathologic examina-
tion of the brain. Pathologic criteria for the diagnosis
of AD were initially established to confirm the clinical
diagnosis in persons with dementia. These criteria have
changed three times over the past four decades and
have been strongly influenced by the contemporane-
ous views of dementia and the normal aging brain. The
Figure 2.8 Amyloid pathology
in AD. (a) Numerous amyloid
immunostained plaques
in the cortex at low power.
(b) Leptomeningeal arterioles
also may show amyloid
deposition. (c, d) Higher
power of plaque pathology
using amyloid immunostain.
(For a color version, see the
color plate section.)
first set of criteria developed in 1985, termed Khachatu-
rian criteria, used an age-dependent specific density of
senile plaques (Zhachaturian, 1985). More plaques were
required in older persons than younger patients to con-
firm a diagnosis of AD, apparently to allow for sparse
plaques in older individuals without dementia. Plaque
type was not specified. The Consortium to Establish a
Registry for Alzheimer’s disease (CERAD) criteria for
a pathologic diagnosis of AD, developed in 1991, pro-
posed semiquantitative measures of neocortical NP to
establish a probability statement on the diagnosis of AD
(possible, probably, definite) after considering age and
clinical diagnosis (Mirra et al., 1991). Probable or definite
AD required a larger number of plaques in older persons
and a premorbid diagnosis of dementia. NIA–Reagan cri-
teria (The National Institute on Aging, 1997), proposed
in 1997, made a couple of important changes, including
incorporation of NFT—using Braak score (Braak and
Braak, 1991), and included plaque estimates without
regard to age, to allow for probability statements of the
likelihood that dementia occurs as a result of AD (high,
intermediate, low). These criteria were formulated for
pathologic examination of brains with dementia but
do not take into account AD neuropathologic changes
in MCI (Section “Mild cognitive impairment”) and in
persons with no cognitive impairment. Criteria are cur-
rently being revised to allow for the description of AD
neuropathologic changes in persons with MCI and no
cognitive impairment. The presence of significant AD
pathology in normal older persons suggests the pres-
ence of preclinical disease and neural reserve.
 Functional Changes Associated with the Aging Nervous System
Mild cognitive impairment
MCI is a clinical diagnosis and represents an intermedi-
ate stage between normal aging and dementia (Bennett
et al., 2002). Persons with MCI have cognitive impair-
ment, memory, or nonmemory, but do not fulfill the cri-
teria for dementia. In the past decade, there has been
expanding data on the pathologic basis of MCI (Morris et
al., 2001; Markesbery et al., 2006; Petersen et al., 2006). As
with dementia (Section “Mixed pathology (AD, infarct,
and LB Pathology) in dementia”), the underlying pathol-
ogy is heterogeneous, with AD being the most common
underlying pathology, followed by infarcts and then LBs,
supporting that MCI represents a transition between nor-
mal aging and dementia (Bennett et al., 2006). While the
pathology is often intermediate, it is interesting to note
that more than half of persons with MCI have sufficient
pathology to render a pathologic diagnosis of AD (Schnei-
der et al., 2009). This has implications for preventions and
treatments targeting early disease. Infarcts are also com-
mon, especially in persons with nonamnestic MCI and
mixed with AD pathology in persons with amnestic MCI.
LB disease is the third most common pathology in MCI
and is most commonly mixed with AD pathology. FTLD
and related dementias also likely pass through an inter-
mediate clinical stage, but a little is known regarding the
pathologic phenotype.
Vascular cognitive impairment and dementia
Early in the twentieth century, vascular disease was
believed to be the primary pathologic cause of cognitive
decline in older persons, often called senility. Recognition
that AD pathology was the most common pathology under-
lying late-life dementia and the lack of definitive criteria for
a pathologic diagnosis of vascular dementia resulted in a
lesser emphasis on vascular dementia as a pathologic sub-
strate for age-related dementia. More recently, there has been
a resurgence of interest in vascular disease as a pathologic
substrate for age-related dementia, especially as a mixed
disorder (Schneider and Bennett, 2010). Community-based
and population-based prospective epidemiologic studies
have shown that infarcts and other vascular pathologies are
very common in the brains of older persons, from one-third
to one-quarter of older persons with some vascular brain
pathology (MRC CFAS, 2001; White et al., 2005; Schneider
et al., 2007a; Sonnen et al., 2007).
Initial studies suggested that infarcts must be in a cer-
tain volume, such as 100 mL (Lowe et al., 2008) order to
result in dementia, but it was later recognized that mul-
tiple infarcts were also an important factor, so the term
multi-infarct dementia (MID) was coined (Hachinski et
al., 1974). Because myriad vascular lesions, including
smaller strategically located infarcts, can also result in
dementia, the terminology was subsequently changed
to vascular dementia. The alternative nomenclature vascu-
lar cognitive impairment is based on the recognition that
45
vascular lesions may not result in the pattern of cogni-
tive impairment required for the clinical diagnosis of
dementia, which is typically geared toward the diagno-
sis of AD, emphasizing episodic memory impairment
(Hachinski et al., 2006). Indeed, though vascular and
AD pathology may have overlapping phenotypes, stud-
ies show that cerebral infarcts do not affect all cognitive
systems equally, showing the strongest association with
perceptual speed and the weakest with episodic memory
(Schneider et al., 2003). While AD is still considered the
most common pathology underlying dementia, vascular
disease is considered the second leading cause of demen-
tia, representing about 10% of the cases (Roman, 2003).
This number is most certainly greater if one considers
microscopic infarcts, mixed pathologies, and the role of
additional vascular lesions, such as amyloid angiopathy.
No generally accepted pathologic criteria apply for
a diagnosis of VCI or vascular dementia. Vascular sub-
strates for dementia are heterogeneous and include single
strategic infarcts, multiple infarcts, cortical infarcts, sub-
cortical infarcts, and microscopic infarcts. Other vascu-
lar pathology, including global ischemia, white matter
degeneration, and small vessel disease (arteriolosclerosis
and amyloid angiopathy) may also play a role. Finally,
there has been increasing interest in the hippocampal
sclerosis, which is at least partly related to global ischemia
and selective vulnerability.
There are numerous classification schemes used to dif-
ferentiate vascular lesions that may contribute to vascular
dementia, including divisions into large and small vessel
diseases, ischemic and hemorrhagic infarcts, and focal
versus multifocal disease (Hachinski et al., 1974; Romàn et
al., 2002; Roman, 2003; Hachinski et al., 2006; Chui, 2007;
Jellinger, 2008; Schneider and Bennett, 2010). Focal dis-
ease includes single infarcts and hippocampal sclerosis,
whereas multifocal disease includes multiple infarcts, as
well as global ischemia and ischemic white matter disease.
Infarct size, number, and location
It has long been recognized that large infarcts can be related
to dementia, especially in the form of post-stroke demen-
tia. Data from longitudinal clinical pathologic studies of
aging and AD (Schneider et al., 2003) have also shown
that the odds of dementia are higher in persons with large
or clinically evident infarctions. With large infarcts, the
underlying disorder is atherosclerosis affecting large intra-
cranial or extracranial blood vessels, giving rise to local
thromboses or emboli. In addition, cardiac disorders, such
as atrial fibrillation and myocardial infarction, can be the
source of cerebral emboli. The number of lesions also con-
tributes to the development of dementia (Hachinski et al.,
1974). Dementia associated with MID has been reported to
account for a substantial proportion of vascular dementia
and to more frequently involve the dominant hemisphere
(Jellinger, 2008). Indeed, location of lesions may be more
46 The Aging Brain in Neurology
(a) (b)
critical than total volume. In some cases, a single rela-
tively small infarct (strategic infarct) can damage the brain
enough to cause dementia (Chui, 2007). Infarcts in the left
hemisphere disproportionately increase the risk of demen-
tia (Roman, 2003; Kuller et al., 2005) as do infarcts in the
hippocampus, anterior thalamus, genu of internal capsule,
and anterior caudate (Chui, 2007; see Figure 2.9).
Subcortical ischemic vascular dementia
Subcortical ischemic vascular dementia (SIVD) is a sub-
type of vascular dementia defined by the presence of lacu-
nar infarcts and deep white matter changes (Romàn et al.,
2002; Chui, 2007). The syndrome conceptually includes at
least two previously defined pathologies: lacunar states
(état lacunaire), with multiple lacunes in the subcortical
nuclei and softening of the white matter; and Binswanger’s
disease, with white matter degeneration and second-
ary dilatation of ventricles (subcortical arteriosclerotic/
leukoencephalopathy (SAE) and leukoaraiosis (Romàn
et al., 2002; Roman, 2003; Chui, 2007). État crible, which
describes the appearance of multiple enlarged perivascu-
lar spaces in deep gray and white structures, may also be
present (see Figure 2.10). The microangiopathy underly-
ing these changes is thought to be the result of arteriolo-
sclerosis (often erroneously referred to has lipohyalinosis
(LH)) and is related to aging, hypertension, diabetes mel-
litus, and possibly other conditions, such as hyperhomo-
cysteinemia (Esiri et al., 1997; Chui, 2007; Jellinger, 2008;
Schwartz et al., 2010).
Lacunar infarcts, generally about 1 cm or less in diam-
eter, are cavitating lesions in the gray and white matter
(see Figure 2.9). Lacunar infarcts occur predominantly
in subcortical gray matter, predominantly basal ganglia
and thalamus, internal capsule, and brainstem. Subcorti-
cal infarcts may not be clinically recognized and may be
Figure 2.9 An old lacunar infarct in the
anterior thalamic nucleus: (a) gross coronal
brain slab; (b) histologic appearance of old
infarct with few macrophages and cavitation.
(For a color version, see the color plate
section.)
discovered incidentally on neuroimaging (Chui, 2007) or
at autopsy (Schneider et al., 2007b). Lacunar infarcts are
frequently multiple and bilateral and often coexist with
other vascular lesions. These lesions appear as foci of
ischemic necrosis and result from narrowing or occlusion
(arteriolosclerosis) of penetrating (striate) arteries branch-
ing directly from larger cerebral arteries.
White matter degeneration (subcortical arteriolar
encephalopathy and leukoaraiosis) is associated with
small vessel disease with vascular hyalinization (arte-
riolosclerosis), expansion of the perivascular space, pal-
lor of perivascular myelin, and astrocytic gliosis (see
Figure 2.10). Pathologically, ischemic white matter lesions
appear as foci of confluent white matter softening, with
pale staining of myelin, often sparing subcortical U-fibers.
Radiographic studies have proposed that 25–38% of the
cerebral white matter needs to be affected to allow for a
diagnosis of subcortical vascular dementia (Price et al.,
2005). Clinical signs may be the result of disruption of
pathways from the prefrontal cortex to the basal ganglia
and of thalamocortical pathways. Although executive
function is often considered the most commonly affected
cognitive system, subcortical infarcts can also be related
to memory loss (Schneider et al., 2007b) and parkinson-
ism (Buchman et al., 2011) (see Figure 2.10).
Microscopic infarcts
Microscopic infarcts are most commonly defined as the
infarcts visualized by light microscopy in the absence
of the infarcts seen on gross examination. Microscopic
infarcts are found in about 50% of older persons with
macroscopic infarcts but also may be seen in the absence
of macroscopic infarcts (Arvanitakis et al., 2011b ).
When cortical and multiple, these tiny infarcts have
been shown to be a strong correlate and add to the
 Functional Changes Associated with the Aging Nervous System
(a)
Figure 2.10 Subcortical ischemic vascular
disease. Both (a) gross and (b) histologic
brain sections show lacunar infarcts
and enlarged perivascular spaces
predominantly in the caudate in a person
with vascular parkinsonism. (For a color
version, see the color plate section.)
likelihood of dementia even after controlling for macro-
scopic infarcts and AD (White et al., 2005; Sonnen et al.,
2007; Arvanitakis et al., 2011b). These infarcts are not yet
identifiable on neuroimaging, although they have been
found to correlate with measures of white matter pathol-
ogy, including macroinfarcts, hemorrhages, and leuko-
encephalopathy (Longstreth and Sonnen, 2009). The
mechanism by which these tiny infarcts result in demen-
tia is not known. Because only a very small amount of
tissue is sampled in most brains, several microinfarcts
may represent a far greater number of occult infarctions
and a large loss of tissue. Alternatively or in addition,
microinfarcts may be a surrogate for the presence of
other vascular damage.
Dementia with Lewy body disease
Lewy bodies are the pathognomonic inclusion found in
the SN in Parkinson’s disease (PD). Almost five decades
ago, cortical LBs were found in an atypical dementia syn-
drome (Kosaka et al., 1984), variably called diffuse LB dis-
ease (Dickson et al., 1987), DLB (Sima et al., 1986), and LB
variant of AD (Samuel and Galasko, 1996). Most recent
criteria use the term dementia with LBs (DLB; McKeith et
al., 1996). DLB manifests with a decline in cognition with
associated fluctuations, hallucinations, and parkinson-
ism. While pure DLB (without concomitant AD pathol-
ogy) is a relatively uncommon cause of dementia (Schnei-
der et al., 2007a), probably representing only about 5% of
all dementia cases, DLB with concomitant AD pathology
is more common, including about 10–20% of dementia
cases, depending on the cohort. Because of associated
neurobehavioral difficulties, DLB may be more common
in clinic cohorts, compared to the community (Wakisaka
et al., 2003). Overall, DLB is currently considered as
the second most common neurodegenerative cause of
dementia. Similar to AD, diagnosis requires pathologic
confirmation.
47
(b)
Macroscopic and microscopic appearances of DLB
The macroscopic appearance of the brain in DLB is usu-
ally similar to that in PD, including mild cortical atro-
phy of the frontal lobe, with variable pallor of the SN
and locus coeruleus. Pallor of the locus coeruleus also
occurs in AD without LB. In DLB with significant AD
changes, there may be more severe atrophy of the hip-
pocampus and temporal and parietal lobes. LBs and
Lewy neurites (LN) are present in multiple selective
brain regions, including the brainstem, limbic, and
neocortical regions. The olfactory bulb and spinal cord
are also commonly involved in LB disease and may be
related to olfactory and autonomic disturbances. LBs
are believed to progress in a caudal to rostral distribu-
tion; however, amygdala LBs may occur in the absence
of brainstem involvement and may represent a distinct
form of LB disease (Uchikado et al., 2006). The pathol-
ogy of DLB overlaps with the pathology of idiopathic
PD and PD dementia. The neuronal loss from the SN and
locus coeruleus is more variable than in typical PD but
may also be severe. Nigral and other brainstem neurons
often contain classic LBs (see Figure 2.11), and LBs may
also lie free in the neuropil. The cortical LBs (see Figure
2.12) that are predominant in the lower layers of cortex,
particularly in the small-size to medium-size pyrami-
dal neurons, are smaller and less well-defined and lack
halos (see Figure  2.12). LB can be seen in the sections
stained with H&E and ubiquitin immunohistochemis-
try, but α-synuclein is the most sensitive and most spe-
cific stain. LN can be seen in all regions with LBs but
can also be seen separately in CA2-3 region of the hip-
pocampus. In DLB, cortical LB density has been associ-
ated with severity of cognitive impairment (Samuel and
Galasko, 1996). In addition to LB and LN, DLB cases
commonly have transmural spongiform change in the
entorhinal cortex and other temporal regions. Coexisting
AD pathology is very common in DLB; conversely, LBs
48 The Aging Brain in Neurology
(a) (b)
are common in AD, described in more than 50% of cases
(Hamilton, 2000), depending on the cohort and regions
(for example, the amygdala). The presence of significant
AD pathology may modify and obscure the typical DLB
clinical presentation (McKeith et al., 2005).
Diagnostic criteria for DLB
Current criteria for the neuropathologic diagnosis of DLB
require the histologic observation of LB and divide the
disease into three types: brainstem-predominant, limbic
type, and neocortical type (McKeith et al., 1996; McKeith
et al., 2005). Evaluation of LBs in the brainstem is recom-
mended and includes SN, locus coeruleus, and dorsal
nucleus of the vagus. Basal forebrain/limbic system eval-
uation includes the basal nucleus of meynert, amygdala,
anterior cingulate cortex, and entorhinal cortex. Neocor-
tical regions include the middle temporal gyrus, middle
frontal gyrus, and inferior parietal lobule. DLB may be
“pure” without sufficient AD to render an additional
(a) (b)
(c)
Figure 2.11 Substantia nigra
neurons with multiple LBs:
(a) classic dense concentric
appearance with peripheral
halo on H&E; (b) LB
halo stains darker using
antibodies to α-synuclein.
(For a color version, see the
color plate section.)
pathologic diagnosis of AD or mixed with sufficient AD
pathology to render an additional pathologic diagnosis of
AD. It has been suggested that there is an interaction of
β-amyloid and α-synuclein, accounting for the common
co-occurrence of these two types of pathologies (Plet-
nikova et al., 2005).
Mixed pathology (AD, infarct, and Lewy
bodies pathology) in dementia
Both infarcts and LBs more commonly coexist with AD
pathology than as an isolated pathology in older persons
with dementia (MRC CFAS, 2001; White et al., 2005; Schnei-
der et al., 2007a; Sonnen et al., 2007; O’Brien et al., 2009;
Nelson and Abner, 2010). Indeed, mixed brain pathologies
are very common in the brains of community-dwelling
older persons and are more common than any single
pathology in older persons with dementia (Schneider et al.,
2007a). AD pathology mixed with infarcts is the most com-
mon mixed pathology, followed by AD mixed with LBs.
Figure 2.12 Cortical LBs in the superior
temporal cortex. (a) H&E stain shows an
eosinophilic cytoplasmic inclusion without a
clearly defined halo. (b) Low-magnification
view showing numerous α-synuclein-
immunostained cortical LBs. (c) Cortical LBs
may stain uniformly or show a peripheral
halo with α-synuclein immunostain. (For a
color version, see the color plate section.)
 Functional Changes Associated with the Aging Nervous System
The addition of each pathology is not benign but rather
further adds to the likelihood of dementia and the severity
of cognitive impairment (Schneider et al., 2003; Schneider
et al., 2007b; Schneider et al., 2009). Mixed pathologies are
also common in clinically diagnosed probable AD and may
be seen in MCI, particularly amnestic MCI (Schneider et
al., 2009). Clinicians should recognize mixed pathologies
(particularly AD mixed with infarcts and/or LBs) as an
important etiology of dementia in older persons.
Frontotemporal lobar degeneration
FTLD is the designation for a heterogeneous group of
non-AD neurodegenerative disorders typically associated
with frontotemporal dementias (FTD). In contrast to AD,
FTD typically presents with behavioral (behavioral vari-
ant) or language (including primary progressive aphasia
or semantic dementia) disturbances rather than episodic
memory, which is preserved until later in the disease. As its
name implies, FTLD is associated with selective degenera-
tion of the frontal and/or temporal lobes and also variable
involvement of subcortical gray matter. Atrophy may be
asymmetric, with corresponding underlying neuronal loss
and gliosis. Layer 2 spongy change of the cortical regions is
often noteworthy. Clinical phenotypes in FTLD may reflect
the abnormalities associated with these anatomic regions.
The increased application of immunohistochemistry for
tau, ubiquitin, and the recent recognition of TAR DNA-
binding protein 43 (TDP-43) and FUS protein inclusions has
led to increased recognition of FTLD and has enhanced the
two main classification groups: FTLD-tau (tau-associated
disorder) and FTLD-ubiquitin (FTLD-TDP-43 and FTLD-
FUS; Mackenzie et al., 2009). These pathologies (especially
FTLD-TDP-43) are now more easily and commonly recog-
nized, which will allow for increased detection and a recal-
culation of the frequency of the different subgroups of dis-
ease (Cairns et al., 2007; Mackenzie et al., 2009). When no
inclusions are identified (FTLD-NI), this is often referred to
as dementia lacking distinctive histology (DLDH). Clinical
phenotypes of dementias are currently being investigated
in relation to the broadening spectrum of inclusions that
are now recognized in the FTLD spectrum.
FTLD-tau and other tauopathies
The non-Alzheimer tauopathies are characterized by
the accumulation of abnormal tau protein in neurons or
glial cells or both. The major tauopathies associated with
dementia under the rubric of FTLD-tau include Pick’s dis-
ease, corticobasal degeneration (CBD), progressive supra-
nuclear palsy (PSP), and multisystem tauopathy with
dementia. Most of these disorders can be distinguished
by characteristic patterns of pathologies, inclusions,
and predominant tau isoforms. FTD with parkinsonism
linked to chromosome 17 (FTLD17) is also a FTLD-tau
that is linked to MAPT mutations and typically has three
and four repeat isoforms of tau-tangles, but it does not
49
have a characteristic pattern of pathology (Mackenzie
et al., 2009). Other disorders more variably linked to the
typical FTD syndrome that have characteristic tau pathol-
ogy include agyrophilic grain disease, chronic traumatic
encephalopathy, and tangle-predominant dementia.
Pick’s disease
Pick’s disease was first described in 1892 by Albert Pick.
The histopathology was detailed by Alzheimer and Alt-
man two decades later (Lowe et al., 2008). In the past, the
designation of Pick’s disease was synonymous with FTLD;
we now recognize that Pick’s disease is one of the multiple
pathologic subtypes of FTLD, specifically one of the sub-
types of FTLD-tau (Mackenzie et al., 2009). Gross pathol-
ogy includes frontotemporal atrophy, usually superior
temporal gyrus, with relative sparing of the posterior two-
thirds of cortex. With severe atrophy, the involved corti-
cal gyri have a so-called knife blade appearance. There
is variable atrophy of the caudate and SN. Microscopi-
cally, in addition to severe neuronal loss and gliosis in the
described regions, the pathognomonic finding is the Pick
body, which is the cytoplasmic inclusion found in neurons
in the frontal and temporal cortices, as well as in the lim-
bic and paralimbic cortices and temporal lobe, especially
the granule cell layer of the hippocampus. Pick bodies are
commonly found in layers II and IV, are argyrophilic, and
stain with antibodies to abnormally phosphorylated tau
protein. Pick bodies consist of mostly straight but also
twisted filaments, compared to the paired helical filaments
of AD (Lowe et al., 2008). Biochemically, Pick bodies con-
sist primarily of the three repeat-tau isoform. In addition
to Pick bodies, cases often show ballooned neurons, called
Pick cells, in the involved regions of cortex. These can be
highlighted using antibodies to neurofilament.
Corticobasal degeneration
CBD was first described in 1967 as “corticodentatonigral
degeneration with neuronal achromasia” (Gibb et al.,
1988). The patients with classic CBD develop an atypi-
cal parkinsonian disorder, asymmetrical clumsiness, and
stiffness or jerking of a limb, commonly an arm. Dystonic
rigidity, akinesia, and myoclonus develop after 2–3 years.
Many patients develop the “alien limb” phenomenon
(Gibb et al., 1988; Paulus and Selim, 2005; Lowe et al.,
2008). It has been increasingly recognized that CBD may
also be associated with focal cortical syndromes, such as
frontal lobe dementia or progressive aphasia, with the
clinical phenotype of CBD corresponding to the specifi-
cally affected cortical regions of damage (Dickson, 1999).
For example, in cases with language abnormalities, the
brunt of the pathology may be in the peri-Sylvian region.
Macroscopically, typically there is asymmetrical cortical
atrophy of the posterior frontal, parietal, and perirolandic
cortex. The superior frontal and parietal gyri are usually
more involved than the middle and inferior frontal gyri
50 The Aging Brain in Neurology
and the temporal or occipital lobes. There is usually pal-
lor of the SN. Histologically, there is neuronal loss with
astrocytosis, which is often most severe in the superficial
cortical laminae and associated with superficial spon-
giosis similar to that seen in FTLD. Ballooned neurons
(see Figure 2.13) are seen usually in layers III, V, and VI
(Lowe et al., 2008). The ballooned neurons are enlarged
eosinophilic and are weakly argyrophilic, lack Nissl
substance, and are occasionally vacuolated; and this is
referred to as neuronal achromasia (Dickson, 1999). The
presence of these ballooned neurons in the cortical areas
of the cerebral convexities is important for the diagnosis
of CBD. These ballooned neurons are immunoreactive for
phosphorylated neurofilaments and αβ-crystallin and are
variably reactive for tau protein and ubiquitin (Dickson,
1999). The SN typically usually shows moderate-to-
severe neuronal loss with gliosis. The remaining neurons
may contain ill-defined neurofibrillary inclusions or cor-
ticobasal bodies (Riley et al., 1990; Schneider et al., 1997).
Immunohistochemistry shows widespread tau-positive
inclusions within glial processes in the involved regions
and abundantly in white matter. These can be a helpful
diagnostic feature. Tau-positive, argyrophilic granular,
and coiled bodies (oligodendroglial filamentous inclu-
sions) are also widespread in the cortex and white matter.
Another helpful diagnostic feature is astrocytic plaques
(see Figure  2.14), which consist of a collection of tau-
immunoreactive processes of astrocytes that surround
unstained neuropil and are frequent in premotor, prefron-
tal, and orbital regions, as well as the striatum, caudate,
and putamen. There is regional and immunohistochemi-
cal heterogeneity of CBD pathology; and the distinction
between CBD and PSP can be difficult in some cases
(Bergeron et al., 1997; Schneider et al., 1997). Extensive
neuropil tau-positive threads, ballooned neurons, and
astrocytic plaques are of significant value in the diagnosis
of CBD (Bergeron et al., 1997; Dickson, 1999).
Figure 2.13 Corticobasal degeneration: ballooned neuron (neuronal
achromasia) on H&E stain. (For a color version, see the color
plate section.)
Figure 2.14 Tau-immunopositive astrocytic plaques are
characteristic of CBD (AT8 immunohistochemistry). (For a color
version, see the color plate section.)
Progressive supranuclear palsy
PSP is typically described as sporadic movement disorder;
but as with CBD, it can also be associated with dementia.
While the initial clinical description of PSP by Steele et al.
(1964) (Lowe et al., 2008) emphasized a unique constella-
tion of clinical findings (parkinsonism, supranuclear gaze
palsy, and falls), other presentations may suggest typi-
cal PD, multiple system atrophy (MSA), CBD, or another
degenerative disease (Collins et al., 1995; Bergeron et al.,
1997; Schneider et al., 1997; Dickson, 1999). Macroscopi-
cally, in PSP, the cerebral cortex is usually unremarkable,
but there may be atrophy and discoloration, especially of
the subthalamic nucleus, but also involving globus palli-
dus, dentate nucleus of cerebellum, midbrain, and pontine
tegmentum; there may also be tectal and tegmental atrophy
with dilatation of the cerebral aqueduct. Decreased pig-
mentation of the SN and locus coeruleus is also typical but
variable (Gibb et al., 1988; Schneider et al., 1997). Histologi-
cally, there is neuronal loss and gliosis predominant in the
subcortical nuclei, particularly in the globus pallidus, sub-
thalamic nucleus, red nucleus, and SN. The subthalamic
nucleus is typically severely involved; the SN shows dif-
fuse involvement but is most severe in the ventrolateral
tier, as in PD and CBD (Dickson, 1999). Cortical pathology
is less severe and may be noted in the precentral cortex
(Dickson, 1999); specific pathology is also typical in the
dentate granule cells (Gibb et al., 1988; Dickson, 1999). The
hallmark of PSP is the presence of NFTs and tau-positive
threads in subcortical gray matter, including subthalamic
nucleus, globus pallidus, and striatum (see  Figure 2.15).
Tau pathology including tangles and threads is detected
using antibodies specific for 4-repeat forms of tau, but
it is negative for 3-repeat forms of tau, consistent with a
 Functional Changes Associated with the Aging Nervous System 51

(a)

(b) (c)

Figure 2.15 Progressive supranuclear

palsy: neurofibrillary tangle (NFT)
pathology. (a) Globose NFT with
basophilic filamentous appearance (H&E).
(b) NFT in SN highlighted with tau
immunohistochemistry. (c) Antibody to
4-repeat tau isoforms labels two NFT. (For a
color version, see the color plate section.)

4-repeat tauopathy (Collins et al., 1995; Katsuse et al., 2003). FTLD-ubiquitin

A distinctive form of astrocytic pathology in gray matter
is designated tufted astrocytes (see Figure 2.16), which
are stellate with fine radiating processes surrounding the
nucleus and contrast with the “astrocytic plaques” of CBD
(Matsusaka et al., 1998; Dickson, 1999). Another distinc-
tive form of inclusions is coiled bodies (see Figure 2.16),
which are tau-immunopositive and silver-positive oligo-
dendroglial inclusions presenting in the white and gray
matter; however, these are identical to those seen in CBD
(Collins et al., 1995; Bergeron et al., 1997; Dickson, 1999).
PSP pathology may also be found in the superior collicu-
lus, tegmentum, periaqueductal gray matter, red nucleus,
oculomotor complex, trochlear nucleus, pontine nuclei,
inferior olives, and cerebellar dentate (Gibb et al., 1988;
Riley et al., 1990; Daniel et al., 1995; Schneider et al., 1997;
Dickson, 1999; Paulus and Selim, 2005).
FTLD-U was originally named for cases in which the
characteristic inclusions were visible only with ubiquitin
immunohistochemistry. TDP-43, a nuclear protein impli-
cated in exon skipping and transcription regulation, was
recently identified as the major ubiquinated component
of the pathologic inclusions of most sporadic and familial
cases of FTLD with ubiquitin-positive, tau-negative inclu-
sions (FTLD-U) with or without motor neuron disease, and
sporadic amyotrophic lateral sclerosis (ALS) (Mackenzie
et al., 2009). Thus, most, but not all, cases that were previ-
ously designated as FTLD-U have been renamed as FTLD-
TDP (Cairns et al., 2007; Mackenzie et al., 2009). This
pathology is associated with several genes, including pro-
granulin, and, much less commonly, mutations associated
with valosin-containing protein (VCP), TDP, and cases
linked to chromosome 9. About 10% of cases that were

(a) (b)

Figure 2.16 PSP: astrocytic pathology. (a)

Tau-immunoreactive tufted astrocyte in
the subthalamic nucleus (AT8 antibody).
(b) Coiled bodies that immunolabel with
antibodies specific to 4-repeat tau. (For a
color version, see the color plate section.)
52 The Aging Brain in Neurology
ubiquitin-positive but not related to TDP-43 have been
subsequently found to consist of FUS (fused in sarcoma), a
protein previously implicated in ALS. The designation of
FTLD-UPS (ubiquitin–proteasome syndrome) now refers
to cases with ubiquitin positivity that have not been linked
to a specific protein (such as familial syndrome of FTD3
as a result of CHMP2B mutations; Mackenzie et al., 2009).
In FTLD-TDP, brain atrophy is variable but may be
severe, especially in frontotemporal distribution and the
hippocampus, and there is associated dilation of the lat-
eral ventricles. There may also be pallor of the SN, atrophy,
and discoloration of the head of the caudate nucleus and
cerebral white matter. Histologically, there is variable neu-
ronal loss in the affected regions, and there may be hippo-
campal sclerosis. Cases may be screened using ubiquitin
immunohistochemistry but must be confirmed by immu-
nohistochemical assessment for TDP-43 protein, which is
translocated from the nucleus to the cytoplasm, ubiqui-
nated, and phosphorylated (see Figure 2.17). Ubiquitin
and TDP-43-positive neuronal cytoplasmic inclusions
(NCIs), neuronal intranuclear (NIIs), dystrophic neuritis
(DNs), and glial cytoplasmic inclusions (GCIs) are most
often seen in neurons in outer cortical layers of the frontal
and temporal lobes, in the dentate layer of the hippocam-
pus, and in the basal ganglia (Cairns et al., 2007).
ALS-dementia
Dementia is now recognized as a common co-occurrence in
ALS, and the neuropathology associated with ALS-demen-
tia shares many of the characteristics of FTLD-TDP, which
is also the major disease protein implicated in the anterior
horn neurons in ALS. TDP-43 pathology is found in mul-
tiple brain areas and in a spectrum of diseases as both a
primary and a secondary pathology, suggesting that ALS is
a disease that not only affects the pyramidal motor system,
but instead it is a multisystem neurodegenerative TDP-43
proteinopathy (Geser et al., 2008). In ALS-dementia cases,
TDP-43 positive inclusions are most predominantly found
in neurons in outer cortical layers of the frontal and tempo-
ral cortices and in the dentate layer of the hippocampus, as
well as in the basal ganglia (Geser et al., 2008).
(a)
(b)
Creutzfeldt–Jakob disease
CJD is a spongiform encephalopathy associated with
a rare form of dementia that may be sporadic (sCJD),
iatrogenic, or familial (Mahadevan et al., 2002; Gam-
betti et al., 2003). sCJD is the most frequently occurring
human prion disease. Prions are infectious proteineous
agents that lack DNA or RNA structure and are nor-
mally produced by cells in a nonpathogenic form. Brains
of CJD patients may be grossly normal or exhibit mild,
diffuse atrophy and are distinguished from other causes
of dementia by histologic examination characterized by
variable distribution and severity of spongiform change,
neuronal loss, and reactive astrocytosis in the frontal,
temporal, and occipital lobes; basal ganglia; and cerebel-
lum. Ten percent of cases of sCJD show amyloid plaques
composed of prion protein (kuru plaques; Mahadevan
et al., 2002; Gambetti et al., 2003). Prion protein (PrP)
immunohistochemistry is used routinely to aid diagno-
sis (Mahadevan et al., 2002; Gambetti et al., 2003). Vari-
ant CJD (vCJD), first reported in the United Kingdom,
is believed to occur as a result of the transmission of an
animal prion disease, bovine spongiform encephalopa-
thy, to humans. vCJD is characterized by severe neu-
ronal loss and severe astrocytosis in the posterior tha-
lamic nuclei, particularly the pulvinar, with spongiform
change most severe in the basal ganglia, particularly
the putamen and caudate nucleus (Ironside et al., 2002).
Florid plaques encircled by a rim of microvacuolar spon-
giform change are immunopositive for PrP and are espe-
cially prominent in the occipital and cerebellar cortices
(Ironside et al., 2002).
Wernicke–Korsakoff syndrome
Two overlapping clinical pathologic entities exist within
the WKS spectrum: Wernicke’s encephalopathy (WE) and
Korsakoff’s psychosis (KP). Wernicke’s and Korsakoff’s
are generally considered to be different stages of the
same disorder, WKS, caused by the deficiency of thiamine
(Vitamin B1). It is most commonly seen in persons with
alcohol abuse, dietary deficiencies, prolonged vomiting,
eating disorders, or the effects of chemotherapy. Clinical
Figure 2.17 FTLD-TDP: TDP-43 immunoreactive
inclusions in the neurons of the dentate layer
of hippocampus. (a) Low magnification
shows diffuse nuclear staining and numerous
TDP-43 positive inclusions (arrows). (b) High
magnification shows cytoplasm inclusions with
nuclear clearing in affected neurons. (For a color
version, see the color plate section.)
 Functional Changes Associated with the Aging Nervous System
features of WE include mental confusion, visual impair-
ment, and ataxia and hypotension/hypothermia. Patients
with KP have a memory disorder with amnesia, con-
fabulation, attentional deficits, disorientation, and vision
impairment. KP may be the end result of the repeated
episodes of WE, but it has also been described without a
known episode of WE. The characteristic lesions of WKS,
particularly WE, are surrounding the third and fourth
ventricles and include the mamillary bodies, which show
atrophy and brown discoloration from old hemorrhage.
Other regions of similar involvement include the hypo-
thalamus, thalamus, periaqueductal gray matter, collic-
uli, and floor of the fourth ventricle (oculomotor nuclei,
dorsal motor nuclei of vagus, vestibular nuclei). Lesions
of the medial dorsal nuclei or, alternatively, the anterior
nucleus of thalamus (Harper, 2009) showing neuronal
loss and gliosis, with or without hemorrhages, have been
postulated to be responsible for the memory defect of KP.
More recently, it has been postulated that an interruption
of complex diencephalic-hippocampal circuitry including
thalamic nuclei and mamillary bodies rather than a sin-
gle lesion in the thalamus is responsible for KS (Harper,
2009). In about 27% of cases, there is degeneration of the
anterior superior aspect of the cerebellar vermis (Harper,
2009). Other changes may be seen specifically as a toxic
effect of alcohol, including neuronal loss and white mat-
ter degeneration; some changes may be temporary, with
others permanent (Harper, 2009).
Neuropathology of other dementias
Numerous other rare forms of dementia exist, including
neurodegeneration with brain iron accumulation, adult-
onset polyglucosan disease, adult-onset leukodystrophy,
adult neuronal ceroid lipofuscinosis, and some of the
spinocerebellar atrophies. In addition, nondegenerative
dementias may result from inflammatory, neoplastic, and
demyelinating conditions. The following sections discuss
some of these more common conditions.
Cerebrovascular disease in the elderly
Vascular disease is common with aging, and the patho-
logic classification of cerebrovascular disease is similar
to other age groups; it includes large vessel disease, small
vessel disease, ischemic parenchymal injury, and hemor-
rhagic parenchymal injury. Older persons are particularly
prone to large vessel disease in the form of atheroscle-
rosis, small vessel diseases including arteriolosclerosis
and CAA, and ischemic and hemorrhagic parenchymal
injury. In addition, older persons are more likely to expe-
rience global hypoxic events from cardiac disease result-
ing in global/hypoxic ischemic encephalopathy and are
more prone to subdural hematomas (SDH) from falls.
Because cerebrovascular disease is a common underlying
53
pathology in dementia, some of these conditions have
already been reviewed in Section “Neuropathology of
other dementias.”
Atherosclerosis
Atherosclerosis of the cerebral vasculature is common in
older persons and represents the most common under-
lying pathology for large territory and embolic cortical
infarcts. As might be expected, the risk factors for ath-
erosclerosis are similar as those for stroke and include
hypertension, diabetes, dyslipidemia, and cigarette
smoking. White people have been described to more
often harbor atherosclerotic lesions in extracranial ves-
sels, whereas Afro-Caribbean populations are more
likely to have intracranial atherosclerosis (Moossy, 1993).
Atherosclerosis affects medium and large arteries, par-
ticularly in the major branches of the Circle of Willis
and occurs when fat, cholesterol, and other substances
build up in the walls and form plaques (see Figure 2.18).
Sufficient blood flow is often maintained in spite of sig-
nificant narrowing and rigidity from plaques. Compli-
cated plaques with damage to the endothelium are the
key triggers for the development of thrombus, occlusion,
and emboli (Ferrer et al., 2008). Emboli cause abrupt
occlusion of distal downstream arteries, whereas local
thrombotic processes are typically slower, allowing time
for collateral channels to develop. Clots can also form
around tears (fissures) in the plaques. In some cases,
the atherosclerotic plaque is associated with a weak-
Figure 2.18 Atherosclerosis, the Circle of Willis. Note the
asymmetric involvement of vertebral arteries, extension into
basilar artery, and posterior cerebral arteries. (For a color version,
see the color plate section.)
54 The Aging Brain in Neurology
ening of the wall of an artery, leading to an aneurysm.
Severe atheroma, especially in the basilar artery, may
cause fusiform enlargement (see Figure 2.19), or fusiform
aneurysm, and result in mechanical compression, clini-
cal cranial nerve palsies, excitation, and hydrocephalus.
While hemorrhage is rare, ischemia and infarction may
result from thrombi or fragments of plaques that embo-
lize (Ferrer et al., 2008).
Small vessel disease
Small cerebral vessels include perforating arteries with
diameters of 40—900  μm (Ferrer et al., 2008). Diseases of
small vessels have been associated with lacunar infarcts
(Sections “Vascular cognitive impairment and dementia”
and “Infarction”), subacute ischemic vascular demen-
tia, and primary intraparenchymal hemorrhages (Sec-
tion “Intraparenchymal hemorrhages”). The most com-
mon small vessel disease in aging is arteriosclerosis/
arteriolosclerosis (AS; see Figure 2.20). Arteriolosclerosis
affects arteries 40–150 μm in diameter (Ferrer et al., 2008).
Microscopic features of AS include hyaline thickening,
intimal fibromuscular hyperplasia, luminal narrow-
ing, thinning of the media, and concentric onion-skin-
type smooth muscle cell proliferation, with or without
the presence of foamy macrophages in the arterial wall
(Vinters, 2001; Yahnis, 2005; Ferrer et al., 2008). Although
the term lipohyalinosis (LH) is often used synonymously
with AS, LH was initially used to describe small blood
vessels that first underwent fibrinoid change and then
subsequent hyalinization, especially in association with
Figure 2.19 Fusiform aneurysm of the basilar artery. Artery is
dilated and tortuous and may compress and distort the brain stem.
(For a color version, see the color plate section.)
Figure 2.20 Arteriolosclerosis: hyaline thickening of two small
vessels in the deep white matter. Note that the upper vessel
appears occluded. (For a color version, see the color plate section.)
hypertension. The uniform eosinophilia on H&E-stained
sections may result from either fibrinoid change (necrosis)
or collagenous fibrosis (hyalinosis). Special stains may
be needed to distinguish the two changes. Traditionally,
hypertension, age, and diabetes mellitus are the main risk
factors for small vessel disease (Yahnis, 2005).
Cerebral amyloid angiopathy
Cerebral amyloid angiopathy affects capillaries, arte-
rioles, and small-size and medium-size arteries of the
cerebral and cerebellar cortex and leptomeninges (see
Figures 2.8 and 2.21), with the subcortical regions and
brain stem relatively spared (Mandybur, 1986; Vonsattel
et al., 1991; Ellis et al., 1996; Vinters, 1998). The distribu-
tion is very patchy, and heavily involved vessel segments
alternate with amyloid-free regions (Mandybur, 1986).
The most common form of CAA is sporadic and associ-
ated with deposition of Aβ, the same protein implicated
in AD (Vinters, 1998). Indeed, most AD cases have con-
comitant CAA (Ellis et al., 1996; Arvanitakis et al., 2011a),
but CAA also increases in extent and severity with age
and is common in older persons without a pathologic
diagnosis of AD. When CAA appears to be “leaking”
from the capillary wall into the adjacent brain, the latter is
described as dysphoric angiopathy (Attems and Jellinger,
2004). The affected blood vessels in Aβ-CAA may show
segmental dilations, micro-aneurysms, fibrinoid necro-
sis (Ellis et al., 1996), and inflammation (Vonsattel et al.,
1991). In general, the extent of amyloid deposition within
vessel walls correlates with the increasing risk of cerebral
lobar hemorrhage (Ellis et al., 1996). CAA has also been
associated with microbleeds and cognitive impairment
(Arvanitakis et al., 2011a). Hereditary forms of CAA may
be associated with Aβ or other amyloid-forming proteins
(Yahnis, 2005).
 Functional Changes Associated with the Aging Nervous System
(a)
Figure 2.21 Cerebral amyloid
angiopathy. (a) Cortex
involves small-size and
medium-size arteries,
arterioles, and capillaries
(arrows; small arrow also
(c)
shows dysphoric change).
(b) Leptomeninges vessels.
(c) Amyloid alternating
with amyloid-free regions.
(d) “Double-barrel”
appearance from separation
of endothelium from the
affected muscularis. (a–c, Aβ
immunostain.) (For a color
version, see the color plate
section.)
Vasculitis
Vasculitis refers to a heterogeneous group of disorders
that are characterized by inflammatory destruction of
blood vessels. Vasculitis is classified according to vessel
size, systemic versus primary CNS localization, and the
presence or absence of giant cells. Vasculitis may also be
secondary to infections such as syphilis, tuberculosis, or
fungal infections. Giant cell arteritis (GCA, temporal arte-
ritis) is particularly important in the aging brain.
Giant cell arteritis occurs in adults older than 50 years
and has a peak incidence between 75 and 85 years of
age. Women are affected twice as often as men. The clas-
sic symptoms are headache, scalp tenderness, jaw clau-
dication, and blindness. The blindness occurs usually
as a result of the extension of the disease into the ocular
(most commonly, the ophthalmic) arteries and/or their
branches (Weyand et al., 2004; Yahnis, 2005; Ferrer et al.,
2008). Extracranial branches of the aorta are also typically
involved, especially the external and internal carotid arter-
ies and vertebral arteries, which may lead to brain infarct
in a small percentage of cases (Yahnis, 2005). The affected
vessel becomes tortuously thickened and tender, with
diminished pulsations. Microscopically, there is intimal
proliferation with a transmural infiltration by lympho-
cytes, including CD4+ T-lymphocytes, and lesser num-
bers of CD8+ T-lymphocytes, monocytes/macrophages,
and giant cells. A definitive diagnosis can be made only
by temporal artery biopsy. The changes are most often
focal and patchy rather than generalized, thus a negative
biopsy cannot completely rule out GCA (Yahnis, 2005).
Multiple other pathologies can affect large and small
cerebral vessels, including other types of emboli (septic,
55
(b)
(d)
fat, tumor), vasculitis (infectious, systemic), hereditary
angiopathies (CADASIL), arterial dissection, and vascular
malformations. Saccular aneurysms are discussed later in
this section. In spite of a multitude of vessel pathologies,
the final common pathway of most, if not all, of the ves-
sel pathologies is cerebral ischemia, infarction, and/or
hemorrhage.
Infarction
Brain infarction accounts for the majority of strokes and
has been related to both cognitive and motor changes
in aging (Schneider et al., 2003; Buchman et al., 2011).
However, it is very common to find brain infarcts in older
persons without a history of clinical stroke (Schneider
et al., 2003). Pathologically, gross (macroscopic) infarcts
are the infarcts that can be visualized by the naked eye.
Similar to neuroimaging studies, about one-third of the
older persons have evidence of chronic gross infarcts at
the time of autopsy (Schneider et al., 2003). Gross infarcts
can be described as acute, subacute, or chronic. At around
8–12 hours, there is blurring of the cortical white mat-
ter junction and, microscopically, red or ischemic neu-
rons appear. Cytotoxic edema reaches a maximum at
48–96 hours, during which time there is a higher risk of
herniation. If reperfusion occurs, as is typical for most
embolic infarcts, the area of ischemia may become hemor-
rhagic. At the same time, macrophages infiltrate, and by
10 days, there is a reactive gliosis. At 3 weeks, the infarct
begins to cavitate (liquefaction necrosis) and there are
abundant macrophages by microscopy. Eventually, the
infarct is filled with fluid and traversed by a network of
small vessels. The subpial cortex, which has a separate
56 The Aging Brain in Neurology
blood supply, is typically preserved in cortical infarcts.
Lacunar infarcts refer to small (10 or 15  mm maximal
dimension) regions of cystic cavitation most often seen
within basal ganglia, thalamus, pons, internal capsule,
and deep subcortical white matter. Microscopic infarcts
are lesions that are not visible on macroscopic inspection
but are observed during the examination of the histologic
sections (Arvanitakis et al., 2011b).
Anoxic/hypoxic encephalopathy
In older persons, this is most often the result of cardiac
arrest with low blood flow and oxygenation and tissue
anoxia. The brain shows selective regional and cell type
vulnerability, with the neurons of the CA1 sector of the
hippocampus, Purkinje cells of the cerebellum, and
layers III and V of the cortex preferentially damaged.
There is variable damage of the basal ganglia. If the per-
son survives, these regions acutely show red neurons,
followed by infiltration of macrophages and liquefac-
tion necrosis, typically in a linear pattern called laminar
necrosis. Carbon monoxide results in an acute pink dis-
coloration of the brain, followed by bilateral necrosis of
the globus pallidus.
Intraparenchymal hemorrhages
Intraparenchymal hemorrhage most often occurs from the
rupture of small blood vessels, such as lenticulostriate or
pial perforating artery, in association with hypertension,
CAA, or other predisposing factors. Hypertensive hemor-
rhage typically occurs from rupture of the lenticulostriate
branches of the middle cerebral artery or pontine perfo-
rators of the basilar artery, accounting for the common
subcortical distribution of hypertensive hemorrhage in
the deep cerebral nuclei (putamen, thalamus) and pons/
cerebellum (Ferrer et al., 2008). Massive hemorrhages are
manifested as foci of acutely clotted blood that displace
and disrupt, resulting in mass effect and possible hernia-
tion. Although Charcot–Bouchard microaneurysms (see
Figure 2.22) formed by focal weakening and aneurysmal
dilatation of small vessels are often reported as the clas-
sic underlying pathology of hypertensive hemorrhage,
these are rarely found on pathologic examination and
rupture of nonaneurysmal, but damaged vessel walls
have been argued as the more common pathophysiology
(Yahnis, 2005; Ferrer et al., 2008). Sporadic CAA accounts
for about 10% of primary nontraumatic intraparenchy-
mal hemorrhage and is the most common cause of lobar
intracerebral hemorrhage in normotensive older persons
(Vonsattel et al., 1991; Ferrer et al., 2008). CAA hemor-
rhages tend to superficial and may also cause subarach-
noid hemorrhage (SAH). Microhemorrhages from arterio-
losclerosis and CAA are probably even more frequent (see
Figure 2.22) and can be detected using special neuroimag-
ing techniques.
Subarachnoid hemorrhage
By definition, a SAH is located between the meninges
and the pial surface of the brain. SAH is most commonly
caused by the rupture of a cerebral artery aneurysm
or trauma. The annual incidence of aneurysmal SAH
increases with age, with a median age of onset in the fifth
or sixth decade (Fogelholm et al., 1993; Yahnis, 2005).
Saccular aneurysms (berry aneurysms) typically arise at
the points of bifurcation of intracranial arteries, within
the Circle of Willis. Aneurysms increase in size with
time, and size is closely associated with rupture (Yahnis,
2005). Pathologically, aneurysms have a narrow neck
and thin walls and show attenuation and disruption of
Figure 2.22 Charcot–Bouchard aneurysm; note the
markedly thinned region of the vessel wall. (For
a color version, see the color plate section.)
 Functional Changes Associated with the Aging Nervous System
the internal elastic lamina and fibrosis of the vessel wall.
Although rupture typically causes SAH, blood may also
penetrate into brain tissue (intracerebral hemorrhage).
Rebleeding may rise during the first 24 hours and at 1–4
weeks after the initial hemorrhage (Inagawa et al., 1987).
One of the complications of SAH is arterial vasospasm
and associated delayed cerebral ischemia and infarction
about 4–7 days post-hemorrhage. SAH is also a common
consequence of trauma. Older persons at risk of falling
are particularly prone to focal SAH, along with contu-
sions of the frontal orbital and anterior temporal super-
ficial cortex.
Movements disorders
The most commonly diagnosed movement disorder asso-
ciated with aging is PD. Parkinsonism also occurs with
other neurodegenerative diseases, including CBD, PSP,
and MSA. In addition, older persons often show mild
motor problems, including problems with gait and slow-
ing that does not easily fit into a specific disease category.
Other subclinical degenerative and vascular diseases
(Buchman et al., 2011) in the aging brain likely can disturb
the nigrostriatal and frontostriatal pathways.
Parkinson’s disease
Idiopathic PD describes the common idiopathic disorder
that shows a slowly progressive course and is character-
ized by bradykinesia, rigidity, gait disorder, and tremor.
Gross pathologic features include pallor of the SN and
locus coeruleus, with severe loss of the melanin-containing
dopaminergic neurons with melanin-containing macro-
phages and free melanin pigment in the SN pars com-
pacta, most prominently in the ventrolateral portion of
SN. It has been estimated that symptoms of PD occur
when more than 50% of nigra neurons have been lost, but
recent data challenge this notion (Ince et al., 2008). LBs,
the pathologic hallmark of PD (see Figures 2.11 and 2.12),
not only occur in the SN in PD but also are found in the
dorsal motor nucleus of the vagus, substantia innomi-
nata, other brainstem nuclei, the intermedolateral cell col-
umns of the spinal cord, and sympathetic ganglia (Braak
et al., 2003). More caudal structures, including brainstem,
olfactory bulbs, spinal cord, and peripheral nervous sys-
tem, are believed to be involved prior to the SN (Braak
et al., 2003; Beach et al., 2009), and the development of
LB probably follows a caudal-to-rostral progression in
most cases of PD. Extension into cortical regions is com-
mon and associated with DLB as well as PD dementia. PD
dementia is clinically separated from DLB by the tempo-
ral sequence of motor signs being established before the
onset of dementia (McKeith et al., 2005). LBs and LN are
the central pathology of DLB and PD, and there is signifi-
cant overlap between the pathologic features. Synuclein
57
has been reported in the olfactory bulbs of subjects with
PD and DLB, suggesting that olfactory bulb involvement
is common to all LB disorders and occurs at an early stage
of the disease (Beach et al., 2009).
Pathologic staging of PD has been suggested based on
anatomic distribution and severity of LB and LN (Braak
et al., 2003). In stages 1 and 2, the pathology is restricted to
the brainstem and olfactory bulb. Involvement of the pars
compacta of the substantia nigra (SNc) occurs in stage
3, without degeneration until stage 4. In stages 5 and 6,
the α-synuclein pathology involves the neocortex (Braak
et al., 2003; Ince et al., 2008; Beach et al., 2009; Jellinger,
2009). Motor and cognitive manifestations have been pro-
posed to depend on the anatomic distribution and load
of α-synuclein pathology (Braak et al., 2005; Beach et al.,
2009).
Dementia is seen in a large number of PD patients
(Braak et al., 2005; Ince et al., 2008; Beach et al., 2009), and
although the pathologic correlates of dementia have been
debated, cortical LBs are believed to play a role (Braak
et al., 2005; Beach et al., 2009). In PD dementia, the amount
of concomitant AD pathology is typically less than that in
classic DLB (Cummings, 2004), but cortical LBs are said to
be present in small numbers in virtually all cases of idio-
pathic PD, with or without a history of dementia (Ince
et al., 2008).
Incidental LB disease is the term used when LBs are
pathologically found in the nervous system in subjects
without clinically documented parkinsonism or cogni-
tive impairment. Epidemiologic studies indicate that
autonomic symptoms, REM sleep behavioral disorder,
and olfactory dysfunction may precede the presentation
of parkinsonian motor signs and symptoms by years and
may be related to LBs and LNs in these more caudal struc-
tures (Jellinger, 2009).
Multiple System atrophy
MSA is a sporadic neurodegenerative disease that pres-
ents with the cardinal features of orthostatic hypoten-
sion, parkinsonism, and cerebellar signs and symptoms
(Gilman et al., 1998; Gilman et al., 2008); it encom-
passes the previous nomenclature of olivopontocerebel-
lar atrophy, Shy–Drager syndrome, and striatonigral
degeneration. Diagnostic criteria for MSA proposed by
a Consensus Conference in 1998 (Gilman et al., 1998)
recommended MSA to encompass two groups, includ-
ing MSA-P (parkinsonian-predominant) and MSA-C
(cerebellar-predominant). α-synuclein immunoreactive
glial cytoplasmic oligodendroglial inclusions in areas of
degeneration are a required feature for a definite diag-
nosis of both MSA-P and MSA-C (Gilman et al., 1998;
Gilman et al., 2008).
MSA-P accounts for the majority of the cases of MSA.
Pathologically, there is atrophy and grayish discolor-
ation of the putamen, pallor of the SN, and slight cortical
58 The Aging Brain in Neurology
atrophy. Neuronal loss and gliosis are most severe in the
dorsolateral zone of the caudal putamen and lateral por-
tion of the SN. MSA-C shows grayish discoloration of the
cerebellum, middle cerebellar peduncle, and the pons.
There is Purkinje cell loss and proliferation of Bergmann
glia, especially in the vermis. In addition, neuronal loss
and gliosis are prominent in the basis pontis and acces-
sory and inferior olivary nuclei, and the cerebellopontine
fibers are degenerated. Both MSA-P and MSA-C may
have degeneration of the SN, intermediolateral cell col-
umn, and locus coeruleus (Watanabe et al., 2002).
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis is a neurodegenerative dis-
ease characterized by the degeneration of upper (UMN)
and lower motor neurons (LMN). There is progres-
sive and often asymmetric weakness and wasting, with
involvement of the bulbar/respirator muscles, but spar-
ing of ocular, urinary, and anal sphincter muscles. Fasicu-
lations are a prominent feature, reflecting LMN involve-
ment. Pseudo-bulbar palsy, progressive atrophy, and cor-
ticospinal signs may be present. Sensory nerves and the
autonomic nervous system are generally unaffected but
may be involved for some patients. Patients with familial
ALS associated with an SOD1 mutation frequently have
degeneration of the posterior columns, Clarke’s column,
and spinocerebellar tracts (Ince et al., 2008). At autopsy
the cervical and lumbosacral enlargements of the spinal
cord may be atrophic, and anterior motor roots shrunken
and gray. The brain may show frontal or temporal lobe
when there is coexisting dementia. The key histology
is loss of motor neurons, with associated astrocytosis,
in anterior horns of the spinal cord. In the medulla, the
hypoglossal nucleus is most obviously degenerated, and
the nucleus ambiguous, motor nuclei of the trigeminal
and facial nerves, and motor cortex may be affected. The
nuclei of cranial nerves III, IV, and VI and Onufrowicz
nuclei are preserved, consistent with the preservation of
(a) (b)
eye movements and sphincter control. Axonal spheroids
are frequently seen in the anterior horns but are not spe-
cific for ALS. The spinal cord typically shows myelin pal-
lor in the anterior and lateral corticospinal tracts, which
can be demonstrated using immunohistochemistry for
microglial markers (see Figure 2.23). Myelin loss is most
evident in lower cord segments. Muscle morphology at
biopsy or autopsy shows neurogenic atrophy, including
grouped atrophy and fiber-type grouping affecting type
1 and type 2 fibers.
A variety of inclusion bodies are seen in surviving
motor neurons (Ince et al., 2008). Bunina bodies (see
Figure 2.24) are thought to be a specific feature of ALS
and are small intracellular eosinophilic inclusions, often
arranged in small beaded chains. Ubiquitin-immunos-
tained inclusions (see Figure 2.25) are typically seen
in both UMN and LMN and include skein inclusions
or threadlike structures, and hyaline-like or Lewy-like
inclusions. It is now recognized that the underlying
ubiquinated protein in these inclusions is TDP-43 (see
Figure 2.24), the same protein of FTLD. Indeed, in some
cases of ALS, TDP-43 positive inclusions are also seen in
the neurons of dentate nucleus of hippocampus, basal
ganglia, and cortex.
Accordingly, ALS may affect cognition and is associated
with FTLD. Patients with ALS may have subtle executive
deficits, and a small number will have a clinical subtype
of FTLD (Geser et al., 2008). Indeed, cognitive and behav-
ioral symptoms in association with ALS and an associa-
tion between ALS and FTD were considered in the earlier
part of the twentieth century. Indeed, it now appears that
ALS and FTLD may represent a multiple-system TDP-43
proteinopathy, with ALS and FTLD at two ends of the dis-
ease spectrum (Geser et al., 2008; Traub et al., 2011).
Huntington’s disease
Huntington’s disease (HD) is an autosomal domi-
nant disorder caused by a mutation in the HD gene on
(c)
Figure 2.23 Amyotrophic
lateral sclerosis. (a) Pallor of
the lateral corticospinal tracts
of spinal cord on myelin
stain. (b) Low and (c) high
magnification show CD8
immunostained macrophages
indicative of degeneration.
(For a color version, see the
color plate section.)
 Functional Changes Associated with the Aging Nervous System
Figure 2.24 Amyotrophic lateral sclerosis anterior horn cell with a
Bunina body. (For a color version, see the color plate section.)
chromosome 4p16.3 that typically manifests as chorea
and psychiatric symptoms and progresses to demen-
tia (Yahnis,  2005; Ince et al., 2008). HD results from an
expansion of the trinucleotide repeat CAG to over
36 repeats, compared to normal repeats of 26. Onset is
usually in midlife, with a mean survival of 17 years. The
first clinical manifestation of the hyperkinetic form is
chorea, but neuropsychological problems such as person-
ality change, depression, and psychosis can antedate the
onset of the movement disorder (Yahnis, 2005). Neuro-
pathologically, the brain is atrophic, with specific atrophy
of the caudate and putamen and compensatory enlarge-
ment of the lateral ventricles. Histologically, there is neu-
ronal loss, especially of the GABAergic medium spiny
neurons (Joel, 2001) of the striatum. Ubiquitin-positive
intranuclear inclusions and abnormal neurites are pres-
ent in degenerated regions (Yahnis, 2005; Ince et al., 2008;
Cochran, 2005).
(a)
(c)
Figure 2.25 Amyotrophic lateral sclerosis.
Hyaline inclusions in an anterior horn
motor neuron on H&E (a) and ubiquitin
(b). (c) Skein-like inclusions in the anterior
horn cells in ALS also stain with antibodies to
ubiquitin. (For a color version, see the color
plate section.)
59
Brain tumors
The overall incidence of brain tumors appears to be
increasing, with the highest increase noted in patients
older than 60 years of age (Flowers, 2000). The average
annual percentage increases in primary brain tumor inci-
dence for ages 75–79, 80–84, and 85 and older are 7, 20.4,
and 23.4%, respectively (Flowers, 2000). These tumors
include astrocytoma, glioblastoma multiforme (GBM),
meningioma, schwannomas, primary malignant lympho-
mas of the brain, and metastatic brain tumors.
Glial neoplasms
Glial neoplasms include astrocytomas, GBMs, oligoden-
drogliomas, and other glial neoplasms. These tumors
develop in all ages but are particularly challenging in
geriatric patients.
Astrocytomas
Diffuse astrocytomas (WHO grade II) including fibro-
blastic, protoplasmic, and gemistocytic variants, occur
at any age but most frequently in the sixth decade of life
(Perry, 2005). Like most tumors, they may present with
headache, seizures, or focal signs, depending on the loca-
tion. Astrocytomas are most frequent in the cerebral white
matter, where they appear as ill-defined, slightly firm,
yellow-white, homogeneous tumors that enlarge and
distort the hemisphere. Tumor cells individually and dif-
fusely infiltrate surrounding normal tissue without obvi-
ous borders between normal and diseased tissue (Louis
et al., 2008). There is increased cellularity with mild pleo-
morphism; mitoses, vascular proliferation, and necrosis
are absent, and the proliferative index (MIB1/Ki67) tends
(b)
60 The Aging Brain in Neurology

to be low (less than 5%). Tumor cells are confirmed as

astrocytes using antibodies against glial fibrillary acidic
protein (GFAP). Diffuse astrocytomas frequently undergo
malignant transition to anaplastic astrocytoma and GBM
multiforme.

Anaplastic astrocytoma
Anaplastic astrocytomas (WHO grade III) may arise from
diffuse astrocytoma, WHO grade II or de novo, without
the evidence of a less malignant precursor. They tend to
occur in slightly older individuals, compared to diffuse
astrocytomas, and are located in the hemispheres, leading
to enlargement of invaded structures and a more discern-
ible mass, compared to diffuse astrocytomas (Louis et al.,
2008). There may be edema, mass effect, and increased
intracranial pressure. Anaplastic astrocytomas show
histologic features of malignancy, including cellular and
nuclear pleomorphism, increased cellularity and mitotic
activity, and Ki-67/MIB-1, usually in the range of 5–10%.

Glioblastoma
Figure 2.26 Glioblastoma multiforme: gross appearance with
Glioblastomas are malignant (WHO grade IV) glial neo-
variegated necrotic-appearing mass without definite borders. (For
plasms that manifest at any age but preferentially affect a color version, see the color plate section.)
older adults (Ohgaki et al., 2004; Louis et al., 2007).
Primary GBMs develop in older patients (mean age about
62 years), whereas secondary GBMs derived from lower- between 40 and 45 years of age (Ohgaki and Kleihues,
grade astrocytomas usually occur in younger patients 2005). Oligodendrogliomas are diffusely infiltrating low-
(mean age about 45 years). Clinical presentations depend grade (WHO grade II) gliomas and often harbor deletions
on the region involved; with frontal lobe tumors, exten- of chromosomal arms 1p and 19q (Louis et al., 2007; Louis
sive growth may already be evident at the time of pre- et al., 2008). These tumors account for approximately 2.5%
sentation. GBMs occur most often in the subcortical white of all primary brain tumor and 5–6% of all gliomas (Louis
matter and may spread along myelinated tracks across et al., 2007; Louis et al., 2008). They develop in the cortex
corpus callosum, giving rise to a characteristic butter- and white matter of the cerebral hemispheres, and calci-
fly pattern. Although they may appear discrete, distant fications are frequent. Histologically, they are diffusely
cellular spread is extensive, making complete surgical infiltrating gliomas composed of uniform round nuclei
resection impossible in most cases (Louis et al., 2008). with perinuclear halos, resulting in the characteristic
Pathologically, GBM shows variable colors with gray-
ish tumor masses and central areas of yellowish necrosis
and hemorrhages (see Figure 2.26). Histologically, there is
high cellularity, pleomorphism, mitoses, and microvascu-
lar proliferation and/or necrosis. Necrosis characteristi-
cally has a pseudopalisading pattern (see Figure 2.27) of
large necrotic areas surrounded by viable tumor cells at
the periphery. Recent data show that the cellular pseudo-
palisades are hypoxic, thereby overexpressing hypoxia-
inducible factor (HIF-1), and secrete proangiogenic factors
such as VEGF and IL-8 (Rong et al., 2006). Proliferative
activity is usually prominent, and the proliferative index
determined using Ki-67/MIB-1 may reach very high per-
centages. GFAP immunopositivity is variable but, if posi-
tive, may be helpful in the diagnosis.

Other glial neoplasms Figure 2.27 Glioblastoma: histologic appearance of

Oligodendrogliomas can develop at any age, but the pseudopalisading necrosis. (For a color version, see the color plate
majority of tumors arise in adults with an incidence peak section.)
 Functional Changes Associated with the Aging Nervous System 61

“fried-egg” appearance on paraffin sections. Extracellular

mucin and microcysts are frequent, and a dense network
of branching capillaries resembles the pattern of chicken
wire (Herpers and Budka, 1984; Louis et al., 2007; Louis
et al., 2008). Ependymomas are slowly growing gliomas,
originating from the cells of the ventricular walls or spinal
canal, and are composed of neoplastic ependymal cells.
Ependymomas correspond histologically to WHO grade
II. These tumors develop in all age groups ranging from 1
month to 81 years (Louis et al., 2007), but most commonly
in the fourth ventricle in children and in the spinal cord in
adults. A specific variant, called myxopapillary ependy-
moma, is found at the filum terminale in adults. The key
histologic features are perivascular pseudorosettes and
ependymal rosettes. Subependymomas of the fourth ven-
tricle are typically an incidental finding in older adults
and uncommonly are symptomatic.

Metastatic lesions
Metastatic tumors originate outside the CNS and spread
secondarily to the CNS via blood or by direct invasion.
Metastatic tumors to the brain are approximately 10 times
more common than primary intracranial neoplasms
(Ellison et al., 2008) and are arguably the most common
CNS neoplasm in older persons. About 25% of patients
who die from cancer have CNS metastases detected at
autopsy (Gavrilovic and Posner, 2005). Lung (espe-
cially small cell and adenocarcinoma), breast, and skin
(melanoma) are the most common sources (Soffietti et
al., 2002). More than 80% of brain metastases are located
in the cerebral hemispheres, 10–15% in the cerebellum,
and 2–3% in the brain stem. Because they are typically
of hematogenous origin, their distribution is generally
in arterial border zones and at the junction of cerebral
cortex and white matter (Louis et al., 2007; Ellison et al.,
2008). Melanoma and lung carcinoma more often cause
multiple lesions, whereas breast carcinoma frequently is
single (Delattre et al., 1988; Ellison et al., 2008). Patho-
logically, they are usually well-demarcated, rounded
masses that displace the surrounding brain parenchyma
(see Figure 2.28). Malignant melanoma, lung carcinoma,
renal cell carcinoma, and choriocarcinoma tend to be
hemorrhagic and may present as intracranial hemor-
rhages (Nutt and Patchell, 1992; Louis et al., 2007). His-
topathologic features of metastatic tumors are usually
similar to those of their primary lesions, but there may
be less differentiation. For example, metastatic melano-
mas may be amelanotic.
Primary CNS lymphoma
Primary CNS lymphomas (PCNSL) are malignant lym-
phomas that occur in the CNS without evidence of a coex-
isting systemic lymphoma. The incidence of PCNSL has
markedly increased, at least partly because HIV-positive
patients develop CNS lymphomas. PCNSL affect all ages,
Figure 2.28 Metastatic adenocarcinoma: cortical lesion appears well
demarcated and necrotic. (For a color version, see the color plate
section.)
with a peak incidence in immunocompetent subjects
during the sixth and seventh decades of life (Koeller et al.,
1997; Louis et al., 2007). More than half of PCNSLs involve
the supratentorial space, most commonly frontal, tempo-
ral, or parietal cortex, and they are occasionally multiple
(Louis et al., 2007). PCNSLs also have a propensity to
involve periventricular regions. The tumors are often cen-
trally necrotic or focally hemorrhagic, and visible demar-
cation from surrounding parenchyma is variable (Koeller
et al., 1997). Tumor cells typically form concentric collars
of perivascular cuffs, packing the perivascular spaces and
creating a concentric pattern of reticulin-positive material
around vessels. Tumor cells also invade the surrounding
parenchyma and may form tumor masses. The vast major-
ity of CNS lymphomas are classified as diffuse large B-cell
lymphoma (Koeller et al., 1997; Louis et al., 2007; Ellison
et al., 2008). Reactive small T-lymphocytes are identified
among the tumor cells, usually in moderate numbers.
Most B-cell PCNSLs have a very high Ki-67 labeling index
(Koeller et al., 1997; Louis et al., 2007; Ellison et al., 2008).
Because individual tumor cells extensively invade the
surrounding parenchyma, similar to most glial tumors
and unlike metastases, complete resections are typically
not feasible. PCNL are, at least initially, steroid responsive
and also responsive to radiation and chemotherapy; how-
ever, long-term prognosis remains poor.
Meningiomas
Meningiomas are derived from meningothelial (arach-
noid) cells and are typically attached to the dural inner
62 The Aging Brain in Neurology
surface. Most meningiomas are benign and correspond to
WHO grade I. Meningiomas account for about 24–30% of
primary intracranial tumors occurring in the United States
(Louis et al., 2007) and can occur at any age but most com-
monly are seen in middle-aged and elderly patients, with
a peak during the sixth and seventh decades (Louis et al.,
2007; Ellison et al., 2008). They are significantly more
common in women than in men, with a female:male ratio
of nearly 2:1 (Louis et al., 2007). Meningiomas are well-
circumscribed spherical growths that are firmly attached
to the dura. Dural and bone invasion are common and
do not indicate malignancy; brain invasion is relatively
rare. Meningiomas present a wide range of histologic
patterns, and mixed patterns are frequent. Characteristic
histologic features include whorls and psammoma bod-
ies. The atypical designation is largely based on histologic
features, especially mitoses, and specific morphologic
patterns rather than brain invasion, although the latter is
also associated with higher recurrence (Louis et al., 2007).
Anaplasia (malignancy) is also based on histology/mor-
phology and is associated with aggressive behavior, but
metastases are rare.
Schwannomas
Schwannomas are benign nerve sheath tumors (WHO
grade I) and represent about 8% of intracranial tumors,
85% of cerebellopontine angle tumors (acoustic neuro-
mas), and 29% of spinal nerve root tumors (Louis et al.,
2007). Approximately 90% of the cases are solitary and
sporadic. All ages are affected, with the peak incidence
from the fourth to sixth decade. Schwannomas are gen-
erally well-encapsulated globoid tumors and may have
cysts, lipid accumulation, and hemorrhage. The histology
shows a spindle cell neoplasm with dense (Antoni A) and
loose (Antoni B) areas and characteristic nuclear pali-
sades (Verocay bodies). Schwannomas are adjacent to the
involved nerve and, therefore, can be surgically removed
with preservation of some, if not all, nerve function in
many cases (Ellison et al., 2008).
Neurofibromas
Neurofibromas consist of a mixture of cell types, includ-
ing Schwann cells, perineurial-like cells, and fibroblasts.
Solitary neurofibromas are the most common tumor of
peripheral nerves. They may be well-demarcated intra-
neural lesions or diffusely infiltrative extraneural tumors.
Multiple and particularly plexiform neurofibromas are
associated with neurofibromatosis type I (Louis et al.,
2007; Ellison et al., 2008). Unlike schwannomas, neurofi-
bromas are extremely rare within the cranium; in addi-
tion, they show a tendency to undergo malignant trans-
formation, which occurs in about 5–10% of plexiform
neurofibromas (Ellison et al., 2008). Complete resection of
neurofibromas is difficult, because tumor cells are inter-
mixed within the nerve.
Toxic metabolic encephalopathy
Primary metabolic encephalopathies are those resulting
from inherited metabolic abnormalities. Secondary or
acquired metabolic encephalopathies describe the abnor-
malities of the water, electrolytes, malnutrition, alcohol,
blood sugar, and other chemicals that adversely affect
brain function.
Hepatic encephalopathy
Hepatic encephalopathy occurs in patients with signifi-
cant liver disease and conditions in which blood circula-
tion bypasses the liver. Neuropathologically, astrocytes,
particularly in the basal ganglia, undergo Alzheimer
type II change, which includes enlarged, pale nuclei,
with a rim of chromatin and prominent nucleoli. These
astrocytes lose GFAP immunoreactivity and contain
increased numbers of mitochondria; in severe cases, the
nuclei may be lobulated and contain glycogen granules
(Norenberg, 1994). It is hypothesized that elevated ammo-
nia levels impair postsynaptic inhibitory neurotransmis-
sion, eventually resulting in impaired uptake of synaptic
glutamate, increased extracellular glutamate, and the
downregulation of glutamate receptors (Norenberg, 1994;
Harris et al., 2008).
Alcohol
Alcohol may be related to a host of acute and chronic
brain impairments. WKS, related to thiamine defi-
ciency, was described with pathologies of cognitive
impairment (Section “Wernicke-Korsakoff syndrome”).
Atrophy of the cerebellum may occur separate from
WKS and is less clearly linked to thiamine deficiency.
In addition, long-term alcohol use has been related to
atrophy involving both gray and white matter, which
may be reversible with cessation of drinking. Neuronal
loss appears to be specific to the superior frontal cortex
(Smith et al., 1992).
Central pontine myelinolysis
Central pontine myelinolysis (CPM) is a relatively
uncommon disorder with a very high mortality, usually
occurring in alcoholics with WKS, severe liver disease,
severe burns, malnutrition, anorexia, and severe electro-
lyte disorders (Harris et al., 2008). Too-rapid correction
of a profound hyponatremia gives rise to the absolute
change in serum sodium and appears to be an impor-
tant contributing factor. Macroscopically, the area of
demyelination is often triangular- or butterfly-shaped
and symmetrical in transverse sections. Histopathologi-
cally, myelin-stained sections show a relatively sharply
demarcated area of pallor within the basis pontis, with
a relative preservation of axons. Extrapontine regions of
demyelination have been reported to occur in over half
the cases (Harris et al., 2008).
 Functional Changes Associated with the Aging Nervous System
Infections and inflammation of the CNS
Older persons are more susceptible to specific infec-
tions, probably reflecting an age-associated decline in
cell-mediated immunity and antibody responses (Smith
et al., 1992; Kipnis et al., 2008). In aging, immune com-
petence declines with an alteration of T-cell populations
and monocytes/macrophage cell efficiency. This may also
make older persons more susceptible to certain inflamma-
tory conditions.
Bacterial meningitis
More than half of deaths from meningitis occur in per-
sons over the age of 60 and are most commonly the result
of Streptococcus pneumoniae, Neisseria meningitidis, Listeria
monocytogenes, Haemophilus influenzae, and Staphylococcus
aureus (Chimella, 2001). Bacterial meningitis may result
from hematogenous spread or from local extension. Signs
and symptoms may progress rapidly and include head-
ache, fever, lethargy, and confusion. The brain is swol-
len and congested and is surrounded by creamy yellow
or green pus. On microscopic exam, neutrophils fill the
subarachnoid space and the perivascular spaces within
the brain parenchyma. Unless there was treatment prior
to death, Gram stain often demonstrates bacteria. Com-
plications include cerebral ischemia, infarction, hydro-
cephalus, subdural effusion, sagittal sinus, or cortical vein
thrombosis (Chimella, 2001; Gyure, 2005).
Viral infections
Viral infections of the CNS may result in aseptic meningitis
or meningoencephalitis. Viral meningitis is typically less
severe than bacterial, and most patients recover without
complications. This disorder is usually caused by entero-
virus and is uncommon in older adults (Chimella, 2001).
The meninges may be slightly opaque, and inflammatory
infiltrate is composed almost exclusively of lymphocytes.
Herpes simplex encephalitis
Herpes simplex virus (HSV) encephalitis, the most com-
mon sporadic, nonseasonal encephalitis, occurs at all
ages, and about half are in patients older than 50. Indeed,
in older age groups, HSV (typically, HSV-1) is the most
prevalent cause of encephalitis (Chimella, 2001). Clini-
cally, patients present with a subacute onset of fever,
headache, and confusion. Grossly, HSV encephalitis typi-
cally shows bilateral, asymmetric, hemorrhagic necrosis
affecting the temporal lobes, the insula, the cingulate gyri,
and the posterior orbitofrontal cortices (Chimella, 2001;
Gyure, 2005). Histology shows hemorrhagic necrosis
with perivascular and parenchymal chronic inflamma-
tion, macrophages, and microglial nodules. Cowdry A
intranuclear inclusions are a characteristic feature of HSV
encephalitis. Immunohistochemistry and electron micros-
copy may be helpful in identifying the organisms.
63
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML)
is an infectious demyelinating disease of the CNS
that results from the infection of oligodendroglial
cells by JC virus, a papovavirus. It occurs most com-
monly in immunocompromised patients and has been
described as a complication of specific drugs, cancers,
and aging; it is commonly associated with HIV infec-
tion (Gyure, 2005). Clinical presentations include focal
signs/symptoms and cognitive impairment. Grossly,
the white matter shows small foci of gray discolor-
ation, often forming large confluent areas of abnormal
parenchyma. Lesions are typically subcortical in the
cerebral hemispheres and have a predilection for the
parieto-occipital regions (Chimella, 2001; Gyure, 2005).
Microscopic examination shows foci of demyelination
with surrounding infected enlarged and hyperchro-
matic oligodendroglial nuclei. Astrocytes in PML often
appear “neoplastic” and show lobulated, hyperchro-
matic nuclei (Gyure, 2005).
Cryptococcosis
Cryptococcosis infections are caused by the fungus Cryp-
tococcus neoformans, a common environmental fungus
that infects mostly immunocompromised humans via
the lungs. It is associated with lymphoproliferative dis-
orders, alcoholism, advanced age, generalized malnutri-
tion, corticosteroid therapy, organ transplantation, and
HIV (Chimella, 2001). It signifies transition into AIDS in
patients with HIV who present as subacute meningitis.
In patients without HIV, it is usually diagnosed post-
mortem, as these patients rarely present with the clinical
signs and symptoms of subacute or chronic meningitis.
Grossly, the leptomeninges are thickened and opaque,
and there might be associated hydrocephalus. There
might be a Swiss cheese-like appearance, especially in
the basal ganglia. The fungi are budding oval yeasts and
typically have an empty-looking appearance. They can
be highlighted with PAS stain and may be found around
blood vessels.
Toxoplasmosis
Toxoplasmosis is caused by the intracellular protozoan
toxoplasma gondii. The definitive hosts for this parasite
are domestic cats and other feline species. It is most com-
monly associated with HIV, but other causes of immu-
nosuppression can also underlie reactivation (Chimelli
et al., 1992; Chimella, 2001). Brain lesions may produce
focal signs and symptoms. The brain lesions are typi-
cally necrotic, with focal hemorrhage, acute and chronic
inflammation with neutrophils, mononuclear cells, newly
formed capillaries, astrocytes, and microglial cells. The
organisms are characteristically located at the periphery
of the necrotic areas, either free in the parenchyma or
within cysts.
64 The Aging Brain in Neurology
Other infectious and inflammatory diseases
of the brain
Over the past decades, there has been a growing list of
inflammatory conditions of the nervous system (Rosen-
bloom and Smith, 2009). These diseases typically have a
subacute presentation with the evidence of pathologic anti-
bodies and/or extensive inflammation. Signs and symp-
toms vary but, in older age groups, commonly include a
subacute onset of cognitive and behavioral changes, as
seen in limbic encephalitis. These conditions may or may
not be associated with specific antibodies, and those asso-
ciated with antibodies may or may not be paraneoplastic.
Small-cell lung carcinomas are one of the more common
underlying tumors of the paraneoplastic syndromes,
so determining whether there is a history of smoking is
important. Some diseases have been associated with spe-
cific pathologies, such as limbic encephalitis and systemic
lupus erythematosus, whereas the underlying pathology
of some of the other conditions (such as Hashimoto’s
encephalitis) is less clear. There is also a group of inflam-
matory diseases without specific antigen or antibodies,
such as sarcoidosis and primary CNS vasculitis. Over-
all, these diseases are uncommon, and late presentations
in the geriatric population are relatively rare. Pathology
may show a fulminant encephalitis, with inflammation,
neuronophagia, and microglial nodules (as seen in lim-
bic encephalitis), or inflammation and necrosis focused
primarily at the blood vessels (vasculitis). Some of these
pathologies have been described in the previous sections,
and a complete review of these neuropathologies is out
of the scope of this chapter. Finally, markedly improved
treatments have significantly increased longevity in per-
sons with HIV, and some studies suggest that aging HIV
patients may be at higher risk for specific age-related con-
ditions, such as AD; interestingly, IV drug abusers without
HIV may also be at higher risk (Anthony et al., 2010).
Trauma
Acute hemorrhages and chronic traumatic encepha-
lopathy are significant in the geriatric population. Both
conditions can significantly increase the morbidity and
decrease the functional ability.
Subdural hematomas
Subdural hematomas (SDHs) may be acute or chronic.
Acute traumatic SDHs may be associated with diffuse
cerebral contusions and lacerations and adjacent intra-
cerebral hematoma. These patients are typically uncon-
scious from the time of injury (Blumbergs et al., 2008).
More commonly, there is a less severe type of acute SDHs
that may not be associated with obvious trauma and
that is the result of rupture of bridging veins, with little
or no associated brain damage (Blumbergs et al., 2008).
Pathologically, SDHs are considered chronic when at
approximately 3 weeks of age or status post injury.
Chronic SDHs may or may not be associated with rec-
ognized trauma and are usually the result of rupture of
bridging dural arachnoid veins. Chronic SDHs occur most
commonly in patients over the age of 50 years and are
most common in those from 70 to 80 years old (Blumbergs
et al., 2008). Cerebral atrophy seems to be an important
predisposing factor, supposedly secondary to tension on
bridging veins. This atrophy may allow hemorrhage with-
out a significant mass effect. The age of the SDH may be
approximated by the microscopic examination of the clot
and subdural membranes. In the first few days, the outer
dural membrane shows a few layers of fibroblastic mem-
brane; this progresses to equal the dura thickness after 4–6
weeks (Blumbergs et al., 2008). The membrane is highly
vascular, which predisposes to rebleeding; thus, an SDH
may show hemorrhage and membranes of varying age.
Chronic traumatic encephalopathy
It has long been recognized that boxers with repeated
head injury and concussions are predisposed to an early-
onset dementia syndrome often referred to as dementia
pugilistica. The pathology underlying this syndrome has
been shown to have similarities but also distinctions com-
pared to AD. This relationship is intriguing, given that
repeated head trauma has been shown to be a risk factor
for sporadic late-onset clinical AD. More recent studies
have provided a more in-depth description of this dis-
order. Clinical symptoms include changes in memory,
personality, and behavior with parkinsonism. The syn-
drome is not only in boxers, but also in those involved in
other competitive sports, such as football (McKee et al.,
2009). The pathology shows what appears to be a sepa-
rate degenerative tauopathy with tangles and threads in
a patchy but unique distribution, with a predilection for
superficial cortex, sulcal depths, and perivascular regions
in the frontal and temporal cortices. Diffuse amyloid is a
common but variable feature (McKee et al., 2009). Further
work is needed to determine the relationship between
chronic traumatic encephalopathy and AD.
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Part 2
Assessment of the Geriatric
Neurology Patient
 Chapter 3
Approach to the Geriatric Neurology
Patient: The Neurologic Examination
Marwan N. Sabbagh1 and Anil K. Nair2
1
Banner Sun Health Research Institute, Sun City, AZ, USA
2
Clinic for Cognitive Alzheimer’s Disease Center, Quincy Medical Center, Quincy, MA, USA

Summary
• Neurologic examinations of geriatric patients must focus on the patient’s overall functional ability according to his or
her physical, neurologic, behavioral, and cognitive changes that occur with aging.
• A review of medications and physical, head and neck, and cardiovascular examinations are essential.
• Neurologic examinations include/assess:
• Mental status testing using a cognitive screen such as the MOCA.
• Speech articulation, loudness, and phonation.
• Language comprehension, repetition, naming, ability to follow commands, fluency, and prosody.
• Cranial nerves.
• Muscle bulk, tone, and strength as well as pronator drift and other abnormal movements.
• Sensory perception, loss, neglect, pain, and proprioception.
• Deep tendon and primitive reflexes, as well as clonus.
• Coordination/Cerebellar function.
• Gait and posture.
• Careful investigation of the nervous system can reveal underlying causes of various symptoms and prompt further
investigation and treatment. Examinations can also provide information that helps to improve care.

Introduction further investigation. In this chapter, we review the neu-

As the population ages, the number of patients over age
65 is expected to grow almost exponentially. In fact, the
geriatric population is the fastest-growing segment of the
population. The geriatric population has unique medical
challenges. Their physical and neurologic findings have
different root etiologies from their younger counterparts.
Thus, there is a consideration for reviewing the neuro-
logic examination for the geriatric patient.
Like geriatrics and geriatric psychiatry, which are well-
established subspecialties of primary care and psychiatry,
respectively, geriatric neurology is emerging as a sub-
specialty of neurology. This emergence reflects the grow-
ing understanding that geriatric patients have different
neurologic conditions that require different diagnostic
evaluations and, ultimately, different features. As such,
clinical syndromes can have features common to younger
patients, but the etiologies are frequently different.
Careful attention to features of the physical and neu-
rologic examination as findings, as with the younger
patient, frequently points to root causes, prompting
rologic examination of the geriatric patient and briefly
review key elements of the physical examination. Physi-
cal and neurologic findings are also detailed throughout
the textbook and are cross-referenced accordingly.
The geriatric neurologic examination
with a focus on function
The focus of the geriatric neurologic examination is dif-
ferent from an examination for a typical patient seen at
a neurology service or in an office setting. For the latter,
the primary purpose of the examination is to localize the
site of the lesion and guide the appropriate workup to
determine the diagnosis and most appropriate treatment
for the condition (Bickley, Szilagyi, and Bates, 2007). In
contrast, the focus of the geriatric neurology examination
is determining the physical, neurologic, cognitive, and
behavioral deficits that will impair a patient’s functional
ability, as well as identifying his or her ability to carry out
specific tasks. The geriatric neurologist must go beyond

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

71
72 Assessment of the Geriatric Neurology Patient
neurologic impairment and assess the impact that other
diseases, such as arthritis, chronic obstructive pulmo-
nary disease, and cardiovascular disease, may have on
the patient’s function, in a way a primary care physician
would not be able to do. For example, muscle rigidity
may affect a person’s ability to transfer, dress, or walk
independently. Spasticity might impede nursing care by
causing difficulty in catheterization or by causing prob-
lems with positioning in a wheelchair or bed. Identifying
these deficits and determining their effect on function
allows the care team to set appropriate goals and develop
specific treatment strategies to address a patient’s needs.
This also allows the team to plan for a patient’s continued
functioning at home and within the community. Serial
examinations in a patient may also provide useful infor-
mation regarding prognosis for functional recovery.
The initial evaluation of a patient in the geriatric setting
should include a detailed history, including the history of
psychiatric disorders. Because many patients with cogni-
tive and language impairments have difficulty commu-
nicating, obtaining the history from family and medical
records may be necessary. Additional information about
the inciting event should be sought. In patients with mild
cognitive impairment (MCI), the presence and duration of
amnesia is important. Concurrent medical problems, such
as strokes, brain hemorrhage, hypoxia, hypotension, and
seizures; systemic injuries, including skeletal fractures
and peripheral nerve injuries; and the presence of intoxi-
cant drugs and alcohol may help in establishing a cogni-
tive prognosis. Knowledge of premorbid cognitive and
functional status is important. An education and employ-
ment history is essential.
A general physical examination is to be performed on all
patients. This examination should include the assessment
of the level of consciousness, as detailed in Chapter 4.1,
“Mental Status Examination in the Geriatric Neurology
Patient.” The skin should be examined for evidence of
skin breakdown (decubitus ulcers). A thorough muscu-
loskeletal examination should be performed, focusing on
joint range of motion, skeletal deformities, and abnormal
postures of limbs. Finally, a detailed neurologic exami-
nation should be performed, including an assessment of
mental status, cranial nerves, motor and sensory systems,
reflexes, coordination, and gait.
Physical examination
The physical examination of the geriatric patient is quite
important and might be considered part of the neurologic
examination.
Biometrics
Gathering vital signs and body weight is seemingly
obvious and is routine. Nevertheless, complaints of
syncope and dizziness might prompt checking ortho-
static blood pressures, as orthostatic hypotension is
common in the elderly (see Chapter 14, “Autonomic
Dysfunction and Syncope,” and Chapter 16, “Vertigo
and Dizziness in the Elderly”). Additionally, hypoten-
sion can be caused by neurologic conditions (see Chap-
ter 12.1, “Parkinson’s Disease”). Similarly, checking
pulse is important, as bradycardia can be symptomatic
as syncope and dizziness. Tachyarrhythmias can also
present as dizziness and syncope. Serial weight mea-
surements over time might be important. For example,
weight loss is common in the elderly. It is particularly
common in degenerative diseases such as Alzheimer’s
disease (AD) and Parkinson’s disease (PD) and can
portend a negative prognosis. Alternately, weight loss
might be related to medication consumption, as many
medications can cause anorexia.
Taking the temperature of the geriatric patient is also
important. Geriatric patients do mount fever, but in many
cases, the hyperthermia can be mild, even in the setting
of significant infections. Conversely, hypothermia could
indicate sepsis.
Medications
The assessment of the geriatric patient, including the neu-
rologic patient, should start with a review of the medica-
tions. Patients are unaware of their medications, in many
cases. Redundancy is common, and medication errors are
frequent. Another confounding feature in the elderly is
polypharmacy. The elderly tend to consume more medi-
cations and more classes of medications than other groups
of patients. Thus, drug–drug interactions emerge, which
can contribute to symptoms.
Medications frequently have neurologic side effects
(dizziness, lightheadedness, confusion, tremor, som-
nolence). Thus, a common therapeutic approach might
be to reduce medication or reduce the doses of medi-
cation rather than add medication to treat specific
symptoms.
Head and neck examination
The assessment of the head and neck is important as
well, primarily with vision and hearing. Vision and hear-
ing loss are ubiquitous among the elderly and can cause
significant challenges in assessing the patient in other
areas, such as mentation, and so should be accounted for.
Patients with severe hearing loss can present as cogni-
tively impaired.
Examination of the neck for bruit, carotid hypersensi-
tivity, and thyromegaly should be routine. The presence
of a unilateral bruit can be an indication of vascular ste-
nosis in the carotids but is unreliable as a marker of vascu-
lar disease (see Chapter 11, “Cerebrovascular Diseases in
Geriatrics”), whereas bilateral bruit can be referred from
the chest from aortic stenosis.
 Approach to the Geriatric Neurology Patient: The Neurologic Examination
Cardiovascular
Though neurologists are unlikely to suddenly become
cardiologists, they should have a solid grasp of common
cardiac findings, as these findings can manifest as neuro-
logic conditions. For example, bradycardia can be symp-
tomatic as syncope and dizziness. Tachyarrhythmias can
also present as dizziness and syncope. Atrial fibrillation is
very common in the elderly and can manifest as tachy- or
bradyarrhythmias. A right apical crescendo decrescendo
murmur might indicate aortic stenosis, which is often
referred to the neck as bilateral bruit.
Neurologic examination
Changes in the nervous system that occur with aging (see
Table 3.1) are to be considered when a geriatric patient is
examined (Rathe, 1996).
Mental status testing
Mental status testing, including the assessment of cog-
nition, alertness, concentration, praxis, speech, and lan-
guage, is covered in detail in Chapter 4.1, “Mental Status
Examination in the Geriatric Neurology Patient.” A cog-
nitive screen such as www.mocatest.org is typically used
(Figure 3.1). As mentioned earlier, this can be confounded
by hearing and vision loss, so patients should be screened
for impairments of vision and acusis in the context of the
mental status examination. In many cases, their cognitive
assessment might appear artificially worse because of
visual or auditory impairment.
Speech
Several elements of speech need to be evaluated, includ-
ing articulation, loudness, and phonation. When listen-
ing to your patient, pay attention to the articulation. Are
the words spoken clearly? Disturbances in articulation of
speech are called dysarthria. Dysarthria refers to defective
Table 3.1 Changes in the neurologic examination with age
Localization Diminished modality
CN I Diminished smell
CN 2 Diminished pupil size
Abnormal pupillary reaction time
Diminished accommodation
Abnormal upward gaze
CN 8 High-tone hearing loss
Motor system Diminished bulk and power
Prolonged reaction time
Diminished coordination
Sensory Diminished vibration
Reflexes Diminished ankle jerk
Gait Diminished fluidity of movement
Diminished coordination
73
articulation without ascribing etiology. It could be from
mechanical issues (such as dentures) but also can reflect
neurologic conditions, such as cerebrovascular accidents
(CVAs), amyotrophic lateral sclerosis (ALS), Parkinson’s
disease, and progressive supranuclear palsy. Loudness
also needs to be assessed. Loudness is compromised in
PD and progressive supranuclear palsy (PSP) but can be
seen in depression. Phonation refers to the utterance of
vocal sounds. It also refers to the production of voiced
sound by means of vocal cord vibrations. Phonation can
be impaired in cranial neuropathies and in bulbar condi-
tions such as ALS.
Language
Language evaluation includes the assessment of compre-
hension, repetition, naming, ability to follow commands,
fluency, and prosody. Prosody is the rhythm, stress, and
intonation of speech. Aprosodia is the impairment in com-
prehending or generating the emotion conveyed in spoken
language. Producing these nonverbal elements requires
intact motor areas of the face, mouth, tongue, and throat.
Damage to areas 44/45 produces motor aprosodia, with
the nonverbal elements of speech being disturbed (facial
expression, tone, rhythm of voice). Right-hemispheric
area 22 aids in the interpretation of prosody, and damage
causes sensory aprosodia, with the patient unable to com-
prehend changes in voice and body language. Prosody is
dealt with by a right-hemisphere network that is largely a
mirror image of the left perisylvian zone. Damage to the
right inferior frontal gyrus causes a diminished ability
to convey emotion or emphasis by voice or gesture, and
damage to right superior temporal gyrus causes problems
comprehending emotion or emphasis in the voice or ges-
tures of others.
Disorders of comprehension, repetition, naming, and
fluency are broadly subsumed under the category of the
aphasias. Aphasia refers to impairment of language ability
(Aphasia Symptoms, Causes, Treatment–-How Is Apha-
sia Diagnosed? 2011).
Aphasia disorders have multiple etiologies in the elderly.
Among the more common considerations in the geriatric
population are head injury, stroke, brain tumor, infec-
tion, and dementia. Degenerative forms of aphasias are
referred to as the progressive aphasias. (See Chapter 9.6,
“Primary Progressive Aphasias,” for more details.) The
area and extent of brain damage determine the type of
aphasia and its symptoms. Aphasia types include Broca’s
aphasia, nonfluent aphasia, motor aphasia, receptive
aphasia, global aphasia, and many others. Broca’s aphasia
(also termed expressive aphasia) is caused by lesions to
the medial insular cortex. In contrast to Broca’s aphasia,
damage to the temporal lobe may result in a fluent apha-
sia that is called Wernicke’s aphasia (also termed sensory
aphasia). The other types of aphasia in the localizationist
model include pure word deafness, conduction aphasia,
74 Assessment of the Geriatric Neurology Patient

Image not available in this digital edition.

Figure 3.1 Montreal cognitive assessment (MOCA)—http://www.mocatest.org (accessed on April 8, 2013).

global aphasia, transcortical motor aphasia, transcortical Cranial nerves

sensory aphasia, and anomic aphasia. In most cases in the The cranial nerve examination is routinely performed,
geriatric population, cerebrovascular disease is the lead- but findings from the examination may have different eti-
ing cause, followed by progressive aphasias. However, ologies than similar findings from younger individuals.
anomic aphasia is commonly seen in AD. Start with observation of the individual. Consider these
 Approach to the Geriatric Neurology Patient: The Neurologic Examination
possibilities when examining a patient for ptosis (III),
facial droop or asymmetry (VII), hoarse voice (X), artic-
ulation of words (V, VII, X, XII), abnormal eye position
(III, IV, VI), and abnormal or asymmetrical pupils (II, III).
Cranial nerve I
Olfaction is frequently impaired in the elderly. It is not
routinely assessed. This is manifested as anosmia, ageu-
sia, or dysgeusia. Etiologies of olfactory dysfunction
include sinus disease, medication, and degenerative neu-
rologic disorders such as AD and PD. Though olfaction is
not routinely assessed in neurologic practice, smell test-
ing is available and can be a sensitive detection method
for neurodegenerative disease; however, the specificity is
somewhat lacking. Although uncommon except following
stroke, anosmia (olfactory dysfunction) occurs in 13–50%
of patients with AD, most commonly because of malfunc-
tion to olfactory pathways. Anosmia also develops in 18%
of patients following ruptured cerebral aneurysms, cor-
relating to the presence of intraventricular hemorrhage.
Anosmia can cause decreased life satisfaction and lead
to safety concerns, as with, for example, the inability to
smell smoke, gas, or spoiled food. Standardized, commer-
cially available “scratch-and-sniff” tests may be used for
formal testing.
Cranial nerve II
The optic nerve and anterior visual pathways are affected
in many patients with dementia and other geriatric ill-
nesses, resulting in impaired visual acuity, visual field
defects, or blindness. Stroke can affect the visual path-
ways anywhere along their course, with monocular blind-
ness from optic nerve injury or retinal lesions, bitemporal
hemianopsia from the optic chiasm, homonymous hemi-
anopsia from injury to the optic radiations, and cortical
blindness from an insult to the calcarine cortex in the
occipital lobes. Visual acuity may be affected by direct
injury to the optic nerve or by diffuse occipital lobe injury.
Loss of vision can significantly impair function by affect-
ing the ability to read, navigate safely, and perform activi-
ties of daily living (ADLs), and is important to document
at each visit.
Vision and fundoscopy are very important. Presbyopia
is expected. Diminished vision comes from many causes,
including cataracts, glaucoma, and macular degen-
eration. Age-related macular degeneration is a medi-
cal condition that usually affects older adults, resulting
in a loss of vision in the macular (central) region of the
retina. It occurs in “dry” and “wet” forms. It is a major
cause of visual impairment in adults older than 50 years
(de Jong, 2006). Macular degeneration can make it dif-
ficult or impossible to read or recognize faces, although
enough peripheral vision remains to allow other activi-
ties of daily life. Other forms of macular degeneration
include dry central geographic atrophy, the “dry” form
75
of advanced age-related macular degeneration (AMD).
It results from atrophy to the retinal pigment epithelial
layer below the retina, which causes vision loss through
loss of photoreceptors (rods and cones) in the central part
of the eye. Neovascular or exudative AMD, the “wet”
form of advanced AMD, causes vision loss due to abnor-
mal blood vessel growth (choroidal neovascularization)
in the choriocapillaris, ultimately leading to blood and
protein leakage below the macula. Bleeding, leaking, and
scarring from these blood vessels eventually cause irre-
versible damage to the photoreceptors and rapid vision
loss if left untreated (Horton, 2005).
Glaucoma is an ocular disorder that is common in the
elderly. With glaucoma, the optic nerve is damaged, per-
manently damaging vision in the affected eye(s) and pro-
gressing to complete blindness if untreated. It is often, but
not always, associated with increased pressure of the fluid
in the aqueous humor (Rhee, 2008). The two subtypes of
glaucoma are termed open-angle and closed-angle glau-
coma. Closed-angle glaucoma can appear suddenly and
is often painful; visual loss can progress quickly, but the
discomfort often leads patients to seek medical attention
before permanent damage occurs. Open-angle, chronic
glaucoma tends to progress at a slower rate, and patients
may not notice that they have lost vision until the disease
has progressed significantly.
Cataracts are among the most common age-related ocu-
lar changes. Cataracts affect the anterior chamber of the
eye, where clouding develops in the crystalline lens. Cata-
racts vary in degree from slight to complete opacity and
obstruct the passage of light. Cataracts typically progress
slowly to cause vision loss and are potentially blinding
if untreated. The condition usually affects both eyes, but
almost always one eye is affected earlier than the other
(Pavan-Langston, 2007). The senile cataract is character-
ized by an initial opacity in the lens, subsequent swell-
ing of the lens, and final shrinkage with complete loss of
transparency (Quillen, 1999).
Testing cranial nerve II
• Test visual acuity:
1 Allow the patient to use his or her glasses or contact
lens, if available. You are interested in the patient’s best
corrected vision.
2 Position the patient 20 feet in front of the Snellen
eye chart (or hold a Rosenbaum pocket card at a 14 in
“reading” distance).
3 Have the patient cover one eye at a time with a card.
4 Ask the patient to read progressively smaller letters
until he or she can go no further.
5 Record the smallest line the patient can read success-
fully (such as 20/20 or 20/30). Visual acuity is reported
as a pair of numbers (20/20); the first number is how
far the patient is from the chart, and the second number
is the distance from which the “normal” eye can read a
76 Assessment of the Geriatric Neurology Patient
line of letters. For example, 20/40 means that, at 20 feet,
the patient can read only letters a “normal” person can
read from twice that distance.
6 Repeat with the other eye.
• Screen visual fields by confrontation:
1 Stand 2 feet in front of the patient and have him or
her look into your eyes.
2 Hold your hands about 1 foot away from the patient’s
ears, and wiggle a finger on one hand.
3 Ask the patient to indicate on which side he or she
sees the finger move.
4 Repeat two or three times, to test both temporal
fields.
5 If an abnormality is suspected, test the four quad-
rants of each eye while asking the patient to cover the
opposite eye with a card (optional).
• Test pupillary reactions to light:
1 Dim the room lights as necessary.
2 Ask the patient to look into the distance.
3 Shine a bright light obliquely into each pupil, in turn.
4 Look for both the direct (same eye) and consensual
(other eye) reactions.
5 Record pupil size in millimeters and any asymmetry
or irregularity.
6 If abnormal, proceed with the test for accommoda-
tion.
• Test pupillary reactions to accommodation (optional):
1 Hold your finger about 10 cm from the patient’s nose.
2 Ask the patient to alternate looking into the distance
and at your finger.
3 Observe the pupillary response in each eye.
Pupillary abnormalities need to be assessed in the
elderly but are confounded by the frequent use of
ophthalmic treatments for glaucoma and macular degen-
eration. Considerations include anisocoria, posterior
communicating artery aneurysm, diabetes, Adie’s tonic
pupil, and surgical coloboma following cataract surgery.
Evaluation of papillary abnormalities is done in conjunc-
tion with the ophthalmologist.
Cranial nerves III, IV, and VI
Injury to the oculomotor, trochlear, or abducens nerves
can occur following a brainstem stroke or contusion,
orbital wall fracture, or basilar skull fracture resulting in
cavernous sinus injury. Patients may complain of double
vision and dizziness, and findings on examination may
include eye deviation, dysconjugate gaze, abnormal head
postures, and problems with balance and coordination.
Alternate eye patching may be beneficial, especially dur-
ing therapy sessions.
Evaluation of the extraocular movements can be reveal-
ing of specific pathologies. Eye movement abnormali-
ties are referable to nuclear lesions in the form of cranial
neuropathies (III, IV, and VI) or in the form of supra-
nuclear impairment. Cranial neuropathies affecting eye
movement most commonly present as diplopia. Cranial
neuropathies affecting ocular movements have many
causes, including sarcoid, DM, cavernous sinus throm-
bosis, aneurysms, and CVAs. Supranuclear oculomo-
tor impairments are common in the elderly also. These
types of impairments affect vertical gaze, smooth pursuit,
and saccades. Saccades are the very quick, simultaneous
movements made by the eye to receive visual information
and shift the line of vision from one position to another
(Iwamoto and Yoshida, 2002). The area of the brain that
controls saccades is the superior colliculus, specifically
the fastigial oculomotor region (FOR) (Iwamoto et al.,
2002). The information is received from the retina, trans-
lated into spatial information, and then transferred to
motor centers for motor response. A person with saccadic
dysmetria constantly produces abnormal eye movements,
including microsaccades, ocular flutter, and square wave
jerks, even when the eye is at rest (Schmahmann, 2004).
During eye movements, hypometric and hypermetric sac-
cades occur, and interruption and slowing of normal sac-
cadic movement is common (Schmahmann, 2004). Ocular
dysmetria makes it difficult to focus vision on one object.
Impairments in vertical gaze are typical of progressive
supranuclear palsy. Impairments of smooth pursuit gaze
reflect abnormal function of the frontal eye fields and
can be seen in neurodegenerative diseases such as PD
and AD.
Testing cranial nerves III, IV, and VI
• Observe for ptosis.
• Test extraocular movements:
1 Stand or sit 3–6 feet in front of the patient.
2 Ask the patient to follow your finger with the eyes
without moving the head.
3 Check gaze in the six cardinal directions using a
cross or “H” pattern.
4 Pause during upward and lateral gaze to check for
nystagmus.
5 Check convergence by moving your finger toward
the bridge of the patient’s nose.
• Test pupillary reactions to light.
Cranial nerve V
Trigeminal nerve injuries occur in patients with head
injuries, most commonly because of facial bone fractures.
These injuries can also occur following brainstem stroke
or contusion. Complete trigeminal nerve injury causes
hemianesthesia of the face, whereas partial injuries gener-
ally result in facial pain. Motor branch involvement can
lead to chewing problems, and loss of sensation inside the
mouth may cause pocketing of food and increase the risk
of aspiration.
Facial sensation reflects the trigeminal nerve derma-
tomes (cranial nerve V). The three divisions of the trigemi-
nal nerve include ophthalmic, maxillary, and mandibular.
 Approach to the Geriatric Neurology Patient: The Neurologic Examination
The ophthalmic region includes the forehead, eyebrow,
eyelid, and cornea. The maxillary region includes the
zygomatic arch to the mouth. The mandibular region cov-
ers the mouth to the jaw. The subdivisions overlap. Hypo-
esthesia involving the trigeminal nerve dermatomes can
be caused by either a cranial neuropathy or a CVA in the
elderly. Hyperesthesia/dysesthesia involving the tri-
geminal nerve is referred to as trigeminal neuralgia. The
pain of trigeminal neuralgia originates on the trigeminal
nerve. This nerve carries pain, feeling, and other sensa-
tions from the brain to the skin of the face. It can involve
all divisions. The condition usually affects older adults,
but it may affect anyone at any age. Trigeminal neuralgia
may be part of the normal aging process. Alternatively,
trigeminal neuralgia may be caused by pressure on the
trigeminal nerve from a swollen blood vessel or tumor.
Often no specific cause is found. Symptoms are unilateral
and intermittent and can be triggered by touch or sounds
(such as brushing teeth, chewing, drinking, eating, light
touching, or shaving). The neurologic examination is
usually normal. For additional details, see Chapter 17,
“Disorders of the Special Senses in the Elderly.”
Testing cranial nerve V
• Test temporal and masseter muscle strength:
1 Ask the patient to both open the mouth and clench
the teeth.
2 Palpate the temporal and masseter muscles as the
patient does this.
• Test the three divisions for pain sensation:
1 Explain what you intend to do.
2 Use a suitable sharp object to test the forehead,
cheeks, and jaw on both sides.
3 Substitute a blunt object occasionally and ask the
patient to report “sharp” or “dull.”
• If you find an abnormality:
1 Test the three divisions for temperature sensation
with a tuning fork heated or cooled by water (optional).
2 Test the three divisions for sensation to light touch
using a wisp of cotton (optional).
• Test the corneal reflex (optional):
1 Ask the patient to look up and away.
2 From the other side, touch the cornea lightly with a
fine wisp of cotton.
3 Look for the normal blink reaction of both eyes.
4 Repeat on the other side.
Cranial nerve VII
Facial movement (Bell’s, CVA, hypomimia) involves the
facial nerve (cranial nerve VII). The examination involves
having the patient show the teeth or raise eyebrows.
When the frontalis muscle is spared in an asymmetric
presentation of facial droop, consider a central nervous
system (CNS) event such as a CVA. If the frontalis muscle
is involved, consider Bell’s palsy.
77
Facial muscle weakness is common in patients who
have experienced a stroke or traumatic brain injury (TBI)
and can affect articulation and swallowing. Injury to the
upper motor (corticobulbar) pathways in the frontal lobe,
internal capsule, and upper brainstem causes contralat-
eral facial weakness, usually sparing the forehead. Lower
motor neuron injury in the pons (brainstem stroke or
trauma) results in ipsilateral facial weakness, including
the forehead.
Testing cranial nerve VII
• Observe for any facial droop or asymmetry.
• Ask the patient to do the following, and note any lag,
weakness, or asymmetry:
1 Raise the eyebrows.
2 Close both eyes to resistance.
3 Smile.
4 Frown.
5 Show the teeth.
6 Puff out the cheeks.
Cranial nerve VIII
Hearing loss occurs in the majority of patients with
geriatric neurologic conditions. High-frequency hear-
ing loss from cochlear insensitivity and dislocation and
disruption of the ossicles may be associated with ver-
tigo and disequilibrium due to injury to the acoustic
nerve, cochlea, and/or labyrinths. Brainstem contusion
or stroke, damaging the acoustic or cochlear nuclei, can
result in similar symptoms. Vestibular dysfunction can
lead to problems with balance and coordination. The
presence of horizontal nystagmus is suggestive of uni-
lateral vestibular nerve injury. Vertical nystagmus may
be seen following brainstem or cerebellar injuries. Cer-
tain medications, including anticonvulsants, can also
cause nystagmus.
Testing cranial nerve VIII
• Screen for hearing loss:
1 Face the patient and hold out your arms, with your
fingers near each ear.
2 Rub your fingers together on one side while moving
the fingers noiselessly on the other.
3 Ask the patient to tell you when and on which side
he or she hears the rubbing.
4 Increase intensity as needed and note any asymmetry.
5 If abnormal, proceed with the Weber and Rinne tests.
• Test for lateralization (Weber) (optional):
1 Use a 512 Hz or 1024 Hz tuning fork.
2 Start vibrating the fork by tapping it on your oppo-
site hand.
3 Place the base of the tuning fork firmly on top of the
patient’s head.
4 Ask the patient from where the sound appears to be
coming from (normally in the midline).
78 Assessment of the Geriatric Neurology Patient
• Compare air and bone conduction (Rinne) (optional):
1 Use a 512 Hz or 1024 Hz tuning fork.
2 Start vibrating the fork by tapping it on your oppo-
site hand.
3 Place the base of the tuning fork against the mastoid
bone behind the ear.
4 When the patient no longer hears the sound, hold the
end of the fork near the patient’s ear (air conduction is
normally greater than bone conduction).
• Vestibular function is not normally tested routinely.
Cranial nerves IX and X
The glossopharyngeal and vagus nerves are often affec-
ted in patients with medullary strokes. Injury results in
impaired phonation and swallowing. The gag reflex is
diminished or absent on the side of nerve injury. The
palate and uvula may also be deviated to the opposite
side. The gag reflex may be hyperactive in patients with
injuries to the corticobulbar tracts bilaterally, bilateral
strokes, or injuries to the deep white matter. This is often
accompanied by spastic quadriparesis and emotional
lability.
The oropharynx, soft and hard palates, and tongue
need to be assessed for asymmetry. These are innervated
by cranial nerves IX–XII. Asymmetry of responsiveness
to gag or palatal elevation might represent cranial neu-
ropathies, which, in turn, could reflect brainstem lesions.
These abnormalities would manifest as dysphonia, dysar-
thria, or hypophonia. Ungual paresis could reflect a brain-
stem abnormality as well, but fasciculation or atrophy of
the tongue might represent denervation, which is seen in
ALS. This would also manifest as dysarthria.
Testing cranial nerves IX and X
• Listen to the patient’s voice—is it hoarse or nasal?
• Ask the patient to swallow.
• Ask the patient to say “Ah.”
• Watch the movements of the soft palate and the
pharynx.
• Test the gag reflex (unconscious/uncooperative
patient) (optional).
1 Stimulate the back of the throat on each side.
2 It is normal to gag after each stimulus.
Cranial nerve XI
The spinal accessory nerve, innervating the ipsilateral
stemocleidomastoid and trapezius muscles, is only rarely
injured. Spinal accessory nerve injuries can cause lim-
ited neck rotation and shoulder abduction, affecting the
ability to do activities above the head, such as reach for
objects in a high cabinet.
Testing cranial nerve XI
• From behind, look for atrophy or asymmetry of the tra-
pezius muscles.
• Ask the patient to shrug the shoulders against resis-
tance.
• Ask the patient to turn the head against resistance.
Watch and palpate the sternomastoid muscle on the
opposite side.
Cranial nerve XII
The hypoglossal nerve, which provides motor function to
the ipsilateral tongue, is rarely affected as a consequence
of geriatric neurologic diseases but can be involved in
fracture or medullary stroke. Swallowing difficulties in
dementia and parkinsonism can arise because patients
may have difficulty manipulating a food bolus in the
mouth.
Testing cranial nerve XII
• Listen to the articulation of the patient’s words.
• Observe the tongue as it lies in the mouth.
• Ask patient to:
1 Protrude tongue.
2 Move tongue from side to side.
Motor examination
As with the neurologic examination of the younger patient,
the neurologic examination of the geriatric patient
includes the motor exam. Elements of the motor exami-
nation include tone, bulk, and strength. Other consider-
ations beyond the motor examination include the assess-
ment of kinesis and for tremor. These extrapyramidal
elements are addressed in Chapter 12.1, “Parkinson’s
Disease,” and Chapter 12.2, “Essential Tremor and Other
Tremor Disorders,” respectively. Additional consider-
ations include kinesis.
Muscle bulk
Generalized muscle atrophy can occur because of pro-
longed immobility and poor intake in dementia. Damage
to the lower motor neuron causes focal muscle atrophy.
This can occur as a result of direct trauma to the periph-
eral nerve, plexus, nerve root, or anterior horn cells in the
spinal cord. Focal nerve injuries can also occur because of
limb ischemia following trauma or from improper posi-
tioning or casting (for example, peroneal neuropathy with
a foot drop from an excessively tight leg restraint).
Muscle tone
Spasticity is the most common abnormality of tone seen
in patients with stroke, TBI, and spinal cord injury. Spas-
ticity predominantly affects the flexor muscles of the arms
and extensor muscles of the legs, while in spinal cord
injuries, it predominates in the flexor muscles of both
the arms and legs. Tone may also be increased in trunk
muscles. Spasticity is caused by injury to the corticospi-
nal tracts and is often accompanied by muscle weakness,
hyperreflexia, and an extensor plantar reflex response.
 Approach to the Geriatric Neurology Patient: The Neurologic Examination
Hypotonia may be seen in association with cerebellar
lesions and also often occurs early following stroke and
spinal cord injuries (spinal shock). In the latter, spastic-
ity may develop later, after a period of days to weeks. A
long period of hypotonia in this setting usually suggests a
poorer likelihood of functional motor recovery.
Rigidity generally results from injury to the basal gan-
glia. Common in Parkinson’s disease, rigidity also occurs
in patients who have had subcortical strokes, trauma
involving the basal ganglia, and anoxic brain injury. Para-
tonia is a consequence of bilateral frontal lobe injury or
dementia. Spasticity and rigidity may be painful, can be
accompanied by muscle spasms, and may affect nursing
care by interfering with positioning, bracing, transfer,
nursing care, and ADLs. Neck and head control can be
affected, hampering feeding and grooming. Spasticity of
laryngeal and pharyngeal muscles can affect breathing,
articulation, phonation, and swallowing. Truncal spas-
ticity can affect wheelchair positioning, standing, and
ambulation. If spasticity is severe and prolonged, fixed
joint contractures can develop, further impeding the care
progress.
Testing muscle tone
• Ask the patient to relax.
• Flex and extend the patient’s fingers, wrist, and elbow.
• Flex and extend the patient’s ankle and knee.
• There is normally a small, continuous resistance to pas-
sive movement.
• Observe for decreased (flaccid) or increased (rigid/
spastic) tone.
The tone can be graded as normal, hypertonic, or hypo-
tonic. Also indicate the type of hypertonia, include spas-
tic, rigid, or gegenhalten. Spastic hypertonia, defined as
velocity-dependent resistance to stretch, is referable to
upper motor neuron lesions and occurs because of a lack
of inhibition from the CNS, which results in excessive con-
traction of the muscles. Common considerations include
residua from CVAs or spinal cord injury. Rigid hyperto-
nia is seen in extrapyramidal disorders (such as PD; see
Chapter 12.1). Rigidity, also called increased muscle tone,
means stiffness or inflexibility of the muscles. Gegen-
halten (also known as paratonia) refers to an involuntary
resistance to passive movement as may occur in cerebral
cortical disorders. It may occur as a symptom of catatonia,
in which there is passive resistance to stretching move-
ments, even when the patient attempts to cooperate. The
effect may be psychogenic in origin or may be a sign of
dementia or cerebral deterioration.
Hypotonia is reduced muscle tone (the amount of ten-
sion or resistance to movement in a muscle, also known
as flaccidity), and is usually associated with weakness
(reduced muscle strength). Hypotonia is not a specific
medical disorder, but a potential manifestation of many
different diseases and disorders that affect motor nerve
79
control by the brain or muscle strength. Diminished deep
tendon reflexes also may be noted. Causes of hypotonia
in the elderly include acute changes related to CVAs and
spinal cord injury.
Muscle strength
Assessing the muscle bulk is part of the motor exam.
Atrophy of muscle groups is, by definition, decreased
bulk. Atrophy can occur from myopathies, neuropathies,
or radiculopathies and reflects lower motor neuron lesions.
The most common patterns of weakness are hemipa-
resis or tetraparesis because of injury to the corticospinal
tracts in the cerebral hemispheres or brainstem. Strokes
typically result in hemiparesis, with the arm affected to a
greater extent than the leg in middle cerebral artery dis-
tribution infarcts affecting cortical structures. In patients
with anterior cerebral artery (ACA) distribution infarcts,
the leg is predominantly affected.
Subcortical strokes generally affect the arm and leg
equally. Any deviation from an expected pattern should
trigger a search for additional spinal cord or peripheral
nerve injuries. Cervical spinal cord injuries often result in
tetraparesis, while thoracic and lumbar spine injuries lead
to paraparesis. The level of spinal cord injury is defined
as the most rostral cord level innervating muscles with at
least grade 3 strength.
Testing muscle strength
• Test strength by having the patient move against your
resistance.
• Always compare one side to the other.
• Grade strength on a scale from 0 to 5 out of 5 (see
Table 3.2).
• Test the following movements:
1 Flexion at the elbow (C5, C6, biceps).
2 Extension at the elbow (C6, C7, C8, triceps).
3 Extension at the wrist (C6, C7, C8, radial nerve).
4 Ability to squeeze two of your fingers as hard as pos-
sible (“grip,” C7, C8, T1).
5 Finger abduction (C8, T1, ulnar nerve).
6 Opposition of the thumb (C8, T1, median nerve).
7 Flexion at the hip (L2, L3, L4, iliopsoas).
8 Adduction at the hips (L2, L3, L4, adductors).
9 Abduction at the hips (L4, L5, S1, gluteus medius
and minimus).
Table 3.2 Grading motor strength
Grade Description
0/5 No muscle movement
1/5 Visible muscle movement, but no movement at the joint
2/5 Movement at the joint but not against gravity
3/5 Movement against gravity but not against added resistance
4/5 Movement against resistance, but less than normal
5/5 Normal strength
80 Assessment of the Geriatric Neurology Patient
10 Extension at the hips (S1, gluteus maximus).
11 Extension at the knee (L2, L3, L4, quadriceps).
12 Flexion at the knee (L4, L5, S1, S2, hamstrings).
13 Dorsiflexion at the ankle (L4, L5).
14 Plantar flexion (S1).
Testing pronator drift
• Ask the patient to stand for 20–30 seconds with both
arms straight forward, palms up, and eyes closed.
• Instruct the patient to keep the arms still while you tap
them briskly downward.
• The patient will not be able to maintain extension and
supination.
Assessing the strength of all muscle groups in the
upper and lower extremities is also part of the motor
exam. Similar to younger patients, the motor examination
should be assessed in detail. Focal weakness of a limb
could reflect CVA (ACA infarct leads to monoparesis of
the lower extremity), polyradiculopathy, or plexopathy.
Weakness in a group of muscles could reflect radiculopa-
thy or neuropathy.
Abnormal movements
Abnormal motor movements or postures may result from
dementia or brain injuries. Dystonia can occur because of
basal ganglia injury (trauma or stroke) or may be seen as
an adverse effect of neuroleptic medications and metoclo-
pramide. Dyskinesias of the limbs or orofacial muscles
and choreoathetosis may also result from basal ganglia
injury or adverse effects of anticonvulsants, oral contra-
ceptives, or antipsychotic medications.
Ballismus may occur as a result of trauma or hemor-
rhage involving the subthalamic region. Tremor of the
head or limbs may also result from brain injuries. Myoc-
lonus can be focal, segmental, or generalized, and can
occur as a direct consequence of brain injury, including
anoxic encephalopathy. Myoclonus is also a common
sequela of metabolic abnormalities, including hepatic
and renal failure. Asterixis most commonly manifests as
a wrist flap when holding the arms outstretched. This can
occur in patients with injury to the thalamus, internal cap-
sule, parietal cortex, and midbrain, but is often associated
with liver failure. Post-traumatic parkinsonism can result
from TBI or anoxic brain injury. Abnormal movements or
postures interfere with normal coordinated movements,
hampering a patient’s ability to perform ADLs, such as
feeding and grooming, or to carry out mobility skills,
including wheelchair positioning, sitting balance, stand-
ing, or ambulation.
Sensory examination
The sensory examination encompasses assessing periph-
eral and central sensory elements. The primary periph-
eral sensory modalities include light touch, pinprick,
vibration, and proprioception. Central sensory elements
include face–hand test for asimultagnosia, assessment of
agraphesthesia, stereognosis, and assessment for neglect.
(Also see Chapters 12.2 and 17.)
Sensory perception
Sensory perception is commonly affected in patients
with geriatric neurology, although sensory deficits
are generally overshadowed by motor and cognitive
deficits. Thalamic injuries result in loss of sensation
on the contralateral side of the body. Parietal lobe inju-
ries cause loss of ability to localize the site of sensory
stimulation, with impaired joint position sense, stere-
ognosis, and graphesthesia. Sensory neglect, including
visual neglect, hemi-inattention, tactile extinction, and
anosognosia, may also be present and is more common
following nondominant parietal lobe involvement. Spi-
nal cord injuries result in impaired sensation below the
level of the injury, and even in the absence of weakness,
bilateral lower extremity proprioceptive loss can signif-
icantly impair gait. Sensory deficits can lead to func-
tional impairments. The inability of a patient to detect
or localize pain or the presence of sensory neglect can
result in injury, as patients may be unable to protect
their affected limbs. The inability to control limb posi-
tion in space because of impaired proprioception can
cause problems with feeding and grooming. Lack of
feeling in the hands can lead to difficulty with fine
motor tasks such as buttoning or fastening snaps or zip-
pers. Lower extremity sensory deficits can lead to prob-
lems with transfers and walking because of impairment
in foot placement and balance. Patients with impaired
sensation of the buttocks and lower extremities are at
increased risk of developing decubitus ulcers, espe-
cially if spasticity, impaired mobility, and bowel and/
or bladder incontinence are present.
Testing sensory loss
General
• Explain each test before you do it.
• Unless otherwise specified, the patient’s eyes should be
closed during the actual testing.
• Compare symmetrical areas on the two sides of the body.
• Also compare distal and proximal areas of the
extremities.
• When you detect an area of sensory loss, map out its
boundaries in detail.
Vibration
• Use a low-pitched tuning fork (128 Hz).
1 Test with a nonvibrating tuning fork first to ensure
that the patient is responding to the correct stimulus.
2 Place the stem of the fork over the distal interpha-
langeal joint of the patient’s index fingers and big toes.
3 Ask the patient to tell you if he or she feel the
vibration.
 Approach to the Geriatric Neurology Patient: The Neurologic Examination
• If vibration sense is impaired, proceed proximally
(optional):
1 Wrists.
2 Elbows.
3 Medial malleoli.
4 Patellas.
5 Anterior and superior iliac spines.
6 Spinous processes.
7 Clavicles.
Subjective light touch
• Use your fingers to touch the skin lightly on both sides
simultaneously.
• Test several areas on both the upper and lower
extremities.
• Ask the patient to tell you if there is difference from side
to side or if other “strange” sensations are experienced.
Position sense
1 Grasp the patient’s big toe and hold it away from the
other toes to avoid friction (optional).
2 Show the patient “up” and “down.”
3 With the patient’s eyes closed, ask the patient to iden-
tify the direction you move the toe.
4 If position sense is impaired, move proximally to test
the ankle joint (optional).
5 Test the fingers in a similar fashion.
6 If indicated, move proximally to the metacarpophalan-
geal joints, wrists, and elbows (optional).
Dermatomal testing
If vibration, position sense, and subjective light touch are
normal in the fingers and toes, you may assume the rest of
this examination will be normal (optional).
Pain
• Use a suitable sharp object to test “sharp” or “dull”
sensation.
• Test the following areas:
1 Shoulders (C4).
2 Inner and outer aspects of the forearms (C6 and T1).
3 Thumbs and little fingers (C6 and C8).
4 Front of both thighs (L2).
5 Medial and lateral aspects of both calves (L4 and L5).
6 Little toes (S1).
Temperature
• Examination in this category is often omitted if pain
sensation is normal (optional).
• Use a tuning fork heated or cooled by water and ask the
patient to identify “hot” or “cold.”
• Test the following areas:
1 Shoulders (C4).
2 Inner and outer aspects of the forearms (C6 and T1).
3 Thumbs and little fingers (C6 and C8).
81
4 Front of both thighs (L2).
5 Medial and lateral aspects of both calves (L4 and L5).
6 Little toes (S1).
Light touch
• Use a fine wisp of cotton or your fingers to touch the
skin lightly.
• Ask the patient to respond whenever a touch is felt.
• Test the following areas:
1 Shoulders (C4).
2 Inner and outer aspects of the forearms (C6 and T1).
3 Thumbs and little fingers (C6 and C8).
4 Front of both thighs (L2).
5 Medial and lateral aspects of both calves (L4 and L5).
6 Little toes (S1).
Discrimination
Because these tests are dependent on touch and position
sense, they cannot be performed when the previous tests
are clearly abnormal (optional).
• Graphesthesia:
1 With the blunt end of a pen or pencil, draw a large
number on the patient’s palm.
2 Ask the patient to identify the number.
• Stereognosis:
1 Use this as an alternative to graphesthesia (optional).
2 Place a familiar object in the patient’s hand (coin,
paper clip, pencil, etc.).
3 Ask the patient to tell you what it is.
• Two-point discrimination:
1 Use this when more quantitative data are needed,
such as following the progression of a cortical lesion
(optional).
2 Use an opened paper clip to touch the patient’s fin-
ger pads in two places simultaneously.
3 Alternate irregularly with one-point touch.
4 Ask the patient to identify “one” or “two.”
5 Find the minimal distance at which the patient can
discriminate.
Reflexes
Evaluation of muscle stretch reflexes helps localize the
site of neurologic injury. Hyperreflexia suggests injury to
corticospinal tracts in either the brain or the spinal cord
and is often associated with spasticity and muscle weak-
ness. Hyporeflexia is associated with lower motor neuron
injuries and also occurs in the period of acute spinal shock
below the level of injury. Hyporeflexia may also be seen
in association with peripheral neuropathies and, at times,
with cerebellar disease.
Deep tendon reflexes
Reflexes are frequently diminished in the elderly. A global
diminution might be associated with myopathy or neu-
ropathy (see Chapter 21, “Neuromuscular Disorders”)
82 Assessment of the Geriatric Neurology Patient
Table 3.3 Tendon reflex grading scale
Grade Description
0 Absent
1+ or + Hypoactive
2+ or ++ Normal
3+ or +++ Hyperactive without clonus
4+ or ++++ Hyperactive with clonus
but might also be a reflection of aging. Focal loss of DTRs
is indicative of radiculopathy (cervical or lumbar) or focal
neuropathy (see Chapter 21).
Testing reflexes
• The patient must be relaxed and positioned properly
before starting.
• Reflex response depends on the force of your stimulus.
Use no more force than you need to provoke a definite
response.
• Reflexes can be reinforced by having the patient perform
isometric contraction of other muscles (clenched teeth).
• Reflexes should be graded on a 0–4 “plus” scale (see
Table 3.3):
Biceps (C5, C6)
• The patient’s arm should be partially flexed at the
elbow with the palm down.
• Place your thumb or finger firmly on the biceps tendon.
• Strike your finger with the reflex hammer.
• You should feel the response even if you cannot see it.
Triceps (C6, C7)
• Support the upper arm and let the patient’s forearm
hang free.
• Strike the triceps tendon above the elbow with the
broad side of the hammer.
• If the patient is sitting or lying down, flex the patient’s
arm at the elbow and hold it close to the chest.
Brachioradialis (C5, C6)
• Have the patient rest the forearm on the abdomen or
lap.
• Strike the radius about 1–2 in above the wrist.
• Watch for flexion and supination of the forearm.
Abdominal (T8, T9, T10, T11, T12)
• Use a blunt object such as a key or tongue blade.
• Stroke the abdomen lightly on each side in an inward
and downward direction above (T8, T9, T10) and below
the umbilicus (T10, T11, T12).
• Note the contraction of the abdominal muscles and de-
viation of the umbilicus toward the stimulus.
Knee (L2, L3, L4)
• Have the patient sit or lie down with the knee flexed.
• Strike the patellar tendon just below the patella.
• Note contraction of the quadriceps and extension of the
knee.
Ankle (S1, S2)
• Dorsiflex the foot at the ankle.
• Strike the Achilles tendon.
• Watch and feel for plantar flexion at the ankle.
Testing for clonus
• If the reflexes seem hyperactive, test for ankle clonus
(optional).
1 Support the knee in a partly flexed position.
2 With the patient relaxed, quickly dorsiflex the foot.
3 Observe for rhythmic oscillations.
• Plantar response (Babinski)
1 Stroke the lateral aspect of the sole of each foot with
the end of a reflex hammer or key.
2 Note movement of the toes, normally flexion (with-
drawal).
3 Extension of the big toe with fanning of the other toes
is abnormal. This is referred to as a positive Babinski.
Primitive reflexes
Snout, root, grasp, palmomental, and glabellar can be
examined. Primitive reflexes originate in the CNS and are
exhibited by normal infants but not neurologically intact
adults, in response to tactile stimuli. As the brain devel-
ops, these reflexes disappear or are inhibited by the fron-
tal lobes (Primitive and Postural Reflexes, 2008). Primitive
reflexes may reappear in adults because of certain neuro-
logic conditions, including but not limited to degenera-
tive neurologic conditions such as dementia, traumatic
brain injuries, and cerebrovascular lesions (Schott et al.,
2003; Rauch, 2006).
Coordination and cerebellar examination
Coordination is modulated by a number of peripheral
and central nervous system structures and can be affected
by brain and spinal cord injuries. Injury to the cortico-
spinal tracts results in muscle weakness with slowing of
gross and fine motor tasks. Basal ganglia insults result in
slowed initiation of movements. Cerebellar injuries can
lead to truncal and limb ataxia, dysmetria, dysdiadocho-
kinesia, dyssynergia, and intention tremor. Sensory ataxia
can result from impaired proprioception due to either
peripheral neuropathy or spinal cord injury involving the
posterior columns. Truncal ataxia can affect sitting and
standing balance, impairing the ability to sit upright in
a wheelchair or to walk. Limb ataxia can make ADLs dif-
ficult.
The assessment of coordination and cerebellar func-
tion is part of the geriatric neurologic examination.
Impairment is referred to as dysmetria. Dysmetria refers
to a lack of coordination of movement typified by the
undershoot or overshoot (hypometria and hypermetria,
 Approach to the Geriatric Neurology Patient: The Neurologic Examination
respectively) of intended position with the hand, arm, leg,
or eye. It is sometimes described as an inability to judge
distance or scale. Dysmetria occurs because of disorders
of the cerebellum. Dysmetria of the extremities caused by
hemispheric syndromes is manifested in two ways: dys-
rhythmic tapping of hands and feet and dysdiadochoki-
nesis, which is the impairment of alternating movements
(Schmahmann, 2004). The actual cause of dysmetria
is thought to be caused by lesions in the cerebellum or
lesions in the proprioceptive nerves that lead to the cer-
ebellum that coordinate visual, spatial, and other sensory
information with motor control (Townsend et al., 1999).
Two types of cerebellar disorders produce dysmetria, spe-
cifically midline cerebellar syndromes and hemispheric
cerebellar syndromes (Hain, 2002). Midline cerebellar
syndromes can cause ocular dysmetria, a condition in
which the pupils of the eye overshoot (Hain, 2002). Hemi-
spheric cerebellar syndromes cause dysmetria in the typi-
cal motor sense that many think of when hearing the term
dysmetria (Hain, 2002). A common motor syndrome that
causes dysmetria is cerebellar motor syndrome, which
is also marked by impairments in gait (also known as
ataxia), disordered eye movements, tremor, difficulty
swallowing, and poor articulation (Schmahmann, 2004).
As stated earlier, cerebellar cognitive affective syndrome
(CCAS) also causes dysmetria.
Dysmetria is often found in individuals with ALS and
persons who have suffered from tumors or strokes. Per-
sons who have been diagnosed with autosomal domi-
nant spinocerebellar ataxia (SCAs) also exhibit dysmetria.
SCAs are rarely seen in the elderly. Dysmetria from spo-
radic causes should be considered first (Dysmetria, 2007).
Testing coordination
Rapid alternating movements
• Ask the patient to strike one hand on the thigh, raise
the hand, turn it over, and then strike it back down as fast
as possible.
• Ask the patient to tap the distal thumb with the tip of
the index finger as fast as possible.
• Ask the patient to tap your hand with the ball of each
foot as fast as possible.
Point-to-point movements
• Ask the patient to touch your index finger and his
or her nose alternately several times. Move your finger
about as the patient performs this task.
• Hold your finger still so that the patient can touch it
with one arm and finger outstretched. Ask the patient
to move the arm and return to your finger with the eyes
closed.
• Ask the patient to place one heel on the opposite knee
and run it down the shin to the big toe. Repeat with the
patient’s eyes closed.
83
Romberg
• Be prepared to catch the patient if he or she is unstable.
• Ask the patient to stand with the feet together and eyes
closed for 5–10 seconds without support.
• The test is said to be positive if the patient becomes un-
stable (indicating a vestibular or proprioceptive problem).
Gait and posture
Brain and spinal cord lesions in geriatric neurology often
affect posture and gait because of injury to the sensory
and motor pathways that affect ambulation. Patients
with spastic hemiparesis due to stroke or other brain
injuries often have weakness and spasticity of the chest
and abdominal musculature, leading to trunk instability
and difficulty with weight shifting. Gait deviation may
be observed. Weakness of hip flexors and ankle dorsiflex-
ors results in an impaired swing-through of the limb and
inadequate toe clearance during the swing phase of gait,
resulting in hiking of the hip and circumduction of the
leg. Decreased arm swing on the paretic side may also
occur. Spasticity may limit the range of motion of the hip,
knee, and ankle. Patients with basal ganglia disorders
often have a shuffling-type gait. Cerebellar disorders may
result in gait ataxia. Patients with proprioceptive deficits
may have problems with foot placement and balance. Spi-
nal cord injuries typically result in spastic paraparesis or
quadriparesis, with difficulty walking as a result. Patients
with cervical spinal cord injuries may have weakness of
chest and abdominal muscles, affecting their ability to sit
upright and transfer without support, as well as compro-
mising respiratory reserve.
The evaluation of gait and the features of gait abnor-
malities of neurologic diseases are covered in detail in
Chapter 6, “Gait Disorders in the Elderly.” Features to
evaluate include base, stance, posture, turning, rising
from a chair, arm swing, stride, toe, heel, and tandem.
Disorders of gait are common in the elderly and falls are a
huge risk. Identifying the different gait types helps iden-
tify the underlying etiology. For magnetic gaits, consider
normal pressure hydrocephalus. For shuffling, festinating
gaits, consider parkinsonism, dementia with lewy bodies
(DLB), or idiopathic PD. For ataxic gaits, consider periph-
eral neuropathies or cerebellar disorders. For spastic or
paraparetic gaits, consider spinal cord injuries, or spinal
stenosis. For hemiparesis, consider focal CNS lesions
such as CVAs or mass lesions. Peripheral pathology can
affect gait. Antalgic gaits are attributable to orthopedic or
arthritic changes of the hip, knee, and ankle. Foot drop
from L5 radiculopathy or peroneal neuropathy can affect
the gait also.
Testing posture and gait
Ask the patient to perform the following activities.
• Walk across the room, turn, and come back.
• Walk heel-to-toe in a straight line.
84 Assessment of the Geriatric Neurology Patient
• Walk on the toes in a straight line.
• Walk on the heels in a straight line.
• Hop in place on each foot.
• Do a shallow knee bend.
• Rise from a sitting position.
Conclusion
Careful attention to features of the physical and neuro-
logic examination is essential in a geriatric patient. Careful
examination can frequently point to root causes, prompt-
ing further investigation. A good geriatric neurologic
examination with a focus on functional ability can allow
for improving the quality of care in geriatric neurology.
References
“Aphasia Symptoms, Causes, Treatment—How Is Aphasia Diag-
nosed?” Medicinenet.com, May 2011. http://www.medicinenet
.com/ aphasia/page3.htm (accessed on August 26, 2011).
Bickley, L.S., Szilagyi, P.G., and Bates, B. (2007) Bates’ Guide to
Physical Examination and History Taking. Philadelphia: Lippincott
Williams & Wilkins.
de Jong, P.T. (2006) Age-related macular degeneration. N Engl
J Med, 355 (14): 1474–1485.
“Dysmetria.” Multiple Sclerosis Encyclopaedia, October 2007.
http://www.mult-sclerosis.org/dysmetria.html (accessed on
August 26, 2011).
Hain, T.C. (2002) “Cerebellar Disorders.” http://www.dizziness-
and-balance.com/disorders/central/cerebellar/cerebellar.htm
(accessed on August 26, 2011).
Horton, J.C. (2005) Disorders of the eye. In: D.L. Kasper, E.
Braunwald, S. Hauser, D. Longo, J.L. Jameson, and A.S. Fauci
(eds), Harrison’s Principles of Internal Medicine, 16th edn.
New York: McGraw-Hill.
Iwamoto, Y. and Yoshida, K. (2002) Saccadic dysmetria following
inactivation of the primate fastigial oculomotor region. Neurosci
Lett, 325 (3): 211–215.
Pavan-Langston, D. (2007) Manual of Ocular Diagnosis and Therapy.
Philadelphia: Lippincott, Williams & Wilkins.
“Primitive and Postural Reflexes.” The Institute for Neuro-
Physiological Psychology, October 2008. http://www.inpp.org.uk/
intervention-adults-children/more-information/reflexes/
primitive-postural-reflex (accessed on August 26, 2011).
Quillen, D.A. (1999) Common causes of vision loss in elderly
patients. Am Fam Physician, 60 (1): 99–108.
Rathe, R. (1996) “Neurologic Examination.” University of Florida.
http://medinfo.ufl.edu/year1/bcs/clist/neuro.html (accessed
on August 26, 2011).
Rauch, D. (2006) “Infantile Reflexes on MedLine Plus.” Medline-
Plus. www.nlm.nih.gov/medlineplus/ency/article/003292.htm
(accessed on August 26, 2011).
Rhee, D.J. (2008) “Glaucoma: Eye Disorders: Merck Manual Home
Edition.” The Merck Manuals. www.merck.com/mmhe/sec20/
ch233/ch233a.html (accessed on August 26, 2011).
Schmahmann, J.D. (2004) Disorders of the cerebellum: ataxia, dys-
metria of thought, and the cerebellar cognitive affective syn-
drome. J Neuropsychiatry Clin Neurosci, 16 (3): 367–378.
Schott, J.M. and Rossor, M.N. (2003) The grasp and other primitive
reflexes. J Neurol Neurosurg Psychiatr, 74 (5): 558–560.
Townsend, J., Courchesne, E., Covington, J., et al. (1999) Spatial
attention deficits in patients with acquired or developmental
cerebellar abnormality. J Neurosci, 19 (13): 5632–5643.
 Chapter 4
Assessment of Cognitive Status
in Geriatric Neurology
4.1 Mental Status Examination in the Geriatric Neurology Patient
Papan Thaipisuttikul1,2 and James E. Galvin1,2

4.2 Neuropsychology in Geriatric Neurology

Donald J. Connor3 and Marc A. Norman4

1
Department of Neurology, New York University Langone Medical Center, New York, NY, USA
2
Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA
3
Independent Practice, Consultant Clinical Trials, San Diego, CA, USA
4
Department of Psychiatry University of California, San Diego, CA, USA

Summary
Mental Status Examination in the Geriatric Neurology Patient
• Level of consciousness, general appearance, mood and affect, behavior, movement, speech and communication,
thought form and content, perception, and insight should be observed during an assessment of cognitive status.
• Performance testing provides an objective measure of cognitive performance and the ability to compare with previous
and subsequent tests.
• Individual cognitive domains can be tested including attention, working memory and concentration, orientation,
memory, language, abstract thinking, judgment and problem-solving, visuospatial and construction skills, calculation,
executive function, and world list generation.
• Several brief scales used to detect depression in the elderly include the Geriatric Depression Scale (GDS), the Patient
Health Questionnaire (PHQ-9), and the Hospital Anxiety and Depression Scale (HADS).
• Performance-based cognitive evaluation tools include the mini-mental state examination (MMSE), Mini-Cog, short
blessed test (SBT), and Saint Louis University Mental Status (SLUMS).
• Informant-based tools provide assessments of changes in cognition and its impact on daily function. Questionnaires for
informants include the AD8 and the IQCODE.

Neuropsychology in Geriatric Neurology

• Patient scores collected from standardized instruments are quantified using normative data in order to assess the
individual’s performance relative to a demographically similar cohort.
• Test results are integrated with observation and noncognitive factors that may influence the performance.
• The relative performance on several tests is compared to create a profile of relative strengths and weaknesses.
• Neuropsychological assessments play a role in differential diagnosis, assessment of function, and treatment.
• Five domains of cognition are commonly tested.
• Attention/Orientation: separated into selective, sustained, and divided attention for both verbal and spatial stimuli,
awareness of the self and the environment.
• Language and communication: assessment of aphasia in expression, comprehension, and repetition (e.g.,
Broca’s, Wernicke’s, or conduction aphasia).
• Memory: several models exist for the concept of memory including temporal, characteristic, modality, and stage
models. Within each model are unique terms classifying different types of memory. Neuropsychological tests rely
heavily on verbal episodic memory, and visual episodic memory tasks to assess cognitive function.

(Continued)

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

85
86 Assessment of the Geriatric Neurology Patient

• Executive abilities: the abilities for initiation, organization, abstract thinking, and inhibition of impulsive behavior in
order to complete a goal-oriented task.
• Visuospatial abilities: visual information is separated into two pathways wherein the ventral pathway is involved with
symbolic representation and the dorsal pathway is involved with spatial awareness.
• Neuropsychological profiles of common disorders.
• Mild cognitive impairment (MCI): impaired episodic memory and/or other cognitive functions insufficient to meet
criteria for dementia.
• Alzheimer’s disease (AD): pattern of impaired episodic memory (learning and free recall). As the disease progresses,
impairments in executive functions and recognition memory are noted.
• Frontotemporal dementia (FTD): executive dysfunction (e.g., primary progressive aphasia, semantic dementia).
• Parkinson’s disease dementia (PDD): alterations or fluctuations in arousal and complex attention, impaired executive
dysfunction, impaired memory retrieval.
• Dementia with Lewy bodies (DLB): in mild stages, attentional, visuospatial, constructional, and executive dysfunction
is greater than impairments in memory and naming compared to AD.
• Progressive supranuclear palsy (PSP): characterized by a subcortical profile that includes deficits in attention,
executive function, and visuospatial abilities.
• Corticobasal ganglionic degneration (CBD): characterized by a subcortical profile.
• Vascular dementia (VaD): clinical presentations and neuropsychological profiles vary widely due to the heterogeneity
of the anatomical areas damaged.
• Delirium: deficits in attention, orientation, and fluctuating levels of arousal caused by an underlying medical condition.
• Depression: a risk factor for dementia but the diseases can be separate or comorbid.
• Preclinical states of dementia are currently being studied in hopes of developing methods of slowing or temporarily
halting the disease (disease modification).
 Chapter 4.1
Mental Status Examination in the
Geriatric Neurology Patient
Papan Thaipisuttikul and James E. Galvin
The elements of a comprehensive mental status exami-
nation include observational, cognitive, and neuropsy-
chiatric assessments. Although each of these elements is
presented separately, they are inter-related and collec-
tively characterize the neurobehavioral function of the
patient. The initial contact with the patient affords the
opportunity to assess whether a cognitive, attention, or
language disorder is present. Questioning of an infor-
mant may bring to light changes in cognition, function,
and behavior that the patient either is not aware of or
denies.
Because the frequency of cognitive disorders increases
dramatically with advancing age, examination of mental
status is one of the most important components of the
neurologic examination. Unfortunately, it is often one of
the parts of the examination most likely to be ignored and
amongst the most difficult parts of the examination to be
interpreted. In general, our fund of knowledge continues
to expand throughout life and learning ability does not
appreciably decline. Cognitive changes associated with
normal aging include decrease in processing speed, cogni-
tive flexibility, visuospatial perception (often in conjunc-
tion with decreased visual acuity), working memory, and
sustained attention (Tarawneh and Galvin, 2010). Other
cognitive abilities such as access to remotely learned
information and retention of encoded new information
appear to be relatively spared in aging; allowing their use
as sensitive indicators for onset of cognitive impairment
(Smith, 2003).
Observational and neuropsychiatric
assessment
In addition to detailed history taking and the more
common components of the neurologic examination
(motor and sensory function, gait, balance, etc.), care-
ful and thoughtful observation of the patients’ appear-
ance, behavior, and demeanor can provide insight into
the nature of the cognitive status. Observation of the
patient’s level of consciousness, general appearance,
affect, movements, and speech provide important ini-
tial evaluation of the patient’s mental status, followed
by asking probing questions to sample mood, thought,
perception, and insight.
Level of consciousness
An accurate assessment of a patient’s mental status and
neurologic function must first document the patient’s
alertness or level of arousal. Abnormal patterns of arousal
include hypo-aroused or hyper-aroused states.
Decreasing levels of arousal include lethargy, obtun-
dation, stupor, and coma (Strub and Black, 2000). The
lethargic patient is drowsy or fatigued and falls asleep
if not stimulated; however, while being interviewed
the patient will usually be able to attend to ques-
tioning. Obtundation refers to a state of moderately
reduced alertness with diminished ability to consis-
tently engage in the environment. Even in the pres-
ence of the examiner, if not stimulated, the obtunded
patient will drift off. The stuporous patient requires
vigorous stimulation to be aroused. Responses are
usually limited to simple “yes/no” responses or may
consist of groans and grimaces. Coma, which repre-
sents the end of the continuum of hypo-arousal states,
is a state of unresponsiveness to the external environ-
ment. In the elderly, hypo-arousal states can be asso-
ciated with systemic infection, cardiac or pulmonary
insufficiencies, meningoencephalitis, increased intra-
cranial pressure, toxic–metabolic insults, traumatic
brain injury, seizures, or cerebrovascular disease.
Coma requires either bilateral hemispheric dysfunc-
tion or brainstem dysfunction. Another important
consideration is the role of polypharmacy (Samaras
et al., 2010). Drug interactions are more common in
older adults and can significantly impair conscious-
ness (Samaras et al., 2010).
Hyper-arousal states on the other hand, are charac-
terized by anxiety, autonomic hyperactivity (tachycar-
dia, tachypnea, hyperthermia), agitation or aggression,
tremor, seizures, or exaggerated startle response (Strub
and Black, 2000). In the elderly, hyper-arousal states are
most often encountered in toxic–metabolic disorders
including withdrawal from alcohol, opiates, or sedative–
hypnotic agents. Other causes include tumors (both pri-
mary and metastatic), viral encephalitis (particularly her-
pes simplex), cerebrovascular, and hypoxemia (Caplan,
2010). Some patients, for instance, a patient with herpes
simplex encephalitis may experience fluctuating periods
of both hypo- and hyper-arousal (Ramrez-Bermdez et al.,
2005).
87
88 Assessment of the Geriatric Neurology Patient
General appearance
Assessment of a patient’s physical appearance should
acknowledge body size and type, apparent age, pos-
ture, facial expressions, eye contact, hygiene, dress,
and general activity level. A disheveled appearance
may indicate dementia, delirium, frontal lobe dysfunc-
tion, or schizophrenia (Strub and Black, 2000). Wearing
excessive makeup or flamboyant grooming or attire in
an old individual should raise the suspicion of a manic
episode or frontal lobe dysfunction (Sadock and Sadock,
2007). Patients with unilateral neglect due to dementia,
stroke, or head injury may fail to dress, groom, or bathe
one side of their body (Strub and Black, 2000). Patients
with Parkinson’s disease (PD) may display a flexed
posture, whereas patients with progressive supranu-
clear palsy (PSP) have an extended, rigid posture. The
overall appearance of an individual should also pro-
vide information regarding their general health status.
The cachectic patient may harbor a systemic illness
(e.g., cancer), or have anorexia or depression (Sadock
and Sadock, 2007).
Mood and affect
While mood is a subjective report of the patient’s emo-
tional status that is sustained over time, affect is the
patient’s present emotional response that can be inferred
from facial expressions, vocal tone, and body movements
(Sadock and Sadock, 2007). Affect can change during the
interview, while mood usually remains stable during the
office visit (Sadock and Sadock, 2007).
Constriction or flatness is observed in apathetic states;
for example, in the context of negative symptoms of
schizophrenia, severe melancholic depression, or in
demented patients with apathy (Sadock and Sadock,
2007). Increased intensity, on the other hand, is seen in
mood disorders such as bipolar illness, and in personal-
ity disorders such as borderline personality (Sadock and
Sadock, 2007). Lability is a disorder of emotional regula-
tion. Patients with marked lability are irritable and shift
rapidly among anger, depression, and euphoria com-
monly referred to a pseudobulbar affect (Schiffer and
Pope, 2005). The emotional outbursts are usually short-
lived. Labile mood is seen in mood disorders such as
bipolar illness, and in certain personality disorders such
as borderline personality. It also may occur in frontotem-
poral dementia (FTD), amyotrophic lateral sclerosis, cere-
brovascular disease, multiple sclerosis, and head injury
(Schiffer and Pope, 2005). In its full form as pseudobul-
bar palsy, it is commonly seen with lower cranial nerve
(CN IX-XII) deficits and hyperactive reflexes (Gillig and
Sanders, 2010).
Depression is a common mood disorder in older adults
and can occur in a variety of neurologic disorders, for
example, cerebrovascular disease, Alzheimer’s disease
(AD) and other types of dementia, PD, and epilepsy
(Lyness et al., 2006). Euphoria or full-blown mania occurs
less often than depression in the course of neurologic ill-
ness. Euphoria is most common with frontal lobe dysfunc-
tion (trauma, frontotemporal degenerations, infections)
and with secondary mania (Woolley et al., 2007). Even
though geriatric-onset anxiety disorder is not common in
older adults, anxiety symptoms occur in a variety of neu-
ropsychiatric conditions, for example, depression, AD,
PD, metabolic encephalopathies (hyperthyroid, anoxia),
and toxic disorders (lidocaine toxicity) (Flint, 2005).
Objective and subjective emotional components may be
incongruent in certain psychiatric disorders (e.g., schizo-
phrenia and schizotypal personality disorder), and in
neurologic conditions such as pseudobulbar palsy due to
a variety of underlying illnesses.
Behavior
A variety of personality alterations can be encountered
with focal brain lesions. Orbitofrontal dysfunction may
be characterized by impulsiveness or undue familiarity
with the examiner, lack of judgment or lack of social anxi-
ety, and antisocial behavior (Newcombe et al., 2011). Indi-
viduals with dorsolateral frontal lobe dysfunction may be
inattentive and distractible (Brooks et al., 2010). Apathy
(lack of motivation, energy, emotional reciprocity, social
isolation) may be caused by medial frontal dysfunction
and injury to the anterior cingulate (Roth et al., 2007). The
various dementias are associated with increased rigidity
of thought, egocentricity, diminished emotional respon-
siveness, and impaired emotional control (Pulsford and
Duxbury, 2006). Passivity, social withdrawal and apathy
can be seen in Lewy body disorders (Galvin et al., 2007a).
Movement
Observation of patient’s movements may provide evi-
dence of parkinsonism, chorea, myoclonus, or tics. Psy-
chomotor retardation (i.e., slowed central processing
and movement) may be indicative of vascular dementia
(VaD), subcortical neurologic disorders, parkinsonism,
medial frontal syndromes, or depression (Sadock and
Sadock, 2007). Psychomotor agitation may be indicative
of a metabolic disorder, choreoathetosis, seizure disorder,
mania, or anxiety (Sadock and Sadock, 2007).
Speech and communication
Observation of spontaneous speech is the first step in
formal language testing and can be assessed during his-
tory taking as well as in the course of the mental status
examination. Mutism may be encountered in several neu-
rologic conditions such as akinetic mutism, vegetative
state, locked-in syndrome, catatonic unresponsiveness,
or large left hemispheric lesions (Altshuler et al., 1986).
Spontaneous speech is characterized by its rate, rhythm,
volume, response latency, and inflection (Strub and Black,
2000). Accelerated speech may be encountered in mania,
 Mental Status Examination in the Geriatric Neurology Patient
disinhibited orbitofrontal syndromes, or festinating par-
kinsonian conditions, whereas a reduced rate of speech
output can occur as a component of psychomotor retar-
dation (Sadock and Sadock, 2007). Response latencies
may be prolonged or the patient may impulsively inter-
rupt the examiner, anticipating the question. Perturbed
speech prosody (loss of melody or inflection) can be
encountered in brain disorders affecting the right hemi-
sphere or the basal ganglia (Sidtis and Van Lancker Sidtis,
2003). Empty speech with hesitations or circumlocutions
can be exhibited in patients with word-finding difficulties
(Rohrer et al., 2008). Word-finding impairment may occur
in dementia, aphasia, metabolic encephalopathies, physi-
cal exhaustion, sleep deprivation, anxiety, depression, or
dorsolateral frontal lobe damage even in the absence of an
anomia (Rohrer et al., 2008).
Aphasia is characterized by impairment in oral and/
or written communication. Deficits will vary depend-
ing on the location and extent of anatomic involvement.
Aphasias are generally characterized as nonfluent or flu-
ent. Nonfluent aphasias are characterized by a paucity
of speech, often with a hesitant quality (Strub and Black,
2000). In contrary, fluent aphasias are characterized by
normal word production or may be increased, but there
is a lack of comprehension about what words mean, often
associated with impairment in reading ability (Strub and
Black, 2000).
Thought form and thought content
Thought form or thought process refers to the way
of thinking, where a person puts ideas and associate
them together. Examples of thought form disorders are
circumstantial, tangential, derailment, flight of idea,
thought blocking, loosening of association or incoher-
ence. Perseveration (Sadock and Sadock, 2007) and inco-
herence are disorders of the form of thought that are
common in neuropsychiatric conditions. Perseveration
refers to the inappropriate continuation of an act or
thought after conclusion of its proper context. Intrusions
are a special case of perseveration with late recurrences
of words or thoughts from an earlier context. Persevera-
tions and intrusions can be seen in aphasias and dement-
ing illnesses. Incoherence refers to the absence of logi-
cal association between words or ideas. It is observed in
delirium, advanced dementias, and as part of the output
of fluent aphasia.
Thought content refers to what a person is actually
thinking about, such as ideas, beliefs, preoccupations, and
obsessions. Delusions are the most common manifestation
of psychosis in neuropsychiatric disorders and are charac-
terized by false beliefs based on incorrect inference about
external reality. Common types of delusions encountered
involve being followed or spied on, theft of personal
property, spousal infidelity, or the presence of unwelcome
strangers in one’s home. Theme-specific delusions such as
89
the Capgras syndrome (the belief that someone has been
replaced by an identical-appearing impostor) (Josephs,
2007) may also be observed in neurologic illnesses. Delu-
sions are common in a number of dementia etiologies
including AD and dementia with Lewy bodies (DLB), and
may occur in VaD, FTD, and Huntington’s disease.
Perception
Perceptual disturbances can be classified as hallucination
or illusion/misperception. Hallucination is a false sen-
sory perception that occurs without stimulation of the rel-
evant sensory organ, while, illusion is a misperception or
misinterpretation of real external sensory stimuli.
Hallucinations and delusions frequently occur
together in psychosis; hallucinations are nondelusional
when the patient recognizes the sensory experience
to be unreal. Hallucinations may involve any sensory
modality (visual, auditory, tactile, gustatory, olfactory)
and may be formed (e.g., people or things) or unformed
(flashing lights or colors). Hallucinations occur with
ocular and structural brain disorders as well as Charles
Bonnet syndrome, epilepsy, narcolepsy, and migraine
(Pelak and Liu, 2004). Well-formed visual hallucinations
(children, furry animals) are a prominent early sign in
DLB (Hanson and Lippa, 2009). Less well-formed visual
hallucinations occur in the moderate-to-severe stages of
AD with the patient typically not well able to describe
what they saw. Gustatory or olfactory hallucinations are
most common in seizure disorders, bipolar and schizo-
phrenia, and with tumors located in the medial temporal
lobe (Capampangan et al., 2010). Tactile hallucinations
are most commonly associated with schizophrenia,
affective disorders or drug intoxication, or withdrawal
(Sadock and Sadock, 2007).
Insight
Insight is the patient’s ability to understand the true cause
and meaning of his/her condition, as well as the impli-
cation of diagnosis and its prognosis. Patients with neu-
ropsychiatric disease may display limited insight and be
unaware of their medical conditions or limitations in func-
tion, thus assessment of a patient’s insight into the sever-
ity of their illness can yield useful diagnostic information
and assist in developing a therapeutic plan. For example,
AD patients have impaired insight into their memory and
cognitive difficulties, whereas patients with VaD and DLB
often exhibit more appropriate concern regarding their
cognitive dysfunction (Del Ser et al., 2001). However,
it should not be assumed that the patient is unaware of
problems. Instead, they may be unable to attribute cau-
sality and are usually unable to rate the frequency and
severity of their problems. Lesions of the right parietal
lobe are associated with unawareness, neglect, or denial
of the abnormalities of the contralateral side (anosagno-
sia) (Pia et al., 2004).
90 Assessment of the Geriatric Neurology Patient
Cognitive assessment
Following observation, the clinician should begin a for-
mal assessment of cognitive abilities. The assessment of
cognitive function should be conducted methodically
and should assess comprehensively the major domains
of neuropsychological function (attention, memory, lan-
guage, visuospatial skills, executive ability). The patient’s
age, handedness, educational level, and sociocultural
backgrounds may all influence the cognitive function and
should be determined prior to initiating or interpreting
the evaluation. In general there are two ways to assess the
patient—informant assessments and performance testing.
Using performance testing, the clinician may gain a
sense of the objective performance of the patient in rela-
tion to published normative values, usually corrected
for age and education. If the patient was previously
assessed, comparison to previous tests offers the potential
to measure change. Brief performance tests while provid-
ing a “snap shot” of abilities at the time of examination,
are themselves unable to provide information regarding
the change from previous abilities or how the scores on
the tests interfere with the patients social and occupa-
tional functioning (i.e., their activities of daily living). For-
mal neuropsychological testing provides a more compre-
hensive assessment of cognitive abilities with estimates of
premorbid intelligence (Section 4.2). However, neuropsy-
chological testing is not practical in the office setting and
may not be readily available outside major metropolitan
areas. In this section, we take two approaches— (1) indi-
vidual cognitive domains to create a brief 20–30 minute
(depending on the level of dementia severity and lan-
guage ability) battery of tests that could be done in the
office setting (Table 4.1), and (2) brief global measures.
Table 4.1 Example of a brief neurobehavioral status examination
Verbal memory Animal naming
15-item Boston naming
Working memory Digit span forward
Digit span backward
Episodic memory Word list recall (Hopkins, California, CERAD)
Paragraph recall
Visual construction Clock drawing
Psychomotor speed Trailmaking A
Executive function Trailmaking B
Digit symbol substitution
Abstraction Similarities and differences
Proverb interpretation
Concentration Months in reverse order
Counting backward from 20
Global measurement Mini-mental status examination
(Choose one) Short blessed test
Mood (Choose one) Geriatric depression scale
PHQ-9
Hospital anxiety and depression scale
Attention, working memory, and
concentration
Attention is very important in order to process other cog-
nitive abilities. Two tests are useful in assessing attention:
digit span and continuous performance tests. In the digit
span forward (Strub and Black, 2000) test, the patient
is asked to repeat increasingly long series of numbers
(e.g., 1, 3-7, 4-6-3, 5-1-9-2, etc.). A normal forward digit
span is seven digits; fewer than five is abnormal. Digit
span backward (Strub and Black, 2000) is a test of mental
control, and complex attention, as well as executive dys-
function. It entails saying increasingly long series of num-
bers and asking the patient to say them backward (give
2-5-8, response should be 8-5-2). A normal digit span in
reverse is five digits; fewer than three is abnormal.
Concentration is an ability to maintain attention.
Concentration is evaluated by a continuous perfor-
mance test, for example, ask the patient to count back-
ward from 20, say months of the year backward, and
serial subtraction (100−7 or 20−3). However, serial
subtraction should be used with caution, because of
its dependence on education and mathematical ability
(Karzmark, 2000).
Orientation
Orientation to time is tested by asking the patient to iden-
tify the correct day of the week, date, month, and year.
This could be followed by asking the patient to state the
correct time of the day without looking at a watch or
clock. The patient should be within 1 hour of the correct
time. Orientation to place is assessed by asking about city,
county, state, and current location. Orientation to situa-
tion can be assessed by asking the patient why they are in
the clinic/hospital on the particular day.
Memory
Learning, recall, recognition, and memory for remote infor-
mation are assessed in the course of mental status exami-
nation. Asking the patient to remember three words and
then asking him or her to recall the words 3 minutes later
can help assess learning, recall, and recognition.
In general, the shorter the list, the easier it is to remem-
ber, particularly in high-functioning individuals. When
told to remember items, patients will often remember
the first two items heard (known as “primacy”) and
the last two items heard (known as “recency”), there-
fore longer lists of 10 words may be preferable (Morris
et al., 1989). After a delay, recall of less than five words
is considered abnormal. Patients having difficulty with
recall may be given clues (e.g., the category of items
to which the word belongs or a list of words contain-
ing the target) to distinguish between storage and
retrieval deficits. For example, giving clue to patient
with AD will generally not help a patient to remember
because of his/her primary storage disorder, while giv-
 Mental Status Examination in the Geriatric Neurology Patient 91

Table 4.2 Useful screening tests for office setting

Screening test Numbers of items Scoring system Validity Limitations

MMSE 30 items Cutoff 23–24 Sensitivity 85–100% Score influenced by education,

Specificity 66–100% ethnicity, social class. Not ideal
to identify mild impairment.
Mini-Cog 3 recall with clock drawing Recall 2/3 use clock to Sensitivity and specificity Test focus on recall, visuospatial
determine the problem comparable to MMSE ability and construction.
SBT 6 items of orientation, 5–9/28 questionable 10 or High correlation of 0.52 Test focus on orientation, memory
memory and concentration over/28 dementia between score and and concentration. May not
autopsy detect nonamnestic dementias.
SLUMS 11 items Cutoff of 21–26: mild cognitive Sensitivity 96–98% Limited validation on different
impairment (MCI), 20 and Specificity 61–100% groups of patients from original
below: dementia for high study. Tests are complicated
school education and take time to use in an office
setting.
MoCA 12 items,10 minutes Less than 26 detect MCI Sensitivity of 90 for MCI Takes 10 minutes or more for
administered, multicognitive or dementia and 100 for dementia patients with more severe
domain assessing impairment. Not as extensively
studied as MMSE.
AD8 8 items More than 2 Sensitivity 90% Depends on observant informant.
Specificity 68% In the absence of informant, the
AD8 can be administered to the
patient.
IQCODE 16 items More than 3.44 Sensitivity 76–100% Depends on observant informant.
Specificity 65–86%

ing clue to a patient with DLB may help the patient to
recall since his/her primary deficit might be retrieval
(Hamilton et al., 2004).
To evaluate remote memory, information needs to be
gathered on the patient’s life events and important his-
toric events (marriage, birth of children). An informant
may be helpful to verify the accuracy of the information.
The pattern of memory loss in most forms of dementia
usually starts with short-term (learning, recall, recogni-
tion) memory first, then gradually involving in long-term
memory in the later stages of disease. However, psycho-
genic amnesia memory-loss patterns can be variable and
typically involve both long and short memory (Hennig-
Fast et al., 2008).
Language
Language assessment entails the evaluation of all aspects
of communication including spontaneous speech, com-
prehension, repetition, naming, reading, and writing.
Language comprehension is tested by asking the
patient to follow increasingly complex verbal instruc-
tions. The easiest commands are one-step orders such as
“close your eyes,” or “stick out your tongue” to multistep
commands “take the piece of paper, fold it in half and
place on the floor” to more complex questions, such as “If
a lion is killed by a tiger, which animal is dead?” Impaired
comprehension usually implies dysfunction of parieto-
temporal regions of the left hemisphere. In the elderly, it is
important to establish that hearing is intact before testing
verbal comprehension. Failure to comprehend commands
may reflect the inability to hear as opposed to impaired
comprehension.
Repetition is assessed by asking the patient to repeat
increasingly long phrases or sentences. Repetition is
impaired in Wernicke, Broca, conductive, and global apha-
sia but is generally preserved in transcortical aphasias.
Naming tests involve asking the patient to name objects,
parts of objects, and colors. Aphasic patients may use
descriptive terms rather than give the proper name. Ano-
mia, loss of naming ability, occurs in aphasia, dementia,
delirium, and can sometimes be seen as a consequence of
head trauma. Adequate vision and object recognition must
be ensured before errors are ascribed to naming deficits.
The 15-item Boston Naming Test (Mack et al., 1992) is an
example of a brief measure of confrontational naming.
When assessing reading, the patient’s ability to read
aloud and to comprehend what is read should both be
tested. Adequate vision must be ensured before failures
are ascribed to an alexia. Many aphasias have concomitant
alexias; however, the converse may not be true. In alexia
with agraphia and alexia without agraphia, reading
abnormalities may occur in the absence of other signs of
aphasia (Maeshima et al., 2011).
Patients with agraphia lose their ability to write/
draw things when asked by the examiner. Micrographia
(Gangadhar et al., 2008) is a characteristic aspect of par-
kinsonism in which the script becomes progressively
smaller as the patient writes a sentence or extended series
92 Assessment of the Geriatric Neurology Patient
of numbers or letters, and mechanical agraphias occur
in patients with limb paresis, limb apraxia, or move-
ment disorders such as tremor and chorea (Ferguson and
Boller, 1977). Agraphias may accompany aphasic syn-
dromes and errors found in written language are often
similar to those noted in verbal output. In Gerstmann
syndrome (agraphia, acalculia, right–left disorientation,
finger agnosia), alexia with agraphia, and disconnection
agraphia (occurring with injury of the corpus callosum),
agraphia occurs without aphasia (Rusconi et al., 2010).
Abstract thinking
Abstract thinking is the ability to deal with concepts. Sim-
ilarities, differences, idioms, and proverb interpretation
can all be used to assess abstracting capacity. These tests
are influenced by culture and educational level. Abstrac-
tion abnormalities are a nonspecific indicator of cerebral
dysfunction. Patients with neurodegenerative dementias
typically offer concrete answers to abstract questions,
thus comprehension should always be assessed before
asking the patient to provide interpretations.
Judgment and problem-solving abilities
Assessing judgment assists in exploring the patient’s
interpersonal and social insight. Damage to orbito-
frontal subcortical circuit (e.g., in FTD, trauma, or focal
syndromes) produces marked alterations in social judg-
ment (Gleichgerrcht et al., 2010). Problem solving can be
assessed by giving a scenario “If traveling in a strange
town, how would a person locate a friend they wished to
see?” Correct answers might include use of phone book,
the internet, or city directory.
Visuospatial and construction skills
In the clinic, simple tests that are usually used to evaluate
the patient’s visuospatial abilities are clock-drawing test
and copying intersecting pentagons or cubes.
The clock-drawing test (Libon et al., 1993) assesses the
ability to plan and arrange the numbers on the clock face
and to place the hands at the correct time. The hands
should be of different lengths. Patients with executive
dysfunction may draw a clock face that is too small to
contain the required numbers (poor planning), whereas
patients with unilateral neglect will ignore half of the
clock face. There are a number of different scoring para-
digms for the clock, although the simplest might simply
be scoring the clock as normal or abnormal.
Abnormalities of other copy tests (pentagons, cubes)
include failures to reproduce the shapes accurately, perse-
veration on individual elements, drawing over the stimu-
lus figure, or unilateral neglect. Drawing disturbances are
common with many types of neurologic conditions includ-
ing focal brain damage, degenerative disorders, and toxic
and metabolic encephalopathies (Mechtcheriakov et  al.,
2005).
Calculation
Patients are asked to add or multiply one or two digits
mentally or to execute more demanding problems with
pencil and paper. Calculation abilities are related to
education and occupation. Acalculias may occur in asso-
ciation with a number of aphasic syndromes while visuo-
spatial disorders lead to incorrect alignment of columns
of numbers (Ardila and Rosselli, 1994). Primary anarith-
metias (inability to do math) are produced by damage to
the posterior left hemisphere (Grafman et al., 1982).
Executive function
Executive function, or higher cortical function, has been
mediated by frontal-subcortical system, complex neural
circuits that include the dorsolateral prefrontal cortex,
striatum, globus pallidus/substantia nigra, thalamic
nuclei, and connecting white matter tracts. Patients with
executive dysfunction manifest perseveration, motor pro-
gramming abnormalities, reduced word list generation
(left dorsolateral dysfunction), reduced nonverbal flu-
ency (right dorsolateral dysfunction), poor set-shifting,
abnormal recall with intact recognition memory, loss of
abstraction abilities, poor judgment, and impaired mental
control (Bullock and Lane, 2007).
Simple executive function tests that are useful in clini-
cal settings include Trail making A test that requires the
patient to draw lines sequentially connecting 25 encircled
numbers distributed on a paper. Trail making A (Corrigan
and Hinkeldey, 1987) measures psychomotor speed with
minimal executive function and if completed allows fur-
ther testing with Trail making B (Corrigan and Hinkeldey,
1987) that requires alternating between numbers and let-
ters (1-A-2-B…etc.).
Word list generation
Ask the patient to think of as many members of a specific
category (most commonly animals or vegetables) as pos-
sible within 1 minute. Typically, older adults can name
approximately 18 animals within 1 minute; less than 14
is considered abnormal. Word lists can also be generated
using the first letter (for example S and F (Brandt and
Manning, 2009)). Word list generation deficits occur with
anomia, frontal-subcortical systems dysfunction, and psy-
chomotor retardation. It is a highly sensitive test for impair-
ment but lacks specificity (Brandt and Manning, 2009).
Effects of mood and affect disorder on cognition
Depression is common in older adults. Memory com-
plaints are likely to be the chief complaints in this group
of patients, as known as “pseudodementia” in the past.
When depression improves, the cognitive impairment
often improves as well. However, comorbid depression
and cognitive impairment are a risk for the later emer-
gence of AD (Alexopoulos et al., 1993). Therefore, early
depressive symptoms with mild cognitive impairment
 Mental Status Examination in the Geriatric Neurology Patient
(MCI) may represent a preclinical sign and should be
considered a risk for impending dementia (Li et al., 2001).
Concept of vascular depression or depression-executive
dysfunction syndrome is also famous in older adults
(Alexopoulos et al., 1997). The clinical presentations are
psychomotor retardation, apathy, and severe disability
related to impaired executive function.
Depression in the elderly is not a unitary construct.
There is a wide range of variations in etiologies and
manifestations; therefore, early detection and appropri-
ate management are important. Some brief scales that are
usually used for detecting depression in the elderly are
(1)  Geriatric Depression Scale (GDS), the 15-items and
30-items self-administered questionnaire that usually takes
only 5–10 minutes, was first developed by Yeasavage in 1983
(Yesavage et al., 1983). GDS has shown a good sensitivity
of 80% and specificity of 100% at the cutoff of 14/30 (Brink
et al., 1982). (2) Patient Health Questionnaire (PHQ-9), the
9-item self-administered questionnaire that has been stud-
ied widely in primary care populations (Spitzer et al., 1999)
was found to have overall 85% accuracy, 75% sensitivity,
and 90% specificity for depression diagnosis. (3) Hospital
Anxiety and Depression Scale (HADS), the 7-items depres-
sion combine with 7-items of anxiety self-administered
questionnaire was first developed in the United Kingdom
to use in general medical outpatient clinic settings (Snaith,
2003). HADS-D at cutoff of eight or over had 80% sensitiv-
ity and 88% specificity, while HADS-A at cutoff of eight or
over had 89% sensitivity and 75% specificity from previous
study (Olssn et al., 2005).
Anxiety symptoms are common in the elderly, espe-
cially as a comorbid with late-life depression. In the past,
experts believed that anxiety disorder usually have an
onset in childhood or early adulthood; however, some
researchers also found clinical samples with late-onset
anxiety disorders (Blazer and Steffens, 2009). A pre-
liminary study comparing generalized anxiety disor-
der (GAD) patients, major depressive disorder (MDD)
patients, and healthy elderly individuals found that GAD
patients had impaired short-term and delayed mem-
ory, but no executive deficits as seen in MDD patients
(Mantella et al., 2007).
Apathy, withdrawal or indifference is one of the most
common behavioral symptoms in AD. Apathy defines as
a reduction in a voluntary goal-directed behavior. Studies
found that Alzheimer’s patients with apathy (lacks ini-
tiative) also have problem with multitasking (executive
function) which can be an underlying factor of goal-
directed behaviors (Esposito et al., 2010).
Performance-based tools for
cognitive evaluation
Though creating a unique, brief psychometric battery
might seem appealing, administration of even a brief
battery can take 20–30 minutes. Alternatively, there are
93
a variety of brief, cognitive tests that were developed to
help assess the general cognitive functions. Each has limi-
tations, but in the setting of a busy office, practice may
provide the quickest way to get a global assessment of the
patients’ cognitive abilities (Table 4.2). The following are
examples of general cognitive tests that are practical to
use in geriatric patients in clinical setting.
Mini-Mental Status Examination
The 30-item mini-mental state examination (MMSE) test,
which takes around 10 minutes to complete, has been fre-
quently used for initial assessment of memory problem,
and its sensitivity increases if a decline of the score over
time is taken into account (Folstein et al., 1975). The MMSE
covers six areas: (1) orientation, (2) registration, (3) atten-
tion and calculation, (4) recall, (5) language, and (6) ability
to copy a figure. However, although the MMSE is quick
and easy to administer and can track the overall progres-
sion of cognitive decline, it is not considered to be a good
test for definitive AD diagnosis (deSouza et al., 2009),
particularly because of its greater emphasis on orienta-
tion (10 of 30 points) that is typically not impaired at the
earliest stages of dementia. In addition, there are several
issues associated with the MMSE, including bias according
to age, race, education, and socioeconomic status (Caplan,
2010). There are also copyright issues that may limit its use.
Several diagnostic tests are now available for use in pri-
mary care as alternatives to the MMSE; these are continu-
ally being updated and simplified in order to provide brief,
easy to administer, and effective diagnostic tools.
Mini-Cog
The Mini Cognitive Assessment Instrument (Mini-Cog)
combines an un-cued 3-item recall test with a clock-
drawing test that serves as a recall distractor; it can be
administered in about 3 minutes and requires no special
equipment. (Borson et al., 2005) The Mini-Cog, and the
MMSE have similar sensitivity (76% vs. 79%) and specific-
ity (89% vs. 88%) for dementia, correlating with findings
achieved using a conventional neuropsychological bat-
tery. The Mini-Cog’s brevity is a distinct advantage when
the goal is to improve recognition of cognitive impairment
in primary care, particularly in milder stages of impair-
ment. (Borson et al., 2005) It has also been suggested that
cognitive impairment assessed by the Mini-Cog is a more
powerful predictor of impaired activities of daily living
than the disease burden in older adults. In addition, the
Mini-Cog also has proven good performance in ethnically
diverse populations of the United States, where widely
used cognitive screens often fail, and is easier to adminis-
ter to non-English populations.
Short Blessed Test
Short blessed test (SBT), consisting of the items in the
Blessed orientation–memory–concentration test, includes
94 Assessment of the Geriatric Neurology Patient
three orientation questions (month, year, and time of
day), counting from 20 to 1, saying the months backward,
and recalling a 5-item name and address memory phase
(Katzman et al., 1983). This test was developed using
scores from a validated 26-item mental status question-
naire of two patient groups in a skilled nursing home,
patients in a health-related facility, and in a senior citi-
zens’ center. There was a positive correlation between
scores on the 6-item test and plaque counts obtained from
the cerebral cortex of 38 subjects at autopsy. This test,
which is easily administered by a nonphysician, has been
shown to discriminate among mild, moderate, and severe
cognitive deficits (Katzman et al., 1983).
The SBT is quite sensitive to early cognitive changes
due to AD. Based on clinical research findings from the
Memory and Aging Project at Washington University in
Saint Louis, the proposal of new cut-points, after add-
ing weighting factors (total score of Katzman et al., 1983)
were suggested: 0–4 normal cognition, 5–9 questionable
impairment, and 10 or more impairments consistent with
dementia (Morris et al., 1989).
The Saint Louis University Mental Status
The Saint Louis University Mental Status (SLUMS) is
a 30-point, 11-item, clinician-administered screening
questionnaire that tests for orientation, memory, atten-
tion, and executive functions. The SLUMS is similar
in the format of MMSE; however, it supplements the
MMSE with enhanced tasks corresponding to atten-
tion, numeric calculation, immediate and delayed
recall, animal naming, digit span, clock drawing, fig-
ure recognition/size differentiation, and immedi-
ate recall of facts from a paragraph. In particular, the
clock-drawing test is designed to assess impairment in
executive function (Schiffer and Pope, 2005). At a cut-off
score of 27–30 normal, 21–26 mild neurocognitive disor-
der, and 1–20 dementia for high school education have
0.98 sensitivity and 0.61 specificity for MNCD and 0.96
sensitivity and 1.0 specificity for dementia diagnosis
(Tariq et al., 2006). Therefore, the developer team sug-
gests benefit of SLUMS over MMSE in order to identify
minor neurocognitive disorders early. Due to copyright
issues the Veterans Administration has stopped using
the MMSE and now many use SLUMS. However, to
date the SLUMS has not been validated outside of the
original research sample.
The Montreal Cognitive Assessment
The Montreal Cognitive Assessment (MoCA) is a
10-minute cognitive screening tool developed to assist
physicians in the detection of MCI (Gillig and Sanders,
2010). MoCA is gaining credibility due to improvements
in sensitivity, addressing frontal/executive function-
ing, and decreasing susceptibility to cultural and edu-
cational biases. It has high sensitivity and specificity for
detecting MCI in those patients who perform within the
normal range of the MMSE. Compared with the MMSE,
which had a sensitivity of 18% to detect MCI, the MoCA
detected 90% of MCI subjects and, in patients with mild
AD the MMSE had a sensitivity of 78%, whereas the
MoCA detected 100% (Nasreddine et al., 2005). MoCA is
also well-suited as a screening test for cognitive impair-
ment in PD (Dalrymple-Alford et al., 2010), in which
memory impairment may be involved later in the stage
of disease compared to executive function. The limitation
of the MoCA may be in its more complex interpretation.
Informant-based tools for cognitive evaluation
The diagnosis of dementia is a clinical one, based on
the principles of intraindividual decline in cognitive
function that interferes with social and occupational
functioning. The limitations to all brief performance
measures is that they (1) fail to capture the “change”
and “interference” when used as a dementia screen and
(2) may be biased by age, gender, race, education, and
culture. Informant-based instruments on the other
hand rely on an observant collateral source to assess
whether there have been changes in cognition and if
said changes interferes with function. A particular
strength compared to other cognitive screening tests
is that informant assessments are relatively unaffected
by education and premorbid ability or by proficiency
in the culture’s dominant language. Because each
person serves as their own control, there is little bias
due to age, education, gender or race (Morales et al.,
1997). The disadvantages of informant assessments are
the reliability of the informant and the quality of the
relationship between the informant and the patient.
Because the informant assessments provide informa-
tion complementary to cognitive tests, harnessing them
together may improve screening accuracy.
A gold standard in informant assessment is the Clini-
cal Dementia Rating (CDR) used in many clinical trials
and research projects. However, the length of the inter-
view makes it impractical for use in the busy office set-
ting. The value of including a reliable informant (spouse,
adult child, caregiver) in the evaluation of cognitive and
affective disorders in older adults has been incorporated
into the following questionnaires.
AD8
AD8 screening interview is a brief, sensitive measure
that reliably differentiates between individuals with
and without dementia by querying memory, orientation,
judgment, and function (Galvin et al., 2006). The AD8
comprises eight yes/no questions asked to an informant
to rate changes, and takes approximately 2–3 minutes
for the informant to complete (Table 4.3). In the absence
of an informant, the AD8 can be directly administered to
the patient as a self-rating tool (Galvin et al., 2007b) with
 Mental Status Examination in the Geriatric Neurology Patient 95

Table 4.3 The AD8

Remember, “Yes, a change” indicates that there has been a change in the YES, NO, N/A,
last several years caused by cognitive (thinking and memory) problems. A change No change Do not know

1. Problems with judgment (e.g., problems making decisions, bad financial

decisions, problems with thinking)
2. Less interest in hobbies/activities
3. Repeats the same things over and over (questions, stories, or statements)
4. Trouble learning how to use a tool, appliance, or gadget (e.g., VCR,
computer, microwave, remote control)
5. Forgets correct month or year
6. Trouble handling complicated financial affairs (e.g., balancing checkbook,
income taxes, paying bills)
7. Trouble remembering appointments
8. Daily problems with thinking and/or memory

TOTAL AD8 SCORE

Source: Adapted from Galvin, J.E. et al. (2005) The AD8, a brief informant interview to detect dementia. Neurology, 65: 559–564. Reproduced with
permission of Washington University, St. Louis, MO.

similar large-effect sizes (Cohen’s d for informant = 1.66; Summary

for patient = 0.98 (Galvin et al., 2007b). Use of the AD8
in conjunction with a brief assessment of the participant,
such as a word list, could improve detection of dementia
in the primary setting to 97% and 91% for MCI (Galvin
et al., 2006). The AD8 has a sensitivity of 84%, and
specificity of 80% with excellent ability to discriminate
between nondemented older adults and those with mild
dementia (92%) regardless of the cause of impairment
(Galvin et al., 2006). The AD8 is highly correlated with
the CDR and neuropsychological testing. More recently
the AD8 has been biologically validated against amyloid
PET imaging and cerebrospinal fluid biomarkers of AD
(Galvin et al., 2010). The AD8 has been translated into
Spanish (Muoz et al., 2010), Korean (Ryu et al., 2009),
and Chinese (Yang et al., 2011) with similar psychomet-
ric properties.
The Informant Questionnaire on Cognitive
Decline in the Elderly
The Informant Questionnaire on Cognitive Decline in the
Elderly (IQCODE) was developed as a way of measuring
cognitive decline from a premorbid level using informant
reports. Subsequently, the short version of 16-item corre-
lated 0.98 with the full version and had comparable valid-
ity when judged against clinical diagnosis. Each item is
rated on a 5-point scale from 1-“much better” to 5-“much
worse” and the ratings are averaged over the 16 items to
give a 1–5 score, with three representing no change on any
item. In clinical situations, a screening cutoff of 3.44+ on
the short IQCODE is a reasonable compromise for bal-
ancing sensitivity and specificity. The rating scale was
deliberately designed to reflect cognitive improvement as
well as cognitive decline, to allow for the questionnaire to
be used in treatment trials and following acute illnesses
(Form, 2004).
Cognitive disorders are common in older adults; how-
ever, cognitive complaints may not be readily offered by
patients due to denial, lack of insight, fear of stigma and/
or a general lack of knowledge about what is “normal” for
an age. The elements of a comprehensive mental status
examination include observational, cognitive, and neuro-
psychiatric assessments. In the absence of a comprehensive
approach to evaluate cognitive abilities, it is unlikely that a
clinician will detect impairment at the mildest stages when
intervention may offer the greatest potential for benefit. In
addition, the presence of cognitive impairment leads to
poorer adherence, higher costs, and worse outcomes for
other medical conditions compared with age-matched
older adults without cognitive impairment. Whether the
clinician designs their own unique assessments or utilizes
one of the many standardized instruments available, fail-
ure to include a mental status examination in the assess-
ment of older adults represents a missed opportunity.
Acknowledgments
This work was supported by P30 AG008051 from the
National Institute on Aging, National Institutes of Health.
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 Chapter 4.2
Neuropsychology in Geriatric Neurology
Donald J. Connor and Marc A. Norman
Basis of neuropsychological
assessment
Psychometric testing is based on the administration of
standardized instruments, quantified using appropriate
normative data, to produce a measurement of an indi-
vidual’s relative cognitive strengths and weaknesses.
Ideally, the normative transformation of the raw data
will include factors that may influence test performance
such as age, gender, education, premorbid intelligence,
socioeconomic status, culture, and race (Mitrushina,
1999, pp. 24–27). This allows the examiner to estimate the
relative probability that the test score is abnormal, and
estimate the degree of impairment. Neuropsychological
assessment involves the integration of the psychometric
test results along with medical history, psychological/
psychiatric status, and subjective symptom report by
the patient and family. This integration is done based
on an intimate knowledge of brain–behavior–disease
relationships that are the core of a neuropsychologist’s
training. Neuropsychological testing is similar to a clini-
cian’s mental status testing but differs quantitatively in
the amount of testing and qualitatively in the integration
of differential profiles and use of demographic-based
normative data.
Normative data
The issue of appropriate normative data is critical to the
interpretation of the test profile. If the normative dataset
is not appropriate to the individual patient’s demographic
factors then the validity of the transformed data must be
brought into question. Single cut points as commonly seen
in mental status examinations are useful in clinical prac-
tice but can be misleading. Since the final interpretation of
the data is a synthesis of all information available to the
neuropsychologist, a valid and clinically useful conclu-
sion may be reached despite the norms not accounting for
all variables, but the decrease in the strength of the con-
clusions should be recognized (American Psychological
Association Ethics standard 9.02, 2010). The subject’s per-
formance is most commonly expressed as standard devia-
tions (Z-scores), T-scores, standard scores, scaled scores,
or percentiles. The differences between these transforma-
tions and their implications for interpretation are beyond
the scope of this chapter. However, as a guideline, except
for percentiles, these transformations of the raw scores
assume a normal distribution of the data (e.g., standard
98
bell curve). Z-scores have a mean of 0 with a standard
deviation of 1; T-scores have a mean of 50 with a standard
deviation of 10; standard scores such as those used in IQ
tests have a mean of 100 and a standard deviation of 15;
scaled scores have a mean of 10 with a standard deviation
of 3. Percentiles are expressed somewhat differently as
they are nonlinear and reflect the percentage of scores in
a sample that fall at or below a given raw score. Because
of this, conversion of percentiles into standardized scores
(Z-scores, T-scores, etc.) assumes that the percentile dis-
tribution can reflect the normative curve which may not
be the case in tests with a skewed distribution. However,
assuming a normal distribution of the normative data, a
Z-score = −1.0 (one standard deviation below the mean)
would reflect a percentile score of sixteenth percentile, a
Z-score of −1.5 would be in the seventh percentile and
a Z-score of −2.0 would be in the second percentile. In
general, cut scores of approximately −1 standard devia-
tion may be taken as low average; scores of approxi-
mately −1.5 standard deviations may be taken as border-
line or questionable; and scores of −2 standard deviations
may be taken as impaired (Lezak et al., 2004; pp. 145–149)
although there is significant variability in this and deficits
of −1.0–1.5 have been used in the diagnosis of mild cogni-
tive impairment (MCI) (Albert et al., 2011).
The level of score that is indicative of a clinically relevant
pathologic state is based on multiple factors (premorbid
abilities, profile against other abilities, etc.) and is inter-
preted both as a probability that there is an impairment as
well as the degree of impairment. The level of performance
the practitioner uses to determine the clinical impairment
may be greater or less than what may be considered sta-
tistically different depending on the factors mentioned
above (premorbid abilities, demographics, sensory/motor
deficits, distribution of the normative data, etc.) and the
consequences of a false negative versus false positive result
(Lezak et al., 2004; p. 148; Busch et al., 2006).
Standardized assessment
In addition to limitations imposed by appropriateness of
the normative data, other factors that may influence test
performance must be taken into account. As detailed in a
previous section on mental status testing, all psychometric
testing should begin with at least a cursory examination
of sensory and motor function. For example, if a subject
demonstrates impaired performance on visual memory
tasks but has significant uncorrected visual deficits, then

the results of the testing must be carefully interpreted
or discounted. The breadth of neuropsychological tests
available allows the clinician some ability to measure cog-
nitive function even in the presence of significant sensory
or motor deficits, but ultimately the impact of the deficits
on test performance, the effect on the cognitive profile
and the validity of the results is determined by the clinical
interpretation of the neuropsychologist.
The basis of neuropsychological assessment is that test
instruments are administered in a standardized manner
so that appropriate normative data can be applied for a
valid reflection of the patient’s abilities. Thus, neuropsy-
chological tests tend to have detailed administration man-
uals and highly structured administration procedures.
This quantitative approach emphasizes the final perfor-
mance score as indicative of the patient’s abilities. How-
ever, observations made during the test session (apparent
effort, level of consciousness, acute confusion, etc.) that
may influence the validity of the results are also included
in the interpretation. In some cases, a “process approach”
may be used that emphasizes the method the patient
uses to complete the task (Milberg, 1986). This approach
involves a more sophisticated and complex analysis of
the qualitative aspects of the test behavior and is inte-
grated with the quantitative test scores. Some neuropsy-
chological instruments have attempted to standardize the
qualitative methodology as is reflected in tests such as
the Wechsler Adult Intelligence Scale revised as a neuro-
psychological Instrument (Kaplan et al., 1991). However,
the process approach method is seen as an adjunct to the
quantitative method of analysis rather than a replacement
for it.
Interpretation
It is the integration of the test results into a cognitive pro-
file that is the core feature of a neuropsychological assess-
ment. This integration involves both the awareness of
noncognitive factors that may influence the test results
(mood, effort, sensory/motor, etc.) as well as the inter-
test patterns. Since no single test is a pure measure of any
cognitive construct, using the relative performance of sev-
eral tests compared to each other is necessary to define
the impaired areas of function. One example of this is the
Trail Making Test A/B (Reitan, 1958). This is a sequenc-
ing test consisting of two conditions. The first condition
(Trails A) is a simple sequencing task where the patient is
presented with a paper with numbers scattered over the
page. The patient then draws a line from one number to
the next—in order—with the time to completion and any
errors recorded. The second condition (Trails B) is simi-
lar but involves alternating between numbers and letters
(e.g., 1-A-2-B-3- etc.). Poor performance on Trails B can be
due to visual–motor impairment or difficulties in main-
taining the sequence set (executive dysfunction). By com-
paring the performance on Trials B to the performance on
Neuropsychology in Geriatric Neurology 99
Trails A, the visual–motor component can be accounted
for and a more accurate measure of executive function
(EF) can be obtained.
As mentioned in chapter 4.1, proficiency in mental sta-
tus testing is a necessity in geriatric neurology. However,
the abbreviated nature of the mental status tests tends to
limit its sensitivity and specificity in very mild demen-
tia (Tombaugh and McIntyre, 1992; Tariq et al., 2006) and
the ability to detect relative levels of deficit in different
cognitive domains (e.g., cognitive profiles). Many of the
standard screening instruments (MMSE, MOCA, SLUMS)
are useful for initial detection of clinical dementia based
on their total score (Nasreddine et al., 2005; Ismail et al.,
2010), but their reliability tends to decrease when indi-
vidual items are interpreted. While these tests can be
influenced by age, education, etc., this is often not taken
into account when “cut” or threshold scores are used. In
the MMSE manual (Folstein et al., 2001), a reference to an
extensive normative study is given (Crum et al., 1993) as
a way to take demographics into account. In particular,
this study demonstrates the significant effect that age and
education can have on what is considered a “normal” per-
formance on the test. However, it should be noted that
the administration procedures in the normative study are
different from those described in the test manual, mak-
ing use of the normative data questionable for the copy-
righted version of the MMSE. Therefore, even when using
abbreviated instruments it is necessary to ensure that the
administration methods are appropriate to the norma-
tive data and that the normative data are appropriate for
the individual patient.
As mentioned previously, neuropsychological testing
can be seen as a more extensive and expansive—albeit
more time consuming—extension of mental status test-
ing. Similarly to mental status testing, neuropsychologi-
cal assessment can be done using a series of individual
instruments chosen for the specific referral question or for
appropriateness to the patient. Alternatively, a “compre-
hensive instrument” (Neurological Assessment Battery,
Halstead–Reitan Neuropsychological Battery, Wechlser
Adult Intelligence Scale, etc.) can be used in which the
subtests are all designed to work together (e.g., minimize
interference effects) and are co-normed which facilitates
profile interpretation. A survey of the most common neu-
ropsychological instruments can be found in Rabin et al.
(2005).
Utility of neuropsychological
assessment
Neuropsychological assessment in a geriatric population
can be used for many purposes, but the major applica-
tions fall into three broad categories: diagnosis, effect on
function, and treatment.
100 Assessment of the Geriatric Neurology Patient
Diagnosis
Incorrect diagnosis of an incurable degenerative disease
(false positive) can cause unnecessary stress, pain and
inappropriate choices (financial and social) to the patient
and their family. Conversely, early detection of dement-
ing disorders can have a significant positive effect on the
patient and their family. It has been suggested that starting
treatment early in the course of a dementia optimizes the
treatment effects of medications and allows positive life-
style changes that may slow the decline, although results
of early treatment have been variable (Holt et al., 2009;
Assal and van der Meulen, 2009). Accurate early detection
also has the practical benefit of allowing the patient and
their family to make future plans while the patient is still
cognitively intact. Reaching early agreements on when to
restrict driving, developing safe habits and routines that
may carry forward into the moderate stages of dementia,
and other social and treatment interventions can enhance
the long-term quality of life of the patient and caregiver
(Gessert et al., 2000; Papastavrou et al., 2007).
Along with early and increased accuracy of detection of
suspected dementia, neuropsychology can contribute to
differential diagnosis of the underlying processes. While
AD is the most common cause of dementia in the elderly,
there are many other disease states that can cause dementia
with significant implications for treatment and outcome.
One of the most apparent differentials is when cogni-
tive decline is caused by a delirium rather than a demen-
tia. Delirium is often the result of an underlying medical
condition that is often treatable (unlike most progressive
dementias); however, if left undetected it may progress and
be life-threatening. Differentiating between degenerative
dementias can also have significant clinical utility. Perhaps
the second most common cause of degenerative dementia
is Lewy body disease (LBD). While it may often be found
to have comorbidity underlying AD pathology, there are
differences in presentation and cognitive profiles that can
be used to increase the diagnostic certainty (McKeith et al.,
2005). The clinical treatment implications are significant in
those patients with LBD who show increased sensitivity to
neuroleptics and, when used for treatment of agitation, can
result in permanent rigidity (Weisman and McKeith, 2007).
Treatment implications of differential diagnosis are of
course not limited to medications, but include social inter-
ventions, rehabilitation, and family planning. For example,
AD and FTD have different presentations, progressions,
and treatments (Salmon and Bondi, 2009). Issues on what
the family can expect through different stages, prediction
of possible dangerous situations and behaviors, and cop-
ing programs can be quite different.
Assessment of functional limitations
The impact of the cognitive deficits on a patient’s ability
to function and related safety issues can also be informed
by neuropsychological assessment. While the structure of
most psychometric tests are geared toward measurement
of cognitive abilities, some test batteries have attempted
to include items that are ecologically valid measures of
day-to-day functioning (Farias et al., 2003). However,
while neuropsychological assessment can inform the
level of function and track changes over time, it is not a
replacement for direct evaluation (e.g., on road driving
tests (Brown et al., 2005)). This in part may be due to the
structured nature of the assessment instruments and the
controlled environment in which the testing is adminis-
tered. While this is necessary for accurate measurement of
function, it does not reflect the complex and multimodal
environment patients may find themselves functioning
in. For example, in driving aspects of attention, reaction
time, processing speed (monitoring the environment,
observing traffic signals, traffic conditions), memory and
orientation (getting lost), visual–spatial skills, and execu-
tive abilities (EA) (decision making with regard to other
drivers and road conditions) are all involved in effective
performance. Many patients with early Alzheimer’s dis-
ease (AD) may be able to drive safely in well-known areas
as long as no confusing or conflicting elements occur in
their environment since much of driving skill involves
procedural memory that tends to be spared in the early
stages of this disease. However, if the patient suddenly
comes upon extensive road work with multiple lane
restrictions or finds themselves in an unfamiliar area,
other cognitive abilities that are affected by the disease
(e.g., frontal executive) are necessary, and a dangerous
situation could occur. Neuropsychological test results can
be a useful adjunct to determination of functional prob-
lems, but are insufficient in and of themselves (Iverson
et al., 2010).
Competency is a legal term but is usually based on clin-
ical information. In essence, it reflects the patient’s abil-
ity to make a decision, have a rationale for the decision
and appreciate the consequences of that decision (Mar-
son et  al., 2001; Moye and Marson, 2007). Competency
itself can have multiple areas—such as the ability to make
financial decisions, medical decisions and self-care—and
a patient may be competent in one area and incompetent
in another. As in other aspects of determination of func-
tion, neuropsychological assessment can aid in the deter-
mination of competency by providing information on
deficits in various cognitive domains, but is not in and of
itself sufficient.
Treatment
The importance of neuropsychological testing for treat-
ment extends beyond differential diagnosis or the detec-
tion of comorbid processes. While it is certainly important
to determine the presence of a disorder before treating it
(e.g., MCI), and it is important to make sure the correct
disease is being treated (e.g., AD vs. LBD), the pattern of
strengths and weaknesses a patient presents is important

in any cognitive remediation or social intervention strate-
gies. For example, if memory is a central issue, then elec-
tronic reminders to take medications along with written
notes can prove helpful. Determination of the memory
system affected can further guide intervention as the
type of difficulty (encoding information vs. storage vs.
retrieval) can have significant effects on the type of inter-
vention that will prove most effective (Bayles and Kim,
2003). For example, written notes—while very useful in
patients with AD—lose their impact if the patient devel-
ops an undetected Alexia.
Most interventions in degenerative dementias concen-
trate on compensation and coping strategies, which will
be under constant modification as the course of the dis-
ease progresses (Ptak et al., 2010). Patients who have had
a stroke, traumatic brain injury (e.g., auto accident, falls),
or who are post CNS surgery can benefit from more tradi-
tional rehabilitation treatments that seek to augment the
normal recovery process. A critical step in this treatment
is the identification of specific cognitive areas of impair-
ment and remaining areas of strength (Yamaguchi et al.,
2010).
Cognitive domains in neuropsychology
Multiple approaches, models, and theories have been
created to organize and explain mental processes. In
clinical practice, five general cognitive domains that are
widely recognized include: attention, language, memory,
executive abilities, and visuospatial abilities.
Attention, orientation, concentration
Assessment of attention varies from clinic screening to
longer duration and precision computerized testing to
inferential imaging (i.e., ERP, PET, fMRI, and SPECT).
Attention is a primary component of multifactorial cogni-
tive processing; however, there is no pure test for atten-
tion and there is no test that assesses all components of
attention. Like other cognitive domains, attention is not
a unitary construct and while some measures are very
sensitive, attentional profiles lacks specificity; however,
before interpreting attentional problems arousal and ori-
entation must be adequate (see also previous section on
mental status testing).
Orientation in clinical use can range from a basic aware-
ness of self, body, and immediate environment to under-
standing of time, place, and purpose. At its most basic,
the construct of orientation overlaps with that of alertness
and vigilance. Clinical assessment usually involves basic
questions of person, place, and time (oriented × 3). Atten-
tion requires that sensory events must first be detected
and oriented to, although at the most basic level this may
Neuropsychology in Geriatric Neurology 101
be involuntary. This requires the individual to be suffi-
ciently aroused and have sensory awareness. Those who
are sedated or obtunded will have problems with the first
step of attention.
Attention is a complex construct and there exist many
cognitive models dividing attention into subtypes (i.e.,
selective attention, sustained attention, and divided
attention) and may overlap with the concept of alert-
ness/vigilance on one end and working memory on the
other. Selective attention is the process by which indi-
viduals preferentially select relevant, salient stimuli
over less germane ones. Humans are remarkably fac-
ile in filtering irrelevant stimuli, but this may become
compromised with normal aging, cerebral insults, or
degenerative processes. After a stimulus is selected, sus-
tained attention allows for the maintenance of vigilance,
focused attention, and response persistence. In sustained
attention, tasks measure the ability to hold information,
concentrate, ignore other stimuli, and perform mental
operations (see also working memory). In mental status
testing, the “A” letter test can be used to test sustained
attention where a list of random letters is read to the
patient and is asked to tap the table every time they hear
the letter “A”. Neuropsychologists use tests that may
last from 5 (i.e., digit vigilance test) to 30 minutes (i.e.,
computerized continuous performance tests). These tests
allow the patient to focus their attention on one task,
but there are other measures that assess the ability to
divide attention across two or more tasks, divided atten-
tion. Divided attention is not often challenged within the
clinical setting, but some neuropsychological paradigms
assess this (i.e., paced addition serial attention test, and
consonant trigrams) (Gronwall, 1977; Morris, 1986).
Intact attention is a prerequisite for cognitive func-
tion in any of the other domains. Clinically, impairment
in attention may be reported by the patient or family
as memory disturbance (encoding) or lack of effort.
Patients with poor attention may complain that they
are unable to remember information, but formal testing
may reveal that they are unable to attend to verbal or
visual information. For example, they may notice that
after reading a page they are unable to “remember”
what they have read; however, attentional impairment
may render them unable to direct their attention to the
information to be encoded, thus, it is not a true memory
deficit. This level of differentiation (i.e., attention ver-
sus memory) may only be evident with detailed neu-
ropsychological measures. Even within healthy aging,
attentional resources lessen. This is typically noted in
the diminished ability to attend to multiple stimuli at
the same time (i.e., divided attention). Patients may
complain of the inability to carry out conversations,
because they are unable to focus or are easily dis-
tracted, but this may be a “normal” finding of healthy
aging until it begins to affect function.
102 Assessment of the Geriatric Neurology Patient
Within a clinical population, attention can be used
to distinguish general disorders within the elderly. For
example, in AD, attention tends to be relatively bet-
ter preserved than many other cognitive domains (i.e.,
memory and EF), but attention is more impaired than
in healthy individuals (Rizzo et al., 2000a, 2000b; Peretti
et al., 2008; Duchek et al., 2009). In contrast, attention is
proportionately more impaired in Lewy body dementia
(DLB) than in AD and significant fluctuation in attention
are core characteristics of delirium (Ballard et al., 2001).
Significant impairments of attention up to and including
an acute confusional state, can be seen in metabolic dis-
orders, intoxication, mania, fatigue, psychosis (distracted
from internal stimuli), chronic sleep disorders (i.e., sleep
apnea) and multifocal disorders (i.e., meningitis, enceph-
alitis, acute traumatic brain injury). Because there are
several components to attention, and models involve
multiple neurosubstrates, lesions or neuropathology to
almost any area of the brain may produce a disorder of
attention (or a component of attention).
Although most clinic attention assessment is within
the verbal domain, spatial inattention may be evident in
office screening. An example of verbal attention is a Digit
Span task. Reciting a progressively longer sequence of
digits (digits forward) is seen as a test of simple atten-
tion, and reciting the digit sequence in reverse order
(digit backward) as a test of more complex attention,
which overlaps with the construct of working memory.
WORLD backwards and serial sevens in the mini-mental
state examination (MMSE) are other examples of brief
measures of attention. Information may be briefly held
within working memory, but this is not necessarily stored
for later memory retrieval. A simple spatial task that can
be done within a few seconds is the line bisection test. The
patient is asked to draw a perpendicular line in the center
of the lines drawn on the paper. Figure 4.1 demonstrates
left hemispatial inattention. Not only did the patient omit
drawing the bisecting line in the page’s left hemispace,
the lines they bisected in right hemispace were inaccu-
rately bisected.
Figure 4.1 Line bisection test.
Language and communication
Human expression and communication occurs through
a variety of modalities including speech, writing, read-
ing, drawing, and gestures. Three features can be used
to generally classify broad aphasia subtypes: expres-
sion, reception, and repetition. Although the term apha-
sia (absence of speech) is commonly used and will be
used in this section, in most cases dysphasia (impaired
speech) is more accurate. Informal language assessment
begins during the initial interaction and interview; how-
ever, subtle deficits may only be identified with further
screening or a comprehensive, systematic approach.
Practitioners should observe the quantity and quality of
speech fluency, prosody, articulation, and grammar. As
with any other part of the neurologic/neuropsychologi-
cal examination, aberrant findings should be viewed in
the context of other findings. For example, what may
appear to be comprehension problems may be secondary
to psychiatric or other factors (i.e., poor output second-
ary to depression, minimal motivation, negative attitude,
poor hearing, etc.).
Normal expressive speech should include fluent, spon-
taneous discourse. Expressive changes may range from
mild to profound. Mild paraphasias may be subtle, but
at the other end of the spectrum a patient may be com-
pletely unable to produce verbal language. Most lan-
guage screening includes asking the patient to name
items. Spontaneously naming items on confrontation
requires aspects of object recognition, item identifica-
tion, retrieval, and expression. It is also important to
note that although a patient is unable to name an object,
this may be due to a retrieval deficit, rather than anomia.
In the case of a retrieval deficit, although the person is
unable to spontaneously name the item, he/she would
be able to do so with a phonemic cue (i.e., cuing them
with “com…” for “computer”). In the latter case, ano-
mia, they would be unable to generate the word even
with a cue. Most clinical screening measures include
some aspect of naming (i.e., MMSE, SLUMS, etc.).
Neuropsychological assessments commonly include the
Boston Naming Test (60 items) or other standardized
naming tools.
An often-overlooked aspect of language is automatic
speech that includes overlearned sequences and phrases.
Even when patients may have profound expressive lan-
guage loss, automatic phrases like “hi”, or sequences like
counting or singing the alphabet may be less impaired.
Also, the automatic nature of overlearned songs (like
“Happy Birthday”) can be performed when other speech
is absent. Even when a patient is able to sing the alphabet,
they may be unable to speak it without the prosodic tune.
Comprehension deficits may be more difficult to identify
than expressive ones. Patients display nonverbal commu-
nication (e.g., head nodding) that may mislead others to

believe they understand what is being said when such is
not the case. Practitioners may contribute to the problem
in using their own gestures when asking a question (e.g.,
nodding affirmatively when asking if the person is having
a good day or marriage). Comprehension can be assessed
in several ways including, yes–no responses, responsive
answers, pointing to responses, and simple commands;
however, errors may not be apparent unless complex
questions are asked. Simple yes–no questions may be
needed for those with significant receptive aphasia (i.e.,
“Is your name Jane?”). Increasing complexity includes
“Are the lights on in the room?” With greater complex-
ity, responsive answers require greater understanding
and expression (i.e., “the colors of the flag are red, white,
and  _____”). However, when expression is impaired,
patients may be unable to verbally respond to questions,
so asking them to point toward objects and follow com-
mands can be done. When asking a patient to point or
follow commands, however, it is important to rule out
pointing errors related to apraxia or agnosia.
The third essential language area is repetition. Repeti-
tion of sounds, words, phrases, and sentences should be
assessed. Like expression and reception, patients may
display deficits with only complex items. On the simple
end, noncomplex words can be repeated (i.e., car, house,
etc.). Phrases and sentences offer a greater range of com-
plexity (i.e., “Methodist Episcopal… The door to the office
is closed… No ifs, ands or buts… The phantom soared
across the foggy heath”).
Because of the proximity of other cerebral structures
to eloquent cortices, association cortices or fasciculi
make it possible that other communication deficits
may be present. Although not core pieces of subtyp-
ing aphasia, the neurologic examination may or may
not include academic tasks of reading, writing, and
arithmetic (functions associated with association areas
around the supramarginal gyrus). Because of frontal
and parietal proximity to language eloquent cortices,
motor and sensory dysfunction is common. Reading,
writing, and arithmetic may produce functional limita-
tions, but are often not fully assessed, but changes may
occur due to their proximity to association cortices.
Alexia, apraxia, and agnosia are associated findings
that are typically assessed in a neuropsychologist’s
comprehensive aphasia battery. Also, neuropathologic
correlates may be associated with alexia with (central)
or without (posterior) agraphia.
Many of the language tasks mentioned in the mental
status examination section are used in neuropsychologi-
cal screening (i.e., the Reitan–Indiana Aphasia Screening
Test), but the neuropsychologist’s assessment armamen-
tarium also includes comprehensive batteries including
the Boston Diagnostic Aphasia Examination, Multilin-
gual Aphasia Examination, Western Aphasia Battery,
and a variety of other measures. Each tool assesses
Neuropsychology in Geriatric Neurology 103
expression, reception, and repetition, but vary in their
measures of apraxia, reading, writing, and agnosia.
Also, some tasks are specific to one modality (i.e., com-
prehension). Neuropsychologists may use a tool like the
Token Test to measure aspects of receptive dysfunction.
For the Token Test, an array of various colored and sized
shapes is presented, and the patient is asked to follow
commands such as “touch the small red square with the
large blue circle.”
Once assessment of the disruption and/or preserva-
tion of language components is completed, an aphasia
syndrome may be evident. Acute expressive and recep-
tive changes are most commonly associated with vascu-
lar events; however, progressive changes can occur with
degenerative disorders. There are many models and
nosologies applied to language syndromes, and although
described as discrete syndromes within the literature, they
rarely occur in their purest forms. Generally, acquired lan-
guage disorders can be separated into expressive, recep-
tive, and mixed aphasias (Table 4.1). There are myriad
models of language and aphasia with most language
researchers identifying at least five types of aphasia. The
distinctions vary in the presence or absence of deficits in
expression, reception, and/or repetition.
The most common term associated with expressive
aphasia is Broca’s aphasia, a nonfluent aphasia. Because the
underlying problem is language based, it differs from the
articulation or motor aspects of speech, as in dysarthria
or verbal apraxia. Agrammatism is the primary feature of
Broca’s aphasia, where speech is labored and disjointed.
Anatomically, Broca’s aphasia involves damage to Broca’s
area (Broadmann area 44 and 45), which is within the dom-
inant, posterior inferior frontal gyrus. In Broca’s Apha-
sia connector words are often omitted, making speech
telegraphic. For example, a patient may describe their
appointment as, “Hospital… two o’clock… Dr.  Smith.”
Verbs and prepositions are omitted in this example. In
Broca’s, comprehension is relatively preserved, but rep-
etition is impaired. The latter point is the differential char-
acteristic from Transcortical Motor Aphasia. Transcortical
Motor Aphasia is a nonfluent aphasia, similar to Broca’s,
but repetition is not impaired.
Table 4.1 Aphasias
Expression Reception Repetition
Expressive aphasias
Broca’s or nonfluent aphasia − + −
Transcortical motor aphasia − + +
Receptive aphasias
Wernicke’s or fluent aphasia + − −
Transcortical sensory aphasia + − +
Conduction aphasia + + −
Global aphasia − − −
+ = intact; − = impaired.
104 Assessment of the Geriatric Neurology Patient
Wernicke’s aphasia (a receptive aphasia) is a fluent apha-
sia, involving impairment of receptive language and
repetition, but sparing in expressive speech. Anatomi-
cally, it is thought to involve Wernicke’s area (Broadmann
area 22), an area in the posterior part of the superior tem-
poral gyrus in the dominant hemisphere. Because the
patient is unable to understand oral language, they fail to
appreciate their own spoken language errors, tending to
use real words, but their speech may be incomprehensi-
ble or frequent errors are evident. Their mixture of errors
may produce a “word salad”. Similar to Wernicke’s apha-
sia, transcortical sensory aphasia produces fluent speech
and impaired comprehension; however, repetition is not
impaired.
Conduction aphasia occurs when a patient has spared
expression and reception, but repetition is impaired.
This suggests a disconnection of primary expressive and
receptive cortices and involvement of the arcuate fascicu-
lus, although this has recently been brought into question
(Bernal and Ardila, 2009).
In these acquired aphasia syndromes, the most common
etiologies of aphasia syndromes in the elderly are cerebro-
vascular accidents, and the most common vascular terri-
tory associated with aphasia is the middle cerebral artery.
While cortical lesions are most commonly associated with
aphasia, subcortical lesions may also produce aphasia.
Aphasia can also occur as a primary or secondary feature
of dementia. For example, primary progressive aphasia
and semantic dementia may be categorized as subsets of
FTD, and their primary presentation is that of language
dysfunction.
Verbal and episodic memory
Memory is a complex construct that has many different
but overlapping conceptual models. Terminology varies
widely depending on the orientation of the model and
some are listed in Table 4.2. The major approaches to clas-
sifying memory and the associated terminology are dis-
cussed below.
Table 4.2 Examples of terminology used in conceptual models
of memory
Declarative Explicit
Nondeclarative Implicit
Episodic Representational
Semantic Dispositional
Procedural Familiarity
Skill learning Reference
Immediate Short-term
Secondary Long-term
Primary Conditioning
Working Priming
Temporal model
One approach for classifying memory is to conceptual-
ize it as an organization of systems for progressively
longer periods of storage. In this approach, after attend-
ing to a stimuli (see attention, orientation, concentra-
tion section above) a representation of the material is
kept in an immediate memory store. In immediate mem-
ory the information is stored for only moments. This
memory store is limited not only in time but also can
only hold a limited amount of information. This con-
struct significantly overlaps with that of attention and
working memory. For example, recalling a sequence of
numbers immediately after presentation (e.g., digits
forward) is  seen as a test of attention (“digit span” is
sometimes used synonymously with attention span),
but also meets the definition of immediate memory.
Working memory is also seen as a very short-term store
of information where bits of information are held while
they undergo mental manipulation. Working memory
can also overlap with concepts of attention and other
constructs (e.g., some definitions of short-term mem-
ory). In a test sometimes used to measure “complex”
attention, the patient is asked to repeat a sequence of
numbers in reverse order (digit backward) that requires
them to briefly hold the numbers in memory while
manipulating their order. More complex versions of
this (ordering sequences of numbers and letters, paced
serial addition tasks) can detect subtle cognitive defi-
cits, but tend to be nonspecific because of the overlap-
ping constructs (sustained attention, immediate mem-
ory, working memory). Regardless, immediate memory
can be conceptualized as a momentary memory that
will be quickly degraded unless it is immediately
refreshed (e.g., rehearsal) or transferred into a long-
term memory store.
A second temporal stage is short-term memory. This term
is sometimes used synonymously with immediate mem-
ory in that it is the acquisition and retention of a memory
trace for a measureable but brief period of time. The exact
time period this term refers to is highly variable and some
authors argue that it is not a meaningful construct as it
may use the same neuroanatomic system as long-term
memory, and therefore simply be a different stage of the
same process (Brewer and Gabrieli, 2007). However, for
clinical purposes short-term memory is usually defined
as the retention of the material for a period of seconds
to a few minutes. Thus, in a task requiring the patient to
learn a list of words over a series of trials, the increase in
the number of words recalled after each presentation (e.g.,
learning) is an aspect of short-term memory. The recall of
the words after a delay of a few minutes—whether or not
an interference list is given—has also been termed short-
term recall.
The next temporal stage is long-term memory. As
it implies, this term refers to the semipermanent to

permanent storage of information over long periods of
time. Again, there is no absolute minimum or maximum
time frame that this term refers to. In clinical practice,
retention of material after 20–30 minutes is said to enter
long-term memory, although degeneration of the mem-
ory trace certainly continues after that point. Notably,
significant disruption of long-term memory for hours
or days prior to head injury (e.g., retrograde amnesia)
indicating that the laying down of long-term memories
(consolidation) is a continuing process. Remote memory
is usually taken as a period of autobiographic memory
(in geriatrics where the patient grew up, worked, was
married, etc.), although this may also vary consider-
ably between authors and often is simply considered an
extension of long-term memory.
Characteristic model
Another theoretical model has shown some success in
parceling long-term memory into divisions based on
the characteristics of the memory and the way they are
expressed (Tulving, 1972; Schacter and Tulving, 1994;
Squire and Knowlton, 1994). In this context, long-term
memory is taken as the memory that has been consoli-
dated and exists in a more stable form than immediate or
short-term memory. The basic structure of this model is
as follows.
Declarative (explicit) memory: This type of memory involves
the conscious recall of previous experiences. Two main
divisions of this type of memory are episodic memory
and semantic memory.
• Episodic memory refers to the conscious recall of in-
formation linked to specific events (or episodes) that
occurred in a specific context (time and place). Memo-
ries of specific instances from where someone grew
up, went to school, a conversation with one’s spouse
a week ago, what they had for breakfast today, or of
a list of words they have read several minutes ago are
examples of episodic memory.
• Semantic memory refers to general knowledge about
the world such as vocabulary, facts and concepts that
are not contextually dependent. How we organize the
world and its inter-relationships is an important aspect
of this type of memory. For example, chairs may have
very different forms, but we are able to associate them
under the concept “chair.” Memories that have become
generalized out of specific context (such as where one
lived, who one’s relatives are) are also classified in this
system (Warrington and McCarthy, 1988).
Nondeclarative (implicit) memory: This type of memory
is defined by a memory trace that is not consciously
recalled and manifests in behavioral changes such
as abilities (skill learning or procedural memory),
habit formation, or priming effects. The ability of
amnesic patients to alter behavior based on past
Neuropsychology in Geriatric Neurology 105
events without conscious recall of those events has
led to distinguishing this system from the episodic
memory system (Mosccovitch, 2004). Several sys-
tems classified under implicit memory are clinically
relevant, with procedural memory being perhaps the
most important for patient functioning (Squire and
Knowlton, 2000).
• Procedural memory is based on learned abilities that
we perform without conscious recall. Riding a bicycle,
reading, writing, etc., are activities that we perform
without conscious remembrance of the event or se-
quence. These abilities are often intact in dementia and
other amnesic syndromes.
• Priming phenomena can be seen as a nonconscious ac-
tivation of memory traces that influence responses in
ambiguous situations. The classic experimental dem-
onstration of this is when subjects are asked to gener-
ate whole words from word fragments. Subjects tend
to generate more words that they had been recently
exposed to (primed) than other words that may be of
higher frequency.
• Classical conditioning is one of the earliest theories
of learning in experimental psychology. It is based on
the linking of a stimulus to an associated stimulus such
that the presence of the associated stimulus alone will
produce a similar response to that seen with the origi-
nal stimulus.
Animal studies and work with brain-damaged patients
have indicated that different neural systems and struc-
tures underlie the different memory types above, sup-
porting the validity of the model (Squire and Zola, 1996;
Squire, 2009).
Modality model
The nature of the stimulus can also be used to define
memory systems. There is some evidence from imaging
studies as well as patients with brain injury that differ-
ent sensory systems use different storage networks in the
brain (Wheeler et al., 2000). Clinically, verbal memory and
visual memory are the modalities most often assessed.
However, it should be noted that obtaining a “pure” mea-
sure of either is difficult as patients may verbalize the
visual stimuli (e.g., describing drawings) and some may
visualize the verbal material (e.g., visually linking items
from a list). Other modalities have been assessed in the
research literature, but are not commonly assessed sepa-
rately in clinical practice.
Stage model
Clinically, a useful way of thinking of the memory pro-
cess is by organizing it into a series of stages. Encoding
(acquiring the memory), storage/consolidation (transfer-
ring into long-term stores) and retrieval (accessing the
memory either into consciousness or as evidenced by
106 Assessment of the Geriatric Neurology Patient

behavior) is often used as a general guideline when con- memory self-monitoring-related phenomena (Pannu
ducting an assessment. and Kaszniak, 2005). Prospective memory is the ability to
remember to do something in the future (either time or
Encoding: Seen as the initial stage in memory formation,
event based), and involves not only declarative/episodic
encoding includes several processes. The patient must
memory but also frontal EFs such as self-monitoring (Fish
first attend to the particular stimuli to be encoded; this
et al., 2010).
information is processed by the appropriate modal-
While the above terms may be derived from different
ity systems (e.g., verbal, visual, etc.) and linked with
models of memory, they are complimentary and can be
associated stimuli (context). This is usually seen as
used together. In clinical practice, measurement of mem-
an active process as opposed to a passive reflection
ory weighs heavily on verbal episodic memory tasks with
of sensory information (Blumenfeld and Ranganath,
visual episodic memory also assessed, but often to a lesser
2007).
degree. Semantic memory can be assessed, but it is often
Storage: Consolidation is the transfer of the processed
done as part of the language examination (e.g., category
memory into a form that can be maintained over time
fluency). In geriatric neuropsychology the most com-
without conscious rehearsal. Rather than a unitary pro-
mon tests of memory include learning lists of words (Rey
cess, consolidation appears to take place by multiple
Auditory Verbal Learning Test, California Verbal Learn-
functional systems, molecular mechanisms, and struc-
ing Test, Hopkins Verbal Learning Test-Revised) or short
tural changes. Further processing of the memory may
stories (WMS logical memory), although there are multi-
occur at this stage and some authors have suggested
ple variations on administration (e.g., repeating the entire
that the postencoding process may continue to operate
word list versus selective reminding—repeating only the
for years as new information is acquired and linked to
words not recalled on the last trial) and the nature of the
previous memories (Brewer and Gabrieli, 2007). De-
stimulus (unrelated word lists, semantically related word
layed proactive interference and retroactive interference ef-
lists, etc.). Most of these tests follow the initial learning
fects seen in normal individuals and retrograde amnesia
stage with a free recall after a few minutes delay (short-
that may occur for hours or days prior to brain injury
term delay) and after a longer delay of 20–40  minutes
appear to support this.
(long-term delay). Multiple variations in delayed recall
Retrieval: Retrieval of an encoded and stored memory
conditions are also present including cueing trials, rec-
may take several forms in clinical assessment. Free re-
ognition trials and/or forced choice trials (e.g., choose
call is the ability to bring to consciousness a memory
between the target word and one distractor word). In
without any external or related associated stimulus
addition to individual instruments, most comprehensive
(reminders). Cued recall involves the presentation of
memory batteries will contain these elements (Repeatable
an associated stimulus to aid in recalling. Many mne-
Battery for the Assessment of Neuropsychological Sta-
monic techniques will involve associating an external
tus; Wechsler Memory Scale; Wide Range Assessment of
stimulus with an item to be remembered to both en-
Memory and Learning, etc.).
hance encoding and recall (e.g., a person’s facial feature
with their name). Clinically, cued recall may be done by
providing semantic cues (the word was a type of fruit),
Executive abilities/function
phonemic cues (it began with the sound a…), or oth-
ers (there were two figures on the page). Recognition is
The frontal lobes comprise about 30% of the cortical sur-
a third clinically useful construct where the patient is
face, and EAs/EFs are an important component of fron-
presented with the actual target item and several dis-
tal lobe functioning. Many structures (i.e., temporal lobe,
tracters and asked to identify the original item. Differ-
basal ganglia, cerebellum, etc.) have reciprocal projections
ences in the relative performance on free recall versus
to the frontal lobes, so damage or disconnection to or from
recognition tasks have been suggested to be useful in
these areas may result in executive dysfunction (Ravizza
differentiating between some progressive dementias
and Ciranni, 2002). There is no uniformity in the way
(see preclinical diagnosis of dementia section below).
EFs  are defined, conceptualized, or measured; however,
Familiarity is a related but slightly different construct. In
EAs are broadly related to the higher-order functions that
familiarity the patient is aware of having encountered
co-ordinate and manage other cognitive processes and
the stimulus before, but is not able to attach any context
allow individuals to engage in goal-oriented behavior. EF
to the memory (e.g., source memory).
is measured by behavioral outflow, but involves the steps
Other terms and models exist for memory but they are from ideation to behavioral execution. EF cannot be sim-
less often used in clinical practice and some suggest the ply measured by asking patients what they would do in a
integration of several domains and complex neural cir- certain circumstance, since ideation may be disconnected
cuits. Metamemory is a complex construct that includes from the actual behavior. Patients may be able to verbal-
judgment of learning, feeling of knowing, and other ize what they should do, but they are unable to carry it

out. Efficient EAs allow interaction with the environment
by developing and implementing effective strategies
while inhibiting impulsive, ineffective strategies. Behav-
ior must be analyzed and modified according to internal
and external feedback.
There are discrete components to EF and as with other
models of cognitive functioning there are multiple theo-
retical models of EF (Norman and Shallice, 2000; Miller
and Cohen, 2001). Although separate from other cogni-
tive domains, EAs are both independent and interdepen-
dent from other domains. Aspects of EF are included in
Table 4.3. Neuropsychologists use different measures and
techniques in attempting to isolate these features; how-
ever, task demands make this difficult or impossible. Most
cognitive measures are multifactorial and require several
aspects of EF in addition to other domains. Behavioral
disturbance can be manifested in components of inhibi-
tion, problems stopping a behavior, difficulty in making
mental or behavioral shifts, concrete thinking, and defi-
cits in self-awareness assessment.
Initiation involves spontaneously starting ideation and
behavior. When there is severe impairment in ideation,
patients fail to start thinking or acting. Family members
describe that they have stopped doing activities that they
once enjoyed (i.e., hobbies, reading, etc.), and they may
sit for extended periods of time without doing anything.
Within the clinical setting, they lack spontaneous speech and
may appear lethargic and apathetic. Fluency is a common
metric for assessing initiation within the clinic, but a poor
score may be related to other factors (i.e., retrieval, aphasia,
semantic loss, etc.). As it relates to initiation, verbal or design
fluency may be diminished because of the lack of spontane-
ous creativity, and patients have slow, minimal output.
Once a behavior is started, EAs then must stop the ongo-
ing behavior. The established response tendency must be
inhibited and unwanted responses resisted. Problems in
suppressing activity can result from impulsivity, disinhi-
bition, or over-reactivity. A simple clinical technique for
assessing behavioral disinhibition is a go/no go paradigm. In
screening, a patient can be told to tap his/her leg once when
the examiner touches their leg twice and vice versa. The
task requires the suppression of copying the examiner’s
behavior as well as maintaining the alternate pattern.
Several neuropsychological tests may pull for inhibition,
including proximity errors on Trail Making B and commis-
sion errors on computerized continuous performance tests.
Table 4.3 Functions subsumed under executive functioning (EF)
Organization Abstract thinking Inhibition
Planning Cognitive flexibility Selecting relevant stimuli
Problem solving Initiation Strategizing
Managing time
and space
Neuropsychology in Geriatric Neurology 107
Individuals with executive dysfunction may also have
a deficit in mental or behavioral shifting. Inflexibility, cogni-
tive rigidity, being “stuck” in a response set, and perse-
veration are hallmarks. Asking patients to do a task and
then having them shift their thinking can elicit evidence
of inflexibility. Most neuropsychological tests of EF (i.e.,
Halstead Category Test, Wisconsin Card Sorting, etc.) do
not tell patients what the rules are, and do not tell them
when the rules have changed. Thus, the patient is not only
required to solve the problem to find the correct response
set, but they must then alter their thinking and behavior
in response to negative feedback.
When one examines the quality of error responses, a
pattern of concrete thinking may be apparent. Concrete
thinking may appear as literal explanations and interpre-
tations. As opposed to “being stuck” in a response set,
patient responses lack a deep understanding of concepts,
and stimuli are taken at their obvious face value. Common
clinical assessment involves asking the patient similari-
ties, such as “In what way are an apple and orange alike”.
Concrete answers involve obvious physical characteris-
tics, like the fact that they are round or “can be different
colors”. At times, patients will respond with how they are
different (i.e., “one is red and one is orange”) or they may
personalize the response (i.e., “I like apples, but I don’t
like oranges”). A more integrated response will be the
identification that they are edible and an abstract under-
standing will be that they are both fruits. Longer forms
of the similarities task are found in neuropsychological
testing, in addition to other tests such as the 20-questions
and proverbs subtests of the Delis–Kaplan Executive
Functions System (Delis et al., 2001).
Self-monitoring and self-assessment are critical com-
ponents for effectively appraising oneself and using the
information to effectively alter behavior. In executive
dysfunction, patients may be unable to perceive their per-
formance errors, their impact on others, and lack social
awareness. They make errors, but are unable to accurately
recognize their poor performance. There is no formal test
to measure this ability, but asking patients to evaluate
their clearly poor performances is one way to assess this.
For example in Figure 4.2, the patient was asked to draw
a clock. After doing so, the patient spontaneously offered,
“I’m sure you can’t tell what it is, but it looks right to
me.” In this case, the patient appreciated that something
seemed wrong, but perceived the drawing as correct. This
lack of awareness of his impairment is anosognosia, and
can create problems when a patient wants to continue
activities in which they can no longer do well (driving,
cooking, finances, etc.).
Because patients may lack self-awareness or may inac-
curately assess personality changes, collateral interviews
may prove useful. Family members often raise this issue
as the most disconcerting change in dementia and fron-
tal cerebrovascular accidents. Social interactions may be
108 Assessment of the Geriatric Neurology Patient
Figure 4.2 Clock-drawing test.
marked with disinhibited, inappropriate responses, which
are changes from the patient’s premorbid status, but the
patient is unable to appreciate this. Also, sexual talk and
sexual behaviors (including public masturbation) may
occur. Rating scales, such as the Frontal Systems Behavior
Scale (FrSBE; Grace and Mallow, 2001) can help to detect
and group these behaviors, and provide some measure of
the patient’s insight into them. The patient completes an
FrSBE self-rating that can be compared to the ratings from
an informant who is in regular contact with the patient.
There is considerable variability to the behavioral man-
ifestations of EAs. Not all facets of EF can be measured
through psychometric testing, and there is considerable
variability among patients. Different conceptualizations
may have overlapping neuropathologic correlates and
interconnections. Common frontal subcortical pathways
mediate executive activities, speed of information pro-
cessing and working memory where executive control is
needed; however, these “frontal systems” may have sub-
systems. Miller and Cummings (1999) described three
circuits within the frontal lobe—orbitofrontal, dorsolateral,
and anterior cingulate. Persons with orbitofrontal injuries
may not demonstrate impairment on neuropsychological
testing, but they may display neurobehavioral manifes-
tations of irritability, impulsivity, disinhibition, and they
may show an inappropriate response to social cues, lack
of empathy, and over-familiarity. Dorsolateral lesions have
been associated with poor organizational strategies, poor
memory search strategies, stimulus boundedness, and
impaired set shifting and maintenance. Anterior cingulate
lesions may manifest in apathy, poor response inhibition,
and poverty of speech (Miller and Cummings, 1999). These
theoretical distinctions are infrequently seen in pure forms
because injuries and degenerative processes involve mul-
tiple frontal areas, and damage to other connected areas
may produce behavioral changes.
Executive dysfunction can interfere with the function-
ing of other cognitive (particularly memory) domains. For
example poor organization may be reflected in relatively
poor learning on a memory test that benefits from the abil-
ity to organize a word list into semantic categories (e.g.,
California Verbal Learning Test-II and Hopkins Verbal
Learning Test) (Delis et al., 2000; Brandt and Benedict,
2001). Thus, poor semantic organization (an EF) may be
related to a poor learning score on the CVLT-II. In contrast,
the same patient’s memory score may not be impaired on a
test that does not benefit from this organizational strategy
(i.e., Rey Auditory Verbal Learning Test, etc.) (Rey, 1964).
Similarly, a patient’s visual drawing memory score for
simple figures (i.e., Wechsler Memory Scale-III) (Wechsler,
1997b) may not be impaired, but their figure memory
score may be impaired on a task with high organizational
demand (i.e., Rey–Osterrieth Complex Figure) (Rey, 1941).
Functionally, expression of executive dysfunction may
be dependent on environmental demands. Older indi-
viduals who are still working may demonstrate changes
in organizing time, space, and multitasking beyond
what would be expected with normal aging. Colleagues,
friends, and family may notice these changes before the
person is aware of them. For those no longer working, sub-
tle changes may only be noticed by those living with the
patient, but subtle changes may affect self-care and safety
awareness to the point of the person needing a higher
level of care. Executive dysfunction may predict loss of
autonomy independent of—or more than—memory loss
(Royall et al., 2005; Tomaszewski et al., 2009).
Visuospatial abilities
As with other domains, visual processing and construc-
tion dysfunction can occur due to complex and multifac-
torial reasons, including perceptual, spatial, or processing
errors. For example, impairment in clock drawings may
be secondary to conception, perception, spatial analysis,
or construction. Efficient visuoconstruction relies on cere-
bral integration within the temporal–parietal–occipital
association areas. Thus, lesions or dysfunction in any of
these areas or within their interconnections by-produce
visual misperceptions, such as agnosias (color, familiar or
unfamiliar faces, and objects). In these instances, a patient
may incorrectly name an item they see. It is not uncom-
mon for misperceptions to be misconstrued as naming
deficits.
Visuoperception involves the detection, visual analysis,
and synthesis. Ware (2004) offers a three-step model of
 Neuropsychology in Geriatric Neurology 109

visual perception based on detection, pattern analysis,

and integration of attention and memory. In the first stage
objects undergo detection for color, texture, shape, and
spatial detection. In the second stage regional and simple
pattern analysis occurs, and in the third stage objects are
held in working memory by attention (Ware, 2004). Mish-
kin and Ungerleider 1982 theorized two pathways of
visual analysis—the ventral stream and the dorsal stream.
After visual information leaves the occipital lobe the ven-
tral stream projects to the temporal lobe and is involved
with object identification (the “what pathway”). Sym-
bolic representation takes place within the ventral sys-
tem, drawing from limbic and medial temporal memory
areas. The dorsal stream projects from the occipital lobe to
the parietal lobe where this “where pathway” processes
spatial location. Spatial awareness from the dorsal stream Figure 4.3 Clock-drawing test.
then guides meaningful actions (Mishkin and Ungerleider,
1982). The ventral and dorsal streams are theorized to be
interconnected, thus integrating visual information in
meaning and space; however, this theory is controversial In Figure 4.4, the patient was not only unable to cor-
because of the complexity of the visuoperception. rectly draw the house and cube in three dimensions,
The complexity of this system necessarily means that they demonstrated left hemispatial inattention, although
it does not localize or lateralize. Both hemispheres are they had full visual fields. The left side of the house was
involved with aspects of visual synthesis. Visual images missing, and the patient was unable to effectively scan
are processed as wholes and as parts. Delis et al., 1992 and to the left hemi space. This case highlights the difference
others describe that in analyzing complex visual stimuli, between a field cut (i.e., homonymous hemianopsia) and
the nondominant hemisphere analyzes configural (or hemi-inattention (also called visual inattention, visual
global) features. In contrast, the dominant hemisphere neglect or visual extinction); however, the presence of
processes visual stimulus details (or local features) (Delis the former increases the possibility of coexisting hemi-
et al., 1992). Differences in global–local errors were used inattention (De Renzi, 1978; Diller and Weinberg, 1977).
to identify asymmetric profiles in AD and other cerebral Greater hemi-inattention deficits are generally more com-
changes, and this emphasizes the importance of qualita- mon in acute stages of traumatic event (i.e., CVA) than
tive visual analysis. degenerative disorders.
Spatial cognition can be measured by many techniques
(i.e., discrimination, recognition, drawing, 2D and 3D
construction). Clock drawing and the MMSE figure are
common clinical office drawing tasks. Errors on these
relatively simple tasks can reveal qualitative subtleties,
and these qualitative features may illuminate underly-
ing conceptualization impairment or spatial inattention.
For example, in Figure 4.3, the patient was unable to con-
ceptualize the clock. This type of error is qualitatively
different from errors in which all the numbers are pres-
ent but misplaced (i.e., planning error). Also, persevera-
tion is evident with three numbers being repeated, and
the patient failed to appreciate how poor this drawing
was. Expanded neuropsychological visuospatial testing
may include noncomplex drawings (i.e., Benton Visual
Recognition Test, WMS-III Visual Reproduction Copy)
(Benton et al., 1983; Wechsler, 1997b) and complex draw-
ings (i.e.,  Rey–Osterrieth Complex Figure, Taylor Com-
plex Figure) (Rey, 1941; Taylor, 1969). Block construction
(i.e., WAIS-III Block Construction) and other measures are
commonly used for spatial cognition; however, the timed
nature of these tasks may affect the score (Wechsler, 1997a). Figure 4.4 House-drawing test.
110 Assessment of the Geriatric Neurology Patient
Clock, house, and cube examples of 2D and 3D con-
structional drawing are often used, but because they
involve motor skills, clinicians may not be able to rule out
a perceptual or motor deficit. Perception must be intact
for accurate drawings. Neuropsychologists may use
visual discrimination (Visual Form Discrimination Test)
and line orientation (Judgment of Line Orientation) to
assess nonmotor perception (Benton et al., 1983).
Facial recognition is a complex process, although it is
not typically assessed as part of the neurologic exami-
nation. Healthy adults can discriminate very subtle
aspects of facial features and expressions. Prosopag-
nosia is the inability to recognize familiar faces, but
impaired facial recognition can also occur in discrimi-
nating unfamiliar faces. Neuropsychological assess-
ment can measure facial recognition through a Famous
Faces Test, facial discrimination with the Benton Facial
Recognition Test (Benton et al., 1983), and facial recog-
nition with the Warrington Recognition Memory Test
(Benton et al., 1983). Higher-level visual integration can
be measured with the Hooper Visual Organization
Test (Hooper, 1958), where pictures have been cut into
pieces and must be mentally rotated and spatially inte-
grated before being recognized.
Neuropsychological profiles of disorders in
geriatric neuropsychology
The basis of using cognitive profiles to diagnose disease,
predict behaviors and guide treatment is the principle
that the cognitive deficits accurately reflect a character-
istic dysfunction or degeneration of the underlying neu-
ral network. For example, if the disease primarily affects
the hippocampal system then the cognitive profile should
reflect a primary episodic memory deficit. If the dorso-
lateral prefrontal regions are affected then an executive
dysfunction should predominate (Cummings, 1993). A
caveat to this concept is that if a morphologically defined
disease such as AD (presence of neuritic plaques and neu-
rofibrillary tangles) damages the brain in a distribution
other than what is prototypical for that disease (e.g., as
in a frontal variant of AD, with significant early neurode-
generation in the frontal lobes), then the cognitive profile
can be expected to reflect the neural degeneration pattern
rather than the disease etiology that underlies it.
The following sections provide a brief neuropsycholog-
ical overview of some common disorders that can affect
cognitive function in the elderly. The reader is referred to
individual chapters in this text for more details on each
disease.
Mild cognitive impairment
MCI is an attempt to detect dementia at an early stage,
prior to the impairments becoming clinically significant.
The basis for the diagnosis is performance in one or more
cognitive domains that are lower than expected for an
individual, but do not yet indicate a significant decline in
the ability to function. In the most widely utilized diag-
nostic guidelines (Petersen and Smith, 1999), four crite-
ria are set out for the diagnosis of MCI. Two of these are
based on interview (subjective memory complaint, no
significant decline in daily function), one is based on cog-
nitive assessment (objective impairment in one or more
cognitive domains) and one synthesizes these elements
(does not meet criteria for dementia). These elements have
been retained and further refined in a recent set of diag-
nostic criteria from a joint effort of the National Institute
on Aging and the Alzheimer’s Association (Albert et al.,
2011). Sources of variability in standardization of this
diagnosis include determining if a “significant decline in
daily function” exists (e.g., in the case of a retired senior
with multiple medical issues living in an assisted living
environment) and in the criteria for detecting an objec-
tive impairment in cognition. Because of this, diagnosis
of MCI has ranged from 10% to 74% depending on the
criteria used (Portet et al., 2006; Jak et al., 2009). While
the minimum level of objective cognitive impairment var-
ies in different studies, cut points of 1.0 or 1.5 standard
deviations below the mean are the most commonly used
(Albert et al., 2011).
MCI is not a unitary construct and various “MCI sub-
types” exist. The classic MCI profile is characterized by
impaired performance on standardized episodic memory
tasks (word lists, paragraph recall, selective reminding
test) and is denoted as amnesic MCI (aMCI). This profile
is believed to lead to the most common form of dementia
in the elderly, AD. MCI profiles that indicate nonmemory
systems primarily affected are designated as non-aMCI
and it has been suggested that the cognitive areas affected
have some predictive value for the type of dementia that
will develop (Petersen and Morris, 2005; Petersen, 2003).
For example, if the frontal executive domain is the most
severely impaired, then an FTD might be predicted. Often,
more than one area may show impairment and when
multiple cognitive areas are impaired, this is termed mul-
tidomain MCI. Multidomain MCI is sometimes further
broken down into a multidomain aMCI (characterized by
impairments in memory and at least one other domain)
and multidomain non-aMCI (characterized by relatively
intact memory performance, but impaired performance
in two nonmemory domains) (Petersen, 2003).
Since this diagnosis requires detection of deficits at
an early stage, tests that are prone to ceiling effects (e.g.,
MMSE, Mini-Cog) are often insufficient. Since the pre-
dominant form of MCI is the amnesic type (single or mul-
tidomain), verbal delayed free recall tasks with greater
sensitivity at the higher levels of function (e.g., Rey
Auditory Learning Test, California Verbal Learning Test,
Selective Reminding Test, WMS-R logical memory) tend
to be most sensitive to the early deficits (Jak et al., 2009;
Albert et al., 2011).

While there is some probabilistic validity of using MCI as
a predictor of incipient dementia, it is not entirely accurate.
Studies have shown wide ranges of sensitivity (46–88%)
and specificity (37–90%) in predicting conversion to AD
(Visser et al., 2005; Rasquin et al., 2005). Identification of the
underlying etiology by MCI subtype has also been shown
to be questionable (Jicha et al., 2006). Longitudinal assess-
ment showing further decline in cognitive function may
add to the diagnostic certainty; advanced imaging tech-
niques and biomarkers may further support the diagnosis,
but are not yet suggested for clinical use (Albert et al., 2011).
Alzheimer’s disease
AD is the most prevalent cause of dementia in the elderly.
It frequently is the primary etiology of the cognitive
decline, but also has a high co-occurrence with pathology
seen in other diseases such as LBD and vascular ischemia.
Its clinical diagnosis has traditionally been designated as
either “possible AD” or “probable AD”, with a diagno-
sis of “definite” AD reserved for autopsy confirmation of
the presence of the defining neuritic plaques and neurofi-
brillary tangles (McKhann et al., 1984; Storey et al., 2002;
Hort et al., 2010; McKhann et al., 2011). Revision of the
original NINCDS–ADRDA criteria (McKhann et al., 1984)
by a joint work group of the National Institute on Aging
and the Alzheimer’s Association kept the basic structure
of the probable and possible definitions for their clinical
criteria, while adding an additional division of research
criteria that incorporates imaging and other biomarkers
(McKhann et al., 2011). Cognitive testing with evidence
of impairment in two or more areas is required, with
neuropsychological testing recommended when bedside
mental status testing is not sufficient for a “confident”
diagnosis.
AD has been called the prototypical “cortical” demen-
tia because of the typical clinical presentation of impaired
episodic memory as the first clinical sign. The overall
cognitive decline is characterized by gradual onset and a
progressive course. Neuropsychological tests sensitive to
the typical AD presentation include learning and recall of
word lists or paragraph-length stories, with impairments
noted in learning, free recall, cued recall and recognition
of the material. In the early stages free recall may be the
most notably impaired, as recognition tasks often have
low sensitivity due to ceiling effects. As the pathology
spreads through the frontal lobes, executive dysfunction
is typically noted on such tests as category fluency and
Trails B. In the mild-to-moderate stages, performance
on category fluency (e.g., animals) is typically seen to
be more impaired than letter fluency, reflecting the early
involvement of the frontal systems and the later spread to
the language areas. Impairment in confrontation naming
can be clinically observed in the moderate stages, but can
be detected in earlier stages by instruments such as the
Boston Naming Test.
Neuropsychology in Geriatric Neurology 111
Frontotemporal dementia
FTD encompasses several conditions that are character-
ized by degeneration of the frontal and/or temporal lobes
(Pick’s disease, semantic dementia, primary progressive
aphasia, dementia lacking distinctive histopathology).
The most common presentation of FTD begins with per-
sonality and behavioral changes preceding or concurrent
with the cognitive decline. The nature of the personality
change varies, but may present as apathy (medial frontal/
anterior cingulated syndrome), disinhibition and inap-
propriate social interactions (orbitofrontal syndrome),
loss of insight, or perseverative behaviors. The behavioral
changes can sometimes be striking, and they represent an
important factor in the diagnosis of the disease and as a
target of treatment (Cummings, 1993; Kertesz, 2006).
As would be expected, the profile of cognitive defi-
cits reflects the distribution of the neuronal damage.
FTD may present with executive dysfunction (dorsolateral
prefrontal syndrome), a progressive decrease in speech
output (primary progressive aphasia), or an impairment in
understanding word meaning (semantic dementia) that is
relatively more severe than the deficits in episodic mem-
ory—a profile opposite to that seen in AD (Cummings
and Trimble, 2002). At the earliest stages of the dysexecu-
tive syndrome a formal assessment of cognitive flexibility,
multitasking, set switching, and higher-order conceptu-
alization can detect deficits in the presence of only minor
memory impairment. Performance on verbal fluency
tasks may also show a pattern opposite to that seen in
AD, with letter fluency being relatively more impaired
than category fluency in FTD. The meaning of visuo-
spatial deficits in FTD is somewhat ambiguous, as some
tasks that involve complex stimuli (e.g., Rey–Osterrieth
Complex Figure task) can show proportionate deficits,
while others with a lower degree of complexity appear
relatively spared (e.g., Block Design) (Salmon and Bondi,
2009). At the later stages of the disease, most cognitive
functions can become affected and differentiation from
other dementia types becomes dependent on an accurate
history of the course of the disease.
Primary progressive aphasia is a gradually progressing
nonfluent expressive aphasia that initially presents with
minimal impairment in memory or other cognitive func-
tions, although most patients will progress to dementia
with time (Mesulam, 1982; Rogalski and Mesulam, 2009).
Clinically it is primarily characterized by a nonfluent
expressive aphasia with phonemic paraphasias, anomia,
and deficits in repetition (Neary et al., 1998). Compre-
hension and other cognitive areas are relatively intact in
the initial stages, although the expressive impairments
can make testing of verbal episodic memory difficult.
Semantic dementia is a relatively rare condition that ini-
tially presents as a progressive fluent expressive apha-
sia. In this condition the patient begins to lose the mean-
ing of words and concepts despite intact grammar and
112 Assessment of the Geriatric Neurology Patient
syntax (Snowden et al., 1996). Patients demonstrate fluent
but empty spontaneous speech, semantic paraphasias,
impaired naming, and comprehension due to loss of word
meaning, while reading, writing, and repetition are typi-
cally intact (Neary et al., 1998).
Parkinson’s disease dementia
Parkinson’s disease is initially a predominately motor
disorder characterized by rigidity, bradykinesia, and
tremor. The morphologic characteristics are defined by
neuronal death and presence of Lewy bodies in brain-
stem nuclei (particularly the substantia nigra), and loss of
dopaminergic inputs into the neostriatum and neocortex
(Levy and Cummings, 2000). As the disease progresses,
cognitive impairment becomes more prevalent, and esti-
mates of dementia range from 25% to 40% prior to death
(Hughes et al., 1993). Autopsy studies show that comor-
bid AD pathology occurs not infrequently, but the devel-
opment of dementia is more strongly correlated to the
presence of Lewy bodies in the cortex than AD pathology
(Hurtig et al., 2000).
Cognitive characteristics of PDD can include altera-
tions/fluctuations in arousal and complex attention,
impairment in EFs and memory retrieval deficits. Visuo-
spatial deficits are also reported (Emre et al., 2007) but
there is some controversy in the literature as to whether
these are primary deficits or a consequence of other defi-
cits (e.g., executive dysfunction) (Grossman et al., 1993).
The pattern has been classified as a typical “subcortical”
dementia because of the early prevalence of the atten-
tional, visuospatial, and executive deficits combined
with the type of memory impairment observed (Albert
et al., 1974; Bondi et al., 1996). This memory deficit dif-
fers from the characteristic “cortical” amnesia (e.g., as
in AD) in that the performance on recognition memory
tasks appears relatively better than free recall, suggesting
a problem with the retrieval mechanism rather than stor-
age (as in AD). The executive dysfunction can be seen in
tasks that involve set shifting (e.g., Wisconsin card sort,
Trails B) and concept formation (Category test) (Duke
and Kaszniak, 2000). Attempts to diagnose PDD at a MCI-
type stage have indicated significant early heterogeneity
(Caviness et al., 2007; Adler, 2009). Notable AD pathology
can occur in PDD and may result in a “mixed” cortical/
subcortical profile (Levy and Cummings, 2000).
Dementia with Lewy bodies
The morphologic basis of DLB overlaps with that of
Parkinson’s disease and the diseases can be difficult to
distinguish at autopsy. Clinically, the disorders are distin-
guished by the relative appearance of significant motor
signs sufficient for the diagnosis of Parkinson’s disease
(PD) at least 1 year before the dementia (PDD), or the
cognitive impairment is observed in the early stages of
the extrapyramidal motor symptom onset (DLB). In DLB
eosinophilic intracytoplasmic neuronal inclusion bodies
are present in both cortical and subcortical areas. Like
PD, the Lewy bodies are prevalent in substantia nigra
and locus coeruleus; however, the distribution tends to
be more widespread across the cortical and limbic areas
(McKeith, 2000). Clinical presentation includes mild par-
kinsonism (rigidity, bradykinesia, and masked facies),
recurrent and well-formed hallucinations, and fluctuating
cognition (McKeith et al., 2005; Weisman and McKeith,
2007). However, these clinical signs are not present in all
patients with autopsy-confirmed DLB (Tiraboschi et al.,
2006), and differential diagnosis with other conditions
continues to be a challenge.
Comorbid AD pathology is common, and can make
the cognitive profiles difficult to be distinguished in indi-
vidual patients (Hohl et al., 2000). However, at the mild
stage, DLB may manifest greater attentional, visuospatial,
constructional, and executive deficits relative to the mem-
ory and naming impairments than is typical for AD, and
the pattern of impairments between category and letter
fluency tend to be the reverse of that seen in AD (e.g., in
DLB, letter fluency is as impaired or more than category
fluency) (Metzler-Baddeley, 2007). Profiles on the subtests
of the Mattis Dementia Rating Scale (Connor et al., 1998)
and on the California Verbal Learning Test (Hamilton
et  al., 2004) have been moderately successful in distin-
guishing the two diseases in autopsy-verified cases. Dis-
tinguishing LBD from other neurodegenerative disorders
such as PDD, PSP, and corticobasal degeneration (CBD) is
often based on the characteristic motor findings and clini-
cal progression of each disease.
Progressive supranuclear palsy
PSP is a tauopathy that is clinically diagnosed by the
presence of a supranuclear gaze palsy, axial rigidity,
pseudobulbar palsy, and falls. Tremor is not usually pres-
ent. Autopsy results show neurofibrillary tangles, granu-
lovacuolar degeneration, and cell loss in the midbrain,
globus pallidus, and thalamus. Dementia is characterized
by a subcortical profile including deficits in attention, EF,
and visuospatial abilities early in the course of cognitive
decline (Albert et al., 1974). While neuropsychological
testing is useful for early detection of the cognitive defi-
cit, differential diagnosis from other parkinsonian-like
dementias (corticobasal ganglionic degeneration, mul-
tiple system atrophy, etc.) is usually based on the neuro-
logic signs.
Corticobasal ganglionic degeneration
Corticobasal ganglionic degeneration (CBGD) is a rela-
tively rare disease with notable asymmetrical degenera-
tion of the frontal–parietal cortex and substantia nigra
degeneration. Clinically, it often presents with an asym-
metrical, focal motor apraxia, and asymmetrical dystonia,
rigidity, bradykinesia, and tremor. In a subset of patients,

the cognitive changes may be evident prior to the motor
signs (Murray et al., 2007). As mentioned for PSP, it pres-
ents with a subcortical profile and the cognitive profile
is difficult to distinguish from other Parkinson-plus syn-
dromes (Wadia and Lang, 2007).
Vascular dementia
VaD is a heterogeneous dementia that can result from a
single large stroke, multiple smaller infarctions (mul-
tiinfarct dementia), or small vessel diseases that cause
ischemic damage to multiple areas of the brain. As such
the clinical presentation and neuropsychological profile
varies widely. A detailed history (step-wise pattern of
deterioration), neurologic examination, and imaging com-
bined with the psychometric testing can both solidify the
diagnosis and provide valuable information regarding the
nature of the cognitive deficits for treatment planning.
Some forms of VaD may not show the step-wise decline
and the results of imaging may be unclear (e.g., diffuse
white matter pathology). In these cases a “subcortical”
pattern of deficits on formal testing may help differenti-
ate the etiology of the dementia. As such, impairments
of EF that equal or exceed those of memory function are
more indicative of a subcortical process than a cortical
dementia (e.g., AD) (Reed et al., 2007). However, a broad-
based neuropsychological battery that encompasses all
cognitive domains (attention, language, visuospatial,
memory, EF) is usually necessary to identify and charac-
terize the impairments.
Delirium
Delirium is an acute confusional state characterized by
fast onset, deficits in attention, orientation, and fluctuat-
ing levels of arousal. It may present as a sudden change in
a cognitively intact adult, or as a sudden decline in a cog-
nitively impaired patient. It is important to diagnose this
condition early and run a full medical work-up as a seri-
ous and life-threatening medical condition may underlay
the delirium. Brief cognitive assessment is sufficient to
detect most cases. Neuropsychological assessment may
be of use in differentiating mild cases (medication interac-
tions, low-grade infections, etc.) from the normal progres-
sion in a patient who already has dementia.
Depression
There is a complex relationship between depression and
dementia as each can be a risk factor for the other and they
often co-occur (Wright and Persad, 2007). In the elderly,
depressive symptoms often include memory complaints
and the cognitive inefficiencies of depression can be diffi-
cult to distinguish from early dementia. However, quanti-
tative and qualitative assessment can aid in the diagnosis
and treatment of each as individual or comorbid diseases
(Kaszniak and DiTraglia-Christenson, 1994; Potter and
Steffens, 2007).
Neuropsychology in Geriatric Neurology 113
Preclinical diagnosis of dementia
Despite the advances in neurosciences of the last few
decades, no treatment or intervention has been shown
to halt or reverse the course of most progressive demen-
tias. It has been suggested that if treatments are instituted
before extensive damage has been done to the neural
network, then disease progression is more likely to be
slowed (disease modification) or even temporarily halted
(DeKosky, 2003). In an elderly population, even a delay in
onset of 5 years has been suggested to reduce the occur-
rence of the disease by half. The concept of diagnosing a
disease before the clinical symptoms become apparent is
not new and is used in many branches of medicine (e.g.,
cardiovascular, hepatic, etc.). In most of these conditions,
a laboratory test indicates an abnormal value either in
the presence of only minimal (or no) clinical complaints.
As discussed in a previous section on MCI, a cluster of
symptoms (MCI) have been suggested to be predictive of
progression to a clinical dementia. However, most defi-
nitions of MCI require some clinical signs/impairments
that, while not reaching the full criteria for dementia, may
only be apparent after there has been significant damage
to the underlying neural network.
In the diagnosis of dementia, research into a preclinical
diagnosis has several significant challenges including lack
of a definition of “preclinical”, inability to sample brain
tissue while the patient is alive, questionable specificity
and sensitivity of noninvasive biomarkers in the general
population, and poor prediction of progression to MCI
or dementia in patients who may be positive for the bio-
marker (Backman et al., 2005). The accepted definitions
of preclinical dementia vary widely and may overlap
with those of MCI or similar classifications (e.g., cognitive
impairment not demented) or may be seen as the stages
preceding any abnormal cognitive measures (Backman,
2008; Guarch et al., 2008). This range of definitions has led
to significant confusion in the literature and in estimates
of prediction of progression to dementia.
Recently a definition of preclinical dementia for AD has
been published offered by a joint NIA–Alzheimer’s Asso-
ciation workgroup for Preclinical dementia (Sperling et al.,
2011). As emphasized several times in their publication,
this definition is for research purposes only and should
not be used in clinical practice. In their conceptualization
of preclinical dementia there are no notable declines in
the patient’s ability to function and no evidence of sig-
nificantly impaired cognitive function, thus it prestages
MCI. The three-stage categorical model suggested by the
workgroup reflects the current beliefs in the development
of the pathology underlying AD. Briefly, the first stage
reflects detection of amyloidosis in the brain (by CSF- or
PET-amyloid imaging), in the second stage there is addi-
tional evidence of neuronal degeneration (by FDG-PET,
volumetric MRI, etc.) and the third evolutionary stage
114 Assessment of the Geriatric Neurology Patient
includes the presence of the previously mentioned mark-
ers along with “subtle cognitive decline”. As the authors
point out, this third stage approaches the border of the
definition of MCI, the main differential being that the sub-
tle cognitive decline here may only be evident as a change
from the individual patient’s previous level of functioning
and not be abnormally below the performance of an age
and education-matched cohort. This general approach of
identifying changes in the basic elements that define the
disease (amyloid for AD, Lewy bodies for LBD, etc.) fol-
lowed by the physical/physiologic consequences of those
elements (disruption of neural transmission, neuronal
cell death, etc.) and finally by subtle clinical signs (decline
in function from previous abilities) appear a reasonable
approach toward guiding the investigation into the “pre-
clinical” evolution of various dementias.
It should be emphasized that the preclinical diagnosis
of any of the dementing disorders (AD, vascular, Lewy
body, FTD, etc.) is a vital and important research area.
However, until appropriate definitions can be agreed on,
clarification of concepts provided (e.g., determining if a
marker is a risk factor or an early stage of the disease)
and predictive values assessed for the individual patient,
it appears far too early to utilize the research results in
clinical guidelines.
Conclusion
Neuropsychological assessment utilizing well-established
techniques can be a useful addition to the physician’s
resources in geriatric neurology. Assistance in early diag-
nosis, differential diagnosis, assessment of the patient’s
deficits and remaining strengths as well as information to
help guide the treatment may be obtained from a proper
assessment. While there are many theories and models
in cognitive psychology, several that address five major
domains of cognition (attention, language, memory, EF,
visuospatial skills) have shown to be useful in modeling
the functions affected in dementia and brain dysfunction.
As technology advances and biomarkers (e.g., biochemi-
cal and imaging) of the central nervous system disorders
become a more important part of the clinician’s resources,
careful direct assessment of cognitive functions will con-
tinue to offer complementary information for the best
treatment of the patient.
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 Chapter 5
Cognitive Reserve and the Aging Brain
Adrienne M. Tucker1 and Yaakov Stern2
1
Cognitive Science Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands
2
Cognitive Neuroscience Division, Department of Neurology, Columbia University Medical Center, New York, NY, USA
(Financial support provided by National Institute of Aging (NIA)—grants T32 AG00261 and R01 AG026158)

Summary
• Cognitive reserve, which is often estimated with education and IQ, is the ability to make flexible and efficient use of
available brain reserve during tasks. It has been found to be protective against the cognitive outcomes of brain injury.
• Cognitive reserve is reflected in neural reserve and neural compensation.
• Neural reserve allows healthy individuals more efficient processing (processing which requires less neural activity) as
well as higher processing capacity (the ability to recruit more neural activity when task demands are high).
• Neural compensation is the activation of alternate brain regions to compensate for deficiencies in individuals with brain
impairments.
• Young adults with high cognitive reserve display greater neural efficiency. This may be a result of better or more
efficient use of strategies.
• Neural markers for cognitive reserve may differ between younger and older adults. This may be an indication of
compensatory reorganization during aging.
• Activation patterns related to cognitive reserve are reversed between healthy older adults and individuals with Alzheimer’s.
• Individuals with high cognitive reserve may present with pathology without functional deficits. Thus, accounting for
cognitive reserve in addition to the underlying pathology may aid clinical judgment.

Introduction manifest and suggests that individuals with more brain

The theory of reserve against brain insult arose to explain
individuals who continue to function clinically despite
brain pathology (Gertz et al., 1996; Davis et al., 1999;
Gold et al., 2000; Jellinger, 2000; Riley et al., 2002). In an
early example, the brains of 10 cognitively normal elderly
women were found to have Alzheimer’s plaques at autopsy
(Katzman et al., 1988). These women’s brains were heavier
and contained more neurons, which were thought to pro-
vide “reserve,” to help the women function despite their
pathology. Indeed, later studies found that 25–67% of sub-
jects characterized as cognitively normal throughout longi-
tudinal assessments meet pathologic criteria for dementia
at autopsy (Crystal et al., 1988; Morris et al., 1996; Price and
Morris, 1999; Ince, 2001; Mortimer et al., 2003).
Two types of reserve contribute to maintaining func-
tioning after brain insult: brain reserve and cognitive
reserve. Standard proxies for brain reserve include brain
size (Katzman, 1993) and/or neuronal count (Mortimer
et al., 1981). For any level of pathology, more brain reserve
is associated with better functional outcomes (Satz, 1993;
Graves et al., 1996; Jenkins et al., 2000). The brain reserve
model posits a threshold at which functional deficits
reserve will accumulate more pathology before reaching
that threshold. For example, in the case of Alzheimer’s,
the disease will advance longer and additional pathology
will be acquired before deficits are seen in individuals
who start with more neurons and/or a bigger brain.
The initial brain reserve model was entirely quantitative:
a given brain injury affects each individual in the same man-
ner, and brain injuries throughout the lifespan sum together.
Evidence indicates that some brain deficits do sum across
the lifespan. For example, the risk for Alzheimer’s rises with
each psychiatric episode (Kessing and Andersen, 2004) and/
or concussion (Guskiewicz et al., 2005). A limitation of this
model, however, is that brain reserve is thought to constitute
the only meaningful difference between individuals, with
the idea that accumulated damage either does or does not
reach the threshold necessary for functional deficits.
Although the brain reserve model explains some obser-
vations, the generalization that more is better may be
too simple. As one example, autism is associated with
a brain that is bigger than normal, perhaps reflecting a
failure of pruning mechanisms that eliminate unused or
faulty neural connections, or a larger glia/neuron ratio
(Redcay and Courchesne, 2005). Furthermore it has been

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

118

found that in healthy children, young adults, and elderly
samples, more gray matter is associated with worse
memory performance (Salat et al., 2002; Van Petten, 2004).
This strongly suggests that those with the biggest brains
are not always at the biggest advantage. Another limita-
tion of brain reserve theory is that it does not explain the
counterintuitive finding that, once Alzheimer’s is diag-
nosed, higher IQ and more education are associated with
faster deterioration and more rapid death (Stern et al.,
1994; Stern et al., 1995; Teri et al., 1995; Stern et al., 1999;
Scarmeas et al., 2006; Hall et al., 2007; Helzner et al., 2007).
By contrast, cognitive reserve refers to the ability to
make flexible and efficient use of available brain reserve
when performing tasks (Stern, 2002). Cognitive reserve
has been most often estimated using education (Stern et
al., 1992) and IQ (Alexander et al., 1997), although other
variables have also been used, including literacy (Manly
et al., 2003; Manly et al., 2005), occupational complexity
(Stern et al., 1994; Richards and Sacker, 2003; Staff et al.,
2004), participation in leisure activities (Scarmeas et al.,
2001; Wilson et al., 2002; Scarmeas et al., 2003a), and
the cohesion of social networks (Fratiglioni et al., 2000;
Bennett et al., 2006). Recently, personality variables have
also been incorporated (Wilson et al., 2006; Wilson et al.,
2007). Those with higher cognitive reserve tend to have
better clinical outcomes for any level of pathology and
brain reserve.
As one example, Mortimer et al. (2003) found that those
with smaller brain reserve, operationalized with head
circumference, were at increased risk of Alzheimer’s. Yet
this relationship was moderated by cognitive reserve such
that those with smaller heads and more education were
not at increased risk. This suggests that cognitive reserve
allowed individuals to compensate for any pathology
present in their smaller brains by making more opti-
mal use of that brain reserve present. It further suggests
that the threshold of brain reserve necessary to maintain
functioning is not fixed, but instead varies among people
such that those higher in cognitive reserve can maintain
functioning at lower levels of brain reserve.
Although cognitive reserve is discussed most often in
the context of Alzheimer’s disease and normal aging, it
has also been demonstrated to provide benefit in vascular
injury (Dufouil et al., 2003; Elkins et al., 2006), Parkinson’s
disease (Glatt et al., 1996), traumatic brain injury (Kesler
et al., 2003), HIV (Farinpour et al., 2003), and multiple
sclerosis (Sumowski et al., 2009). While it has been estab-
lished in these diverse conditions that cognitive reserve
is protective against brain injury for cognitive outcomes,
it remains to be determined whether cognitive reserve is
similarly protective for affective or psychiatric outcomes.
One report found that higher cognitive reserve is not pro-
tective against the depressive symptoms that arise with
the early stages of Alzheimer’s (Geerlings et al., 2000);
however, other reports of healthy individuals have found
Cognitive Reserve and the Aging Brain 119
that higher cognitive reserve does protect against psy-
chiatric diseases such as depression (Barnett et al., 2006;
Koenen et al., 2009).
Many aspects of cognitive reserve are intercorrelated.
For example, people with higher IQs obtain more edu-
cation, which, in turn, increases IQ (Ceci, 1991). Yet,
although they are intercorrelated, these aspects of cog-
nitive reserve impart both independent and interactive
effects that accrue over the lifespan. Richards and Sacker
(2003) examined how cognitive reserve variables col-
lected at different points in the lifespan affected cogni-
tive function at midlife. The authors found that the earli-
est point, childhood IQ, had the strongest effect; a later
point, educational attainment by early adulthood, less
effect; and the latest point, occupation in middle age, the
least strong effect. These results suggest that while early
childhood factors are crucial for the buildup of cognitive
reserve, cognitive reserve continues to be influenced by
circumstances throughout the lifespan.
It has been pointed out that many of the variables used
to measure cognitive reserve, such as education, are con-
flated with socioeconomic status (SES). However, Karp
et al. (2004) found that while less education and lower
SES are independently associated with higher risk for
Alzheimer’s disease, with both in the model simultane-
ously, only education is significant. Thus, the lower risk
for Alzheimer’s in those more highly educated is not
mediated by SES. Furthermore, Turrell et al. (2002) found
that a relationship between more years of education and
better cognitive outcomes in middle age was independent
of both childhood and current SES. Thus, the benefits aris-
ing from cognitive reserve are not reducible to SES.
Another potential limitation is that individuals with
more education and higher IQ display superior perfor-
mance on the tests used to measure cognitive decline and
diagnose dementia; this has been called the ascertainment
bias (Tuokko et al., 2003). In other words, although an
individual high in cognitive reserve might slip from the
previous high level of performance as a result of pathol-
ogy or aging, this deterioration might go unnoticed in test-
ing, because performance may still be average. Yet cogni-
tive reserve still provides benefit even when dementia is
diagnosed with measures of daily functioning instead of
neuropsychological tests (Liao et al., 2005). Further, cogni-
tive reserve has been demonstrated even in longitudinal
studies with a clear baseline for each subject from which
to assess performance (Scarmeas and Stern, 2004).
Unlike brain reserve, cognitive reserve makes clear
why those with higher IQ, more education, and/or more
participation in leisure activities have poorer outcomes,
in that they deteriorate more quickly and proceed to
death soon after Alzheimer’s is diagnosed (Stern et al.,
1994; Stern et al., 1995; Teri et al., 1995; Stern et al., 1999;
Scarmeas et al., 2006; Hall et al., 2007; Helzner et al., 2007).
The cognitive reserve model posits that those with higher
120 Assessment of the Geriatric Neurology Patient
reserve are able to compensate for pathology early on in
the course of Alzheimer’s disease. Not until the pathology
is more advanced and the patient is nearer to death are
deficits observable in an individual with high cognitive
reserve. This also implies that, for any given functional
level, those higher in reserve will have more pathology
(Bennett et al., 2003; Bennett et al., 2005; Serra et al., 2011).
Although the initial conception of brain reserve was
entirely quantitative, recent evidence suggests that this
concept is more nuanced. First, brain and cognitive reserve
share some overlap. For example, IQ and brain volume
show a small but significant correlation (McDaniel,
2005). More importantly, stimulating environments–-a
component of cognitive reserve measured in humans by
variables such as engagement in leisure activities and
occupational attainment–-foster the growth of new neu-
rons (Churchill et al., 2002) and upregulate brain-derived
neurotrophic factor (BDNF), which fosters neural plastic-
ity. Furthermore, animal studies suggest that enriching
environments may reduce Alzheimer’s pathology directly
(Costa et al., 2007). In humans, it has been demonstrated
that higher IQ reflects higher metabolic efficiency in the
brain, which may slow the development of neuropathol-
ogy (Yeo et al., 2011). Nonetheless, although they are in
some ways interdependent, brain reserve and cognitive
reserve make independent yet synergistic contributions
to understanding individual differences in clinical resil-
ience to brain pathology.
In terms of cognitive performance, cognitive reserve
may help by enabling more flexible strategy usage, a
skill tapped by executive function tasks. In support of
this, structural equation modeling performed in nonde-
mented older adults aged 53–97 revealed that cognitive
reserve–-as measured using years of education, Wide
Range Achievement Test (WRAT) score or, for Spanish
speakers the Word Accentuation Test (WAT) score, and
picture vocabulary from the Peabody Picture Vocabulary
Test, 3rd edition (PPVT-III)–-overlapped greatly with
executive functioning measured using the letter-number
(LN) sequencing subtest of the third version of the
Wechsler Adult Inventory Scale (WAIS-III), the odd-man-
out task, and the difference score from the Color Trails
Test (Siedlecki et al., 2009). In healthy adults aged 20–81,
cognitive reserve measured as mentioned previously
(education, WRAT, and picture vocabulary) was found to
entirely overlap with executive functioning as measured
using the same LN sequencing subtest and also the Wis-
consin Card Sorting Task and the Matrix Reasoning Test.
These results suggest that cognitive reserve could involve
fluid executive abilities.
In terms of neuroimaging, cognitive reserve is thought
to be reflected in neural reserve and neural compensa-
tion. Neural reserve provides young, healthy individu-
als the ability to process tasks with more efficiency and
greater capacity. For tasks of low-to-moderate difficulty,
those higher in cognitive reserve may display less neural
activation, because they are able to process the task with
greater neural efficiency. Opposingly, when tasks involve
high levels of difficulty, those higher in cognitive reserve
may display more neural activation, because they have a
greater neural capacity to use when performing the task.
Attending to difficulty is thus vital for understanding
the meaning of differences in neural activation between
groups. Neural reserve operates similarly to mitigate the
effects of aging and brain pathology. Those higher in neu-
ral reserve are expected to perform better than or equiva-
lently to those with lower neural reserve.
Neural compensation is defined as the activation of
alternate brain regions not often used by healthy young
adults, to compensate for deficiencies in primary routes to
effectual task performance. As defined, then, neural com-
pensation occurs not in healthy young adults, but only
in those with brain deficits. As for neural reserve, attend-
ing to difficulty is vital for accurately identifying neural
compensation. For example, neural compensation may be
suspected if a region is activated in older adults and not in
younger adults. Yet in a more difficult version of the task,
this region might also be activated by the young adults.
Sometimes, it is even the case that young adults are using
the brain area, but this is missed because of the statistical
threshold chosen to define brain activation.
Neural compensation can sometimes be accompanied
by worse performance, although this is not always the
case. In some instances, neural compensation could act
like a cane, which enables individuals to walk but will
not return the ability to sprint. As this metaphor sug-
gests, neural compensation is sometimes associated with
slower performance (Zarahn et al., 2007; Steffener et al.,
2009). Some think that this happens because, with neu-
ral compensation, processing travels across more brain
regions, each of which may take some additional amount
of time. An alternate idea is that, with neural compensa-
tion, processing shifts from a primary network to a slower
secondary network. It should be remembered that neu-
ral compensation has been found to correlate with better
performance in terms of accurately remembering more
words (Stern et al., 2000). To sum, neural compensation
can accompany performance that is either enhanced or
degraded.
A further consideration is that when additional brain
areas are activated in the presence of pathology, this does
not always indicate compensation. The activation of addi-
tional regions can be malfunctional when it arises from
detrimental processes such as dedifferentiation (blurring)
of sensory maps (Park et al., 2004), deficits in handling
competition between brain regions (Logan et al., 2002),
or a deficit in the ability to inhibit the default network
(Lustig et al., 2003). Thus when performance is worse, it
is necessary to rule out these detrimental processes before
labeling the activation of neural compensation.

An implicit assumption is that neural compensation
differs from task to task (that is, it is an emergent prop-
erty of the task at hand). Yet, as cognitive reserve protects
functioning on a wide variety of tasks, it is possible that
one generic cognitive reserve network subserves one gen-
eral cognitive function. Some evidence in support of this
idea (Stern et al., 2008) is reviewed in the next section. If
this is true, activation of this network would likely indi-
cate a positive, helpful form of neural compensation.
Neural markers of cognitive reserve in
young, healthy adults
Stern et al. (2003) conducted an event-related fMRI analy-
sis of young adults performing a nonverbal serial recog-
nition task, looking for regions whose activation changed
with difficulty. Low-difficulty trials involved one shape
to remember, while the number of shapes to remember
for high-difficulty trials was customized for each subject
to achieve 75% accuracy. Univariate analyses were per-
formed to find regions where the change in activation
with difficulty was associated with cognitive reserve, here
measured using the National Adult Reading Test (NART)
IQ score. Such regions were found for both study and test
task phases. These results indicate that cognitive reserve
is linked to differential task-related activation (neural
reserve) even in healthy young adults. These differences
in task-related processing may provide benefits to those
higher in cognitive reserve when they become challenged
by age-related brain changes or pathology.
The previous data were re-examined using multivariate
analyses (Habeck et al., 2003). For this study, first a net-
work of regions was sought that changed activation with
difficulty. Next, it was investigated whether this network
showed differential expression as a function of cognitive
reserve. First, a difficulty-related network was found in
the study phase. As hypothesized, individuals higher in
cognitive reserve expressed this network less (r2 = 0.24),
demonstrating higher neural efficiency. Then forward
application of this network to the test phase similarly
found that those higher in cognitive reserve had lower
network activation (r2 = 0.23). Thus, even with this more
conservative method, young adults higher in cognitive
reserve displayed evidence for greater neural efficiency.
Habeck et al. (2005) explored the same question on
another task: delayed letter recognition. In this task,
memory set sizes of one, three, and six letters consti-
tuted the manipulation of difficulty. At the study phase,
the difficulty-related network was not associated with
cognitive reserve as measured by NART IQ. At the reten-
tion phase, or 7-second delay over which items had to be
actively held in mind, a difficulty-related network was
found that was expressed less by those higher in cognitive
reserve (r2 = 0.15). In a second task, then, neural efficiency
Cognitive Reserve and the Aging Brain 121
was again detected in young adults higher in cognitive
reserve, here during retention.
To some extent, individuals higher in cognitive reserve
may have higher neural efficiency as a result of employ-
ing better performance strategies. This idea is supported
by a study that failed to find the usual neural efficiency
advantage with intelligence after controlling for strategy
usage (Toffanin et al., 2007). Further support comes from a
study that found that more activation was associated with
trying out more strategies. The idea is that those with
higher intelligence are able to decide on a good strategy
more quickly and, as a result, show less activation (Jaeggi
et al., 2007).
Gray et al. (2003) examined healthy young adults per-
forming a three-back working memory task. In this study,
event-related activation differed as a function of fluid
intelligence, as measured with the Raven’s Advanced
Progressive Matrices, for trials at various levels of dif-
ficulty, here manipulated through high-interference as
opposed to low-interference items. Although this was
not explicitly a study of cognitive reserve, fluid intelli-
gence would be expected to be a good proxy for cogni-
tive reserve (Siedlecki et al., 2009). The authors found that
activation on the most difficult trials was greater for those
higher in fluid intelligence. Higher fluid intelligence was
also associated with improved accuracy for lure trials.
Interestingly, the increase in activation from nonlure to
lure trials mediated the intelligence–accuracy relation-
ship on lure trials by 99%. These results provide support
for the idea that those higher in cognitive reserve have
greater neural capacity to use, which provides an advan-
tage when tasks are highly difficult.
One limitation of these studies is that the tasks used did
not have the range of difficulty needed to see neural effi-
ciency and neural capacity operating in the same individu-
als. There is thus an outstanding research need to find neu-
ral efficiency and neural capacity operating with higher
cognitive reserve in the same task in young people. Our
group has one such report (Stern et al., 2012).
Neural markers of cognitive reserve in
healthy young and older adults
In older as compared to younger adults, the neural acti-
vation associated with cognitive reserve is sometimes the
same but can be altered as well. Scarmeas et al. (2003b)
examined PET activation in healthy younger and older
adults on a nonverbal serial recognition task; cognitive
reserve was measured by a factor score extracted from
years of education, NART, and age-scaled vocabulary
scores from the revised version of the Wechsler Adult
Intelligence Scale (WAIS-R). The low-difficulty condition
was a single shape, while the high-difficulty condition
was adjusted to each subject so that they achieved 75%
122 Assessment of the Geriatric Neurology Patient
accuracy. Univariate analyses were used to find regions
associated with cognitive reserve for each group sepa-
rately and next to find regions differentially associated
with cognitive reserve between the young and the old.
The first analyses found some regions associated with
cognitive reserve only for the young and other regions
associated with cognitive reserve only for the old. The sec-
ond analyses found three types of differential expression
between the two groups: some regions were positively
expressed with higher cognitive reserve in the young and
negatively expressed with higher cognitive reserve in the
old; some regions showed the opposite pattern; and some
regions were positively expressed with cognitive reserve
in the young and positively, albeit more faintly expressed
with cognitive reserve for the old. The authors posit that
these differences between young and old in cognitive
reserve expression indicate that compensatory reorgani-
zation happens with aging.
Stern et al. (2005) re-examined the data with multi-
variate analyses to find regions that were differentially
activated with difficulty and age. The authors found a
network of brain regions that were activated differently
between young and older individuals. Expression of this
network was positively associated with cognitive reserve
in the young (r = 0.45), indicating higher neural efficiency,
and negatively associated with cognitive reserve in older
individuals (r = −0.50), indicating higher neural capacity.
To sum, young and older individuals expressed the cogni-
tive reserve pattern in opposite ways. The authors posit
that this difference reflects helpful reorganization of brain
networks in aging, or neural compensation.
Stern et al. (2008) next examined in young and older
adults whether cognitive reserve might operate similarly
in different tasks. Event-related fMRI was used to probe
for a cognitive-reserve-related network shared by two dif-
ferent tasks: delayed letter and shape Sternberg. Cognitive
reserve was measured with the NART and the vocabulary
subtest of the WAIS-R. The letter task contained difficulty
levels of one, three, and six letters, while the shape task
contained difficulty levels of one, two, and three shapes.
On the whole, the shape task was considerably more chal-
lenging than the letter task. Two networks were found for
the study phase. While the first network was used only
during the letter task, the second network was used dur-
ing both the letter and shape tasks. For young subjects,
network activation in both tasks was negatively associ-
ated with cognitive reserve, indicating higher neural effi-
ciency in those with greater cognitive reserve. For older
subjects, network expression was negatively associated
with cognitive reserve only for the less challenging let-
ter task. These results suggest a generic “cognitive reserve
network” that can be utilized for performing many tasks.
This is concordant with the observation that cognitive
reserve provides benefits against brain pathology for
many different tasks and real-world functions.
Steffener et al. (2009) examined event-related fMRI acti-
vation between young and older subjects performing a
delayed letter recognition task. Memory set sizes of one,
three, and six letters comprised three levels of difficulty;
networks were found that changed expression with increas-
ing difficulty during retention. While young adults utilized
a single network, older adults utilized this network along
with an additional network. The authors demonstrated that
greater pathology in the primary network, operationalized
here as more atrophy in the precentral gyrus, was associ-
ated with greater utilization of the secondary network in the
elders. Because the young subjects did not use the secondary
network, it can be presumed to reflect neural compensation
in the older subjects. Importantly, older individuals with
more cognitive reserve were able to tolerate greater pathol-
ogy before having to employ the secondary network.
Neural markers of cognitive reserve in
healthy elderly and Alzheimer’s patients
Scarmeas et al. (2004) examined PET activation in healthy
older and Alzheimer’s patients performing a nonver-
bal serial recognition task. The low-difficulty condition
involved a single shape, while the high-difficulty condi-
tion was adjusted so that each subject achieved 75% accu-
racy; cognitive reserve was measured using a factor score
extracted from years of education, NART IQ, and the
vocabulary subtest of the WAIS-R. Activation patterns dif-
fered between healthy older and Alzheimer’s patients. In
some regions, Alzheimer’s patients with higher cognitive
reserve displayed greater activation, while healthy older
individuals with higher cognitive reserve displayed less
activation, while in other regions, the relationships were
reversed. These region-specific differences were posited to
reflect compensatory reorganization of brain networks in
Alzheimer’s patients.
Solé-Padullés et al. (2009) compared cognitive-reserve-
related fMRI activation on a recognition task between
healthy old, mild cognitive impairment patients and
Alzheimer’s patients. Stimuli were images of land-
scapes and people engaging in outdoor activities; cogni-
tive reserve was measured with a composite score of the
vocabulary subtest of the WAIS-III, an education–occu-
pation scale, and a scale of participation in leisure activi-
ties. Univariate analyses were performed after adjusting
for the differential performance between the groups. In
healthy older individuals, more cognitive reserve was
associated with less activation, indicating higher neural
efficiency. Conversely, in mild cognitive impairment and
Alzheimer’s disease, those with more cognitive reserve
displayed greater activation, thought to indicate greater
neural capacity. Taken together with the previous study,
reverse cognitive-reserve-related brain activation is seen
between healthy and diseased older individuals.

Implications of cognitive reserve for
diagnosis and prevention
Individuals with greater cognitive reserve create a diag-
nostic challenge, as pathology may be present without
functional consequences. Furthermore, for patients
with dementia at any stage of clinical severity, indi-
viduals with greater cognitive reserve will have more
advanced pathology. Neuroimaging biomarkers are
currently being developed to assist in early detection
of Alzheimer’s pathology, even prior to clinical conse-
quences. Complicating this endeavor, individuals with
greater cognitive reserve can tolerate more decreases
in cortical thickness (Querbes et al., 2009), levels of
amyloid peptides in cerebrospinal fluid (Shaw et al.,
2009) and plasma (Yaffe et al., 2011), and more regional
atrophy (Hua et al., 2008) before clinical consequences
emerge. For these reasons, the predictive accuracy of
biomarkers is improved when adding cognitive reserve
variables to the model (Roe et al., 2011). More gener-
ally, clinical status can best be understood when both
underlying pathology and cognitive reserve are taken
into account.
With the future growth of the aging US population,
the number of dementia cases will triple by 2050 if inter-
ventions are not applied (Hebert et al., 2003). Katzman
(1993) reasoned that as higher education staves off
Alzheimer’s for 5 years, it may considerably lessen
its prevalence. Thus, cognitive reserve interventions
may constitute a chief nonpharmacologic approach
for preventing this disease (Stern, 2006). Although
Alzheimer’s has a large genetic component (Gatz et al.,
2006), behavioral and environmental factors still exert
considerable influence over its expression and timing
of onset. Even in early-life onset Alzheimer’s, which
has a stronger genetic component than does late-life
onset Alzheimer’s, cognitive reserve has recently been
demonstrated to play a protective role (Fairjones et al.,
2011). Future studies might elucidate optimal strate-
gies for augmenting cognitive reserve in order to delay
or prevent Alzheimer’s disease and other age-related
afflictions.
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 Chapter 6
Gait Disorders in the Graying Population
Joe Verghese and Jessica Zwerling
Department of Neurology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

Summary
• Gait disorders can increase the risk of falls, disability, and mortality in the elderly. Gait dysfunction is also common in
individuals with cognitive impairment.
• Gait disorders can be classified as neurologic or non-neurologic. Within these classifications, the disorder can also fall
under different subtypes. Gait is assessed by standard neurologic examinations, visual screens, and the Romberg test
for balance.
• Neurologic gait disorders can have several underlying etiologies including myelopathy, Parkinson’s disease (PD),
vascular or other structural causes, normal pressure hydrocephalus (NPH), strokes, disorders of the cerebellum, and
subacute or chronic sensorimotor axonal neuropathy.
• Prevention strategies and treatment should be tailored to each individual according to their underlying etiology.

Introduction: a historical perspective Epidemiology

What has four legs in the morning, two legs in the after-
noon, and three legs at nighttime? Man.
This riddle illustrates three phases of life. The first
phase represents an infant crawling. In the second
phase, the child progresses to walking. The third stage
then describes a phase in which man requires assis-
tance for walking. In this latter stage, identifying gait
disorders is crucial to prevent morbidity and mortality
in the elderly.
The locomotor system of the animal is based on a spi-
nal neural network (Grillner, 1975; Mor and Lev-Tov,
2007). From the four-legged animal in early evolution-
ary stages to modern upright man, the advantage of
bipedalism has enabled humans to have a unique inter-
action with the environment. The upright structure has
both advantages and disadvantages. The “three legs
at nighttime” represents the downside of bipedalism.
This locomotor strategy can be fraught with “slipped
disks, dislocated hips, wrenched knees, fallen arches,
and a whole catalog of associated woes” (Tattersall,
1998). Identifying gait disturbances is crucial. It enables
efficient diagnosis of neurologic illnesses in clinical set-
tings as well as facilitates the identification of high-risk
older individuals to institute interventions to prevent
outcomes such as falls that are associated with high
personal and societal costs.
In older adults, gait disturbance is common and can be
associated with pain, functional impairment, and falls.
The ability to ambulate independently is a major con-
tributor to overall well-being and autonomy in elderly
individuals. In the “oldest-old” (over age 85) living in
the community, the prevalence of walking limitations
approaches more than 50% (Ostchega et al., 2000). In
an urban community-based study, abnormal gaits were
reported in one-third of older persons and accounted for
58% of the overall number of deaths and institutionaliza-
tions over 5 years in this sample (Verghese et al., 2006).
The prevalence of clinically diagnosed gait abnormalities
was 35% in this sample (Verghese et al., 2006). Incidence
of abnormal gait was 168.6 per 1000 person years, and
increased with age (Verghese et al., 2006).
Gait and adverse outcomes
Falls
Falls are a significant health concern because they cause
significant morbidity and mortality in the elderly and
result in a significant burden on a socioeconomic level.
Over age 65, falls are the leading cause of fatal injuries
(Stevens et al., 2008). About one-third of the community
population over age 65 falls each year (Gillespie et  al.,

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

126

2009). Emergency departments are frequently over-
whelmed with older adults who have unintentional falls.
In 2005, 1.8 million elderly people were admitted in emer-
gency rooms across the country (Stevens et al., 2006). Falls
are predictors of future falls; in other words, patients
who have fallen are more likely to fall again, especially if
there are detected abnormalities of gait (Ganz et al., 2007).
The latter fact underscores the importance of identifying
patients who fall with simple screening questions. In addi-
tion, falling occurs in the setting of “fear of falling”; there-
fore identification of patients with this particular “fear”
is also essential. Fear of falling is a well-known indepen-
dent risk factor for falls (Delbaere et al., 2010). Race has no
preference when it comes to falls; African Americans and
White elderly individuals fall at the same rate. However,
African Americans are more likely to have a traumatic
brain injury, and women are more likely to experience a
fracture (Ganz et al., 2007; Delbaere et al., 2010).
Clinical gait abnormalities predict future risk of falls
(Tinetti et al., 1994, 1995; Verghese et al., 2006; DeMott
et al., 2007; Ganz et al., 2007). In a prospective study of
community-residing elderly, the presence of neurologic
gaits was a strong risk factor for falls and was associated
with a 49% increased risk of falls over a 20-month period
(Verghese et al., 2010). Unsteady and neuropathic gait
were the two gait subtypes among the six studied that
predicted risk of falls (risk ratio: 1.52, and 1.94, respec-
tively) (Verghese et al., 2010). This study showed that clas-
sifying gait disorders is crucial to identifying individuals
at risk for falls, as well as to identifying gait problems to
institute preventative measures. Gait should be treated as
a potential modifiable risk factor for falls (Tinetti et al.,
1994, 1995; Mor and Lev-Tov, 2007; Delbaere et al., 2010;
Verghese et al., 2010).
Gait and disability
The risk of developing disability can be predicted in com-
munity elders by lower-extremity performance tests, of
which gait speed is the main factor in community-based
cohort studies (Verghese et al., 2010). Gait speed is a key
component of the clinical definition of frailty (Gill et al.,
2010), which is conceptualized as a state of heightened
vulnerability to stressors and increases the risk of disabil-
ity in older adults. Gait speed is a potentially modifiable
risk factor to prevent disability and related outcomes.
Gait and survival
Gait speed and survival are associated (Markides et  al.,
2001; Boyle et al., 2005; Louis et al., 2005; Stevens et  al.,
2006; Ganz et al., 2007; Cesari et al., 2009; Gillespie
et al., 2009; Delbaere et al., 2010). In a pooled analysis,
Studenski et al. found that slower gait speed is an absolute
risk for shorter survival in older adults (Studenski et al.,
2011). Improvement in gait speed by 0.1 m/s over 1 year
has been termed as a meaningful clinical difference, and
Gait Disorders in the Graying Population 127
this change has been associated with reduced mortality
in prospective cohort studies (Perera et al., 2006; Hardy
et al., 2007). Variability in gait is an important predictor
of mobility difficulty in older adults. In a small sample of
subjects in the Einstein Aging cohort, meaningful changes
in various quantitative indices of gait were determined
(Brach et al., 2010). Preliminary criteria for meaningful
change are 0.01 seconds for stance time and swing time
variability, and 0.25 cm for step length variability (Perera
et al., 2006).
Cognition and gait
Gait disorders are common in the elderly, particularly in
patients with cognitive impairment (Verghese et al., 2008).
Studies have shown that there is likely a link between
the cognitive and motor systems (Verghese et al., 2008).
Furthermore, Verghese et al. underscored that clinical and
quantitative gait dysfunction is common in mild cogni-
tive impairment (MCI) and is associated with poorer
status (Verghese et al., 2007). In this same elderly cohort,
subjects with amnestic-MCI (a-MCI) had worse swing
time and stride length variability than those with non-
amnestic-MCI (na-MCI) (Verghese et al., 2008). Subjects
with a-MCI had worse performance on rhythm and vari-
ability gait domains than age-matched and sex-matched
controls and those with na-MCI (Verghese et al., 2008).
Neurologic gaits were more common in subjects with
a-MCI (Verghese et al., 2008). Parkinsonian signs in MCI
were related to the severity and type of cognitive impair-
ment in another elderly cohort (Boyle et al., 2005) Another
community-based study reported that mild parkinsonian
signs were associated with a-MCI but not na-MCI (Louis
et al., 2005; Verghese et al., 2008).Motor decline as indexed
by gait speed declined up to 12 before other cognitive
domains in patients with MCI (Buracchio et al., 2010).
The “aging” of walking
Changes that are seen with aging include shorter and
broad-based strides, as well as a reduction in pelvic rota-
tion and joint excursion (Sudarsky, 1990, 2001). In the
Einstein Aging Study cohort, gait velocity and stride
length decreased with advancing age (Oh-Park et al.,
2010). However, the aging effect on walking was less
pronounced when clinical and subclinical disease influ-
ence on gait was taken into account. These results sug-
gest that gait changes with aging are better explained by
age-related diseases than they are age-associated. Hence,
underlying causes for gait changes need to be investi-
gated regardless of the age of the patient.
In a study of community elders, the most important
factors associated with walking speed were leg extensor
power, standing balance, and physical activity, regardless
of body mass index or gender (Sallinen et al., 2011). These
128 Assessment of the Geriatric Neurology Patient
are all potentially modifiable risk factors that interven-
tions aimed at improving lower extremity impairments
can improve (Sallinen et al., 2011). Cross-sectional con-
ventional norms may underestimate gait performance in
aging (Oh-Park et al., 2010). Longitudinal robust norms
provide more accurate estimates of normal gait per-
formance and thus may improve early detection of gait
disorders in older adults (Oh-Park et al., 2010). Robust
norms consider subjects with prevalent or “in transition”
gait abnormalities to develop clinical gait abnormalities
and exclude them (Oh-Park et al., 2010). This allows for a
gait to reflect more of the “normal” elderly population, so
that targeted interventions can be more accurately guided
(Oh-Park et al., 2010).
The following sections contain a discussion of clinical
gait evaluation and classification, quantitative indices of
gait, and performance-based measures.
Clinical gait classification
Several different clinical classification systems exist for
gait and have been described. All these clinical gait clas-
sifications rely on the clinician’s observation of walking
patterns.
Nutt and colleagues proposed a system that classifies
clinical gait abnormalities based on abnormal sensorim-
otor levels as low, middle, and high (Nutt et al., 1993).
Higher-level gait disorders are thought to stem from
pathology in the frontal lobes and their connections with
parietal lobes, subcortical structures (cerebellum and
basal ganglia), and the upper brainstem (Nutt et al., 1993).
Lower-level gait disorders can be divided into motor and
sensory systems. Lower-level gait disorders are thought
to arrive from perturbation of the muscle or peripheral
nerve. An example of lower-level gait disorder is neuro-
pathic gait secondary to neuropathy (see the description
in the Section Case Discussions, later in this chapter).
Lower-level gait dysfunction is also classified secondary
to disorders of vision, vestibular sensation, and proprio-
ception (Nutt et al., 1993). The middle-level gait disorder
is thought to originate from “motor” dysfunction. This
level includes causes such as spasticity due to spinal cord
pathology, cerebellar ataxia, and dystonia. Patients with
Parkinson’s disease (PD) have dysfunction at the high or
cortical level of processing and the middle level (subcor-
tical structures), as they may have rigidity and bradyki-
nesia. The higher-level disorders primarily involve prob-
lems integrating information in the environment (Nutt et
al., 1993). For example, the execution of locomotion is the
main higher-level disturbance in the “freezing” phenom-
enon during walking seen in patients with PD.
Gait is evaluated as part of the standard neurologic
examination to test cranial nerves, strength, sensation,
and deep tendon reflexes. Visual screening should be
included, along with evaluation for range of motion.
The Romberg test is used to assess standing balance with
visual cues removed or eyes closed. A positive test refers
to a patient’s inability to maintain balance when stand-
ing erect with feet together and eyes closed. Cognitive
screening is also important to include, given the correla-
tion between the motor and cognitive functions (Verghese
et al., 2008).
We have been using a clinical gait classification dur-
ing our clinical evaluation at the Einstein Aging Study
for the past two decades. In the Bronx Aging Study (now
known as the Einstein Aging Study), clinicians blinded to
the gait evaluation of the subjects showed 89% agreement
(κ = 0.6) on gait classification, specifically whether the gait
was neurologic or non-neurologic (Verghese et al., 2002b).
Inter-rater reliability (normal vs any abnormal gait), stud-
ied prospectively, between two study clinicians who inde-
pendently assessed gait in 30 subjects was good (κ = 0.8)
(Verghese et al., 2004).
At each visit, study clinicians observe gait patterns and
turns while subjects walk up and down a well-lit path
(Verghese et al., 2002b, 2006, 2010; Oh-Park et al., 2010).
The first step in clinical gait analysis is the recognition
that gaits are either normal or abnormal; then abnor-
mal gaits are subtyped as either neurologic (one of eight
subtypes discussed shortly) or non-neurologic (arthritic,
vascular claudication, or secondary to cardiopulmonary
issues, and so on). In our large community-based study
(the Bronx Aging Study, now known as the Einstein Aging
Study (Verghese et al., 2002b, 2006, 2010; Oh-Park et al.,
2010), neurologic gaits are subtyped. Neurologic gait
abnormalities are subtyped as unsteady if subjects experi-
enced marked swaying or lost balance under two or more
of the following conditions: while walking in a straight
line or in tandem or while making turns. Ataxic (cerebel-
lar) gait is wide based, with other cerebellar signs such
as intention tremor. Ataxic and unsteady gaits were com-
bined, because they share clinical features such as wide
base and poor balance. Patients with neuropathic gaits
have foot drop, sensory loss, and depressed deep tendon
reflexes. Short steps, wide base, and difficulty lifting the
feet off the floor characterize frontal gait. Older people
with parkinsonian gaits have small shuffling steps, flexed
posture, absent arm swing, en bloc turns, and festination.
Frontal gait is characterized by short steps, wide base,
and difficulty in lifting the feet off the floor. Patients with
hemiparetic gait swing a leg outward and in a semicircle
from the hip (circumduction). In addition to lower motor
neuron/lower-level causes of foot drop, ankle dorsiflex-
ion can be affected in patients with upper motor neuron
disorders. Ankle dorsiflexion plays a role in the initial
stance phase of the gait cycle and the wing phase, and
can be impaired in upper motor neuron lesions, as part of
the hemiparetic gait (Verghese et al., 2007). In spastic gait,
both legs circumduct and, when severe, cross in front of

one another (scissoring). See web links (Verghese et al.,
2002b) to videos of abnormal neurologic gait subtypes.
Psychogenic gait disorders
Gait disorders that are nonorganic/nonphysiologic/
functional are called psychogenic gait disorders. Astasia-
abasia is a Greek term that means “inability to stand and to
walk.” Paul Blocq described this phenomenon in the late
1800s, which he characterized in a series of patients who
did not have the ability to maintain an upright posture,
despite normal function of the legs in bed (Blocq, 1888).
Sudarsky et al. found that, in elderly patients, 3.3% of gait
disorders were psychogenic (Sudarsky and Tideiksaar,
1997). A functional disorder has several features, such
as momentary fluctuations, excessive slowness of move-
ment or hesitation, “psychogenic” Romberg with a silent
delay or improvement with distraction, uneconomic pos-
tures (wasting of energy), small cautious steps with fixed
ankle joints (“walking on ice”), and sudden buckling of
knees with and without falls. The caveat is that gait dis-
orders develop over time, and repeated examination and
history taking is necessary to truly characterize a gait dis-
order as psychogenic. Elderly patients may showcase a
“cautious gait,” with reduced stride, widened base, and
lowered center of gravity (Sudarsky and Tideiksaar, 1997).
Cautious gait may be a reaction to a previous fall, may be
psychogenic, or may be a representation of a larger gait
disorder that has not manifested yet. The main risk fac-
tors for developing the fear of falling are at least one fall,
female sex, and increasing age (Tinetti and Mendes de
Leon, 1994; Sudarsky and Tideiksaar 1997; Scheffer et al.,
2008). This can cause significant psychosocial limitations
for an individual. Treatment relies on a multidisciplinary
team, including psychiatry and rehabilitation experts.
An additional syndrome important to discuss is camp-
tocormia, or “bent spine syndrome.” This syndrome is
characterized by forward flexion of the trunk in the erect
position and reduced flexion when in the supine position
(Azher and Jankovic, 2005). The etiology was originally
thought to be a form of “conversion” or psychogenic dis-
order; however, the underlying cause encompasses many
aspects of the neuraxis. The etiology involves neuromus-
cular disorders, including amyotrophic lateral sclerosis
(ALS), facioscapulohumeral muscular dystrophy (FSHD),
mitochondrial myopathy, and dysferlinopathy, as well as
PD and dystonia (Van Gerpen, 2001; Schabitz et al., 2003;
Azher and Jankovic, 2005; Gomez-Puerta et al., 2007;
Seror et al., 2008).
Quantitative assessment of gait: creating a
scorecard for prediction of falls
Walking is the repetitive sequence of limb motion to push
the body forward while maintaining stance and stability
Gait Disorders in the Graying Population 129
(Perry, 1992). Although clinical observation alone is an
important component of gait analysis, it depends on
the examiner’s expertise. On the other hand, criticisms
of quantitative gait analysis methods may state that the
assessment protocols are cumbersome and vary in the
level of detailed analysis required. Recent technologic
advances in quantitative assessment of gait have enabled
faster acquisition of kinematic data and an in-depth mea-
surement of various gait variables (Verghese et al., 2002b;
Abellan van Kan et al., 2009). It is important to measure
variables such as normal gait measures, as well as vari-
ability within these measures. Gait speed has been associ-
ated with good health and functional status (Cesari et al.,
2005; Rolland et al., 2006; Rosano et al., 2008; Abellan van
Kan et al., 2009; Verghese et al., 2009). Normal older adults
with increased stride-to-stride or stance time variability at
baseline assessments were reported to have increased risk
of falling, mobility disability, and dementia (Brach et al.,
2005; Cesari et al., 2005; Perera et al., 2006; Verghese et al.,
2009; Verghese and Xue, 2011).
Timed gait
Simple timed gait is recommended by a number of stud-
ies and can be done in most clinical settings (Abellan van
Kan et al., 2009; Studenski, 2009; Verghese et al., 2009).
An abundance of gait norms exist for elderly individuals,
which presents difficulty for clinical application because
of the variation in the reported values. Mean gait veloc-
ity varied in older adults from 89  cm/s to 141  cm/s in
previous community-based studies (Murray et al., 1969;
Winter et al., 1990; Oberg et al., 1993; Samson et al., 2001;
Bohannon, 2008). Gait velocity decreased with advancing
age in the Einstein Aging cohort (Verghese et al., 2009).
In this prospective study of a large, well-characterized
cohort of community-residing elders, quantitative gait
markers were independent and strong predictors of inci-
dent falls (Verghese et al., 2009). Each 10  cm/s decrease
in gait speed was associated with a 7% increased risk for
falls (Verghese et al., 2009). Participants with slow gait
speed (≤70  cm/s) had a 1.5-fold increased risk for falls,
compared with those with normal speed (Verghese et al.,
2009).
Computerized assessments for gait are varied. Subjects
in the Einstein Aging Study protocol are asked to walk on
a mat at their normal pace for two trials in a quiet, well-lit
hallway with comfortable footwear on the GAITrite sys-
tem. Footfalls are recorded and gait variables are recorded
over two trials. Eight gait parameters are reported, based
on previous studies of their associations with adverse
outcomes: velocity (cm/s), cadence (steps/min), stride
length (cm), swing time (s), stance time (s), and double
support phase (%). (See Table 6.1 for definitions.) The
standard deviation (SD) of stride length and swing time
is used for variability (Verghese et al., 2007). Gait vari-
ability in each measure of gait was defined as the within-
130 Assessment of the Geriatric Neurology Patient

Table 6.1 Definition of quantitative gait parameters.

Variable Unit Definition

Velocity cm/s Distance covered on two trials by the ambulation time

Stride length cm Distance between heel points of two consecutive footfalls of the same foot. Variability in length
between strides is reported as standard deviation (SD).
Cadence steps/min Number of steps taken in a minute
Double support s Time elapsed between the first contact of the current footfall and the last contact of the previous
footfall, added to the time that elapsed between the last contact of the current footfall and the
first contact of the next footfall
Swing time s Duration when the foot is in the air and is the time taken from toe-off to heel strike of the same
foot. Variability in swing time is reported as SD.
Stance time s Duration when the foot is on the ground and is the time taken from heel strike to toe-off of the
same foot

Source: Adapted from Snijders et al. (2007), with permission from Elsevier.
All quantitative parameters described are automatically calculated as the mean of two trials by the gait software.

subject SD derived from all the right steps recorded over
two trials (Brach et al., 2005). Gait variability is an impor-
tant indicator of impaired mobility in older adults (Brach
et al., 2005).
Performance-based tests
A number of performance-based assessments can be used
in any office setting to assess risks for falls. A quick tool
that has been well validated is the Timed Up and Go test
(Podsiadlo et al., 1991). The patient is timed from rising
from a chair, walking 3 m, turning, and returning to the
chair. A timing of 14 seconds or more has been shown to
be an indicator for a fall risk (Podsiadlo et al., 1991). A
unipedal stance of less than 5 seconds has been associ-
ated with increased risk of falls in the elderly (Vellas et al.,
1997).
Walking while talking
The task of walking while talking (WWT) requires divided
attention and harnesses the bridge between cognitive and
motor disorders. Although walking at a normal pace is
thought to be “reflexive,” WWT requires a shift of atten-
tional resources and places cognitive demands on indi-
viduals. In subjects with imbalance, this can lead to pos-
tural instability and falls (Verghese et al., 2002a; Beauchet
et al., 2009). In a review of dual-task conditions such as
WWT, the pooled odds ratios showed a statistically sig-
nificant increase in the risk of falls while performing the
dual task of WWT (5.3 (95% CI, 3.1–9.1)) (Beauchet et al.,
2009).
Etiology of gait disorders: a window into
diagnosis and workup
General medical examinations, especially during visits
to emergency rooms, often neglect gait examination.
Yet it is a crucial part of the neurologic examination.
The following discussion includes etiologies of six main
subtypes of neurologic gait disorders, described in our
clinical gait classification in the previous sections and
related investigations.
The cause of spasticity can be multifactorial in the
elderly. Myelopathy from structural causes such as spon-
dylotic ridges and ligamentous hypertrophy contribute
to spinal canal narrowing and cord impingement. As
a result of cord compression, especially in the posterior
columns, which contain vibration and proprioception
fibers, patients often complain of imbalance. The physi-
cal examination includes mild spasticity (especially in
the legs), hand numbness, reports of urinary urgency
and incontinence, and a positive Romberg test. The gait
is described as stiff-legged with reduced toe clearance
and a tendency toward circumduction. Patients may also
have pseudoathetosis, or abnormal writhing movements,
usually of the fingers, caused by a failure of joint position
sense (proprioception). It is important to keep in mind
that presentations may be asymmetric or may appear as a
central cord syndrome with possible associated syringo-
myelia, with sensory deficits in a cape-like distribution.
Nonstructural causes of myelopathy can be caused by
demyelinating diseases such as multiple sclerosis, vita-
min B12 deficiency, trauma to the spinal cord, vitamin E
deficiency, post-radiation, herpes zoster infection, or cop-
per deficiency. Further evaluation of the brain and spine
with MRI, as well as screening bloodwork for nonstruc-
tural causes, may be indicated.
Parkinsonism is characterized by bradykinesia, resting
tremor, rigidity, and loss of postural reflexes. PD is common
in the elderly population, with a prevalence of approxi-
mately 0.5–1% among persons 65–69 years of age, rising
to 1–3% among persons 80 years of age and older (Tanner
and Goldman, 1996). Other disorders, including those
from neuroleptic drugs and arteriosclerotic parkinsonism
as a result of multiple subcortical infarcts, may cause simi-
lar gait and balance problems mimicking idiopathic PD. If
idiopathic PD is suspected, no further workup is necessary
unless secondary causes are suspected.

Hemiparetic gait is characterized by asymmetric weak-
ness and may be attributable to vascular causes; however,
other structural causes, such as AVM, subdural hema-
toma, metastases, must be ruled out with imaging of the
head.
Frontal gait includes the disorders of normal pressure
hydrocephalus (NPH), as well as multiple strokes. As pre-
viously discussed, patients may have a “magnetic gait,”
with difficulty lifting the feet off the floor (Sudarsky and
Simon, 1987). Imaging of the brain often reveals exten-
sive white matter disease when the etiology is vascular.
NPH is characterized by frontal gait disorder, urinary
incontinence, and cognitive impairment. This syndrome
requires a lumbar puncture for diagnosis, and improve-
ment in gait monitored by the clinician underscores the
NPH diagnosis. The response to the removal of 30–50 cc
or a large volume of the cerebrospinal fluid is character-
ized by improvement of gait. The response or rating of
improvement to spinal tap is not well standardized. Treat-
ment requires shunting of the cerebrospinal fluid.
Ataxic gait includes unsteady gait and includes dis-
orders of the cerebellum. The disorders can be because
of neurodegenerative causes, as in olivopontocerebellar
degeneration, a disorder that is within the category of
Parkinson’s plus syndromes. Paraneoplastic degeneration
of the cerebellum associated with antibodies against dif-
ferent cells can cause ataxic gaits. One example includes
Anti-Yo antibodies, found mostly in women with cerebel-
lar degeneration accompanying gynecologic and breast
malignancies (Peterson et al., 1992). The antibodies recog-
nize cytoplasmic proteins of Purkinje cells, contributing
to their degeneration. Anti-Hu antibody, found predomi-
nantly in paraneoplastic neurologic syndromes associated
with small-cell carcinoma of the lung, reacts with proteins
present in nuclei and cytoplasm of virtually all neurons
(Mason et al., 1997). Chronic alcoholism can contribute to
atrophy of the anterior vermis of the cerebellum (Victor
et al., 1959). Treatment includes elimination if thought
to be because of toxins. Screening for underlying malig-
nancy and with labwork to identify antibodies is crucial
in ataxia as a result of paraneoplastic degeneration.
Individuals with neuropathic gait have unilateral or
bilateral foot drop and may have a “stocking” pattern of
sensory loss and absent deep tendon reflexes. Etiology
depends on the type of neuropathy. Several causes of
subacute/chronic sensorimotor axonal polyneuropathy
include, but are not limited to, diabetes, hypothyroid-
ism, vitamin B12 deficiency, connective tissue disease
(Sjorgren, rheumatoid arthritis), paraproteinemia, and
toxic neuropathy (alcohol). Clinical cues must be taken
from the history and examination. Workup as suggested
for the first tier by Herskovitz et al. is complete blood
count, chemistry, HgA1C, oral glucose tolerance test,
vitamin B12 (methylmalonic acid/homocysteine), ESR,
serum protein immunofixation, and toxic exposure his-
Gait Disorders in the Graying Population 131
tory (Herskovitz et al., 2010). The authors encourage
consideration of urinalysis, chest X-ray, thyroid testing,
lipid profile, antinuclear antibody (ANA), rheumatoid
factor, Lyme disease, hepatitis C titre, and angioten-
sin-converting enzyme (ACE) level (Herskovitz et al.,
2010).
Summary
A detailed history taking that includes an assessment of
home safety, complemented with a complete cognitive
and gait examination, is crucial to identifying patients
with gait disorders. Prevention strategies should be tai-
lored to each individual, depending on the etiology such
as stroke, neurodegenerative, neuropathic, psychogenic,
or ataxic. Treatment is targeted at controlling underlying
conditions that have caused the gait disturbance. Close
follow-up is important to ascertain changes in gait pat-
terns over time.
Gait disorders follow the same evolutionary principle
as the development of man. They evolve over time. The
astute clinician must help the patient identify the underly-
ing problem, highlight the obstacles, and help the patient
adapt to the environment.
Suggested citations
Nutt, J.G., Marsden, C.D., and Thompson, P.D. (1993) Human
walking and higher-level gait disorders, particularly in the
elderly. Neurology, 43: 268–279.
Snijders, A.H., van de Warrenburg, B.P., Giladi, N., and Bloem,
B.R. (2007) Neurological gait disorders in elderly people: clinical
approach and classification. Lancet Neurol, 6: 63–74.
Sudarsky, L. (1990) Geriatrics: gait disorders in the elderly. N Engl J
Med, 322 (20): 1441–1446.
Verghese, J., Lipton, R., et al. (2002) Abnormality of gait as a predic-
tor of non-Alzheimer’s dementia. N Engl J Med, 347: 1761–1768.
Verghese, J., Wang, C., Lipton, R.B., et al. (2007) Quantitative gait
dysfunction and risk of cognitive decline and dementia. J Neurol
Neurosurg Psychiatry, 78: 929–935.
Verghese J., Holtzer, R. et al. (2009) Quantitiative gait markers and
incident fall risk in older adults. J Gerontol A Biol Sci Med Sci, 64:
896–901.
Case discussions
The following section illustrates the major subtypes of
gait disorders. It is a useful tool for teaching and can be
utilized with the videos from Verghese et al. ( 2002b).
Case 1: history
The patient is a 65-year-old right-handed man with
a four-year history of intermittent distal symmet-
ric paresthesias of the legs. Over the past year, the
132 Assessment of the Geriatric Neurology Patient
paresthesias has caused his legs to become numb to
the mid-calf at all times. He had a recent fall in which
he “tripped over the curb.” Over the last several
months, he has complained of difficulty buttoning
his shirt and opening jars. He denies bowel/blad-
der symptoms or autonomic symptoms. There is no
allodynia. There are no constitutional symptoms. He
remarked that although it is winter, he finds it uncom-
fortable to sleep with the sheet on the bed. He denies a
family history of neuropathy, high arches, or hammer
toes. He has significant thirst, but he attributes it to
the use of his inhaler for chronic obstructive pulmo-
nary disease (COPD).
Physical examination
The general medical examination is unremarkable. The
mental status examination was normal. Cranial nerves
were normal. The strength examination revealed a
weakness of toe flexion and extension, with an MRC
grading of 4, with slight asymmetry or worsening on
the right. Deep tendon reflexes were absent at the toes
and knees but were present and normal at the arms.
Plantar responses were flexor. There was no tremor or
other adventitious movements. Light touch and vibra-
tion were decreased to midshin bilaterally with pin-
prick and proprioception mildly affected. There was
sensitivity to touch at the soles of the feet. He was able
to toe-walk and heel-walk but had extreme difficulty.
Romberg showed swaying. There was no pseudoath-
etosis. Tone was normal. The lower legs were signifi-
cantly atrophic.
Gait
Bilateral foot drop—neuropathic. There is a “stocking”
pattern of sensory loss and absent deep tendon reflexes.
Comment on case: Upon further questioning, there was
significant erectile dysfunction for 5 years beforehand.
Labwork revealed significantly elevated HgA1C.
Case 2: history
This is an 85-year-old woman with a history of
“unsteadiness” for several months. She reports inter-
mittent paresthesias of the hands, which began several
months ago and now has affected the feet. She reports
that when she is in the shower, she is unable to wash
her hair with her eyes closed. She feels as though she
will fall over, and she reports “electricity” in both arms
with tilting of her head and neck in a certain direction.
There are no bowel/bladder symptoms or constitu-
tional symptoms. She reports recent dental work with
injection only (no gas) for poorly fitting dentures. There
are no falls. She is on Coumadin for an “abnormal heart
rate. She also notes that she has been forgetting where
she put her keys a lot more often and got lost driving
home on her usual route.
Physical examination
The general medical examination is unremarkable except
for poor dentition. The mental status examination was
normal. Cranial nerves were normal. The strength exami-
nation was normal. Deep tendon reflexes were absent
at the toes and brisk 3+ knees but present and normal
at the arms. Plantar responses were extensor. There was
no tremor or other adventitious movements. Light touch
and pinprick were affected to midshin bilaterally. Vibra-
tion was decreased to anterior iliac spine, and proprio-
ception required large excursions. Tone was increased
throughout. Romberg was positive. There was significant
pseudoathetosis.
Gait
Sways slightly while walking with occasional mis-
step. Worse with tandem. Wide-based ataxic gait with
spasticity.
Diagnosis
Myeloneuropathy secondary to hyperzincemia causing
hypocupremia (Kumar et al., 2004; Nations et al., 2008).
Comment on case: Vitamin B12 levels were normal. The
patient admitted to using denture cream in significant
amounts over the past several months (Herskovitz et al.,
2010). Copper levels were low. Serum zinc levels were
high. There was an associated anemia on complete blood
count. The previous discussion includes description of
two subtypes of gait: ataxic and spastic gait.
Case 3: history
This 78-year-old right-handed writer presents with a
two-year history of changes in his handwriting. He
used to take notes throughout the day and night to keep
track of new book ideas. His handwriting has become
progressively smaller. He notes that, at nighttime, he has
increasing difficulty turning in bed. While watching tele-
vision, he also noted a right-hand tremor. He has lost his
balance occasionally but has no falls. He denies hallucina-
tions or autonomic symptoms. Family history is noncon-
tributory. Past medical history is significant for depres-
sion without neuroleptic use.
Physical examination
The general medical examination is unremarkable. The
mental status examination was normal. Cranial nerves
were normal. The strength examination was normal. Deep
tendon reflexes were normal. Plantar responses were
flexor. There was a rest tremor on the right hand. Light
touch, pinprick, vibration, and proprioception were nor-
mal. There was cogwheeling with activation of the right
upper extremity. Pull test was positive. Romberg was neg-
ative. He pushed with arms to elevate from a seat. Frontal
release signs were negative. Fine finger movements were
slowed throughout.

(a)
(c)
Figure 6.1 Footfall patterns recorded on an
instrumented walkway: (a) frontal gait;
(b) parkinsonism; (c) ataxic gait;
(d) left hemiparetic.
Gait
Small shuffling steps, flexed posture, absent arm swing
on right, turns en bloc, and festination (acceleration while
walking). He does not swing his arms and has difficulty
with initiating a turn. (See Figure 6.1.)
Diagnosis
Idiopathic PD.
Comment on case: The patient exhibits typical features of
PD that hallmark symptoms of tremor, bradykinesia, rigid-
ity, and postural instability. His gait was parkinsonian.
Case 4: history
This 85-year-old right-handed woman presents with
a two-year history of difficulty walking. She feels as
though she just cannot move forward or that there is glue
under her feet. She is independent at home; however,
she recently stopped going to the movies with friends
because of incontinence over the last several months. She
spends her time reading multiple books at a time and has
no trouble keeping up with them.
Physical examination
The general medical examination is unremarkable. The
mental status examination was normal. Cranial nerves
were normal. The strength examination was normal. Deep
tendon reflexes were normal. Plantar responses were
flexor. There were no adventitious movements. Light
touch, pinprick, vibration, and proprioception were nor-
mal. Tone and bulk were normal. Pull test was positive.
Romberg was negative. She pushed with arms to elevate
from a seat. Frontal release signs showed positive snout
and palmomental. Fine finger movements were slowed
throughout. No pseudobulbar affect.
Gait
Frontal gait is characterized by short steps, wide base, and
difficulty lifting the feet off the floor (magnetic response).
Diagnosis
NPH (Figure 6.1–-the wide base can be visualized).
Gait Disorders in the Graying Population 133
(b)
(d)
Case 5: history
This is a 65-year-old left-handed woman with history
of hypertension who had acute onset of “inability to
speak” and weakness of her right-side arm/leg. She was
unable to lift her right leg and arm at first. She noted
that her drink was coming out of her mouth. She went to
the emergency room after 48 hours of symptoms. After
further questioning, she noted an increasing headache
over the past several weeks, with a “worse” headache
the day of maximal symptoms. She has a remote history
of melanoma. She was noted to have an elevated blood
pressure.
Physical examination
The general medical examination is unremarkable. The
mental status examination was normal. Cranial nerves
revealed a right central facial. Strength examination
showed right triceps, right hamstring, psoas weakness
grade 4/5. There was a positive fixed arm roll, as well
as pronator drift. Coordination showed difficulty with
finger–nose–finger test not out of proportion to weak-
ness. Deep tendon reflexes were hypoactive on the right.
Plantar responses were extensor on the right. There were
no adventitious movements. Light touch and pinprick
were decreased on the right upper and lower extremity.
Vibration and proprioception were normal. Tone and
bulk were normal.
Gait
She swings her leg outward and in a semicircle from
the hip (circumduction) and displays external rota-
tion of the right foot. She does not swing her right
arm, and her right leg is slower than the left (see
Figure 6.1).
Diagnosis
Hemiparetic gait. Imaging revealed a hemorrhage in the
left basal ganglia; detailed imaging with MRI revealed
an underlying lesion with hemorrhage, likely because of
metastatic melanoma.
134 Assessment of the Geriatric Neurology Patient
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 Chapter 7
Imaging of the Geriatric Brain
7.1 Structural Neuroimaging in Degenerative Dementias
Liana G. Apostolova1

7.2 Functional Imaging in Dementia

Adam S. Fleisher2 and Alexander Drzezga2

7.3 Amyloid Imaging
Anil K. Nair3 and Marwan N. Sabbagh4

1
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
2
Banner Alzheimer’s Institute, Department of Neurosciences, University of California, San Diego, CA, USA and Department
of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany
3Clinic
for Cognitive Disorders and Alzheimer’s Disease Center, Quincy Medical Center, Quincy, MA, USA
4Banner
Sun Health Research Institute, Sun City, AZ, USA

Summary
Structural Neuroimaging in Degenerative Dementias
• Neurodegenerative disorders cause brain changes that can be detected with structural imaging.
• Hippocampal atrophy, cortical atrophy, ventricular enlargement, and white matter changes are structural biomarkers for
the presence of AD.
• Structural biomarkers for frontotemporal dementias (FTDs) (differ by phenotype) are as follows:
• fvFTD: frontal atrophy, which is often asymmetrical.
• Nonfluent PPA: left perisylvian atrophy.
• Fluent PPA: anterior temporal lobe involvement.
• Structural biomarkers for dementia with Lewy bodies (DLB):
• Mild-to-moderate, nonspecific, generalized brain atrophy.
• Atrophy of dorsal midbrain, hypothalamus, and substantia innominata.
• Structural biomarkers of Parkinson’s disease dementia:
• Widespread cortical atrophy of the limbic, temporal, parietal, frontal, and occipital regions.
• Atrophy of caudate nuclei and lateral and third ventricular enlargement.
• Structural biomarkers of corticobasal degeneration:
• Asymmetric frontoparietal atrophy that involves the sensorimotor strip.
• Structural biormarkers of progressive supranuclear palsy:
• Atrophy of the midbrain tegmentum, enlargement of the third ventricle.
• Structural biomarkers in Creutzfeldt–Jakob disease:
• Increased T2, fluid attenuation inversion recovery (FLAIR) and diffusion-weighted abnormalities in the cortical ribbon
and basal ganglia.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

136
 Imaging of the Geriatric Brain 137

Functional Imaging in Dementia

FDG-PET
• Currently a complementary procedure in the diagnostic evaluation of dementia.
• Progressive reduction of complete metabolic response (CMR) in hippocampal, temporoparietal, and posterior cingulate
areas occur years before the onset of clinical AD.
• It is 94% sensitive and 73% specific for AD and shows reduced temporoparietal glucose utilization may be detectable
before notable amyloid pathology.
• In frontotemporal dementias (FTDs), it shows frontal or temporal hypometabolism with relative sparing of the parietal
lobes.
• In dementia with Lewy bodies (DLB), glucose utilization is impaired in the primary visual and occipital association
cortices in addition to the precuneus and posterior cingulate areas; and dopamine PET scans may show reduced striatal
dopaminergic activity.

SPECT
• Shows decreased temporoparietal perfusion in AD with sparing of primary sensorimotor strip and basal ganglia.
• Isoflupane(IFP)-CIT-SPECT shows nigrostriatal hypoperfusion and is useful to distinguish DLB from Alzheimer’s disease
(AD) and Parkinson’s disease (PD).
• Metaiodobenzylguanine(MIBG)-SPECT may be a good measure of cardiac sympathetic denervation in DLB.
• Vascular dementia shows nonspecific patchy hypoperfusion in the neocortex, subcortical regions, and cerebellum.
• Frontal blood flow has 80% sensitivity and 65% specificity in distinguishing FTDs from AD.

fMRI
• Research tools such as blood-oxygenation-level-dependent (BOLD) imaging and arterial spin labeling (ASL) are magnetic
resonance imaging (MRI) techniques to magnetically tag blood and may have superior temporal and spatial resolution
compared with PET and SPECT.
• Hippocampal and parahippocampal regions show reduced BOLD activations during episodic encoding tasks in clinical
AD.
• In early mild cognitive impairment (MCI) and in APOE4 carriers, there may be a compensatory increase in hippocampal
BOLD response that precedes clinical worsening.
• Default mode networks (DMNs) show reduced resting state connectivity as well as alterations in task-induced
deactivation in MCI, AD, and in APOE4 carriers.

Amyloid Imaging
• Amyloid imaging may help identify individuals at high risk for AD as well as test the efficacy of anti-amyloid therapeutics in
clinical trials.
• It uses two types of radio-labeled agents, (11)C—Pittsburgh Compound B (PiB) and (18)F— florbetapir, florbetaben,
flutemetamol.
• Plasma or cerebrospinal fluid (CSF) amyloid measurements indirectly estimate the extent of cerebral amyloidosis, but
imaging can directly assess amyloid plaque pathology.
• Amyloid imaging will soon supplement clinical evaluation in the diagnosis of AD, while MRI and FDG-PET may supplant
cognitive tests as markers of disease progression.

(11)C LABELED AGENTS

• (11)C has a half-life of only 20 minutes, making large-scale distribution difficult.
• PiB, the most extensively studied isotope, is an analog of the amyloid-binding dye Thioflavin-T.
• It has an on-and-off accumulation pattern unlike the progression of pathologic brain changes.
• BF227 labels dense amyloid deposits like Abeta plaques in AD as well as Lewy bodies in PD.

(18)F LABELED AGENTS

• The 2-hour half-life allows distribution from regional cyclotron facilities to local scanners for up to 10 hours post
manufacture.
• FDDNP-PET provides detailed visualization of both Abeta plaques and neurofibrillary tangles (NFTs) in AD.
• Florbetapir, florbetaben, and flutemetamol show high affinity specific binding to amyloid deposits in the brain.
 Chapter 7.1
Structural Neuroimaging in Degenerative
Dementias
Liana G. Apostolova
Disclosures: This project was supported by a grant from the National Institute on Aging for the UCLA Alzheimer’s
Disease Research Center (P50 16570) and the Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarker
Development.
Dementia is the persistent state of serious cognitive,
functional, and emotional deterioration from a previ-
ously higher level of functioning, leading to impaired
abilities of self-care and independent living. Demen-
tia most commonly results from insidiously progres-
sive neurodegenerative disorders such as Alzheimer’s
disease (AD), dementia with Lewy bodies (DLB),
and frontotemporal dementia (FTD). These disor-
ders invariably cause irreversible brain parenchymal
changes, which can be frequently detected with struc-
tural imaging.
In recent decades, the predementia stages of neurode-
generation have attracted significant attention and have
led to the recognition of a state called mild cognitive
impairment (MCI). MCI (Petersen et al., 2001) and the
related construct of prodromal AD (Dubois and Albert,
2004; Dubois et al., 2007) are increasingly important foci
of research and clinical attention in our efforts to identify
and treat patients early.
The 2001 American Academy of Neurology (AAN)
guidelines (Knopman et al., 2001) recommend structural
neuroimaging as part of the routine clinical evaluation of
patients with cognitive impairment supported by class
II evidence of nondegenerative lesions, such as a slow-
growing brain neoplasm, subdural hematomas, or nor-
mal-pressure hydrocephalus, being the culprit for cogni-
tive decline (Chui and Zhang, 1997). Although magnetic
resonance imaging (MRI) is preferred, if MRI technology
is not available or an MRI is contraindicated (such as in
patients with pacemakers), computed tomography (CT)
should be used.
Recently, the role of structural and functional neuro-
imaging in the initial assessment and outcome prediction
for subjects with cognitive decline has expanded with the
newly proposed prodromal AD diagnostic criteria. This
criteria is based on a combination of characteristic cog-
nitive features and a well-established positive disease
biomarker such as hippocampal atrophy or cerebrospinal
fluid Abeta, and tau levels or a positive amyloid PET scan
suggestive of AD (Dubois et al., 2007).
138
The role of structural neuroimaging in
Alzheimer’s disease
Hippocampal atrophy
Atrophy of the medial temporal lobe structures—the
entorhinal cortex and the hippocampus—are considered
the classic structural imaging hallmark of AD (Jack et
al., 2004; Apostolova et al., 2006b; see Figure 7.1). These
changes can be easily appreciated as early as the prodro-
mal AD stages. As the disease evolves into a full-blown
dementia syndrome, significant global brain atrophy with
temporoparietal predilection and ventricular enlargement
develops (see Figures 7.1 and 7.2; Thompson et al., 2003;
Apostolova et al., 2007). These are easily appreciated on
conventional CT or structural MRI sequences. In addition,
MRI gradient echo sequences can reveal another common
finding in AD patients—multiple small hemorrhages in
the brain and spinal cord. These are due to accompanying
amyloid angiopathy, which can also result in large, life-
threatening lobar hemorrhages in late life.
The hippocampal imaging research field has been
particularly productive in the past decade. Imaging bio-
markers are presently being developed as diagnostic and
prognostic biomarkers and as surrogate biomarkers for
clinical trials. Hippocampal atrophy, the most validated
structural biomarker, is already being accepted as a bio-
marker criterion for AD presence in the prodromal AD
stages (Dubois et al., 2007).
The hippocampus undergoes age-related structural
changes. Hippocampal atrophy has been found to accom-
pany normal aging with an estimated volume loss rate
of around 1.6–1.7% annually (Jack et al., 1998, 2000).
MCI subjects who eventually convert to dementia and
AD subjects show a hippocampal volume loss of 3.7%
and 3.5–4% per year, respectively, but MCI subjects who
remain cognitively stable show an annual atrophy rate
of 2.8% (Jack et al., 1998, 2000). Although this volumet-
ric measure is seemingly useful and intuitive, it cannot
capture the complex pattern of disease progression within
the hippocampal structure (Schonheit et al., 2004).
 Structural Neuroimaging in Degenerative Dementias 139

NC AD

Mid-sagittal view
hippocampal head
Coronal view

Figure 7.1 7T structural MRI hippocampal

images from a normal elderly person
hippocampal body

(normal control (NC), left column) and

Coronal view

an advanced AD patient (right column).

Significant hippocampal atrophy can be easily
appreciated in the sagittal (top row) and
coronal sections through the hippocampal
head (middle row) and body (bottom row).
Cortical thinning of the entorhinal and
parahippocampal cortex is also evident in AD.

New and advanced methodologies provide a unique

Figure 7.2 Brain atrophy in prodromal and advanced AD. In the
prodromal stages, mild hippocampal and global brain atrophy
and mild ventriculomegaly are noted. In advanced AD, severe
hippocampal and global brain atrophy and ventriculomegaly are
easily identified.
opportunity to study the earliest AD-associated changes
in the hippocampal structure. Advanced computational
anatomy, hippocampal shape, and deformation tech-
niques allow us to study the subregional hippocampal
changes (Csernansky et al., 2000; Thompson et al., 2004).
For example, the hippocampal radial distance mapping
approach (which models the hippocampal structure in 3D)
computes hippocampal thickness at each surface point.
Using the radial distance or other conceptually related
approaches, researchers have now mapped the progression
of AD pathology through the hippocampal structure in
vivo (Csernansky et al., 2000, 2005; Apostolova et al., 2006a,
2006b, 2010c) and documented the spread of hippocam-
pal atrophy from the subiculum and CA1 subfield to the
CA2-3 region—a pattern that was previously captured
in only postmortem studies (Schonheit et al., 2004). The
unsurpassed precision of surface-based approaches has
allowed us to also document subtle hippocampal struc-
tural changes years before the onset of cognitive decline,
suggesting a potential role of such technologies in pres-
ymptomatic diagnosis and risk assessment.
For example, subtle atrophy can be readily detected in
the prodromal AD stages as early as 3 years before evi-
dent cognitive impairment, warranting a diagnosis of MCI
in cognitively normal elderly patients who eventually
140 Assessment of the Geriatric Neurology Patient
develop full-blown dementia syndrome of the Alzheimer’s
type (Apostolova et al., 2010b; see Figure 7.3). In addition,
CA1 atrophy of the hippocampus at baseline was recently
shown to increase the future risk of conversion to dementia
in the MCI stage (Apostolova et al., 2010c).
The next major advance in structural hippocampal
imaging is the recent development of automated hip-
pocampal segmentation techniques (Fischl et al., 2002,
2004; Yushkevich et al., 2006; Morra et al., 2008a), which
has allowed rapid and successful analyses of very large
datasets such as the Alzheimer’s Disease Neuroimaging
Initiative (ADNI; Morra et al., 2009a).
ADNI data analyses have confirmed previous findings
from smaller studies and helped us map the expected
associations between hippocampal atrophy and cognitive
deterioration (Apostolova et al., 2006d; Morra et al., 2008b;
Mormino et al., 2009; Beckett et al., 2010). Important obser-
vations from the ADNI study have also linked genetic risk
factors and rates of hippocampal atrophy. The hippocampi
of APOE ε4 allele carriers were reported to atrophy faster
than those of noncarriers (Morra et al., 2009b; Schuff et al.,
2009; Beckett et al., 2010). MCI subjects with a maternal his-
tory of dementia had greater atrophy at baseline and greater
12-month atrophy rates relative to those who had a negative
maternal history of dementia (Andrawis et al., 2012).
Cortical atrophy
Cortical atrophy, a classic feature of AD, has also been
heavily researched in recent years with advanced and
more precise techniques and approaches. The contem-
porary cortical thickness approaches currently offer the
most precise cortical mapping (Fischl et al., 1999; Fischl
and Dale, 2000; Thompson et al., 2003). Using these
techniques has allowed us to document in vivo the pro-
gressive spread of cortical atrophy in subjects with AD
Figure 7.3 3D hippocampal atrophy maps
showing the amount of atrophy (in %)
accumulated over a 3-year period in
cognitively normal elderly patients who
remained cognitively normal for 6 years
or longer since baseline (NL–NL) and
cognitively normal elderly patients who
were diagnosed with amnestic MCI at 3
years and AD at 6 years (NL–MCIAD). (For a
color version, see the color plate section.)
(Thompson et al., 2003), to identify the excess cortical
damage in subjects with very mild AD compared with
those with MCI (see Figure 7.4; Apostolova et al., 2007),
and to ascertain the cortical subregions that most sen-
sitively predict AD type dementia in the elderly (Lerch
et al., 2005; Bakkour et al., 2009). Cortical areas that are
affected early include the entorhinal, parahippocam-
pal, inferior, and lateral temporal cortices, with disease
changes spreading next to the parietal and frontal asso-
ciation cortices (see Figure 7.4; Thompson et al., 2003).
It is now well established that MCI subjects have inter-
mediate cortical thickness relative to cognitively normal
elderly and AD subjects in the normal aging–dementia
continuum (Singh et al., 2006).
Similar to hippocampal atrophy, cortical atrophy shows
robust correlations with cognitive impairment (Thomp-
son et al., 2003; Apostolova et al., 2006c, 2008a). Because
the association cortex is highly specialized, the observed
brain–behavioral associations have been very insightful.
Global measures of cognitive decline, such as the mini–
mental state examination (MMSE), show a widely distrib-
uted pattern of association with cortical atrophy, includ-
ing the entorhinal, parahippocampal, precuneal, superior
parietal, and subgenual cingulate association cortices
(Apostolova et al., 2006c). However, impaired language
function showed associations with the perisylvian corti-
cal areas thought to play an important role in lexical and
semantic storage and retrieval and language processing
(Apostolova et al., 2008a).
Investigating the effects of APOE4 genotypes on cor-
tical atrophy has resulted in several interesting reports.
Several groups recently reported that APOE4 carriers
show a more aggressive involvement of the temporal
association cortices relative to noncarriers (Filippini et al.,
2009; Gutierrez-Galve et al., 2009; Pievani et al., 2009).
 Structural Neuroimaging in Degenerative Dementias
Figure 7.4 Cortical atrophy in AD. Relative
to patients with amnestic MCI, patients
with very mild AD show extensive cortical
atrophy of the entorhinal, parahippocampal,
inferior, and lateral temporal cortices, with
disease changes spreading next to the
parietal and frontal association cortices (left
column). The pattern is strikingly similar to
the amyloid deposition described in Braak
and Braak amyloid stage B (right column).
(For a color version, see the color plate
section.)
Ventricular enlargement
Ventricular enlargement is another consistent finding in
AD. The radial distance approach has also been applied
to study the changes in the ventricular system in AD.
Although ventricular enlargement is largely nonspecific
and occurs in many degenerative and nondegenerative
neurologic conditions, it is a robust imaging biomarker in
AD. MCI subjects show a posterior-predominant enlarge-
ment of the lateral ventricles; however, when subjects are in
the dementia stages of AD, a panventricular enlargement is
readily observed (Chou et al., 2008). APOE4 carriers show
a frontal-predominant dilatation pattern relative to APOE4
noncarriers. Cognitive measures show the expected strong
linkage in an AD-like pattern (Chou et al., 2008).
White matter changes
White matter changes have been long implicated in neu-
rodegeneration (Bartzokis et al., 2004; Bartzokis, 2007)
and have been associated with cognitive decline in the
elderly (Debette et al., 2010). In the ADNI sample, greater
white matter hyperintensity burden at baseline was asso-
ciated with greater cognitive decline during the following
12 months (Carmichael et al., 2010).
Diffusion-weighted imaging (DWI) sequences have
been recently utilized to study white matter integrity.
Microstructural changes in the myelin sheath result in
greater diffusivity and reduced fractional anisotropy on
DWI sequences, and are positively correlated with wors-
ening cognition in MCI and AD (Wang et al., 2010). A
comprehensive meta-analysis recently revealed that the
white matter changes in AD are nonuniform. The great-
est changes in fractional anisotropy and mean diffusivity
were seen in the uncinate fasciculus (the white matter
141
tract connecting the hippocampus and amygdala with
the anterior temporal lobe) and the superior longitu-
dinal fasciculus (a white matter tract connecting the
anterior (frontal) with the posterior (temporal, parietal,
and occipital) association cortices; Sexton et al., 2011.).
Medium effect size was seen in the genu and splenium of
the corpus callosum and the frontal and temporal white
matter (Sexton et al., 2011). Among subjects with MCI, the
most pronounced differences relative to normal controls
were seen in the hippocampus and parietal white matter
(Sexton et al., 2011). Decreased fractional anisotropy has
been reported in preclinical presenilin mutation carriers
in the fornix and orbitofrontal white matter, suggesting
that brain parenchymal changes begin years and possibly
decades before dementia onset (Ringman et al., 2007).
The role of structural neuroimaging
in the frontotemporal dementia (FTD)
spectrum
The FTDs are a group of neurodegenerative disorders
affecting the frontal or temporal lobes disproportionately to
the rest of the brain with variable post-mortem pathologic
findings. The group comprises several distinct phenotypes:
the classic frontal or behavioral variant FTD (fvFTD), two
language variants—primary progressive aphasia (PPA)
and semantic dementia (SD)—and one variant with associ-
ated motor neuron disease (MND), FTD-MND.
At the time of diagnosis patients with fvFTD usually
reveal substantial frontal or temporal (often asymmetri-
cal) atrophy (see Figure 7.5). The classic MRI feature of
nonfluent PPA is left perisylvian atrophy, particularly in
142 Assessment of the Geriatric Neurology Patient
the inferior frontal cortex and insula; however, fluent PPA
patients tend to show inferior, middle, and polar temporal
lobe involvement. SD patients usually present with bilat-
eral anterior temporal lobe involvement (Gorno-Tempini
et al., 2004; Chao et al., 2007).
DWI imaging in FTD has also shown abnormalities.
Reduced fractional anisotropy has been reported in the
frontal and temporal lobe white matter and the ante-
rior cingulate (Zhang et al., 2009). Reduced fractional
anisotropy in the uncinate fasciculus and the occipito-
frontal fasciculus have recently been reported in still
asymptomatic Progranulin mutation carriers, suggest-
ing that brain parenchymal changes begin years and
possibly decades before the onset of dementia (Borroni
et al., 2008).
The role of structural neuroimaging in
dementia with Lewy bodies
On the basis of structural imaging alone, DLB is difficult
to distinguish from AD. Upon visual inspection of clinical
CT or MRI scans, patients with DLB often have mild-to-
moderate nonspecific, generalized brain atrophy. Hippo-
campal involvement may be present.
After a larger number of DLB subjects scans are ana-
lyzed, some atrophy patterns emerge. DLB has been
associated with diffuse temporal, parietal, and frontal
cortical atrophy (Burton et al., 2002; Ballmaier et al., 2004;
Beyer et  al., 2007b), as well as with atrophy of the dor-
sal midbrain, hypothalamus, and substantia innominata
(Whitwell et al., 2007).
Diffusion tensor imaging (DTI) signal changes in DLB
are somewhat similar to patients with AD. Decreased
fractional anisotropy was found in the inferior longitudi-
nal fasciculus—the white matter tract connecting the tem-
poral with the occipital lobes—in both disorders (Kantarci
et al., 2010). In the DLB group, this finding showed a
strong association with visual hallucinations (Kantarci et
al., 2010). Another study compared the DTI characteristics
between DLB and Parkinson’s disease dementia (PDD).
Relative to the PDD group, DLB subjects showed more
severe and more extensive abnormalities, with fractional
Figure 7.5 Brain atrophy in FTD. Frontal variant
FTD is characterized by prominent frontal lobe
atrophy. Primary progressive aphasia subjects
have asymmetric left-predominant perisylvian
atrophy most pronounced in the posterior
portions of the inferior frontal gyrus. SD patients
characteristically present with left-predominant
anterior temporal atrophy.
anisotropy decreases in the posterior cingulate and visual
cortices (Lee et al., 2010).
The role of structural neuroimaging in
Parkinson’s disease dementia
Cognitive impairment is arguably the most understud-
ied nonmotor syndrome in Parkinson’s disease (PD).
Yet as many as 90% of all PD subjects develop demen-
tia during the disease course (Buter et al., 2008). In PD,
the clinical indications for obtaining an MRI would be
to rule out basal ganglia strokes, diffuse white matter
ischemic changes, features associated with other par-
kinsonian disorders, such as midbrain atrophy, which is
commonly seen in progressive supranuclear palsy (PSP),
or an asymmetric frontoparietal atrophy that could sug-
gest corticobasal degeneration (CBD). Yet widespread
cortical atrophy in PDD- and PD-associated MCI does
occur and involves the limbic, temporal, parietal, frontal,
and occipital cortical regions and caudate nuclei (Burton
et al., 2004; Beyer et al., 2007a; Meyer et al., 2007; Apos-
tolova et al., 2010a; Hwang et al., 2013). These cortical
changes are also accompanied by atrophy of the caudate
nuclei and lateral and third ventricular enlargement
(Meyer et al., 2007; Apostolova et al., 2010a). As previ-
ously mentioned, PDD subjects also show decreased
fractional anisotropy in the frontal, temporal, and pari-
etal white matter (Lee et al., 2010).
The role of structural neuroimaging
in other parkinsonian dementias and
Creutzfeldt–Jakob disease
The frequently asymmetric clinical cortical features
of CBD—cortical sensory loss, and limb apraxia—are
reflected in often strikingly asymmetric contralateral
frontoparietal atrophy, with clear involvement of the
motor and sensory cortices. High T1 signal intensity of
the subthalamic nucleus, midbrain atrophy, and T2 stria-
tal hypointensity can also be seen (Sitburana and Ondo,
2009; Tokumaru et al., 2009).
 Structural Neuroimaging in Degenerative Dementias
Figure 7.6 Diffusion-weighted imaging findings in CJD. Extensive
cortical hyperintensities can be identified in the right temporal,
the bilateral insular and frontal cortex, and the caudates.
The classic structural MRI abnormalities of PSP are
atrophy of the midbrain tegmentum, enlargement of the
third ventricle, hyperintensity of the midbrain, and infe-
rior olives (Oba et al., 2005; Boxer et al., 2006). Some stud-
ies have also reported frontal and temporal cortical atro-
phy and hypointensity of the red nucleus and putamen
(Gupta et al., 2010).
The classic MRI findings in Creutzfeldt–Jakob disease
(CJD) are increased T2, fluid attenuation inversion recov-
ery (FLAIR), and diffusion signal of the basal ganglia and
the cortical ribbon. Such findings are essentially pathog-
nomonic for CJD (see Figure 7.6; Milton et al., 1991; Hirose
et al., 1998; Yee et al., 1999; Zeidler et al., 2000; Matoba
et al., 2001).
Conclusions
Structural neuroimaging almost invariably shows signifi-
cant abnormalities in most neurodegenerative disorders.
The most prevalent neurodegenerative disorder—AD—
is one of the leading health concerns of the twenty-first
century, with an increasing elderly population and its
exponentially increasing social and economic impact.
Researchers are already tuned into developing powerful
biomarker strategies that can potentially identify the cog-
nitively normal elderly who have entered the presymp-
tomatic (prodromal) AD stages, as these subjects would
be the ideal therapeutic target for any disease-modifying
drug. In the recent two decades, neuroimaging research-
ers have developed major revolutionary technologic
advances in both structural and functional neuroimag-
ing fields. The rapid development of new promising
techniques capable of reliable, sensitive, and power-
ful detection of focal disease-induced changes instills
optimism that disease course and therapeutic response
could be carefully monitored and appraised. With several
143
promising disease-modifying agents in the pharmaceuti-
cal pipeline, AD researchers are hopeful to soon be able to
cure and prevent this most devastating neurodegenera-
tive disorder.
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 Chapter 7.2
Functional Imaging in Dementia
Adam S. Fleisher and Alexander Drzezga
Alzheimer’s disease (AD) is pathologically manifested
as synaptic loss and neuronal death, with subsequent
reduction of metabolic activity and brain volume loss.
Although the specific neurodegenerative pathway in
AD is unknown, it is believed to predominantly be an
amyloid protein-mediated process (Braak and Braak,
1991, 1994; Selkoe, 2000). It is most widely accepted
that beta amyloid (Aβ) is poorly cleared in AD patients,
leading to increased soluble and insoluble extracellular
Aβ, also leading to fibrillar amyloid plaque deposition
and downstream neurotoxic pathways (Selkoe, 2008).
According to this hypothesis, excess Aβ leads to loss of
neuronal synapses, intracellular neurofibrillary tangles
(NFTs), and cellular toxicity, resulting in mitochondrial
dysfunction and, ultimately, cell death (Mirra et al., 1991,
1993). This pathologic process progresses in predictable
regional patterns predominantly involving structures in
the basal forebrain, medial temporal lobes (MTLs), and
parietal cortex (Braak and Braak, 1996). In addition, neu-
ropathology and synaptic dysfunction may occur several
decades before clinical manifestations (Braak and Braak,
1991; Reiman et al., 2004; Engler et al., 2006; Mintun et al.,
2006). And it is likely that neuronal synaptic dysfunction
precedes Aβ plaque deposition and the gross pathologic
changes associated with AD (Selkoe, 2002). If physiologic
changes can be identified before clinical and gross patho-
logic changes, this provides a potential opportunity for
sensitive presymptomatic imaging biomarkers of disease.
Standards for the diagnosis of dementia today are
based entirely on clinical symptoms (McKhann et al.,
1984). Medical history of progressive cognitive decline
consistent with AD, ruling out active confounding comor-
bidities, and neuropsychological evaluations are the
mainstays for establishing a diagnosis of dementia. Neu-
ropsychological evaluations, however, have a relatively
low sensitivity and specificity of 80% and 70%, respec-
tively, for identifying pathologically confirmed demen-
tia of the Alzheimer’s type (Jobst et al., 1998; Knopman
et al., 2001; Silverman et al., 2002b; Lopponen et al., 2003;
Petrella et al., 2003; Zamrini et al., 2004). Guidelines rec-
ommend imaging predominantly as a tool for excluding
other causes of dementia, such as cerebrovascular dis-
ease, infection, normal pressure hydrocephalus, and other
structural lesions (Knopman et al., 2001; http://www.
aan.com/professionals/practice/pdfs/dementia_guideline.
pdf). New advancements in functional imaging may pro-
vide tools for identifying neurodegenerative brain disease
146
for clinical decision making and treatment development.
Recently, the European Federation of the Neurologi-
cal Societies (EFNS) recommended the use of functional
imaging as part of the routine diagnostic workup of clini-
cally questionable dementia cases (Hort et al., 2010).
What is functional imaging?
Unlike imaging of gross brain structures or even micro-
pathology, functional imaging is defined as any imaging
modality that represents an underlying physiologic pro-
cess. This type of imaging can capture static average brain
function while a participant is resting with eyes open or
closed, or can identify dynamic brain activity in response
to a task being performed during image acquisition. Such
tasks may be cognitive in nature, such as with memory
or language, or reflect sensory-, motor-, visual-, or even
smell-related brain activity. Common physiologic targets
of functional imaging include brain oxygen utilization,
blood perfusion, and glucose metabolism. Various modal-
ities of imaging can be used to identify these physiologic
brain functions. In dementia, the most frequently utilized
imaging modalities include magnetic resonance imaging
(MRI), single photon emission computed tomography
(SPECT), and positron emission tomography (PET). All
three of these techniques are capable of imaging brain
pathology and functional brain physiology. In addition,
imaging methods that identify pathologic and physi-
ologic changes associated with disease progression may
be superior to neuropsychological testing regarding early
and reliable diagnosis of AD (Lim et al., 1999; Hoffman
et al., 2000; Silverman et al., 2001). But many techniques
in dementia imaging are predominantly used for research
and are not approved for clinical purposes. Therefore, this
chapter focuses on functional imaging techniques that are
available and practical in clinical dementia evaluations
for the purpose of guiding physicians in clinical deci-
sion making. Structural MRI and amyloid imaging are
addressed elsewhere.
Positron emission tomography
in dementia
PET imaging facilitates the detection of subtle changes
in brain physiology. PET uses positron emitters to label

target physiologic or pathologic brain processes. Posi-
trons are positively charged unstable particles that inter-
act with electrons while traveling through brain tissue.
This interaction produces photons. These coincident tis-
sue interactions are detected by sensitive detector rings
in the PET scanner that make it possible to identify
both spatial and intensity information. Various types of
positron-emitting nuclei can be used to label tracers to
identify physiologic targets of interest in vivo. The most
common are 15O, 11C, and 18F, with 18F being the most
widely used in clinical practice, mostly because its longer
half-life makes it a more practical molecular isotope. In
particular, PET imaging with a glucose analog, 18F fluo-
rodeoxy glucose (FDG), has been used to identify subtle
changes in metabolic glucose utilization in the brain. In
AD, reductions in regional glucose metabolism, repre-
senting cellular metabolic activity, may be one of the earli-
est detectable brain dysfunctions accompanying the onset
of AD pathology. In fact, there is reason to believe that
FDG-PET may be able to detect brain dysfunction prior
to notable amyloid pathology in the brain (Reiman et al.,
2001; Alexander et al., 2002; Caselli et al., 2008; Langbaum
et al., 2009). However, this idea is somewhat controver-
sial, given our poor understanding of the relationship
between amyloid deposition and glucose metabolism. In
fact, there are examples of comparable FDG-PET uptake
in amyloid PET positive healthy patients compared with
amyloid negative patients, and areas of increased glucose
metabolism associated with increased amyloid binding in
mild cognitive impairment (MCI) patients (Cohen et al.,
92 AD < 104 NC
Figure 7.7 FDG-PET in 92 AD
and 184 MCI participants
48 mm
from the Alzheimer’s Disease
Neuroimaging Initiative
(ADNI; Mueller et al., 2006;
Jack et al., 2008a), compared
with 104 cognitively normal
elderly controls. Top images
show typical patterns of
glucose hypometabolism in 184 MCI < 104 NC
Alzheimer’s disease (AD),
compared with normal. Bottom
images show similar AD-like
patterns, but to a less spatial
and intensity extent in MCI. 48 mm
See Langbaum et al. (2009)
for methodology details. (For
a color version, see the color
plate section.)
Functional Imaging in Dementia 147
2009). Currently, the use of FDG-PET is recommended as
only an optional complementary procedure in the diag-
nostic evaluation of dementia. However, as more infor-
mation becomes available, it is more likely that functional
imaging will play a more prominent role in early clini-
cal diagnosis, risk assessment, and treatment–response
monitoring.
As a measure of neuronal dysfunction, radiolabeled
glucose using FDG-PET allows tracking of glucose metab-
olism in the brain. It is well understood that glucose uti-
lization parallels neuronal activity as its primary energy
source. After intravenous injection, FDG is phosphoryl-
ized and incorporated into cells. The amount of regional
FDG uptake then provides a spatial and intensity repre-
sentation of brain cell cerebral metabolic rates of glucose
metabolism (CMRgl; Phelps et al., 1983). Synaptic activity
of neurons drives glucose utilization, perhaps indirectly,
with increased glucose uptake in surrounding glial cells.
Lactate is subsequently transferred to neurons for energy
metabolism (Magistretti and Pellerin, 1999). In the rest-
ing state, FDG uptake is driven mostly by basal neuronal
activity. In general, basal state FDG-PET imaging repre-
sents underlying neuronal integrity, with decreased func-
tion leading to regional reduction in glucose turnover
(Rocher et al., 2003).
In AD, patients have characteristic patterns of glucose
hypometabolism. This consists of reduced FDG-PET sig-
nal in temporal–parietal, posterior cingulated, and frontal
cortices (see Figure 7.7). These regions are well known to
be associated with cognitive function such as memory
40 mm 32 mm 24 mm 16 mm 8 mm 0 mm −8 mm
40 mm 32 mm 24 mm 16 mm 8 mm 0 mm −8 mm
0.005 7 e-16
p value
148 Assessment of the Geriatric Neurology Patient
and spatial orientation. Likewise, brain regions spared of
early hypometabolism in AD include the primary visual,
sensory, and motor cortices, consistent with spared asso-
ciated symptoms in clinical AD (Herholz, 1995; Silver-
man et al., 2001; Minoshima, 2003). This pattern is also
consistent with known patterns of AD pathology (Braak
and Braak, 1996; Klunk et al., 2004). Minoshima et al.
(2001) found that patients with postmortem histopatho-
logic proof of AD showed typical temporal–parietal,
posterior cingulate, and frontal hypometabolic changes
in prior FDG-PET scans. Hoffman et al. (2000) reported
that temporal–parietal hypometabolism is the typical
abnormality in patients with pathologically verified AD.
Recently, one autopsy comparison study demonstrated
longitudinal decline in FDG-PET CMRgl in cognitively
normal individuals followed an average of 13 years
(Mosconi et al., 2009b). Two of four patients declined to
clinical AD in that time period. The authors observed
that progressive CMRgl reductions on FDG-PET occurred
years in advance of clinical AD symptoms in patients with
pathologically verified disease. Deficits in CMRgl dem-
onstrated progressive AD-like patterns, with most promi-
nent reductions in the hippocampus, temporal–parietal,
and posterior cingulate cortices. The FDG-PET profiles in
life also were consistent with the postmortem diagnosis of
AD. This small case series supports the idea that FDG-PET
is a valuable preclinical marker of AD pathophysiology.
(a)
48 mm 40 mm 32 mm 24 mm 16 mm
(b)
48 mm 40 mm 32 mm 24 mm 16 mm
0.005
p value
Disease severity and cognitive decline is strongly asso-
ciated with glucose hypometabolism in AD (Kawano et
al., 2001; Alexander et al., 2002; Bokde et al., 2005; Lang-
baum et al., 2009). In fact, regions of brain glucose hypo-
metabolism that correlate with measures of global cogni-
tion are similar to patterns characteristic for AD (Lang-
baum et al., 2009). Figure 7.8 shows patterns of glucose
hypometabolism correlated with the mini–mental state
examination (MMSE) scores (Folstein et al., 1975), a brief
global test of cognition commonly used in clinical prac-
tice, and the Clinical Diagnostic Rating scale (CDR; Berg,
1988), which is a functional and global cognitive assess-
ment tool commonly used as an endpoint measure in AD
clinical treatment trials.
FDG-PET is highly sensitive and moderately specific
for dementia of the Alzheimer’s type, with superior accu-
racy compared with neuropsychological testing. In a large
multicenter trial, Silverman et al. (2001) found a sensitiv-
ity of 94% and a specificity of 73% for identifying histo-
pathologically proven AD. Comparatively, when using
pathologically confirmed AD as a diagnostic gold stan-
dard, neuropsychological testing has shown a sensitivity
of 85% and specificity of 55% (Lim et al., 1999; Hoffman
et al., 2000). These studies provide convincing evidence
that diagnostic workups for AD that include FDG-PET
are more accurate than neuropsychological and medical
evaluation alone. In addition, it has been demonstrated
Figure 7.8 FDG-PET in 298
participants with varying
degrees of MCI and AD, and
cognitively normal elderly from
8 mm 0 mm −8 mm ADNI ( Mueller et al., 2006;
Jack et al., 2008a). (a) Areas
of correlated FDG-PET
binding representing glucose
hypometabolism associated
with CDR scores. (b) Areas
of correlated FDG-PET
binding representing glucose
hypometabolism associated
with MMSE scores. Regions
associated with cognitive
impairment are similar to those
associated with a diagnosis
8 mm 0 mm −8 mm of clinical AD (Figure 7.7).
See Langbaum et al., 2009 for
1 e-15 methodology details. (For a
color version, see the color plate
section.)

that FDG-PET is cost-efficient and can lead to improved
management, including therapeutic decision-making
and overall patient care (Silverman et al., 2002a, 2002b;
Moulin-Romsee et al., 2005). Although there is some con-
troversy regarding whether glucose hypometabolism is a
cause or consequence of AD, FDG-PET represents a valu-
able tool for early diagnosis and differential diagnosis in
AD (Silverman et al., 2002b; Minoshima, 2003). FDG-PET
is the most validated functional imaging technique avail-
able to most clinicians for evaluating dementia patients.
AD is a clinical diagnosis in evolution, with a push to
define the disease by pathologic biomarkers as part of
clinical diagnostic criteria (Dubois et al., 2007). Efforts
are currently underway by the National Institute on
Aging and the Alzheimer’s Association to revise existing
NINCDS-ADRDA diagnostic criteria to better reflect this
emphasis on biomarker evidence of disease. Recent rec-
ommendations from the EFNS include use of FDG-PET
or perfusion SPECT in patients where there is diagnostic
doubt in clinical dementia presentation (Hort et al., 2010).
Functional imaging also may play an important role in
identifying the earliest clinical stages of the disease pro-
cesses. FDG-PET has been shown to be valuable in detect-
ing early disease such as MCI, as a transitional stage
between normal aging and clinical dementia. In addition,
FDG-PET may be capable of identifying AD-like hypome-
tabolism in asymptomatic people at increased risk factors
for AD, suggesting its potential use as a presymptomatic
predictor of future cognitive decline.
FDG-PET in MCI
A clinical diagnosis of MCI is defined as a loss of cognitive
function that exceeds common age-associated changes
but does not meet the diagnostic criteria for dementia
(Petersen et al., 1999, 2001; Petersen, 2000). Thus, MCI
is regarded as a risk population for AD. Consequently,
current guidelines of the American Academy of Neurol-
ogy recommend that patients with MCI be identified and
monitored for progression to AD (Knopman et al., 2001).
Glucose hypometabolism occurs in MCI patients in pat-
terns similar to those with AD, but to a lesser degree (see
Figure 7.7). A number of studies have evaluated the value
of FDG-PET in the diagnostic assessment of MCI. Several
cross-sectional studies (some of them large, multicenter
studies with more than 100 MCI subjects) have consis-
tently demonstrated that FDG-PET imaging can reli-
ably differentiate groups of MCI patients from healthy
controls and on the basis of specific hypometabolic pat-
terns (Minoshima et al., 1997; Drzezga et al., 2003, 2005;
Del et al., 2008; Nobili et al., 2008). A number of studies
have identified a predictive value of FDG-PET as a bio-
marker for determining future AD (Herholz et al., 1999;
Arnaiz et al., 2001; Silverman et al., 2001; Chetelat et al.,
Functional Imaging in Dementia 149
2003; Drzezga et al., 2003, 2005; Mosconi et al., 2004;
Hunt et al., 2007; Nobili et al., 2008; Landau et al., 2011).
All these studies were able to identify typical hypometa-
bolic changes in FDG-PET baseline examinations of MCI
patients, associated with later conversion to AD demen-
tia, whereas stable subjects showed fewer or no abnor-
malities. Generally, high sensitivity and specificity values
were calculated (75–100%). Drzezga et al. (2005) demon-
strated a sensitivity of 92% and a specificity of 89% (posi-
tive predictive value 85%, negative predictive value 94%)
for predicting conversion to AD within 16 months. A
number of studies were also able to demonstrate higher
accuracy of FDG-PET for prediction of AD dementia in
MCI patients, compared with neuropsychological exami-
nation (Silverman et al., 2001; Mosconi et al., 2004). While
postmortem neuropathologic evaluation was considered
as the gold standard, it is clear that adding FDG to the
diagnostic evaluation improves prediction accuracy (Sil-
verman et al., 2001).
It is commonly agreed that brain pathology in AD
begins many years prior to clinical symptoms of cognitive
impairment. In fact, this pathologic burden may begin as
many as 20 years before clinical manifestations (Mintun
et al., 2006; Fagan et al., 2007). Functional imaging there-
fore affords us the opportunity to potentially identify AD
before clinical symptoms develop. This is critically impor-
tant for developing treatments to prevent future demen-
tia and screening for individuals at increased risk for
AD. Current diagnostic guidelines recommend against
cognitive screening in asymptomatic individuals. There-
fore, use of known risk factors for AD in healthy elderly
individuals may provide guidance in determining which
individuals should be screened for the pathologic hall-
marks of AD. For example, patients with a strong family
history of dementia and those with known genetic risk
factors may have detectible presymptomatic biomarkers
of AD pathology and represent such a risk population
(Fratiglioni et al., 1993; Corder et al., 1998; Ghebremedhin
et al., 1998).
FDG-PET in the evaluation of
presymptomatic risk for AD
Early-onset familial Alzheimer’s disease (FAD) is associ-
ated with autosomal-dominant inheritance of mutations
in the presenilin and amyloid precursor protein genes
(Goate, 1997; Ermak and Davies, 2002). Regional glucose
hypometabolism on FDG-PET has been associated with
asymptomatic FAD gene carriers, consistent with the
typical AD PET pattern in the relative absence of struc-
tural brain atrophy (Mosconi et al., 2006; Nikisch et al.,
2008). However, cases of FAD with autosomal-dominant
inheritance represent only a small percentage of all AD
cases and have a very different clinical onset and course
150 Assessment of the Geriatric Neurology Patient
compared with the more common late-onset sporadic AD
(LOAD). Thus, findings obtained in this population may
not be generalizable to LOAD.
The apolipoprotein E (APOE) e4allele (ε4) is currently
the most potent known genetic risk factor for LOAD
(Corder et al., 1993; Farrer et al., 1997). It is associated with
the subsequent presence of NFTs and amyloid plaques
in the brain (Corder et al., 2004) and plays a key role in
coordinating the mobilization and redistribution of cho-
lesterol, phospholipids, and fatty acids. It also is impli-
cated in the mechanisms of neuronal development, brain
plasticity, and repair (Mahley, 1988; Mahley and Rall,
2000). Evidence indicates that it promotes formation of
the beta-pleated sheet conformation of Aβ peptides into
amyloid fibers and inhibits the neurotoxic effect of Aβ in
an allele-specific manner (E3 > E4; Strittmatter et al., 1993;
Ma et al., 1996; Jordan et al., 1998). The APOEε4 gene also
appears to modulate Aβ toxicity to vascular endothelium
(Folin et al., 2006). Having a family history of dementia is
independent and additive to the risk associated with the
APOE ε4 allele (Cupples, Farrer et al., 2004). For these rea-
sons, presymptomatic pathologic and physiologic brain
changes may be identifiable in individuals with genetic
risk factors for AD by using FDG-PET.
Several studies have been able to demonstrate hypomet-
abolic abnormalities in cognitively impaired individuals
at increased risk for AD, including carriers of the APOE ε4
allele and those with family histories of AD. For example,
Left lateral
Parietal Parietal
Prefrontal
Temporal
Left medial
Cingulate
Reiman et al. (1996) showed reduced glucose metabolism
in ε4 homozygotes, compared with age- and education-
matched noncarriers (ages 50–65 years). This occurred in
the same brain regions as in patients with probable AD
(posterior cingulate, parietal, temporal, and prefrontal
regions). These same authors later demonstrated that
even relatively young (20–39 years) ε4 homozygotes had
abnormally low rates of glucose metabolism bilaterally in
the posterior cingulate, parietal, temporal, and prefron-
tal cortex, and that the ε4-gene dose is correlated with
lower glucose metabolism in each of these brain regions
(see Figure 7.9; Reiman et al., 2004, 2005). Furthermore, in
several studies, decline of glucose metabolism over time
in AD-typical regions has been demonstrated in cogni-
tively healthy ε4 carriers (Small et al., 2000; Reiman et al.,
2001). Correspondingly, more pronounced hypometabo-
lism was detected in ε4-positive subjects with clinical AD,
compared with age-matched ε4–negative AD patients
(Drzezga et al., 2005). Recent studies have also shown
hypometabolic changes in subjects with maternal his-
tory of AD who are at higher risk for dementia, suggest-
ing additional genetic or environmental risks for LOAD
(Mosconi et al., 2007, 2009a). For these reasons, functional
brain imaging may be useful for evaluating putative AD
prevention therapies in cognitively normal individuals at
increased genetic risk for AD near the age of mean clini-
cal dementia onset (Reiman, 2007; Fleisher et al., 2009a;
Reiman et al., 2010).
Right lateral
Prefrontal
Temporal Figure 7.9 Regions of the brain with
abnormally low CMRgl in young adult
carriers of two copies of the APOE ε4-allele
Right medial and their relationship to brain regions with
abnormally low CMRgl in patients with
Cingulate probable AD. Purple areas are regions in
which CMRgl was abnormally low only
in patients with AD. Bright blue areas are
regions in which CMRgl was abnormally
low in both the young adult e4 carriers
and patients with probable AD. The muted
blue areas are regions in which CMRgl
was abnormally low only in the ε4 carriers.
Source: Reiman et al. (2004). Reproduced
with permission from National Academy of
Sciences. (For a color version, see the color
plate section.)

FDG-PET and other dementias
FDG-PET may be particularly useful to clinicians in dis-
tinguishing AD from other dementias. As seen, typical
patterns of hypometabolism can be identified in patients
with AD. Likewise, other dementias show patterns of
glucose metabolism that distinguish them from normal
controls and AD patients. These disease-specific pat-
terns can be used for differential diagnosis decisions and
subsequent clinical management. However, much less
data is available on other neurodegenerative dementias,
given their relatively low prevalence compared with AD.
FDG-PET can often be useful for diagnostic differential
conclusions based on patterns of hypometabolism in indi-
vidual patients. Yet, in common clinical dementia evalu-
ation guidelines(Knopman et al., 2001), routine FDG-PET
scans are not recommended in dementia evaluations
because the added value over structural imaging has not
been well established in individual patients. However it
is reimbursable under Medicare, as noted, to distinguish
clinically ambiguous cases of AD versus frontal temporal
lobar dementia (FTLD). The EFNS guidelines now sup-
port its use in such cases (Hort et al., 2010).
Frontal temporal lobar dementia
FTLD is a heterogeneous disorder representing a mix of
pathologies and clinical presentations (Rabinovici and
Miller, 2010). Pathologic features in FTLD syndromes
include either tau-positive (FTLD-TAU) or TAR DNA-
binding protein 43 (TDP-43)-positive (FTLD-TDP) inclu-
sion bodies. FTLDs are clinical syndromes of progressive
dysfunction of the frontal and/or temporal lobes, bilater-
ally or unilaterally, with clinical decline in behavior and/
or language, resulting in dementia. It is recognized as one
of the leading causes of dementia before age 65. These dis-
orders are clinically distinct from AD in most cases, but
have overlapping syndromes with atypical parkinsonism,
such as corticobasal degeneration (CBD) and progressive
supranuclear palsy (PSP), as well as with amyotrophic
lateral sclerosis.
Three primary types of FTLD syndromes exist, includ-
ing behavioral variant (bvFTD), FTD associated with
motor neuron disease (FTD-MND), and primary progres-
sive aphasia (PPA). PPA is subsequently broken down
into three aphasia variants: semantic, logopenic, and non-
fluent/agrammatic. It has been demonstrated that forms
of AD with atypical clinical appearance can be confused
with the FTLD syndromes. Diagnosis based on neuro-
psychological criteria alone cannot assess underlying
pathology or reliably differentiate such cases of nonamy-
loid pathology in atypical AD clinically presenting with
FTLD-like symptoms (Neary et al., 1998). Postmortem
studies demonstrate that clinical diagnosis alone may
lead to confusion of FTLD and AD in some cases (Godbolt
et al., 2005). With this degree of clinical and pathologic
Functional Imaging in Dementia 151
variability, it is not surprising that functional imaging
may be just as heterogeneous in presentation.
In many cases, functional neuroimaging can improve
diagnostic accuracy in distinguishing clinical syndromes
of FTLD with AD. Typical patterns of hypometabolism
in FTLD include a combination of frontal or temporal
predominant CMRgl reductions. At least early on in the
course of the disease, these patterns show relative sparing
of the parietal lobes, distinguishing them from AD (Ishii
et al., 1998, 2000; Silverman et al., 2001; Ishii, 2002; Foster
et al., 2007). When seen in individual patients, these pat-
terns are useful in distinguishing FTLD from AD (see
Figure 7.10). Foster et al. (2007) demonstrated that add-
ing FDG-PET to clinical diagnostic criteria can signifi-
cantly increase the accuracy of diagnosis. In comparison
of 31 AD patients to 14 FTD patients, they were able to
achieve a specificity of 97.6% and sensitivity of 86% for
distinguishing AD from FTD. This was particularly true
with visual inspections of individual images projected
onto stereotactic brain surface projections. Unfortunately,
this holds true at the group level but cannot always be
identified in individual patients (Silverman et al., 2001).
Nonetheless, when typical frontal and/or anterior frontal
hypometabolism is seen, it can improve clinical diagnos-
tic accuracy. Figure 7.10D demonstrates an example of
frontal hypometabolism on FDG-PET in a patient with
bvFTD.
Dementia with Lewy bodies
Approximately 15% of dementias occurring over the age
of 65 result from dementia with Lewy bodies (DLB), as
the second most common type of late-onset dementia
(Heidebrink, 2002). DLB involves widespread neuronal
degeneration with deposition of Lewy bodies and Lewy
neurites, which contain alpha-synuclein as a major fila-
mentous component (Galvin et al., 1999). Similar to AD
in its progression with prominent memory dysfunction,
DLB also typically presents with fluctuations in cogni-
tive impairment, prominent visuospatial dysfunction and
visual hallucinations, and early parkinsonism (McKeith
et al., 2005). In fact, DLB is often an overlap syndrome
with the majority of DLB patients also meeting pathologic
CERAD criteria for AD, with the addition of diffuse corti-
cal Lewy bodies (Fleisher and Olichney, 2005). There have
been relatively few investigations of DLB with functional
imaging, compared with AD. But consistent with struc-
tural findings, there appears to be a relative sparing of the
MTL and an overall pattern of glucose hypometabolism,
similar to AD (Burton et al., 2002; Weisman et al., 2007). In
addition to precuneus and posterior cingulated hypome-
tabolism, decreased glucose utilization is often seen in the
primary visual and the occipital association cortices, con-
sistent with the clinical presentation of DLB (see Figure 9.4;
Minoshima et al., 2001; Gilman et al., 2005). This pattern
of hypometabolism is consistent with a finding of diffuse
152 Assessment of the Geriatric Neurology Patient
Lewy bodies on autopsy (Albin et al., 1996; Minoshima
et al., 2001; Gilman et al., 2005; Mosconi et al., 2009b). One
such study by Minoshima et al. (2001) comparing 11 DLB
with 10 AD patients, showed significant metabolic reduc-
tions in DLB compared with AD, with 90% sensitivity
and 80% specificity. In addition, dopaminergic loss and
dopamine transport loss in the striatum has been demon-
strated at autopsy to be similar in magnitude in DLB to
that seen in Parkinson’s disease (PD) (O’Brien et al., 2004).
Experimentally, PET ligands that bind to dopamine ([18F]
fluorodopa) and monoamine transporters ([11C]DTBZ)
have demonstrated reduced striatal dopamine activity in
DLB compared with AD, consistent with the high preva-
lence of parkinsonism in this dementia (Hu et al., 2000;
Koeppe et al., 2008; Klein et al., 2010). These dopamine
PET imaging techniques are not widely available and are
not recommended for routine evaluations of DLB. How-
ever, SPECT tracers for imaging of dopamine transporters
may have clinical value and have recently been demon-
strated to reliably differentiate between DLB and AD.
Vascular dementia
Vascular dementia is typically diagnosed with a com-
bination of clinical and MRI findings (van Straaten et
al., 2003). Functional imaging would be used only for
cases with equivocal findings. In addition, 15–20% of
vascular dementia patients will have a combination of
AD and vascular pathology (Chui et al., 2000). Findings
of patchy deficits rather than typical patterns of pari-
etotemporal dysfunction may help distinguish vascular
dementia from AD (Talbot et al., 1998; Jagust et al., 2001).
However, MRI imaging for ischemic disease is routinely
recommended over functional imaging for diagnostic
evaluation.
FDG-PET in the clinic
FDG-PET scanning, in general, is approved for clinical
use. However, Medicare in the United States has specific
National Coverage Determinations for use of FDG-PET
as a diagnostic test for dementia and neurodegenerative
diseases (Medicare Manual Section Number 220.6.13). In
general, Medicare covers FDG-PET scans for the differen-
tial diagnosis of frontotemporal dementia (FTD) and AD.
An FDG-PET scan is considered reasonable and necessary
in patients with a recent diagnosis of dementia and docu-
mented cognitive decline of at least 6 months who meet
diagnostic criteria for both AD and FTD. These patients
have been evaluated for specific alternate neurodegenera-
tive diseases or other causative factors, but the cause of
the clinical symptoms remains uncertain. Coverage varies
from state to state, and there is no guarantee that a private
insurance carrier will cover the cost or approve the imag-
ing procedure. Costs can be as high as $4000 if not covered
by the patient’s insurance, so it is important to have these
discussions with patients before ordering scans. When
used in individual patients in the clinic, the typical pat-
tern of glucose hypometabolism for MCI, AD, FTLD, and
DLB is often identifiable and potentially useful for diag-
nosis and clinical decision-making (see Figure 7.10).
Single photon emission computed
tomography
SPECT imaging uses gamma photon–emitting radio-
isotopes attached to biologically relevant molecules
that have been injected intravenously and distributed
throughout the body. As gamma-emitting molecules
are dispersed in the body, they are attenuated as they
pass through different types of tissue. This attenuation
is assumed to be homogenous throughout the brain. A
gamma camera is used to detect the photon signal, and
collimators funnel photon activity to the camera as they
are emitted in defined directions, allowing for the detec-
tion of spatial patterns. This directional filtering allows
only a small portion of photons to be detected, which
limits the sensitivity of SPECT compared with PET. The
gamma camera rotates around the patient, generating 2D
images projected from various angles. Three-dimensional
reconstruction of these 2D images facilitates the modeling
of biologically meaningful physiologic processes such as
blood flow and receptor-binding capacity. Modern cam-
eras use dual- or triple-head cameras to reduce acquisi-
tion times. With regard to neurologic indications, SPECT
most commonly is used to measure cerebral blood flow
by using common gamma-emitting tracers such as Tech-
netium 99-hexamethylpropylene amine oxime (99mTc-
HMPAO) and 99mTc-ethylenedicysteine-folate (99mTc-
EC-folate; Shagam, 2009).
SPECT has historically been widely available and
well studied in AD (Silverman, 2004). It continues to
be widely available and somewhat less expensive than
FDG-PET scanning. It is approved by the FDA for gen-
eral medical use but has no specific Medicare indication
for dementia. Insurance coverage for use in dementia is
therefore variable but generally good. Similar to hypo-
metabolism seen on FDG-PET imaging, SPECT shows
decreased cerebral perfusion in bilateral temporal-
parietal lobes (Table 7.1). As in PET, the frontal lobes are
also affected in AD (often in the later stages of demen-
tia), but the primary sensorimotor strips and basal gan-
glia are typically spared (Silverman et al., 2001; Dou-
gall et al., 2004; Pakrasi and O’Brien, 2005). SPECT in
MCI has likewise revealed consistent patterns of cere-
bral hypoperfusion, though to a lesser degree than that
seen in AD, and has shown some predictive value for
AD (Johnson et al., 1998; Huang et al., 2002; Staffen
et al., 2006). One recent study demonstrated a limited
 Functional Imaging in Dementia 153

(a)

Figure 7.10 Individual FDG-PET

scans in a patient with (a) normal
cognition, (b) MCI, (c) AD, (d)
bvFTLD, and (e) DLB. Images
on the left are individual FDG- (b)
PET CMRgl binding, showing
areas of significant glucose
hypometabolism compared
with normal controls (blue). An
automated algorithm was used
to transform individual patient
images into the dimensions of (c)
a standard brain and compute
statistical maps of significantly
reduced glucose metabolism
relative to 67 normal control
subjects (mean age 64 years). Red-
outlined regions represent areas
of mean hypometabolism seen in (d)
FDG-PET scans from 14 patients
with AD (mean age 64 years),
compared with the same 67
normal controls. On the right are
raw FDG-PET color maps from
the same corresponding patients.
Here we can see the use of FDG-
(e)
PET for identifying disease-
specific patterns of glucose
metabolism for clinical use in
individual patients, to assist with
diagnostic decision-making. (For
a color version, see the color plate
section.)

utility of SPECT for predicting progression to AD from
MCI. The authors found that visual ratings of SPECT
in the temporal and parietal lobes did not distinguish
eventual MCI converters to AD (N = 31) from noncon-
verters (N = 96), whereas a global rating of dementia
did (41.9% sensitivity and 82.3% specificity, Fisher’s
exact test p = 0.013; Devanand et al., 2010). Only when
dichotomized at the median value of the patients with
MCI did low flow increase the hazard of conversion to
AD for parietal (hazard ratio: 2.96, 95% CI: 1.16–7.53,
p = 0.023) and medial temporal regions (hazard ratio:
3.12, 95% CI: 1.14–8.56, p = 0.027). In a 3-year follow-up
sample, low parietal (p <0.05) and medial temporal (p
<0.01) flow predicted conversion to AD, with or with-
out controlling for age, MMSE, and APOE ε4 genotype.
However, these measures lost significance when other
strong predictors were included in logistic regression
analyses such as verbal memory and social/cognitive
functioning. Overall, the literature on predementia and
risk for dementia is considerably scarce for perfusion
SPECT compared with that for FDG-PET.
Other dementias show similar regions of hypoperfusion
on SPECT scanning to glucose hypometabolism. FTLD
patients often show expected patterns of frontal and ante-
rior temporal lobe hypoperfusion (Coulthard et al., 2006;
McNeill et al., 2007). McNeill et al. (2007) found that frontal
blood flow had a sensitivity of 80% and specificity of 65%
in distinguishing AD from FTD. DLB shows expected pat-
terns of cerebral hypoperfusion similar to AD, but as with
FDG-PET, it reveals relatively more blood flow reduction
in the visual cortex (Donnemiller et al., 1997; Lobotesis et
al., 2001). However, modest sensitivity and specificity of
around 60–65% suggest limited usefulness of HMPAO
SPECT to distinguish AD from DLB (Lobotesis et al., 2001).
Yet, DLB offers an opportunity to explore other molecular
targets with SPECT imaging. As noted previously, dopa-
minergic loss in the striatum is present in DLB on autopsy
with a similar magnitude as seen in idiopathic PD(O’Brien
et al., 2004). 123ioflupane (IFP)-CIT (DAT-SCAN) is a
SPECT ligand that enables visualization of nigrostria-
tal dopaminergic neurons. Studies have demonstrated
IFP-CIT SPECT imaging to have  an overall accuracy of
154 Assessment of the Geriatric Neurology Patient
around  86%, with a sensitivity of 78% and specificity of
90% for distinguishing DLB from other dementias (pri-
marily AD), and 78% sensitivity and 94% specificity for
distinguishing it from PD (O’Brien et al., 2004; McKeith et
al., 2007). Another interesting SPECT finding is reduced
cardiac uptake of metaiodobenzylguanine (MIBG) in DLB
patients, compared with normal controls and AD. MIBG
SPECT is thought to be a measure of cardiac sympathetic
denervation in DLB patients. MIBG cardiac imaging has
shown sensitivities of 95–100%, and specificity of 87–100%
for distinguishing DLB from AD and normal controls
(Hanyu et al., 2006a, 2006b; Yoshita et al., 2006; Kobayashi
et al., 2009). This association also appears to be related to
clinical symptoms of orthostatic hypotension (Kobayashi
et al., 2009). For these reasons, dopamine imaging has been
included as a “suggestive feature” in the International
Consensus criteria for diagnosis of DLB. MIBG SPECT and
perfusion SPECT have been included as “supportive fea-
tures” (McKeith et al., 2005; McKeith, 2006). Dopaminergic
SPECT is also now recommended, with strong evidence
for clinical evaluations to distinguish AD from DLB by the
EFNS (Hort et al., 2010).
SPECT compared with PET
In general, diagnostic accuracy of SPECT is not as good
as that of PET (Silverman, 2004). This is partly due to
the reduced magnitude of changes in cerebral perfusion
compared with glucose hypometabolism in AD, and
partly due to reduced spatial resolution compared with
modern PET scanners (Masterman et al., 1997; Silverman,
2004). One review of SPECT literature in AD revealed
71% sensitivity and 90% specificity for AD versus normal
elderly controls, with 76% specificity for other dementias
(Dougall et al., 2004). As previously noted, PET studies
have shown sensitivity of 94%, with specificity similar to
SPECT at 73% (Silverman et al., 2001). One study compar-
ing FDG-PET with HMPAO SPECT in distinguishing AD
(n = 20), nonAD dementias (n = 12), and cognitively normal
elderly found a 90% diagnostic accuracy with FDG-PET
and 67% accuracy using SPECT. When looking at patients
with MMSE scores greater than 20, SPECT accuracy did
not improve (Herholz, 1995). Consistent with this, several
studies utilizing high-resolution SPECT and PET sys-
tems have suggested 15–20% increased sensitivity with
FDG-PET, compared with perfusion SPECT for detect-
ing AD (Messa et al., 1994; Mielke et al., 1994; Mielke and
Heiss, 1998). PET and FDG SPECT and HMPAO SPECT
changes are highly correlated with each other (r = 0.90),
particularly in the posterior cingulated and temporopa-
rietal regions, with significantly more pronounced abnor-
malities in tracer uptake of FDG, compared with HMPAO
(Herholz et al., 2002). Despite the reduced cost and wide
availability of SPECT, its limitations and the increasing
Table 7.1 FDG-PET and SPECT perfusion findings in dementia
Dementia type Deficits in nuclear imaging
Alzheimer’s disease Early regional hypoperfusion and glucose
(AD) hypometabolism in parietal, temporal, and
posterior cingulated cortices, with relative
sparing of primary visual and sensorimotor
cortex, striatum, thalamus, and cerebellum.
Findings can be asymmetric in early disease.
Dementia with Lewy Similar deficits as seen in AD, plus hypoperfusion
bodies (DLB) and hypometabolism in the primary visual cortex.
Frontotemporal lobar Hypoperfusion and hypometabolism in the
dementia frontal, anterior temporal, and mesiotemporal
regions early in disease, with later involvement
of parietal cortex. Sensorimotor and visual
cortices are typically spared.
Vascular dementia Patchy hypoperfusion and hypometabolismin
nonspecific patterns within the neocortex,
subcortical regions, and/or cerebellum.
Source: Adapted from Silverman (2004).
availability of advanced PET scanners and tracers have
made PET imaging much more prominent both in clinical
research and for diagnostic evaluations by clinicians.
Functional magnetic resonance imaging
MRI can generate images of the brain with superior spa-
tial and temporal resolution, compared with SPECT or
PET scanning. It also has the advantage of generally being
less costly to perform and does not use any form of radia-
tion, unlike SPECT, PET, and computed tomography (CT).
MRI measures variance in magnetic fields and changes
produced by radio frequency pulses against the magnetic
dipoles of hydrogen molecules in the body and brain.
By measuring the various magnitudes and directions of
magnetic field distortion, MRI scanners can reconstruct
2D and 3D images of the brain. By adjusting the radio fre-
quency pulses and assessing the amount of time it takes
the magnetic dipole distortion to return to its equilibrium
state, MRI imaging can be adjusted to measure specific
types of tissue. Not only can this be done to produce high-
resolution anatomic images, but it can be used to measure
physiologic processes as well. The most common types
of functional MRI (fMRI) are blood-oxygenation-level-
dependent imaging (BOLD) and arterial spin labeling
(ASL). Despite the high potential of fMRI as a tool for
clinical diagnosis of early functional biomarkers in AD, it
has yet to be proven useful in individual patients. These
techniques require sophisticated statistical data analysis
and are plagued by intra- and intersubject and scanner
variability. For these reasons, fMRI is currently used only
as a research tool in the field of dementia.
fMRI can measure brain physiology during the resting
state or in response to a cognitive task, such as memoriza-
tion. When a region of the brain is active or stimulated,

the metabolic rate of oxygen consumption (CMRO2)
is increased locally. This drives a perfusion response to
increase oxygenated blood flow to that region of the brain
(Fox and Raichle, 1986). This influx of oxygenated blood
effectively decreases the local level of deoxygenated
hemoglobin (Buxton et al., 2004). As deoxygenated hemo-
globin levels go down, the fMRI signal goes up. In short,
increasing oxygenated blood increases the local fMRI
signal, which can be detected at a volumetric resolution
of about 1–3 mm3. This allows determination of variable
levels of brain activity in disease states such as AD. ASL
imaging allows quantifiable measures of cerebral blood
perfusion in physiologic units ([ml of blood]/[100 gm of
tissue]/min). First developed in 1992, ASL was later modi-
fied for human use (Alsop and Detre, 1996). The princi-
ples of ASL are similar to those underlying PET studies
with H215O. In this fMRI technique, blood is magnetically
“tagged” before entering the brain; after waiting for a
predetermined time and distance for the tagged spins to
arrive at the brain region of interest, an MRI image is col-
lected (tag image). A second image is then collected in an
identical way, but without tagging the blood (the control
image). A subtraction of the tagged image from the con-
trol image results in an fMRI signal that represents the
magnitude and quantity of blood perfused to the brain in
each MRI voxel.
fMRI in response to a memory task
fMRI has been used to identify patterns of brain abnor-
malities in AD, MCI, and genetic risk for AD based on
the presence of the apolipoprotein epsilon4 (APOE4)
genotype. A number of fMRI studies in patients with
clinically diagnosed AD have identified reduced BOLD
activations in hippocampal and parahippocampal
regions, compared with control subjects during epi-
sodic encoding tasks (Small et al., 1999; Rombouts et al.,
2000; Machulda et al., 2003; Sperling et al., 2003). Over-
all, the BOLD response to a memory task is consistently
decreased in AD (Dickerson et al., 2005; Dickerson and
Sperling, 2009). However, increased activation has been
reported in prefrontal regions performing memory tasks
(Sperling et al., 2003). In MCI, fMRI studies have reported
similar reductions in MTL BOLD activation, compared
with controls (Small et  al., 1999; Machulda et al., 2003;
Johnson et al., 2006a). Yet, there may be an early phase of
the disease in which the MTL BOLD signal is increased
in MCI, compared with controls (Dickerson et al., 2005;
Hamalainen et al., 2007). One study of 32 MCI patients
showed an increase in MTL BOLD activation, which
correlated with better memory performance. Increased
right parahippocampal activation also was associated
with greater clinical decline over 2.5 years (Dickerson
et al., 2004). A later study demonstrated that increased
Functional Imaging in Dementia 155
hippocampal BOLD response predicted rate of clinical
decline over the next 4 years in MCI patients and sub-
sequent loss of hippocampal signal over time (Miller et
al., 2008b; Dickerson and Sperling, 2009). These authors
hypothesized that hyperactivation in MTL regions may
reflect a compensatory response to accumulating AD
pathology and may be a harbinger of hippocampal
degeneration, serving as a marker for impending clinical
decline. Similarly, increased encoding-associated MTL
BOLD activity has been demonstrated in cognitively nor-
mal elderly carriers of the APOE ε4 allele, perhaps rep-
resenting a similar compensatory response (Bookheimer
et al., 2000; Fleisher et al., 2005). However, depending
on age and the memory task used, some studies have
shown decreased or mixed BOLD responses to encoding
(Bondi et al., 2005; Johnson et al., 2006b; Trivedi et al.,
2006). Also, simply having a family history of AD may
influence the fMRI signal (Fleisher et al., 2005; Johnson
et al., 2006b). Notably, one must be careful in interpret-
ing BOLD because increased BOLD activation does not
translate directly to increased neuronal activity (Fleisher
et al., 2009b). Due to these complexities in interpreting
task-related BOLD fMRI, these techniques remain pre-
dominantly used for research purposes. New, simplified
uses of fMRI during the resting state are being explored.
Resting state fMRI
The default mode network (DMN) represents a network
of coordinated low-frequency fluctuation in specific func-
tional neuronal networks. It is manifested in key brain
regions that are elevated in states of relative rest, which are
responsible for attention to environmental stimuli, review
of past knowledge, and/or planning of future behaviors
(Binder et al., 1999; Raichle et al., 2001). These regions pre-
dominantly consist of midline and lateral frontal regions,
and medial and lateral parietal regions extending into
posterior cingulate/retrosplenial cortex (Buckner and Vin-
cent, 2007). These same regions that are activated at rest
appear to be suppressed during various cognitive activi-
ties, including encoding of new memories (Rombouts et
al., 2005; Sorg et al., 2007; Pihlajamaki et al., 2008). For
this reason, two strategies have been developed utiliz-
ing the DMN to identify diseases of cognition and risk
for dementia in the BOLD fMRI literature. One strategy
explores task-related deactivations; the other focuses on
differences in resting state BOLD networks. These default
networks may be particularly affected by the neurode-
generative process of AD (Buckner et al., 2008). With this,
several groups have reported both reduced resting state
connectivity (Buckner et al., 2005) and alterations in fMRI
task-induced deactivation responses in aging (Lustig
et al., 2003; Andrews-Hanna et al., 2007), MCI (Rombouts
et al., 2005; Sorg et al., 2007), and AD patients (Lustig et al.,
156 Assessment of the Geriatric Neurology Patient
2003; Greicius et al., 2004; Rombouts et al., 2005; Wang
et al., 2006, 2007; Buckner and Vincent, 2007; Persson et
al., 2008), compared with healthy controls. Additionally,
older adult APOE4 carriers have reduced DMN deactiva-
tion, compared with noncarriers (Persson et al., 2008) and
alterations in resting state connectivity differences in both
older adults (Fleisher et al., 2009c) and in APOE4 carriers
as young as 20–35 years of age (Filippini et al., 2009).
Abnormalities of the DMN seen with fMRI may signify
underlying physiologic defects associated with AD. Evi-
dence that supports this includes findings that the cortical
regions that make up the DMN are similar to areas of early
brain atrophy, hypometabolism, decreased perfusion,
and fibrillar amyloid deposition in early AD and MCI
(Minoshima et al., 1997; Johnson et al., 1998; Klunk et al.,
2004; Buckner et al., 2005, 2009; Edison et al., 2007; Fors-
berg et al., 2008; Jack et al., 2008b), as well as in cognitively
normal elderly (Sperling et al., 2009). In particular, the
posterior cingulate and precuneus cortex are regions that
have the most prominent deactivations during cognitive
tasks and are increased during the resting state (Greicius
et al., 2004; Buckner et al., 2005). Furthermore, failure to
deactivate medial posterior DMN during encoding is
associated with worse memory performance (Miller et al.,
2008a). Also, suppression of the DMN during a memory
task is associated with increased cortical fibrillary amy-
loid in cognitively normal elderly individuals (Hedden
et al., 2009; Sperling et al., 2009) and reduction of struc-
tural white matter integrity (Greicius et al., 2009). Overall,
these findings suggest that “suspending” the default net-
work during working memory is necessary for successful
encoding, is impaired in AD, and is potentially associated
with preclinical amyloid pathology. For these reasons,
resting state fMRI techniques may hold great potential as
sensitive preclinical biomarkers of AD pathology.
Perfusion fMRI using arterial spin
labeling
ASL has been used to distinguish AD and MCI subjects
from normal controls (Alsop et al., 2000; Johnson et al.,
2005). Small studies also have been able to use ASL per-
fusion MRI to distinguish cognitively normal individuals
based on family history of AD and APOE ε4 allele status
(Fleisher et al., 2009b). This technique has not been widely
studied, and little is known about its sensitivity for dis-
tinguishing AD, MCI, and healthy elderly controls. This
technique does have advantages over SPECT perfusion,
with improved spatial and temporal resolution, the abil-
ity to measure resting perfusion as well as change in per-
fusion with a functional task, relatively inexpensive cost,
and absence of radiation in testing. For these reasons, it
has potential as a useful future biomarker of AD patho-
physiology.
Summary
Functional imaging has become an important tool
for understanding the pathophysiology of dementia.
Because most dementias stem from underlying pathol-
ogy that is present many years before clinical symp-
toms, identifying biomarkers of disease is critical for
preventative treatment development. In the clinic, PET
and SPECT scanning are currently available as tools
to assist in diagnostic decision-making, with a vast
amount of research data supporting their utility. More
recently, additional biomarker tools have been emerg-
ing that will soon play an important role in clinical
management, diagnosis, and ultimately screening for
presymptomatic disease. Spinal fluid levels of Aβ and
tau proteins have proven to be sensitive predictors of
disease and progression (De Meyer et al., 2010) and are
becoming more readily accessible and cost-effective for
clinicians and patients. The advent of amyloid imaging
using PET ligands is a promising research technique
that provides an opportunity to identify Alzheimer’s-
associated pathology in patients and will likely be avail-
able in the clinic in the near future. Combining these
pathologic markers of disease with functional markers
of impaired brain physiology will ultimately provide
important tools for clinicians to accurately diagnose
dementing diseases at the earliest possible stages. In
fact, there has been increasing emphasis on includ-
ing pathologically linked biomarkers of AD as part of
clinical diagnostic criteria (Dubois et al., 2007), with
efforts currently underway by the National Institute on
Aging and the Alzheimer’s Association to revise exist-
ing NINCDS-ADRDA diagnostic criteria to include
functional imaging in diagnostic decision-making. Use
of biomarkers such as functional imaging likely will
become standard practice in dementia care.
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 Chapter 7.3
Amyloid Imaging
Anil K. Nair and Marwan N. Sabbagh
Introduction
The diagnosis and treatment of Alzheimer’s disease (AD)
are hampered by the lack of noninvasive biomarkers of
the underlying pathology. There is a need for a diagnostic
biomarker to help clinicians separate patients who have
AD pathology from those who do not. Biomarkers of brain
amyloid deposition can be measured either by cerebrospi-
nal fluid beta amyloid (Aβ)42 or by radiolabeled mark-
ers on positron emission tomography (PET) imaging.
In this chapter, we survey the current amyloid imaging
techniques using 11C-labeled (11C) agents such as Pitts-
burgh compound B (11C-PiB) or 18F-ligands (18F) such
as Florbetapir F 18 (18F-AV-45), 18F-flutemetamol (18F-
GE067), Florbetaben (18F-BAY94-9172), 18F-FDDNP, and
NAV. Among these, PiB is the most studied Aβ-binding
PET radiopharmaceutical in the world. The histologic
and biochemical specificity of PiB binding across differ-
ent regions of the AD brain was demonstrated by show-
ing a direct correlation between Aβ-containing amyloid
plaques and in vivo (11C)PiB retention, measured by PET
imaging. Because 11C is not ideal for commercialization,
(18F)3’-F-PiB (Flutemetamol), 18F-AV-45 (Florbetapir),
and 18F-AV-1 (Florbetaben) are undergoing extensive
Phase II and III clinical trials.
Clinical trials have clearly documented that PET radio-
pharmaceuticals capable of assessing Aβ content in vivo in
the brains of AD subjects and subjects with mild cognitive
impairment (MCI) will be important as diagnostic agents
to detect in vivo amyloid brain pathology. In addition,
early PET amyloid imaging will help test the efficacy of
anti-amyloid therapeutics currently under development
in clinical trials.
AD is the most common cause of dementia in the
elderly, affecting more than 4 million people in the USA
and approximately 7.3 million people in Europe (Wilmo
and Prince, 2010). Although diagnosis based on consensus
criteria (McKhann et al., 1984; American Psychiatric Asso-
ciation, 2000) is reasonably accurate by comparison with
the gold standard of pathology at autopsy (Jobst et al.,
1998; Knopman et al., 2001), approximately 10% of com-
munity-dwelling elderly still have undiagnosed dementia
(Solomon et al., 2000; Lopponen et al., 2003). Community
physicians may fail to diagnose up to 33% of mild demen-
tia cases (Lopponen et al., 2003). Additionally, the medical
system does not have the resources to routinely send all
162
elderly subjects with memory complaints for comprehen-
sive expert evaluation.
Furthermore, upon comprehensive diagnostic testing,
many patients are found to have cognitive impairment
but are not demented, and thus, do not meet diagnostic
criteria for AD (for example, people with MCI). Some, but
not all, of these patients will go on to develop AD within
3–5 years (Petersen et al., 2001a). A reliable biomarker
might aid diagnosis by documenting the presence or
absence of disease-related pathology. A biomarker could
also be useful for early identification of subjects at risk for
developing AD (Thal et al., 2006).
Although the underlying etiology of AD is not estab-
lished, the Aβ peptide is important in the pathogenesis of
the disease. Accumulation of Aβ in the form of amyloid
plaques is one of the hallmarks of the disease and is a key
component of the preclinical neuropathologic criteria for
diagnosis (Mirra et al., 1991; Hyman and Trojanowski,
1997; Albert et al., 2011; Pontecorvo and Mintun, 2011).
Most cases of AD are thought to occur sporadically, but
rare familial mutations are known to produce an autoso-
mal dominant form of the disease. All forms directly or
indirectly increase production or accumulation of specific
forms of Aβ peptide and lead to the formation of amyloid
plaques (Hardy and Higgins, 1992; Hardy and Selkoe,
2002). Transgenic mice that express one or more of these
mutant human genes develop amyloid plaque, and behav-
ioral/cognitive deficits that are similar in some respects to
those seen in AD (Hsiao, 1998; Hock et al., 2003; Gotz et
al., 2004). Finally, experimental treatments that reduce Aβ
peptide production or increase the clearance of Aβ from
amyloid plaques have been successful in reversing behav-
ioral deficits in these mice; some of these treatments are
now being tested in patients with AD (Hock et al., 2003).
The most widely accepted and validated biomarkers
in AD fall into two categories: imaging and CSF chemical
analytes (Shaw et al., 2007; Hampel et al., 2008). Different
biomarkers serve as in vivo indicators of specific patholo-
gies. Measures of brain atrophy on a magnetic resonance
imaging (MRI) are biomarkers of neurodegenerative
pathology (Bobinski et al., 2000; Gosche et al., 2002; Jack
et al., 2002; Silbert et al., 2003; Jagust et al., 2008; Vemuri
et al., 2008; Whitwell et al., 2008), while both PET amyloid
imaging (Klunk et al., 2004; Edison et al., 2007; Rowe et
al., 2007; Drzezga et al., 2008; Ikonomovic et al., 2008; Lei-
nonen et al., 2008; Frisoni et al., 2009; Tolboom et al., 2009)

and decreased CSF Aβ 42 (Clark et al., 2003; Strozyk et al.,
2003; Schoonenboom et al., 2008; Buchhave et al., 2009; Tap-
iola et al., 2009) are indicators of brain Aβ amyloidosis or
Aβ load. A variety of biomarkers for amyloid plaque accu-
mulation have been proposed (Thal et al., 2006). The clini-
cal utility of Aβ imaging at the present time may be par-
ticularly useful in the evaluation of complicated or atypical
cases of neurodegenerative diseases. In the future, the life
cycle plan for broader application of Aβ imaging will likely
include sufficient data to permit thorough examination of
its potential utility in the differential diagnosis of neurode-
generative diseases, in monitoring disease progression, in
therapy monitoring (and for tailoring therapy to individ-
ual patients), and in predicting at-risk patient populations.
Individual amyloid imaging agents
In contrast to techniques designed to indirectly estimate
levels of brain amyloid plaques from Aβ levels in plasma
or cerebral spinal fluid, imaging techniques utilizing
radiolabeled PET tracers that bind to the aggregated Aβ
peptides in amyloid plaques have the potential to directly
assess relative brain amyloid plaque pathology.
The first successful amyloid-imaging agent employed in
humans was 18 fluoro labeled 2-(1-{6-[(2-[fluorine-18]fluo-
roethyl)(methyl)amino]-2-naphthyl}-ethylidene)malono-
nitrile (FDDNP), a fluorinated derivative of a nonspecific
cell membrane dye (Agdeppa et al., 2001). FDDNP binds in
vitro to amyloid conformations of Aβ, tau, and prion pro-
tein (Agdeppa et al., 2001; Bresjanac et al., 2003). In 2002,
Shoghi-Jadid and coworkers demonstrated increased
tracer binding on PET in nine patients with AD, compared
with seven matched controls (Shoghi-Jadid et al., 2002).
Tracer retention was highest (30% greater than the pons
reference region) in the medial temporal cortex, hippo-
campus, and amygdala, regions that typically show dense
neurofibrillary tangles (NFTs), and was also increased
10–15% above baseline in the frontal, temporal, and pari-
etal cortex, regions that typically show both Aβ plaques
and NFTs. In one patient who later came to autopsy,
increased FDDNP-PET signal during life co-localized to
regions with significant plaque and tangle pathology post-
mortem (Small et al., 2006).
11C-labeled agents
Most imaging studies of Aβ have been conducted using
[11C] PiB. The half-life of the 11C isotope is 20 minutes,
which makes the manufacturing and wide-scale distribu-
tion to institutions with PET scanning facilities limited
and impractical.
PiB
The most widely studied amyloid-imaging agent is PiB,
an analog of the amyloid-binding dye Thioflavin-T. It
Amyloid Imaging 163
was the first tracer to show a clear correspondence to the
known regional distribution of postmortem Aβ pathology
in AD. To date, more [11C]PiB scans (>2000) have been
performed at more PET centers worldwide (more than
40 sites) than any other Aβ imaging tracer. In vitro, PiB
binds specifically to extracellular and intravascular fibril-
lar Aβ deposits in postmortem AD brains (Bacskai et al.,
2003; Klunk et al., 2003; Lockhart et al., 2007; Ikonomovic
et al., 2008). At PET tracer concentrations, PiB does not
appreciably bind to other protein aggregates such as NFTs
or Lewy bodies (Fodero-Tavoletti et al., 2007; Lockhart et
al., 2007; Ikonomovic et al., 2008). PiB does bind nonspe-
cifically to white matter, likely due to delayed clearance
of the lipophilic compound from white matter (Fodero-
Tavoletti et al., 2009). In 2004, Klunk et al. reported the
first human study of PiB-PET .
Preliminary studies show that higher levels of radio-
activity can be imaged in the cortex of patients with AD
than in the cortex of healthy controls, presumably reflect-
ing the elevated accumulation of Aβ pathology and con-
sequent binding of PiB in the cortex of patients with AD
(Lopresti et al., 2005). Despite these encouraging results,
the short half-life (20 minutes) of the 11C isotope may
limit the utility of 11C-PiB as a tool for community-based
diagnostic screening and therapeutic evaluation.
PiB accumulation as AD progresses (such as from con-
trols and from MCI to AD) follows a pattern that has been
described as an “on and off” pattern that is typically not
found in pathology specimens (Mintun et al., 2006; Kemp-
painen et al., 2007). Moreover, PiB has signals in AD in
most brain regions except medial temporal, compared
with control patients (Shin et al., 2008), but a signifi-
cant number of controls do present positive PiB binding
(Mintun et al., 2006). Some AD subjects also present nega-
tive PiB binding (Leinonen et al., 2008).
BF227
[C-11] BF-227 (2-(2-[2-dimethylaminothiazol-5-yl]-
ethenyl)- 6-(2-[fluoro]ethoxy) benzoxazole) is a novel
family of benzoxazole compounds that have shown
promise as Aβ imaging agents for detection of dense
amyloid deposits. It was developed at Tohoku Univer-
sity. BF227 labeled both Aβ plaques and Lewy bodies in
immunohistochemical/fluorescence analysis of human
AD and Parkinson’s disease (PD) brain sections, respec-
tively. This study suggests that [(18)F]-BF227 is not Aβ
selective. AD showed higher accumulation of BF-227 in
the parietotemporal, medial frontal, precuneus, and pos-
terior cingulate areas than NCn11 (p <0.05, ext >200). MCI
showed intermediate binding between AD and NCn11
in voxel-based and region of interest (ROI) analyses. The
standardized value uptake ratio (SUVR) ROI value was
inversely correlated with MMSE (p <0.05) and logical
memory II (p <0.05). BF227 is also being investigated as a
potential biomarker for PD.
164 Assessment of the Geriatric Neurology Patient
18F-labeled agents
18F-radiotracers (such as [18F]FDG) are commercially
viable and can be made available through regional
cyclotron facilities that distribute the radiotracers to
local scanners. The half-life of 18F (almost 2 hours)
allows its distribution (subject to shelf-life) for up to
10  hours post-manufacture. The longer half-life also
allows imaging at longer intervals after injection, and
this can be useful when the optimal signal-to-noise
ratio of a tracer is reached more than 90 minutes after
injection. In addition, 18F tracers can often be labeled
at higher specific activities than 11C tracers; hence,
extremely low levels (typically less than 5 μg) of unla-
beled ligand is injected.
Flutemetamol
Flutemetamol, a GE Healthcare PET imaging agent
currently in Phase III development, is being studied to
identify the uptake of Aβ via imaging of the brain tissue
in live humans (Vandenberghe et al., 2010). In 2002, GE
Healthcare acquired a license to access the patent rights
and know-how behind the Thioflavin-T derivatives. 18F
Flutemetamol performs similarly to the (11)C-PiB par-
ent molecule within the same subjects and provides high
test–retest reliability and potentially much wider acces-
sibility for clinical and research use. In a Phase II study
of 27 patients with early-stage clinically probable AD,
20 with amnestic MCI, and 15 cognitively intact healthy
volunteers (HVs) above, and 10 HVs below 55 years of
age, blinded visual assessments of (18)F-Flutemetamol
scans assigned 25 of 27 scans from AD subjects and 1
of 15 scans from the elderly HVs to the raised category;
this corresponds to a sensitivity of 93.1% and a speci-
ficity of 93.3% against the SOT. Correlation coefficients
between cortical (18)F-Flutemetamol SUVRs and (11)
C-PiB SUVRs ranged from 0.89 to 0.92. Test–retest vari-
ability of regional SUVRs was 1–4%.
FDDNP
FDDNP or 2-(1-{6-[(2-[F-18]Fluoroethyl)(methyl)amino]-
2-naphthyl}ethylidene) malononitrile (Agdeppa et al.,
2001; Small et al., 2006; Liu et al., 2007; Shin et al., 2008)
PET provides detailed visualization (Braskie et al., 2010)
of the pattern of beta-amyloid plaques (Aβ) and NFTs in
the living brain of progressive AD. FDDNP cortical bind-
ing is to NFTs and may help determine whether a given
FDDNP brain pattern is compatible with possible AD.
This scan is likely to be complementary to amyloid scans.
PiB binding pattern is different from that of FDDNP and
does not follow the progressive nature demonstrated by
neuropathologic evaluation of autopsy specimens (Braak
and Braak, 1991). One of the explanations for the differ-
ence may be attributed to the fact that PiB does not bind
to NFTs, while FDDNP does (Shin et al., 2008; Tolboom
et al., 2009).
Florbetapir
In contrast, Florbetapir F 18 is a novel amyloid-binding
agent (Zhang et al., 2005, 2006) labeled with 18F. Because 18F
has a radioactive half-life of 110 minutes, regional prepara-
tion and shipping of doses is possible, thereby reducing the
cost and increasing the number of potential imaging centers.
Studies conducted to date suggest that Florbetapir F 18 may
label amyloid plaques in a manner similar to PiB and may
have the potential to serve as an agent for in vivo imaging of
Aβ pathology in humans with AD. Florbetapir F 18 exhib-
its high affinity, specific binding to amyloid plaques with a
Kd of 3.1 nM and thus has the potential to be an imaging
biomarker for amyloid deposits in subjects with cognitive
impairment. In vitro autoradiography studies further con-
firm that, when applied at tracer concentrations, Florbetapir
F 18 labels Aβ amyloid plaques in sections from patients with
pathologically confirmed AD. The nonradioactive version of
Florbetapir F 18 (referred to as “AV-45”) can be prepared at
high concentrations and shows very low to no affinity for all
other central nervous system and cardiovascular receptors
tested, including the hERG potassium channel binding site
(Avid Radiopharmaceuticals, Inc., 2008). The potential toxic-
ity of AV-45 was tested in rats with single acute doses (up
to 100×) and 28 days of repeated doses (up to 25×) of the
maximum human dose (MHD) of 50 μg. No clinically rel-
evant adverse effects were observed on behavior, gross
pathology, or histology in either study. Thus, in both stud-
ies, the no observed adverse effect level (NOAEL) was at or
above the highest dose level tested (100× MHD for acute,
25× MHD for repeat dose, allometrically scaled). In Beagle
dogs, 14- and 28-day repeat-dose intravenous toxicity stud-
ies were performed, and there were no significant adverse
effects based on clinical observations, weight, gross pathol-
ogy, or histopathology at any dose studied (the highest dose
levels were 8.7× and 25× MHD, respectively, allometrically
scaled). In each rat and dog toxicity study conducted, the
NOAEL was determined to be equal to or higher than the
highest dose level tested. Potential genetic toxicity has been
tested in both in vitro and in vivo assays. Bacterial reverse
mutation assay results showed positive responses in two
out of five tested strains. The human peripheral lympho-
cyte chromosomal aberration assay showed no statistically
significant test article-related increases in the percent of cells
with structural aberrations after 3 hours of treatment, but a
statistically significant positive result was seen after 22 hours
of exposure. In the in vivo micronucleus assay, Florbetapir
F 18 produced no evidence of genotoxicity when adminis-
tered at doses up to the highest practically achievable dose
(83× MHD) for 3 consecutive days. The different results in
the in vitro bacterial mutation and chromosome aberration
assays and the in vivo micronucleus study are likely related
to differences in the exposure conditions encountered by
the target cells in the different test systems. AV-45 is cleared
rapidly in vivo, whereas the in vitro experiments employ
static, prolonged exposure of cells to the test article and/or

metabolites. Cardiovascular safety and respiratory functions
were tested in Beagle dogs implanted with subcutaneous
telemetry units to monitor cardiac and respiratory functions
and given doses of AV-45 corresponding to 25, 50, and 100×
MHD (allometrically scaled). No test article-related adverse
cardiovascular or respiratory effects were observed. No
biologically significant prolongation of QTc was observed
in any animal on any study day. To determine the possible
effects of commonly used drugs and drug candidates on Flo-
rbetapir F 18 binding to Aβ, an in vitro drug–drug interac-
tion study was conducted using tissue binding assay and in
vitro film autoradiography techniques. The studies showed
that none of the drugs tested interfered with Florbetapir F 18
binding to Aβ at therapeutically meaningful concentrations.
Florbetapir was FDA approved for clinical use in 2012 under
the trade name “Amyvid.”
Florbetaben
Florbetaben (BAY 94-9172 or ZK 6013443) is another PET
imaging agent for detection/exclusion of cerebral beta-
amyloid when compared with postmortem histopathology.
Florbetaben (18F) is also a promising 18F-labeled amyloid-
β-targeted PET tracer in clinical development (Villemagne
et al., 2011). Eighty-one participants with probable AD and
69 healthy controls were assessed. Independent visual
assessment of the PET scans showed a sensitivity of 80%
(95% CI 71–89) and a specificity of 91% (84–98) for discrim-
inating participants with AD from healthy controls (Bar-
thel et. al., 2011). The SUVRs in all neocortical gray matter
regions in participants with AD were significantly higher
(p <0.0001), compared with the healthy controls, with the
posterior cingulate being the best discriminator. Linear dis-
criminant analysis of regional SUVRs yielded a sensitivity
of 85% and a specificity of 91%. Regional SUVRs also corre-
lated well with scores of cognitive impairment, such as the
MMSE and the word-list memory and word-list recall scores
(r 0.27 –0.33, p ≤0.021). APOE P4 was more common in par-
ticipants with positive PET images compared with those
with negative scans (65% vs. 22% [p = 0.027] in patients
with AD; 50% vs. 16% [p = 0.074] in healthy controls). No
safety concerns were noted.
NAV4694
NAV4694 (2-(2-fluoro-6-methylaminopyridin-3-yl)-1-
benzofuran-5-ol or [18F]NAV4694 or AZD4694) is another
promising 18F-labeled PET tracer targeting fibrillar Aβ. The
initial clinical studies with [18F]NAV4694 determined the
tracer to be well tolerated with a good signal-to-noise ratio
and appears to have less white matter uptake compared
with other Aβ tracers under development. A phase 2 study
involving 24 subjects (10  AD, 10 older HVs, and 4 young
HVs), various analysis methods, including the simple SUVR,
were utilized to quantify Aβ deposition with [18F]AZD4694
and effectively distinguished subjects diagnosed with AD
from older HVs and young HVs. There was excellent test–
Amyloid Imaging 165
retest reliability (3–5%, and intraclass correlation coefficient
was 0.96–1.00 for most regions and methods). The tracer
was well tolerated and no adverse events were considered
to be related to [18F]NAV4694. Studies have demonstrated
that [18F]NAV4694 binds specifically to regions known for
Aβ binding with relatively high specific Aβ-to-white matter
binding. The tracer therefore may have increased sensitiv-
ity in detecting subtle amounts of Aβ plaque and changes in
plaque burden over time. This may offer an advantage over
other tracers currently under development and may permit
the acquisition of an image that can be read more easily and
reliably by nuclear medicine physicians.
Case studies using amyloid imaging
We describe three clinical cases where Amyloid imaging
was of great value. The thealzcenter.org clinic uses Mon-
treal Cognitive Evaluation (MOCA) for regular clinical
assessments, which are more suited in patients with mild
memory loss.
Case 1: Ms. JW, MOCA 18, amyloid negative
Patient Ms. JW, 77, arrived at the thealzcenter.org clinic with
MCI or early dementia of uncertain etiology and a family
history of AD. Her husband had also been previously diag-
nosed with AD. The patient was on prescribed opiate medi-
cations for pain; psychiatric medications including quetiap-
ine, doxepin, and lorazepam for bipolar depression with
anxiety and she suffered from sleep apnea. Upon assess-
ment, the patient showed signs of mild parkinsonism. She
also had prior restless leg syndrome. She also experienced
visual hallucinations during a hospital admission, but did
not have these regularly. At the time of the scan, her MOCA
score had declined to 18 from a prior baseline of 25/30 even
after a reduction of psychiatric medications and controlling
sleep apnea. Underlying dementia was considered, as the
deficits significantly interfered with day-to-day functional
independence. Her Clinical Dementia Rating (CDR) was
0.5; Clock Drawing Test Score (CDT) was 3/ 3 ADL 12/12,
IADL 15/16. (Figure 7.11 top row). An Amyloid PET scan
study was negative (Figures 7.12 and 7.13 top row). The
diagnosis of AD was excluded clinically after incorporat-
ing the amyloid information. She was initiated on Parkin-
son medications. Patient improved mentation with MOCA,
with an improved score of 25/30 and was transitioned into
living on her own in the community with assistance from
VNA and an automated pillbox.
Case 2: Mr. PS, MOCA 22, amyloid PET
scan positive
Mr. PS, 76, had a longstanding history of (h/o) depression,
uncontrolled sleep apnea, diarrhea and urinary inconti-
nence, and was presented to the alzcenter.org memory
clinic with progressive decline in function at home. His
166 Assessment of the Geriatric Neurology Patient

Figure 7.11 Details of Montreal Cognitive Assessment (MOCA) test subsets for cases 1, 2 and 3. Top row is tests performed by Ms. JW,
middle row by Mr. PS and bottom row by Ms.EC. The executive function and memory test performance might have misclassified
the patients without the amyloid imaging test information. Amyloid positive patients outperformed the amyloid negative subject on
executive function. Immediate memory was preserved in all subjects. Short term free delayed recall was impaired in all subjects, and
cued recall was present, contributing to clinical uncertainty. These clinical settings are appropriate to use amyloid imaging for furthering
the diagnosis.

Amyloid negative

R L A P R L

Amyloid positive

R L A
Amyloid positive
R L A
P R L
Figure 7.12 Amyloid Imaging for Cases 1, 2
and 3. Top row is images from Ms. JW,
middle row from Mr. PS and bottom
row from Ms.EC. Even with significant
accumulation of amyloid in their brain, the
amyloid positive patients outperformed
the amyloid negative subject on executive
function tests. Memory evaluations were
P R L worse, contributing to clinical uncertainty.
The amyloid scans facilitated early diagnosis
and appropriate treatment for all three
patients.

Figure 7.13 Falsely colored amyloid images
for cases 1, 2 and 3. Top row is images from
Ms. JW, middle row from Mr. PS and bottom
row from Ms. EC. Even though there images
further highlight the significant differences in
accumulation of amyloid, it is recommended
that black and white images be used in
diagnostic visual evaluation and rating of
amyloid images. This is to minimize machine
and operator factors involved in producing
false color images leading to greater inter
rater variability. (For a color version, see the
color plate section.)
MOCA was 22/30, CDR 1.0; CDT 2/3; activities of daily liv-
ing (ADL) was 12/12, and instrumental ADL (IADL) was
15/16. (see Figure 7.11 middle row). Neuropsychological
tests were inconclusive, but supportive of AD or demen-
tia with deficits in orientation, attention, language, mem-
ory, visual–spatial functioning, depression, and executive
functioning. However, family and patient disagreed with
the diagnosis, as he was able to compensate for these
deficits, achieving day-to-day functional independence.
He was also running his own business, and the diagnosis
had significant financial consequences. Vascular etiolo-
gies were negative on MRI, which only showed mild to
moderate small vessel disease. Labs were negative for
thyroid problems, Lyme, and other reversible causes of
dementia. A spinal tap measured CSF amyloid and tau,
but was inconclusive for AD diagnosis. As he was high
risk for side effects on acetyl cholinesterase inhibitors due
to coexisting cardiac issues, an amyloid scan was pursued
and found to be positive for brain amyloidosis. (see Fig-
ures 7.12, 7.13 middle row). Using the additional infor-
mation, a clinical diagnosis of early AD was made using
the new criteria. The patient was started on acetyl cho-
linesterase inhibitors, but diarrhea prevented dose escala-
tion. Eventually the patient elected to join a clinical trial
for early AD. The patient was able to close his business
without financial ruin, preserved his wealth, even negoti-
ated a settlement from the IRS and is now retired happily.
After 2 years of stability, he is still able to do most IADLs,
however he gave up driving after the scan information
was discussed with him.
Amyloid Imaging 167
Amyloid negative
L A P R
Amyloid positive
L A P R
Amyloid positive
L A P R
Case 3: Ms. EC, MOCA 20, amyloid scan
positive
Ms. EC, 62, arrived at the thealzcenter.org clinic with
memory complaints. She had significant deficits in mul-
tiple domains such as orientation, attention, language,
memory, visual–spatial functioning, and executive func-
tioning. These did not appear to significantly interfere
with her day-to-day functional independence. Her
MOCA was 20/30, CDR 0.5; CDT 2/3. (see Figure 7.11 bot-
tom row). While the underlying etiology could include
AD, there was significant uncertainty due to her higher
functional ability at home. No features of Lewy body
dementia, vascular dementia and reversible causes of
dementia such as in thyroid, infectious or demyelization
processes were found clinically. Additionally, her labs and
MRI did not reveal any additional information, and her
neuropsychology tests were inconclusive. At subsequent
visits the MOCA improved spontaneously to 25. As the
patient and family wanted to know the underlying eti-
ology precisely and did not want a lumbar puncture,
an amyloid scan was pursued. The scan was positive.
(Figures 7.12 and 7.13 bottom row) The clinical diagnosis
was revised to MCI due to AD. As she was of altruistic
nature, the patient elected to join a clinical trial for pre-
venting AD even though the trial included serial lumbar
punctures. She felt joining the trial may not help herself,
but may help others, including her children or grandchil-
dren. After 2 years, she continues to have amnestic MCI,
and no significant decline on clinical memory testing.
168 Assessment of the Geriatric Neurology Patient
Conclusion
Amyloid imaging of the brain and classification of cogni-
tively normal subjects into a high-risk category based on
this imaging represent a major advance in neuroscience.
The detection and quantification of pathologic protein
aggregations in the brain may help advance early detection
and eventual treatment of this group with new biologics.
Multiple tracers that mark PiB binding, specifically to fibril-
lar beta-amyloid (Aβ) deposits, is a sensitive marker for Aβ
pathology in cognitively normal older individuals and in
patients with MCI and AD. Amyloid PET provides us with
a powerful tool to examine in vivo the relationship between
amyloid deposition, clinical symptoms, and structural
and functional brain changes in the continuum between
normal aging and AD. Amyloid-imaging studies support
a risk-evaluation model similar to cholesterol or hyper-
tension in cardiac disease; amyloid deposition is an early
event on the path to dementia. This begins insidiously in
cognitively normal individuals, accompanied by subclini-
cal or subtle cognitive decline, leading eventually to func-
tional and structural brain changes suggestive of incipient
AD. As patients progress to dementia, clinical decline and
neurodegeneration accelerate and proceed independently
of amyloid accumulation, which may be irreversible. In the
future, amyloid imaging is likely to supplement clinical
evaluation in selecting patients for anti-amyloid therapies,
while MRI and FDG-PET may be more appropriate mark-
ers of clinical progression than cognitive tests.
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 Chapter 8
Clinical Laboratory Investigations in
Geriatric Neurology
Geoffrey S. Baird1 and Thomas J. Montine2
1
Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
2
Departments of Pathology and Neurological Surgery, University of Washington, Seattle, WA, USA

Summary
• Bayes’ Theorem dictates that the value of a test is highly correlated with the prior probability of disease.
• Tests with high clinical sensitivity are most useful in screening when prior probability of disease is low. Positive screening
results must be followed by a confirmatory test with high clinical specificity.
• Body fluids (blood, urine, cerebrospinal fluid) are preferred samples for neurological testing. Peripheral nerve biopsies are
generally well-tolerated, but brain biopsies are generally avoided for non-neoplastic cases because of morbidity, mortality,
and low clinical yield.
• In dementia, laboratory testing is primarily used to identify secondary dementias, i.e. resulting from a systemic disorder.
• A reasonable secondary dementia screening panel could include: complete blood count with differential, plasma or serum
sodium, potassium, chloride, bicarbonate, glucose, creatinine, blood urea nitrogen, calcium, vitamin B12, TSH, folate.
• Alzheimer’s disease (AD): Cerebrospinal fluid (CSF) Aβ42 and tau concentrations are known to vary significant between
normal, mild cognitive impairment, and clinical AD.
• Vascular brain injury (VBI): Standard dementia screening panel is recommended, as well as tests for inflammatory conditions
• Lewy body disease (LBD): No specific laboratory tests are available to rule in this disorder.
• Frontotemporal lobar degeneration (FTLD): No specific laboratory tests are available to rule in this disorder.
• Creutzfeldt–Jakob disease (CJD) and prion disorders: Recommended tests depend on the clinical presentation, but could
include complete blood counts, serum electrolytes, urinalysis, assessment of liver function and injury, thyroid function
testing, serum B12, folate assays, humanimmunodeficiency virus (HIV), RPR/syphilis screening, and paraneoplastic
antibody testing. CSF testing can include 14-3-3 and tau.
• Normal pressure hydrocephalus (NPH): No specific laboratory tests are available to rule in this disorder.
• Parkinson’s disease (PD): Laboratory testing is useful for ruling out other possible causes of the clinical phenotype.
• “PD plus” syndromes: Rare genetic causes can be identified with molecular tests.
• Infarction: Standard testing usually includes serum or plasma electrolytes/renal function tests and glucose, Troponin I or T,
complete blood count including platelet count, and coagulation testing including PT/INR and aPTT. Additionally, hepatic function
tests, toxicology screen, blood alcohol assay, pregnancy test, arterial blood gas analysis, and lumbar puncture may also be useful.
• Hemorrhage: Standard testing usually includes complete blood count, electrolytes, blood urea nitrogen and creatinine,
glucose, PT/INR and aPTT. Toxicology screens and pregnancy tests may also be useful. Some evidence supports increased
neutrophil counts and plasma fibrinogen as biomarkers.
• Vasculitis: Standard testing usually includes complete blood count with differential, serum electrolytes and glucose, renal and
hepatic function markers, erythrocyte sedimentation rate and C-reactive protein, CSF analysis, and urinalysis to investigate
potential secondary causes. Tests of autoimmunity may reveal underlying connective tissue disease or systemic vasculitis.
• Headache: Laboratory testing is rarely indicated; specific details of presentation should dictate the testing algorithm if
unusual headache features are found at presentation. Lumbar puncture with analysis of CSF could be indicated if common
headache syndromes are unlikely.
• Depression: Frequently used tests to screen for secondary causes of depression include complete blood count, serum
electrolytes and glucose, urinalysis, blood urea nitrogen and creatinine, liver function tests, TSH, serum B12, folate
concentration, and RPR testing. The benefit of laboratory testing in idiopathic depression is unclear.
• Delirium: many potential causes but selected laboratory tests can identify the most serious or prevalent causes.
• HIV: in addition to HIV testing, cardiovascular risk assessment should not be neglected in the elderly HIV patient.
• Paraneoplastic disorders: Many exist, and specific testing for antibodies associated with the specific presentating
syndrome is recommended.
• Genetic disorders: High costs of large genetic testing panels should be avoided by testing serially. One should seek expert
advice from neurogeneticists in order to select the most appropriate testing for a given patient.
• Cerebral injury: S100B protein and neuron-specific enolase are highly studied markers of brain injury—however, no
FDA-approved assays are available. Quantitation of CK-BB in CSF is an alternate test.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

170
 Clinical Laboratory Investigations in Geriatric Neurology 171

This chapter focuses on the clinical laboratory examina-
tions used to screen, diagnose, predict, and monitor neu-
rologic disorders in geriatric patients. Because the goals
of laboratory testing in this population overlap those of
general laboratory testing, a brief section on test inter-
pretation and general laboratory considerations precedes
the sections devoted to neurologic disorders of geriatric
patients.
Laboratory test interpretation
Laboratory tests have become essential components
of physicians’ armamentaria to approach and man-
age diseases in their patients. These tests can effectively
rule out some disease processes in apparently healthy
patients (screening) and establish a specific diagnosis in
ill patients with nonspecific signs and symptoms. Indeed,
the ubiquity of clinical laboratory testing attests to its util-
ity but also cautions that laboratory tests need to be used
judiciously.
Laboratory tests are often classified by clinical specific-
ity and sensitivity; the concepts are represented graphi-
cally in Figure 8.1.
One of the most important statistical concepts related
to the utility and interpretation of laboratory testing is
Bayes’ theorem (Equation 8.1).
P(B | A) ⋅ P(A)
P(A|B) =
P(B)
This equation states that the conditional probability of
event A, given the occurrence of event B, is equal to the
conditional probability of B, given A times the prior prob-
ability of A divided by the prior probability of B.
Applied to laboratory testing, Bayes’ theorem indi-
cates that the probability of having a disease, given a
Disease
Present Absent
True False
Positive positive positive
Test result
positive laboratory test, P(A|B)—also known as the
posterior probability—is proportional to the prevalence
or prior probability of the disease, P(A), times the prob-
ability that the test is positive in those with the disorder,
P(B|A)—the clinical sensitivity—divided by the proba-
bility that the test result is positive in a population, P(B).
The posterior probability is what clinicians desire—the
probability that a patient has a disease after getting a
test result. Bayes’ theorem states that this probability
depends not only on the test’s clinical performance char-
acteristics, but also on the likelihood that the patient
had the disorder before any testing was done. Therefore,
when testing for conditions that are very unlikely,
(P(A)~0), a positive result still corresponds with a low
posterior probability and is likely a “false positive.”
Conversely, testing for highly likely conditions with
highly sensitive tests is most likely to produce a true
positive result that simply confirms what was already
clinically suspected. Testing in either of these situations
is unlikely to be beneficial or cost-effective.
Bayes’ theorem provides the mathematical underpin-
ning to the obvious but important directive that labo-
ratory testing must be applied in concert with clinical
assessment. When applied in the setting of a low prior
probability, a sensitive but nonspecific test used to
rule in a diagnosis is unlikely to provide a true posi-
tive result. A more appropriate use of a test with high
clinical sensitivity in the setting of low prior probability
(8.1) is to rule out a disease. This is known as screening, in
which negative results are trusted and positive results
are considered only presumptive and must be followed
by a confirmatory test (see Figure 8.2). The best tests for
confirmation of positive screening tests are those with
high clinical specificity. Few tests have sufficient clinical
specificity and sensitivity to perform well in both screen-
ing and confirmatory roles. Additionally, highly reliable
confirmatory assays are usually too costly to employ in
the screening setting.
Bayesian analysis is a useful tool for assessing the
information content provided by laboratory testing, but
it should not be used in isolation to determine the util-
ity of testing. To the contrary, one should always consider
whether the result from a laboratory test—positive or

(TP) (FP)
False True
Negative negative negative
(FN) (TN) Clinical sensitivity
High Low
TP TN Screening or
Sensitivity = Specificity = High Confirmation
TP + FN TN + FP confirmation
specificity
Clinical

TP
Positive predictive value =
TP + FP Low Screening Do not use
TN
Negative predictive value =
TN + FN Figure 8.2 Most appropriate use of laboratory testing based on
Figure 8.1 Definitions of test performance metrics. clinical test performance.
172 Assessment of the Geriatric Neurology Patient
negative—would influence clinical management. Espe-
cially for a disease for which no therapies currently exist,
identifying a root cause with a diagnostic test may not
provide any actionable information. Although there exist
numerous valid reasons to order tests that are not associ-
ated with a specific clinical action–-such as identifying a
genetic defect to aid in family counseling–-the stress, cost,
potential consequences for medical insurability, and other
potentially deleterious consequences of laboratory testing
should always be considered prior to embarking on a lab-
oratory testing odyssey.
General considerations
Clinical laboratory testing is most easily accomplished on
body fluids because they are most easily manipulated by
automated quantitative instruments. Table 8.1 describes
body fluids relevant to geriatric neurologic disorders.
Correctly choosing a specimen collection container,
preservative or anticoagulant, and storage condition—
such as immediately freezing at –70°C versus holding at
room temperature–-is of utmost importance in obtaining
accurate laboratory results. Mistakes in the sampling pro-
cess, known as preanalytical errors, are frequent sources
of unwanted variability in the clinical laboratory.
Although biopsy is a key diagnostic procedure in
cases of suspected central nervous system (CNS) neo-
plasia (such as gliomas), solid tissue is rarely sampled
when evaluating chronic neurologic disorders in the
elderly because of the morbidity, and even mortality, of
sampling procedures. Peripheral nerve biopsies to inves-
tigate neuropathies are generally well tolerated, but
brain biopsy has significant morbidity and is generally
avoided in non-neoplastic cases unless other diagnos-
tic modalities have failed to produce a clear diagnosis.
Examples in which brain biopsies have clinical utility
include rapidly progressive or atypical neurodegenera-
tive diseases (Schott et al., 2010).
Table 8.1 Body fluids used in laboratory testing
Preservative or
Fluid type anticoagulant Target analyses
Whole blood Many possible Gases, culture, cell counts and
analyses, DNA from white blood
cells
Plasma Heparin Electrolytes, plasma proteins
Plasma EDTA Preferred for proteomics
Plasma Citrate Coagulation studies
Serum None Serum proteins, electrolytes
Cerebrospinal None Glucose and protein, pathogen
fluid (CSF) culture or PCR, proteomics
Urine Numerous Culture, electrolytes, proteins
(electrophoresis)
Dementias
Dementia is a clinically defined state with multiple causes
that, either alone or in combination, lead to profound cog-
nitive and behavioral deficits. The most common diseases
contributing to the dementia syndrome in the elderly are
chronic: Alzheimer’s disease (AD); vascular brain injury
(VBI), especially small vessel disease; and Lewy body dis-
ease (LBD). Although each is considered a disease, they
really are clinicopathologic entities that likely have mul-
tiple etiologies. In other words, dementia in the elderly
may be viewed as a syndrome of commonly comorbid
chronic syndromes. Further complexity is added by the
many less common diseases that also can cause dementia
in the elderly, including frontotemporal lobar degenera-
tions (FTLDs) and prion diseases.
Although history, physical examination, and cognitive
testing are the current cornerstones in evaluating sus-
pected dementia, developing clinical laboratory tests for
primary causes of dementia is an area of active research.
A limited number of clinical laboratory tests are available
to aid in diagnosis, such as cerebrospinal fluid (CSF) con-
centrations of 14-3-3 protein and tau in Creutzfeldt–Jakob
disease (CJD), or CSF concentrations of amyloid Aβ42 and
tau in AD. Currently, the major role of clinical laboratory
testing in dementia is to investigate the possibility that
the patient’s dementia is a secondary manifestation of a
systemic disorder or to identify a rare but treatable cause
of dementia (Feldman et al., 2008).
Secondary dementia
The list of metabolic conditions associated with second-
ary dementia is long and includes dysfunction of nearly
every major organ system in the body: hepatic dysfunc-
tion, renal dysfunction, cardiopulmonary failure, anemia
or blood disorders, endocrine or vitamin deficiencies,
and toxic injury by medications or other toxins such as
alcohol. A variety of malignancies can also produce para-
neoplastic cognitive disorders, as can infections, inflam-
mation, or trauma. The complete evaluation of all these
possible contributors to dementia is beyond the scope
of this chapter. A standard screening panel of laboratory
tests intended to identify common occult causes of sec-
ondary dementias based on recommendations from the
Third Canadian Consensus Conference on Diagnosis and
Treatment of Dementia (March 2006) is as follows.
Laboratory tests suggested for comprehensive evalua-
tion of dementia are the following:
• Complete blood count with differential.
• Plasma or serum sodium, potassium, chloride, carbon
dioxide, fasting glucose, creatinine, blood urea nitrogen,
and calcium.
• Serum vitamin B12.
• Thyroid stimulating hormone.
• Serum or red blood cell folate (optional).
 Clinical Laboratory Investigations in Geriatric Neurology
Generally, more testing that further interrogates addi-
tional metabolic pathways is indicated in the context
of increased clinical suspicion, such as folate testing in
patients with evidence of malabsorptive gastrointestinal
disease. The same organization that made the recom-
mendations in Table 8.2 also recommends against spe-
cific tests, such as serum homocysteine concentration
or determination of APOE genotype, citing insufficient
evidence for homocysteine testing and poor positive and
negative predictive value of APOE testing. However, it
should be stressed that these are only recommendations
and that history, presentation, and physical findings
should always guide decisions on the appropriateness of
laboratory tests. If a toxic cause is suspected on clinical
grounds, additional testing for heavy metals may be war-
ranted; if an infectious cause is suspected, testing for the
human immunodeficiency virus (HIV) or syphilis might
be essential.
Alzheimer’s disease
As mentioned earlier, clinical laboratory testing for AD is an
area of active research, but no test or set of tests has achieved
widespread application in the primary care setting.
Despite the obvious convenience to patients, research
efforts have yet to identify reliable blood or urine biomark-
ers of AD. One reason for this is the blood–brain barrier
(BBB), a selectively permeable barrier between the CNS
and the peripheral circulation. In contrast, CSF partially
derives from brain and spinal cord extracellular fluid
and so does not filter through the BBB prior to sampling
(Wood, 1980; Milhorat, 1983), making it more reflective of
CNS metabolism. Although there may be other reasons,
the practical outcome is that research efforts so far have
identified reliable biofluid biomarkers for AD in CSF, but
not in blood or urine. The most widely studied CSF bio-
marker of AD is the combination of Aβ42 and total tau
or some subset(s) of phosphorylated tau isoforms (Son-
nen et al., 2010). Current research findings indicate that
as AD progresses from latent to prodromal to clinically
overt stages, CSF Aβ42 concentration decreases while CSF
tau concentration increases. Association with neuroimag-
ing studies strongly suggests that decreasing CSF Aβ42
concentration in patients with AD reflects Aβ42 accumu-
lation in brain parenchyma. The mechanisms underlying
increased CSF tau concentration are less clear but are not
specific to AD because increased CSF tau concentration
also occurs in other brain diseases.
Other CSF biomarkers of AD have been reported in the
literature, and although several show promise as sensi-
tive indicators of different stages of AD, none have been
validated for routine clinical use. A major problem in CSF
AD biomarker discovery efforts has been cross-platform
inconsistencies–-“hits” determined using one technology
(such as mass spectrometry) commonly have not been
validated with another (such as immunoassay).
173
Vascular brain injury
VBI can manifest as cognitive decline or dementia, condi-
tions referred to in aggregate as vascular cognitive impair-
ment (VCI). Our understanding of VCI has advanced
substantially from the caricature of multi-infarct demen-
tia with stereotypical “stepwise” decline in cognitive
abilities. Although classic multi-infarct dementia clearly
does occur, more subtle forms of VCI, especially from
small vessel disease, can produce a pattern of injury and
functional impairment that is difficult to distinguish from
other common causes of dementia. The situation is fur-
ther complicated because, as with Lewy body dementia
(LBD), VCI is commonly comorbid with AD.
Initial clinical laboratory investigation of VBI should
include tests listed in Table 12.2, and additional testing
for possible inflammatory conditions such as vasculitis
(C-reactive protein (CRP)) and hyperlipidemia (choles-
terol and triglycerides) should be performed if the clini-
cal presentation warrants further investigation. Although
no current clinical laboratory assays exist to definitively
rule in VCI, differentiation among dementia subtypes is
an active area of research. Discrimination between AD
and VCI in small studies has been proposed using AD-
associated CSF biomarkers such as Aβ and phosphory-
lated tau isoforms (Paraskevas et al., 2009), as well as
markers of oxidative damage such as malondialdehyde
(Gustaw-Rothenberg et al., 2010).
Lewy body disease
LBD is a spectrum of clinicopathologic entities that
includes Parkinson’s disease (PD), PD with dementia,
and dementia with Lewy bodies (DLB); all these entities
form intraneuronal α-synuclein-immuonoreactive inclu-
sions called Lewy bodies, but in different regions of the
brain. DLB is a complex entity because it can exist in a
pure form but is more commonly comorbid with AD. No
current clinical laboratory tests can confirm the diagnosis
of LBD or adequately distinguish DLB from AD. Research
studies have identified potential CSF biomarkers of DLB
in small cohorts of patients, such as CART (Schultz et al.,
2009) and α-synuclein (Kasuga et al., 2010).
Frontotemporal lobar degeneration
FTLD is a class of degenerative diseases that include Pick’s
disease. These disorders share some clinical features with
AD but differ in others, such as the marked change in
personality observed early in the course of disease. No
current clinical laboratory tests are able to distinguish
clearly between AD and FTLD, but small research studies
have suggested several CSF biomarkers such as agouti-
related protein (AgRP), adrenocorticotropic hormone
(ACTH), eotaxin-3, Fas, and interleukin 17 (IL-17) (Hu
et al., 2010b). Other studies suggest that the AD markers
Aβ42 and tau, especially their ratio (de Souza et al., 2010;
Hu  et  al., 2010a), can help discriminate between FTLD
174 Assessment of the Geriatric Neurology Patient
and AD. At the time of this writing, however, clinical vali-
dation for these analytes is lacking.
Creutzfeldt–Jakob disease and prion disorders
The prion disorders are caused by misfolded fragments
(prions) of a protein called the prion precursor protein,
and they can present with rapidly progressive dementia.
The United States National Prion Disease Pathology Sur-
veillance Center maintains a helpful website with links to
information on prion diseases, research studies, and test-
ing information, at www.cjdsurveillance.com.
CJD is the most common prion disorder, and it occurs
in several forms (Gambetti et al., 2003): sporadic CJD
(sCJD) with no known cause, familial CJD (fCJD) caused
by mutations in the gene that encodes the prion precur-
sor protein, and acquired forms of CJD called iatrogenic
(iCJD) and variant (vCJD) that are transmitted from con-
taminated instruments or tissues (iCJD) or by ingestion of
tainted animal products (vCJD).
A thorough workup for rapidly progressive dementia
should include complete blood counts, serum electro-
lytes, urinalysis, assessments of liver function and injury,
thyroid function testing (thyroid stimulating hormone),
serum B12 and folate assays, and tests for potential HIV
and syphilis infection (RPR assay). Additional testing
may include paraneoplastic antibody testing (vida infra).
Laboratory testing of sporadic prion disorders may also
include CSF analysis. Because routine CSF test values in
prion disorders are usually normal (protein, glucose, and
cell count), aberrant values for these analytes should
prompt efforts to find a secondary cause for the patient’s
rapid deterioration. One CSF analyte commonly assayed
in suspected prion disorders is 14-3-3 protein, a member
of a family of ubiquitous regulatory proteins released into
CSF as a consequence of the rapid brain tissue destruc-
tion caused by the disorder. Concentrations of CSF 14-3-3
(Chohan et al., 2010) and tau (Wang et al., 2010) are ele-
vated in prion disorders, but because they can also be ele-
vated in other neurologic diseases, testing is useful clini-
cally when other causes of rapidly progressive dementia
have been sufficiently ruled out with the screening tests
noted earlier. Initial reports found that the clinical sen-
sitivity and specificity of CSF 14-3-3 for CJD were both
96% (Hsich et al., 1996), although these values are some-
what misleading because the value of the CSF 14-3-3 test
is highly dependent on clinical presentation and, hence,
prior probability. In addition, subsequent reports have
indicated lower sensitivity of the CSF 14-3-3 test for CJD
associated with alternate prion protein molecular pheno-
types (Castellani et al., 2004; Gmitterova et al., 2009).
Normal pressure hydrocephalus
Normal pressure hydrocephalus (NPH) is a clinical syn-
drome that typically presents with gait or balance dis-
turbance, cognitive impairment, and sometimes urinary
incontinence. Although clinical examination, radiologic
exams (CT and MRI), and response to large-volume CSF
tapping via lumbar puncture have been found to aid
in diagnosis and increase the accuracy of predicting a
response to surgical treatment (Gallia et al., 2006), no cur-
rent clinical laboratory tests help distinguish NPH from
other causes of dementia (Tarnaris et al., 2009). Selected
studies have indicated that phosphorylated tau or total
tau (Kapaki et al., 2007), or combinations of neurofilament
protein (low molecular weight), phosphorylated tau, and
Ab42 may have utility in distinguishing AD from NPH
(Agren-Wilsson et al., 2007).
Movement disorders
Parkinson’s disease
Parkinsonism describes a syndrome of akinetic-rigid
movement disorders; the most common idiopathic form
is PD. As with other idiopathic neurodegenerative dis-
eases, PD is a clinicopathologic entity. Clinically, it is
characterized by bradykinesia, rigidity, and a type of
tremor; pathologically, it is characterized by dopaminer-
gic neuron loss in the substantia nigra with Lewy body
formation, among other features. The current role of clini-
cal laboratory testing is primarily to rule out other pos-
sible causes of the clinical phenotype.
The search for CSF biomarkers of PD is an active area
of research, driven primarily by the desire to aid clini-
cians when the diagnosis in unclear. However, there is
also a need in research studies for surrogate markers of
response to therapy to provide more objective outcome
measures in clinical trials. DJ-1 protein concentration,
in both plasma (Waragai et al., 2007) and CSF, has been
investigated as a possible PD biomarker. Study results
have been conflicting, with earlier studies indicating ele-
vated CSF DJ-1 in PD (Waragai et al., 2006) and later stud-
ies indicating lower CSF DJ-1 in PD (Hong et al., 2010).
α-synuclein, the primary component of Lewy bodies, has
also been measured in CSF. Although results have been
conflicting, a large study that controlled for blood con-
tamination in CSF observed a lower α-synuclein concen-
tration in patients with PD than in controls or in patients
with AD (Hong et al., 2010). Progress in this area has been
limited by several confounding factors, such as the use of
different assays by different research groups and the high
content of DJ-1 and α-synuclein in blood cells that may be
lysed during serum preparation or may contaminate CSF
samples (Shi et al., 2010).
Parkinson-plus syndromes
The Parkinson-plus syndromes include multiple system
atrophy (MSA), progressive supranuclear palsy (PSP),
and corticobasal ganglionic degeneration (CBGD); all
have the hallmark of sharing clinical features with PD but
 Clinical Laboratory Investigations in Geriatric Neurology
are less common and difficult to diagnose because of clini-
cal overlap. Rarely, specific Parkinson-plus disorders have
been associated with genetic causes that can be identified
with specific testing, such as frontotemporal dementia
and parkinsonism linked to chromosome 17 (FTDP-17),
which is linked to both mutations in the MAPT gene that
encodes for tau protein and the PGRN gene that encodes
progranulin (Boeve and Hutton, 2008). Although these
two genes are closely linked to chromosome 17, muta-
tions in each appear to trigger different pathophysiolo-
gies, and it is not well understood why mutations in these
distinct genes lead to similar phenotypes.
Cerebrovascular disorders
Infarction
Infarction of CNS tissue is a highly prevalent cause of
morbidity and mortality, second only to heart disease in
the Western world and responsible for 10% of all deaths.
Pathophysiologically, CNS infarction from reduced blood
flow (ischemia) can be caused by a variety of mechanisms,
such as thrombus formation on a ruptured cerebral artery
atherosclerotic plaque, embolism from a cardiac or carotid
artery source, cerebral artery rupture as a result of hyper-
tension, or arterial injury from inflammation. Of possible
causes, the most important clinical distinction is whether
the infarct is complicated by hemorrhage because this
determines whether anticoagulant or fibrinolytic therapy
can be used. Although radiology plays a far greater role
than clinical laboratory testing in making this diagno-
sis, and immediate noncontrast brain CT or brain MRI
is indicated in all patients suspected of having an acute
stroke, laboratory testing can be helpful. American Heart
Association/American Stroke Association guidelines 2007
(Adams et al., 2007) indicate that all patients suspected of
having an ischemic stroke should undergo laboratory test-
ing for blood glucose; serum or plasma electrolytes/renal
function tests; cardiac markers such as Troponin I or T; a
complete blood count, including platelet count; and coag-
ulation testing, including the prothrombin time/interna-
tional normalized ratio (PT/INR) and activated partial
thromboplastin time (aPTT). In selected patients with clin-
ical indications for more targeted testing, the guidelines
recommend hepatic function tests, a toxicology screen, a
blood alcohol assay, a pregnancy test, arterial blood gas
analysis, and lumbar puncture if subarachnoid hemor-
rhage is suspected and if CT scan is negative for correlates
of hemorrhage. Unless a bleeding disorder is suspected or
the patient is known to be, or suspected to be, on anticoag-
ulants, thrombolytic therapy should not be delayed while
waiting for the results of these tests.
Blood glucose testing warrants specific attention
because of the results of several studies pertaining
to stroke. Immediate assessment of blood glucose is
175
necessary in suspected stroke because hypoglycemia
can mimic the signs and symptoms of stroke. However,
elevated blood glucose has been identified as a poor prog-
nostic marker in several studies (Kruyt et al., 2010), so cor-
rection and continued monitoring of glucose should be
considered in all stroke patients.
Hemorrhage
American Heart Association/American Stroke Asso-
ciation guidelines 2010 (Morgenstern et al., 2010) indi-
cate that patients with intracranial hemorrhage should
have  the following tests ordered: complete blood count,
electrolytes, blood urea nitrogen and creatinine, glucose,
PT or INR, and aPTT. Further specific recommendations
include a toxicology screen for young or middle-aged
persons to rule out cocaine use, as well as a pregnancy
test in women of childbearing age.
Several additional tests have been shown to have prog-
nostic value in the setting of intracranial hemorrhage. Ele-
vated serum glucose has been correlated with poor out-
comes (Kruyt et al., 2009), and increased INR as a result
of warfarin anticoagulation has been (unsurprisingly)
correlated with expansion of hematomas (Cucchiara
et al., 2008; Flaherty et al., 2008). In fact, the risk of any
major bleeding–-intracranial or elsewhere–-increases dra-
matically in patients on warfarin as the INR increases,
approaching 10% if the INR is greater than 9 (Garcia et al.,
2006). Ages older than 65 have also been associated with
a higher risk of bleeding in this setting (Landefeld and
Goldman, 1989).
Other prognostic biomarkers in hemorrhage include
increased neutrophil counts and plasma fibrinogen, both
of which are correlated with early neurologic deteriora-
tion (Leira et al., 2004). Many other serum markers of
intracranial hemorrhage are currently under investiga-
tion (Maas and Furie 2009) but are not yet available in the
routine clinical laboratory setting. These include matrix
metalloproteinase-9 (Abilleira et al., 2003) (concentrations
24 hours after onset of bleeding correlate with edema),
matrix metalloproteinase-3 (Alvarez-Sabín et al., 2004)
(concentrations at 24–48 hours after bleeding correlate
with risk of death), c-Fibronectin and interleukin-6 (Silva
et al., 2005) (each associated with expanding hemor-
rhage), tumor necrosis factor-α (Castillo et al., 2002) (cor-
related with perihematomal edema), glutamate (Abilleira
et al., 2003) (correlated with residual hematoma cavity
size), and many others.
Vasculitis
CNS vasculitis can be idiopathic, as in primary angiitis of
the CNS (PACNS), a cerebral manifestation of a systemic
disorder such as lupus, or it can be caused by infectious
agents (Hajj-Ali, 2010). Clinical manifestations com-
monly include cognitive decline, headache, and seizures.
Because these disorders are rare, there is little evidence to
176 Assessment of the Geriatric Neurology Patient
support the utility of any specific panel of laboratory tests
in the diagnostic approach. Nonetheless, basic laboratory
tests–-complete blood count with differential, serum elec-
trolytes and glucose, renal and hepatic function markers,
erythrocyte sedimentation rate (ESR) and CRP, CSF anal-
ysis, and urinalysis–-can provide information that helps
determine the likelihood of other secondary causes for the
neurologic presentation.
Erythrocyte sedimentation rate and CRP are often ele-
vated in systemic vasculitis but not in PACNS. These mark-
ers can also be elevated in infectious vasculitis; because the
therapies for infectious and noninfectious vasculitis are
markedly different, additional testing is required to evalu-
ate for the presence of specific pathogens. Specific patho-
gens associated with CNS vasculitis include HIV, syphilis,
Varicella zoster virus, mycobacteria, fungi, Borrelia spp.
(Lyme disease), Bartonella spp., Herpes viruses, hepatitis
C, and Taenia parasites (cysticercosis).
Tests for autoimmunity may also help reveal the pres-
ence of an underlying connective tissue disease or systemic
vasculitis such as lupus, Sjögren’s syndrome, Wegener’s
granulomatosis, or Behcet’s disease. Such tests include
antinuclear antibodies (ANAs); rheumatoid factor; anti-
bodies to Ro/SSA, La/SSB, Sm, and RNP antigens; dou-
ble-stranded DNA antibodies; antineutrophil cytoplasmic
antibodies (ANCAs); serum C3 and C4; serum cryoglobu-
lins; and serum/urine protein electrophoresis/immuno-
fixation. Anticardiolipin and antiphospholipid antibod-
ies as part of a hypercoagulability profile may also help
detect an underlying disorder. Although standard CSF
analyses are usually abnormal in PACNS–-demonstrating
modest pleocytosis, normal glucose, elevated proteins,
and occasional oligoclonal bands on electrophoresis–-no
specific test can yet confirm this diagnosis.
Giant cell arteritis, a cause of headache in older adults,
is addressed in the subsequent section on headache.
Other disorders
Headache
Headaches are common in adult patients. Common
categories of idiopathic headache include migraine,
tension-type headache, and cluster headaches. Diagnos-
tic classification of headaches is accomplished by history
and physical examination to detect signs of an underlying
condition that requires prompt medical attention, such as
a cerebral aneurysm, intracranial hemorrhage, or brain
tumor. Typical “red flags” in the investigation of head-
ache include a previous head or neck injury, a new onset/
type/pattern, a patient self-reporting the “worst headache
ever,” an abrupt onset, a “trigger” caused by Valsalva/
exertion/sexual activity, a concurrent pregnancy, an onset
late in life, any coexisting neurologic signs or symp-
toms not classically associated with common headaches,
and any sign of systemic illness or infection. Additional
indications that a more thorough workup is warranted
include concurrent cancer of any sort, immunosuppres-
sion (including HIV infection), and recent travel to an
area with endemic CNS-tropic viruses.
Therefore, laboratory testing for headache is reserved
for cases in which common headache syndromes are
judged unlikely, offending medications have been ruled
out as potential causes, and specific primary etiologies
are suspected. Specifically, when subarachnoid hemor-
rhage, CNS infection, CNS neoplasia, or CNS inflamma-
tion is suspected, lumbar puncture with relevant analyses
on CSF (glucose, protein, cell counts, tests for infectious
agents, flow cytometry, and so on) is advised, following
appropriate radiologic studies.
A relevant consideration in the differential diagnosis of
headache in the geriatric population is giant cell arteritis;
if this is suspected, serum CRP and ESR may be helpful
diagnostic tests, although temporal artery biopsy and
histologic analysis are the preferred modalities used to
confirm the diagnosis. Table 8.2 gives other, less common
causes of headache, along with appropriate diagnostic
tests.
Note that the routine evaluation of headache with labo-
ratory tests is not likely to yield benefits commensurate
with the associated costs, so testing should be directed to
patients with suspicious clinical presentations. Labora-
tory analyses for headache also can pose risks to patients
because CSF sampling by lumbar puncture can rarely
result in persistent CSF leakage, a syndrome character-
ized by severe postural headaches.
Depression
Depression is prevalent in the elderly population, found
at a rate of 6.8% in the United States between 2006 and
2008 ((CDC) CfDCaP 2010). However, the prevalence
increases dramatically in the setting of comorbid illnesses
such as acute coronary syndrome (Amin et al., 2006) or
stroke (Robinson, 2003), and in hospitalized patients
(Cullum et al., 2006), in whom the disorder is often unrec-
ognized. Late-life depression is often undetected in pri-
mary care settings, in men, and in ethnic minorities, and
can be associated with poor quality of life, poor function-
ing, worsening of other chronic medical problems, and
increased morbidity and mortality (Unützer, 2007). In
addition, depression commonly can present in concert
Table 8.2 Laboratory evaluations for unusual causes of headaches
Suspected disorder Laboratory test
Pheochromocytoma Plasma or urine metanephrines
Drug overdose or abuse Toxicology screening
Carbon monoxide poisoning Hemoglobin CO oximetry
Hypothyroidism Thyroid stimulating hormone,
thyroid hormones
 Clinical Laboratory Investigations in Geriatric Neurology 177

with other neurologic disorders prevalent in the elderly, Table 8.3 Specific laboratory tests addressing causes of delirium
such as VBI or AD. Cause Specific test(s)
Diagnostic criteria in the Diagnostic and Statistical
Hypoxia/hypercarbia Blood gas analysis
Manual (Association AP, 2000) for major depression
Hypoglycemia Blood glucose
include numerous historical factors and the requirement
Poisoning Urine toxicology
that idiopathic depression be distinguished from depres- Medication effect Therapeutic drug monitoring
sion secondary to another underlying medical condition. Meningitis/encephalitis CSF analysis/culture/PCR
Depending on the clinical presentation, tests to evaluate Thyroid dysfunction Thyroid stimulating hormone
for possible depression-related conditions in the elderly Electrolyte disturbance Serum electrolytes
population with suspected comorbidities could include Liver failure Hepatic function tests, ammonia
complete blood count, serum electrolytes and glucose, uri- Uremia Blood urea nitrogen, creatinine
nalysis, blood urea nitrogen and creatinine, liver function Myocardial infarction Plasma troponin I or T
tests, thyroid stimulating hormone, serum B12 and folate Adrenal failure Cortisol with ACTH stimulation
Other infections Blood/urine/respiratory culture
concentration, or serologic evaluation for syphilis (RPR
Paraneoplastic syndrome Specific antibodies
testing). However, there is little evidence to support the
practice of using laboratory test screening in all patients
who present with suspected depression, and a study has
demonstrated that thyroid stimulating hormone testing, organ system failures, trauma, metabolic disorders, and
generally accepted as a screening test in patients with primary brain disorders. With so many potential causes, it
depression, is of little clinical value in elderly patients is obvious that no single set of laboratory tests will suffice
with depression (Fraser et al., 2004). for diagnosis in all cases. Nonetheless, several diagnostic
In the research setting, several biomarkers of depression tests can be of value in identifying either the most serious
have been identified. These include decreased platelet or the most prevalent causes of delirium (Han et al., 2010),
imipramine binding, decreased 5-HT1A receptor expres- listed in Table 8.3.
sion, increased serum-soluble interleukin-2 receptor and
interleukin-6, decreased serum brain-derived neurotrophic Human immunodeficiency virus
factor, hypocholesterolemia, decreased blood folate, and HIV infection was historically prevalent in older adults
both hypercortisolemia and impaired suppression on the who received blood transfusions before 1985, when rou-
dexamethasone suppression test (Mössner et  al., 2007). tine testing of the blood supply began. Currently, the
However, many of these biomarkers are associated with prevalence and incidence of HIV in adults older than 50
other conditions; none are specific, nor are they currently is lower than for adults younger than 50 ((CDC) CfDCaP.
used in diagnosing major depression. 2008), but progress in therapy means that the number of
In addition to fluid biomarkers of depression, phar- older patients with HIV should rise in the coming years.
macogenomic studies have illuminated the possible role Because HIV is less common in older patients, however,
of polymorphisms in the serotonin transporter-linked a delay in diagnosis is more likely because the disease is
polymorphic region (5-HTTLPR) in assessing possible not suspected. Neurocognitively, older HIV patients have
resistance to therapy or risk of side effects with sero- been found to be at increased risk for HIV-associated neu-
tonin-selective reuptake inhibitors (SSRIs) (Gerretsen and rocognitive disorders, including HIV dementia (Jayadev
Pollock 2008). Early studies indicate that pretreatment and Garden 2009).
testing for polymorphisms at this locus may lead to ear- Although laboratory testing to diagnose HIV in older
lier remissions during SSRI therapy (Smits et al., 2007). A patients is essentially identical to that in younger patients,
norepinephrine transporter polymorphism (NET-T182C) it is important to consider cardiovascular risk assessments
has also been shown in a study of Han Chinese subjects in these patients. HIV is commonly comorbid with diabe-
to have a link to susceptibility to depression (Min et al., tes, hyperlipidemia (Malvestutto and Aberg 2010), and
2009). cardiovascular risks that are also more prevalent in older
populations. Thus, identifying these risk factors with
Delirium appropriate testing (such as blood glucose/hemoglobin
Delirium is defined by several key features, including A1c, or lipid and cholesterol panel) in older HIV patients,
rapid onset of reduced consciousness, changing cognition and taking appropriate action on the results, should be a
not explained by coexisting dementia, and evidence of a primary concern.
medical condition, intoxication, or medication causing the
disorder. Delirium is commonly encountered in patients Paraneoplastic disorders
with significant medical illness, especially older patients. Paraneoplastic neurologic syndromes (PNS) are increas-
The list of possible etiologic causes of delirium is long and ingly recognized as causes of neurologic dysfunction
includes numerous drugs and medications, infections, in patients with both clinically apparent and occult
178 Assessment of the Geriatric Neurology Patient
malignancies (Didelot and Honnorat 2009). Often the
neurologic manifestations of these disorders antedate the
recognition of an underlying malignancy and thus may
represent the presenting symptoms. Understanding of
these disorders has advanced substantially in recent years
as a result of the identification of specific autoantibod-
ies associated with selected syndromes, many of which
can be tested for clinically. It is worth noting that neuro-
logic symptoms accompanying cancer are most often not
because of paraneoplastic syndromes but instead because
of metastatic or direct involvement of neoplasic disease
with the CNS or because of complications from toxic
therapies or infections. Nonetheless, several associations
between specific antibodies, neoplasms, and syndromes
have been identified and reviewed (Didelot and Hon-
norat 2009); one of the more common is the Hu antibody,
which has been found in patients with small-cell lung
carcinoma and associated with subacute cerebellar ataxia,
limbic encephalitis, and sensory neuropathy.
Testing for paraneoplastic inflammatory syndromes
begins with a high clinical index of suspicion. Routine CSF
analyses indicate mild inflammatory changes and often
oligoclonal banding on electrophoresis. Testing for spe-
cific antibodies, singly or in panels, is also available from
specialized laboratories. Because clinical presentations
differ for these syndromes, it is often helpful to provide
the laboratory with a summary of the clinical phenotype,
to aid in interpreting the results of these assays.
Because PNS are all, by definition, associated with
malignancy, the next step after confirming a diagnosis is
to find the related malignancy. The specific paraneoplas-
tic syndrome identified can often guide this search–-for
example, paraneoplastic encephalomyelitis because of
anti-Hu antibodies is highly associated with small-cell
lung cancer–-but often a whole-body search for a primary
malignancy is required.
Genetic disorders
Diseases caused by inherited mutation are rarely assessed
in the geriatric population, as they tend to manifest in the
young. Nonetheless, some neurologic diseases caused by
inherited mutations impact older patients. Examples of
these include Huntington’s disease, dominant cerebel-
lar ataxias, certain muscular dystrophies, and autosomal
dominant inherited forms of AD, PD, or FTLD. Although
specific management and therapy are often lacking for
these disorders, correctly diagnosing these diseases is not
merely an academic exercise. Identifying a genetic cause
in patients with complicated neurologic disorders can
prevent an otherwise lengthy and costly workup, inform
relatives about genetic risks, and aid researchers who
study these conditions (Bird et al., 2008).
The requirements for diagnosing these diseases in
the elderly include both a high index of suspicion and
an available clinical genetic assay. Complex genetic
assays–-both those that search for specific mutations and
those that sequence large spans of introns or exons–-are
becoming increasingly available in commercial and aca-
demic laboratories. A helpful online resource for clini-
cal genetics testing is the website www.genetests.org,
which is hosted by the United States National Center for
Biotechnology Information. It provides both literature
references and clinical testing sources for thousands of
genetic diseases.
Two general considerations about neurogenetic test-
ing are helpful in deciding on an appropriate diagnos-
tic approach. First, test costs may be highly variant
depending on the laboratory used, so it is important
to pay attention to which component tests comprise
a large panel of assays that are “bundled” together.
A second consideration is that parallel testing for
numerous possible etiologies of a suspected genetic
disorder, so-called “shotgun testing,” may not be the
most cost-effective approach. After consulting with
the laboratory performing the tests, it is often possible
to identify a sequential testing algorithm in which the
most likely genetic alterations are assayed initially
with a lower-cost technique, and only after these tests
come back normal are more expensive large-scale
sequencing tests performed. Because the diagnostic
yield of these tests is increased greatly when they are
ordered in an appropriate setting, many laboratories
that send these tests out to reference laboratories have
moved to testing formularies so that only specific
physicians (neurogeneticists instead of family practice
physicians) can order these complex and often expen-
sive tests.
Assessment of cerebral injury
Often cases arise in which the underlying diagnosis
accounting for a clinical presentation is not in ques-
tion, such as a subarachnoid hemorrhage that is con-
firmed by neuroimaging, or traumatic brain injury
(TBI). Outside of immediate management issues, the
primary concern in such cases may shift to prognosti-
cation about when or whether the patient will regain
consciousness or physical independence after the cur-
rent acute injury is resolved. Numerous studies have
identified CSF and serum biomarkers of the severity of
brain injury. Two of the most widely studied biomark-
ers of injury include S100B protein and neuron-specific
enolase, both of which may be assessed in either the
CSF or serum and are highly correlated to the sever-
ity of brain injury following a number of insults
(Kochanek et al., 2008). However, the primary prob-
lem for using these markers in the United States is that
no Food and Drug Administration (FDA)-approved
assays are available, meaning that only laboratories
willing to develop in-house tests provide this testing
in the United States.
 Clinical Laboratory Investigations in Geriatric Neurology
An alternate test for which an FDA-approved method
exists is quantitation of the BB isoform of creatine kinase
in CSF, so-called CK-BB. CK exists as several isoenzymes
inside cells, including MM (predominantly from muscle),
MB (present in cardiac muscle and used for detecting
myocardial infarction), and BB (the primary isoenzyme in
brain). CK-BB is usually concentrated intracellularly and
is at low concentration in CSF (<10 U/L) so that elevated
CSF CK-BB activity indicates brain tissue destruction and
enzyme leakage from cells. The activity of CK-BB, deter-
mined after electrophoretic separation of CK isoenzymes,
has been correlated with prognosis after a CNS insult
in several studies and can accurately predict whether
patients will regain consciousness or independence
(Kärkelä et al., 1993; Coplin et al., 1999).
Acknowledgements: This work was supported by
AG05136 and the Nancy and Buster Alvord Endowment.
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Part 3
Neurologic Conditions in the Elderly
 Chapter 9
Cognitive Impairment and the Dementias
9.1 Mild Cognitive Impairment
Ranjan Duara1,2,3, Miriam Jocelyn Rodriguez1, and David A. Loewenstein1

9.2 Alzheimer’s Disease

Martin R. Farlow4

9.3 Dementia with Lewy Bodies

Clive Ballard5

9.4 Vascular Cognitive Impairment

Helena C. Chui6 and Freddi Segal-Gidan6

9.5 Frontotemporal Dementia

David Perry7 and Howard Rosen7

9.6 Primary Progressive Aphasia

Maya L. Henry8, Stephen M. Wilson9, and Steven Z. Rapcsak10

9.7 Prion Diseases

Michael D. Geschwind8 and Katherine Wong8

9.8 Normal Pressure Hydrocephalus

Norman R. Relkin11

1Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, FL, USA
2Department of Neurology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
3University of Florida, College of Medicine, University of Florida, Gainesville, FL, USA
4Department of Neurology, Indiana University, Indianapolis, IN, USA
5Wolfson Centre for Age-Related Diseases, King’s College London, London, UK
6Department of Neurology, Keck School of Medicine and University of Southern California, Los Angeles, CA, USA
7Memory and Aging Center, Department of Neurology, School of Medicine, University of California, San Francisco, USA
8Department of Communication Sciences and Disorders, University of Texas at Austin and Memory and Aging Center,

Department of Neurology, University of California, San Francisco, CA, USA

9Department of Speech, Language, and Hearing Sciences, University of Arizona, Tucson, AZ, USA
10Department of Neurology, University of Arizona, Tucson, AZ, USA
11Memory Disorders Program, Department of Neurology and Brain Mind Research Institute, Weill Cornell Medical College,

New York, NY, USA

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

183
184 Neurologic Conditions in the Elderly

Summary
Mild Cognitive Impairment
OVERVIEW
• The term MCI was introduced as a stage in the Global Deterioration Scale to describe the progression
from normal aging to dementia, and later studies showed an increased risk of progression from MCI
to dementia.
• The widely used Mayo Criteria for MCI is based on prodromal amnestic features typical of AD, requiring impairment of
memory on at least one standard test.
• Subsequently, amnestic and nonamnestic types of MCI affecting single and multiple domains were described,
and the term now applies to the predementia phase of any disease that may progress to cause a full-blown
dementia.
• Other predementia entities include benign senescent forgetfulness, age-associated memory impairment (AAMI), age-
associated cognitive decline (AACD), and cognitive impairment no dementia (CIND).
• Mild MCI is likely to be reversible, and this has created some controversy regarding the relevance of the term to clinical
practice and the appropriateness of the term to define a predementia state.
DEFINITION
• Memory complaints, preferably corroborated by an informant.
• Evidence of objective memory impairment for the age of the patient, as assessed by neuropsychological
testing.
• Preserved global cognition.
• Essentially intact activities of daily living (ADLs).
• Absence of dementia.
SUBTYPES
• The most commonly used classification divides MCI into amnestic and nonamnestic types and further into single
domain and multidomain MCI.
• Significant etiologic overlap occurs between these classes, but in general amnestic MCI is more specific for AD and is
characterized by hippocampal and/or entorhinal cortex atrophy.
• Predementia conditions other than prodromal AD which may be present as MCI include vascular cognitive impairment,
Lewy body disease, and various forms of frontotemporal lobar degeneration.
• MCI due to LBD has features of episodic confusion, poor performance on fluency tests requiring attention,
visuospatial deficits, REM sleep behavior disorder, and motor dysfunction, with relatively good performance on
memory tests.
• Multiple-domain MCI is the most common type in vascular MCI, corresponding to the presence of multiple lacunar
infarcts in the basal ganglia, thalamus, and/or subcortical white matter.
• MCI may also be due to medical illnesses, toxins, and neuropsychiatric disorders.
DIAGNOSIS
• Structural imaging is mainly used to rule out conditions like stroke, hydrocephalus, and tumors but may show atrophy of
the hippocampus, parahippocampal gyrus, and amygdala.
• Functional imaging by PET, SPECT, and fMRI may become an integral part of management of MCI in the future.
• Cerebrospinal fluid (CSF) biomarkers and genetic assays can be done to estimate the risk for progression to AD.
TREATMENT
• Donepezil, rivastigmine, and galantamine have shown no effectiveness in decreasing the rate of progression from MCI
to dementia.
• ApoE4 carriers may benefit from treatment with donepezil at the MCI stage.
• Biomarkers may better identify groups which will respond favorably to pharmacologic treatment.
• Nonpharmacologic treatment which is perhaps more effective at this stage includes regular cognitive and physical
activity.
• The effective use of biomarkers as screening tools to identify patients who will benefit the most from early intervention
will make the benefits of treating MCI worth the cost of current treatments.

Alzheimer’s Disease
• General symptoms include poor recall, visuospatial difficulties, executive functioning deficits, possible apathy or
depression, decline in episodic memory, and difficulty with daily activities as symptoms pregress.
• DSM-IV and NINCDS-ADRDA criteria, clinical examinations, lab studies, and scans including MRI and PET are used to
help diagnose.
• Biomarkers associated with Aβ deposition, biomarkers for neuronal injury, and biomarkers associated with biochemical
change are included in criteria for MCI diagnosis.
 Cognitive Impairment and the Dementias 185

• Biomarkers are also incorporated into criteria for probable and possible AD as two groups: indicators of amyloid-β
protein deposition in the brain and indicators of neuronal degeneration with decreased FDG uptake in temporal lobes.
High total tau and phosphorylated-Tau (pTau) levels in CSF is another indicator.
• While genetic components are associated with developing AD such as ApoE which is the highest risk factor, there are
other factors that put patients at risk for developing AD.

Dementia with Lewy Bodies

• Two of the three core symptoms define patients with DLB: motor features of Parkinson’s, visual hallucinations, and
cognitive fluctuations. Other symptoms consist of sleep disturbances, attentional and executive dysfunction. Its loss
in cognition and function is similar to that of AD but differs for DLB derives from associated motor and autonomic
impairments.
• α-synuclein is a protein present in patients with DLB, found in Lewy neurites. DLB patients also have concurrent
amyloid pathology with Aβ-positive plaque, similar to those with AD.
• Similarities in symptoms of DLB and Parkinson’s have led them to be defined as on a spectrum instead of being
completely distinct conditions.

Vascular Cognitive Impairment

• Cerebrovascular disease (CVD) is the second leading cause of dementia. In late life, the two most common
causes of CVD are arteriosclerosis (including atherosclerosis and arteriolosclerosis) and cerebral amyloid
angiopathy. CVD is the primary disease process that leads to vascular brain injury (VBI) and vascular cognitive
impairment (VCI).
• VCI is an umbrella term that includes mild cognitive impairment and dementia attributed to CVD and VBI, and includes
previous labels including multi-infarct dementia, post-stroke dementia, vascular dementia, ischemic vascular dementia
and Binswanger syndrome.
• Currently there are several consensus criteria for VCI, but as yet no well established pathologic criteria.
• The clinical presentation (e.g., cognitive profile, focal neurologic signs, symptom progression) is heterogeneous.
• The subtype of subcortical vascular dementia tends to be associated with greater impairment in executive function
than memory.
• The best treatment for VCI associated with arteriosclerosis is prevention, through early identification and management
of vascular risk factors.

Frontotemporal Dementia
Clinical syndromes of FTD include:
• Behavioral variant of FTD (bvFTD) mainly describes personality and socioemotional function changes, like disinhibition,
apathy, changes in eating behaviors, compulsive behaviors. MRIs depict atrophy in the frontal and/or anterior temporal
lobes.
• Depending on whether atrophy exists in the left or right temporal pole, semantic variant primary progressive aphasia
(svPPA) is distinguished by progressive deterioration in knowledge about words and objects or behavior changes as
seen in bvFTD and difficulties in recognizing famous icons.
• Nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) is characterized by articulation and agrammatism
difficulties.
• As there are no pharmacologic treatments, studies have implemented other drugs, such as antidepressants, sertraline,
trazodone, to control behavioral symptoms.

Primary Progressive Aphasia

• There is a gradual deterioration in communication ability the absence of general cognitive impairment. Several variants
of PPA are associated with impairment of specific speech-language domains.
• Nonfluent/agrammatic:
• Agrammatic language, halting, effortful speech, and speech-sound errors.
• Neuroimaging reveals atrophy of left anterior perisylvian regions.
• Common underlying pathologies include FTLD spectrum disorders (tauopathies and TDP-43 proteinopathies).
• Semantic:
• Gradual deterioration of semantic memory and a reduction in expressive and receptive vocabulary.
• Neuroimaging reveals asymmetrical (left > right) anterior and inferior temporal lobe atrophy.
• TDP-43 FTLD is the most common underlying pathology.
• Logopenic:
• Slow rate of speech, impaired single-word retrieval, and difficulty with repetition.
• Neuroimaging reveals neurodegeneration of left posterior perisylvian cortex.
• AD pathology is most common.
• Behavioral speech-language treatments may result in improved communication abilities in PPA.

(Continued)
186 Neurologic Conditions in the Elderly

Prion Diseases
• Prion diseases can develop spontaneously (sporadic), genetically, and through transmission (acquired).
• Classic EEG finding in sCJD consists of sharp waves (PSWCs) occurring about once every second. CSF biomarkers are
also examined but have been found to vary in sensitivity and specificity. Brain MRIs with DWI and FLAIR sequences
should be examined when CJD is suspected.
• PRNP mutations can cause fCJD, GSS, and FFI.
• Prions are not highly infectious or contagious as an estimated several thousand proteins are necessary to transmit
prion disease.
• There is currently no treatment for prion diseases, and all cases are fatal.

Normal Pressure Hydrocephalus

• NPH is a chronic neurologic disorder characterized by enlargement of the cerebral ventricles, shuffling gait, urinary
incontinence, and dementia.
• It frequently develops in the absence of a macroscopic obstruction to the flow of CSF; however, it is unclear how
disturbances in the CSF compartment translate into brain dysfunction and clinical symptoms in NPH.
• Brain imaging is necessary to identify ventricular enlargement and verify obstruction to CSF flow in NPH. MRI is the
preferred modality for evaluation though CT scans are also common.
• Symptoms fall on a continuum, gait, and balance are typically described as “shuffling”; urinary frequency is part of
urination control problems; and cognitive disturbances manifest in executive dysfunction as NPH often occurs with AD.
• NPS symptoms can be reversed by diverting CSF out of the CNS. Neurosurgical implantation of a ventricular shunt is
the standard of care for NPH.
 Chapter 9.1
Mild Cognitive Impairment
Ranjan Duara, Miriam Jocelyn Rodriguez, and David A. Loewenstein
Development of the concept of
mild cognitive impairment
The concept of mild cognitive impairment (MCI) entity
stemmed from the observation that diseases causing cog-
nitive and functional impairment generally go through a
transitional stage between a cognitively normal state and
a dementia syndrome. “Prediabetes” and “prehyperten-
sion” are examples of conditions that grew to be estab-
lished in the medical lexicon after it became apparent that
these prodromal conditions conferred a very high risk
for developing diabetes and hypertension, respectively.
Moreover, the complications and management of these
prodromal states were found to be similar to the full-
blown conditions.
It is well recognized that cognitive deficits and atro-
phic changes in the brain begin long before a diagnosis
of dementia, in conditions such as Alzheimer’s disease
(AD), Lewy body disease, frontotemporal lobar demen-
tia (FTLD), and vascular dementia. In fact, the pathol-
ogy of a disease such as AD is probably detectable in
the brain several decades before the clinical onset of the
disease becomes evident (Braak and Braak, 1991). One
of the earliest terms used to classify cognitive changes
in the elderly is benign senescent forgetfulness, introduced
in 1962 by Kral, who believed it represented a variant of
normal aging instead of being a predementia term entity.
The Clinical Dementia Rating (CDR) scale, which was
reported in 1982, included the term questionable demen-
tia, or CDR 0.5 (CDR 0 was equivalent to normal cogni-
tion and CDR 1 equated to mild dementia in this scale;
Hughes et al., 1982; Morris, 1993). The term mild cogni-
tive impairment was introduced as a stage in the Global
Deterioration Scale in describing the progression from
normal aging to dementia by Reisberg et al. (1982). Later
studies showed an increased risk of MCI progressing to
dementia (Flicker et al., 1991). The National Institute of
Mental Health (NIMH) introduced the term age-associated
memory impairment (AAMI; Crook et al., 1986) as a vari-
ant of normal aging in which cognitive performance was
substantially worse than in younger healthy individuals.
Subsequently, the International Psychogeriatric Asso-
ciation introduced the term age-associated cognitive decline
(AACD; Levy, 1994) as a variant of normal aging with
dysfunction in multiple cognitive domains, relative to
normal elderly individuals.
The Canadian Study of Health and Aging introduced
the term cognitive impairment no dementia (CIND;
Graham et al., 1997) to enable clinicians to describe a
stage of cognitive and/or functional impairment—not
as criteria for dementia but without the requirement of
formal tests of cognition to characterize the level of cog-
nitive impairment. The Mayo Criteria for MCI (Petersen
et al., 1999, 2003), which have been adopted widely as
the standard criteria for identifying MCI, are based on
prodromal amnestic features typical of AD, requiring,
at minimum, impairment of memory on a single stan-
dard test. Subsequently, single- and multidomain non-
amnestic forms of MCI and multidomain amnestic MCI
(amnestic MCI (aMCI) and nonamnestic MCI (naMCI))
were described (Petersen, 2004). The term MCI is now
widely used to describe the predementia phase of any
disease that may ultimately progress into a dementia
syndrome.
The primary benefit of diagnosing a disorder in the
MCI stage is to recognize the risk for progression to a
full dementia syndrome and to exercise the opportunity
for early therapeutic interventions that may prevent or
delay progression and improve quality of life (Mosconi
et al., 2007). Among the interventions that may be con-
sidered are earlier institution of pharmacologic treat-
ments for the suspected cause of the MCI syndrome,
secondary prevention methods that may delay progres-
sion, and management of a variety of psychosocial issues
that may complicate or aggravate the underlying disease
entity and its management. Individuals identified to be in
the milder stages of MCI are more likely to have readily
reversible factors, such as anxiety and attentional disor-
ders, depression, metabolic or nutritional disorders, and
medication side effects. However, MCI does not merely
represent a point in the transition from normal aging to
dementia; instead, it involves a spectrum of cognitive and
subtle functional impairments. The reversibility of MCI
has given rise to a measure of uncertainty regarding the
utility of the term to describe a predementia state and
its relevance to clinical practice and research studies. In
studies with high base rates of AD, the rate of progression
to AD is approximately 12–15% per year, with a low rate
of reversal (Luis et al., 2003), whereas in epidemiologic
studies there is a lower rate of progression and a high rate
of reversal to a normal state (Larrieu et al., 2002; Ganguli
et al., 2004).
187
188 Neurologic Conditions in the Elderly
How is MCI defined?
A transitional, predementia state between normal cogni-
tion and established dementia is likely to exist for most
recognizable dementing disorders. The best cognitive
biomarker of AD in its predementia state appears to be
impairment of episodic memory, even among asymptom-
atic, community-dwelling elders (Howieson et al., 1997;
Grober et al., 2000; Assal and Cummings, 2002; Small et
al., 2003). Although memory-related symptoms are by far
the most common presentation of early AD, variations
in the onset and progression of AD are also well known,
including aphasic/anomic, visual agnosic, and frontal
(abulic or disinhibited) onset (Galton et al., 2000). In con-
trast to the cognitive deficits seen in dementias, which,
by definition, are acquired, the deficits in MCI, as defined
here, may or may not be acquired.
Especially in community studies, individuals with or
without subjective memory complaints may be found to
have cognitive deficits upon evaluation, and it may be
challenging to determine whether a clear history of cog-
nitive deterioration is present. Correct rates of classifica-
tion in cross-sectional studies are ultimately related to the
sensitivity and specificity of particular test measures and
the thresholds for diagnosing impairment, as well as the
underlying base rates of the underlying condition caus-
ing these impairments in any population (see Brooks and
Loewenstein, 2010, for a more extensive review). Although
diseases that currently require dementia as a criterion for
diagnosis (such as AD) could be diagnosed at an earlier
stage by lowering current thresholds for cognitive and/
or functional impairment, lowering these thresholds may
also enhance false positive diagnoses.
Formal criteria for aMCI proposed by Petersen et
al. (1999) require the following features: (1) memory
complaints, preferably corroborated by an informant;
(2) evidence of objective memory impairment for the age
of the patient, as assessed by neuropsychological testing;
(3) preserved global cognition; (4) essentially intact activi-
ties of daily living (ADLs); and (5) absence of demen-
tia. The specific neuropsychological tests to be used, the
thresholds for defining impairment, the specific ADLs to
be assessed, and the decision regarding whether these
ADLs are intact are left to the judgment of the clinicians.
Nevertheless, subjects diagnosed to have MCI using these
criteria have been found to have a high likelihood of pro-
gression to probable AD in specialty memory disorder
clinics. In a follow-up study of a cohort of 220 subjects
who were diagnosed at baseline to have MCI, about 80%
progressed to develop dementia (Petersen et al., 2003).
Grundman et al. (2004) proposed an adaptation of
Petersen’s MCI criteria for use in clinical trials by speci-
fying the cognitive and functional tests to be used and
the scores for determining impairment in these areas.
They proposed that (1) memory complaints should be
corroborated by an informant; (2) abnormal memory
functioning should be documented by the delayed recall
score for a single standard paragraph from the Logical
Memory II subtest of the Wechsler Memory Scale (WMS),
using 1.5 SD below age and education equivalent cogni-
tively normal subjects as the threshold for impairment; (3)
normal general cognitive functioning should be based on
clinical judgment and an MMSE score of 24 or above; and
(4) no evidence exists of impairment or minimal impair-
ment in activities of daily living, documented by a CDR
global score of 0.5 or higher.
Other predementia entities include CIND (Graham
et al., 1997), the criteria for which are less restrictive
and merely require evidence of cognitive impairment
in a nondemented individual. Galvin et al. (2005) and
Storandt et al. (2006) have suggested that a targeted clini-
cal history that provides evidence of cognitive and func-
tional decline, relative to previously attained abilities, can
identify nondemented subjects who will progress and
be found to have histopathologic AD on autopsy. These
impressive findings may partly be related to the clinical
environment in which these criteria were implemented;
the process of referral may have resulted in them being
preselected to have AD.
Evidence of progression of cognitive deficits, either by
history from an informant or by longitudinal examina-
tion, allows a tentative classification of MCI cases into
progressive versus nonprogressive (even reversible) MCI.
It remains important to consider predementia conditions
other than prodromal AD, which may be present as MCI
or CIND, including vascular cognitive impairment, Lewy
body disease, and various forms of frontotemporal lobar
degeneration.
Neuropsychological tests commonly used to assess
performance in multiple cognitive domains required
to assess MCI include word list tests (such as FAS and
COWAT), logical memory from the WMS third and fourth
editions, memory-delayed recall, and the Stroop color
word test to measure different areas of cognitive func-
tioning (Grober et al., 2000; Small et al., 2003; Backman
et al., 2004). Various cut-off scores have been used for
these tests, although 1.5 SD below age- and education-
adjusted norms for domains of episodic memory, execu-
tive functioning, and perceptual speed appears to be most
effective in identifying MCI (Loewenstein et al., 2006),
even among asymptomatic, community-dwelling elders
(Assal and Cummings, 2002). In some studies, the earli-
est deficits have been noted to be in executive functioning
and perceptual speed, as well as memory and learning
(Vanderploeg et al., 2001; Backman et al., 2004; Loewen-
stein et al., 2004). The use of multiple memory measures
to identify memory impairment, using a cut-off score of
1.0 SD on at least two cognitive tests in the same cognitive
domain, may decrease the false positive rate in classifica-
tion (Jak et al., 2009). As a consequence of the variety of

cognitive tests and cut-off scores are in use to establish
cognitive impairment, considerable variability exists in
the prevalence and incidence rates of MCI in studies con-
ducted in the last decade (see Luis et al., 2003; Brooks and
Loewenstein, 2010).
MCI subtypes
The heterogeneity of MCI is a consequence of a number of
factors, including the methodology used to classify MCI,
the underlying etiology of the MCI syndrome, and the
premorbid status of the patient. Items of particular impor-
tance are the level of education, cultural background, cog-
nitive reserve in various domains, and general medical,
neurologic, and psychiatric status. MCI may be classified
on the basis of the presenting cognitive syndrome (amnes-
tic, nonamnestic, multidomain), the suspected aetiology
(AD, cerebrovascular disease, Lewy body disease), and
the progression rates to dementia (rapid and slow pro-
gressors, nonprogressors, and reversers). Disproportion-
ate involvement in memory, language, visual-spatial, or
other functions results in the two basic subtypes of aMCI
or naMCI. Each of these can be single-domain or multi-
ple-domain MCI. Multidomain aMCI requires impair-
ment in memory and one or more nonmemory domains;
multidomain naMCI requires impairment in two or more
nonmemory domains, such as attention/executive func-
tioning, language, and visuospatial processing (Petersen
et al., 2003; Kantarci et al., 2008).
Nevertheless, considerable overlap occurs between
aMCI and naMCI, depending on the criteria used to clas-
sify impairment. Methodological factors may result in dif-
ferent frequencies of MCI subtypes, thereby contributing
substantially to the heterogeneity of MCI. The prevalence
rates for MCI subtypes depend on the use of different
cut-off scores for memory and nonmemory impairment,
as well as the use of different normative data bases to
derive such cut-off scores. For example, it is evident that
the greater the number required to classify an individual
as being impaired, the lower will be the prevalence rates
of aMCI; a correspondingly higher prevalence rate of
naMCI may then become evident. Reducing the threshold
for classifying impairment in a memory test from 1.5 to
1.0 SD will increase the frequency of aMCI relative to
naMCI. Further complicating the field of MCI research
is the heterogeneity and plethora of memory and non-
memory test measures employed. Individuals with high
premorbid educational attainment or cognitive reserve
may be able to compensate for their deficits because of
their greater knowledge base and familiarity with the
test-taking process and by employing various strategies
that allow them to perform well on cognitive measures,
in spite of their deficits. Those with low cognitive reserve
may perform far worse than would be expected, not only
Mild Cognitive Impairment 189
because of a lower knowledge base, possibly resulting
from a lower educational level, but also because of lack of
familiarity with test taking and the associated anxiety and
attentional problems.
The clinical features of etiologic subtypes of MCI would
be expected to be similar to those of the corresponding
dementia subtype; however, this may depend on a num-
ber of factors, including the duration of the MCI stage
of the dementing disease and the saliency of the clinical
features that generally occur in that stage. For example,
one of the distinguishing clinical features used for diag-
nosing AD is gradually progressive impairment in recent
memory, as opposed to remote memory. This feature is
generally most apparent in the earlier phases of AD and
becomes less distinct in the later stages of the disease. The
most useful distinguishing features of Lewy body disease
in the MCI stage (MCI-LBD; occurring in 79–86% of cases)
are (1) episodic confusion; (2) impaired performance on
fluency tests requiring sustained attention and on visuo-
spatial tests, with relatively preserved performance of
memory tests in spite of frequent memory-related com-
plaints; (3) REM sleep behavior disorder; and (4) motor
dysfunction (Ferman et al., 2002; Claassen et al., 2010).
It has been suggested that aMCI is more likely to reflect
underlying AD pathology, whereas naMCI is more indic-
ative of non-AD pathologies (Petersen, 2004). Indeed, in
the Leipzig Longitudinal Study of the Aged, Busse et al.
(2006) found that naMCI was associated with progression
to dementia of the non-AD type, whereas aMCI was asso-
ciated with progression to AD. Other studies have shown
that memory impairments are common among individu-
als with underlying vascular disease and that the severity
of vascular disease is related to the degree of impairment
in executive function. This makes multiple-domain MCI
the most common subtype among those with vascular
MCI (Villeneuve et al., 2009). Among all MCI subtypes,
the presence of mild parkinsonian signs was associated
with increased dysexecutive function and increased prob-
ability of a vascular dementia diagnosis (Mauri et al.,
2008). Among 1346 patients with Parkinson’s disease
(PD), from eight different cohorts, 25.8% were found to
have MCI. Among them, amnestic impairment (13.3%)
was most common, followed by visuospatial impairment
(11%), and then attention/executive impairment (10.1%;
Aarsland et al., 2010). The frequencies of different MCI
subtypes were as follows: aMCI single domain (8.9%),
aMCI multiple domain (4.8%), naMCI single domain
(11.3%), and naMCI multiple domain (1.3%).
The pattern of cognitive impairment and the number
of domains involved may have diagnostic and prog-
nostic implications (Bozoki et al., 2001). Patients with
aMCI, especially those with impairment in more than one
memory test, have a higher risk of progression to demen-
tia, as compared to normal elderly individuals or those
with naMCI. Patients in the prodromal stages of AD may
190 Neurologic Conditions in the Elderly
present with pure memory impairment, but those who
progress more rapidly are likely to have more widespread
disease, with impairment in cognitive and noncognitive
domains. These noncognitive domains include psychiat-
ric symptoms such as anxiety, depression, paranoia, apa-
thy or disinhibition, and motor symptoms such as parkin-
sonism and abnormalities in posture and gait. Although
not typically considered a noncognitive domain, radio-
logical findings do contribute important diagnostic and
prognostic information. MCI-Vasc usually has evidence
of multiple lacunar infarcts in the basal ganglia, thalamus,
and/or subcortical white matter. MCI-AD is character-
ized by the presence of hippocampal and/or entorhinal
cortex atrophy without obvious cerebral infarctions (Luis
et al., 2003; Burton et al., 2009). MCI-FTD is character-
ized by predominant frontal and/or anterior and lateral
temporal atrophy. Cognitive impairment among nonde-
mented elderly individuals may also be caused by a vari-
ety of systemic medical conditions, effects of medications
and toxins, neuropsychiatric disorders, educational and
sociocultural deprivation, and “frailty related” factors.
Diagnostic issues
The classification of subjects as normal, MCI, or mild
dementia, according to neuropsychological and func-
tional evaluation, is more challenging for MCI than it
is for dementia cases because MCI patients have much
milder and more subtle cognitive and functional deficits
(Luis et al., 2003). The diagnosis of cognitive states relies
on two elements of clinical assessment: the history from
the subject (and/or one or more informants), providing
information about the presence, severity, and course of
functional impairment; and an objective cognitive (neuro-
psychological) assessment. Especially in the early phase
of MCI, the reliability of both these elements is likely to
be suboptimal, for two reasons: (1) It is difficult to dis-
tinguish functional impairment associated with normal
versus abnormal aging, especially in the presence of age-
related conditions such as arthritis or visual and hearing
impairment. (2) Objective assessment of cognitive deficits
tends to be obscured when impairment is mild because
the relative impact is greater for factors such as low or
very high educational levels, practice effects, recruit-
ment/referral bias, cultural and linguistic diversity, pre-
morbid cognitive and functional deficits, and coexisting
psychiatric, medical, or neurologic conditions, including
attention deficit disorder and dyslexia.
The two elements in the clinical evaluation of MCI cases
have been combined to provide a summary score in the
CDR scale (Morris, 1993), although there is often wide
discrepancy, especially in the early stages of cognitive
and functional impairment, between the results of objec-
tive cognitive assessment and the history of functional
impairment. Diagnostic variability between individual
clinicians and diagnostic teams (Rockwood et al., 2000)
reduces reliability of diagnoses in cross-sectional and
especially longitudinal studies. As a consequence, large
number of subjects may be required to power studies in
order to obtain significant results, particularly for subjects
who have been recruited from the community and not the
clinic. Most patients who present to a clinic come with a
reliable informant who can provide a reasonably unam-
biguous account of the mode of onset of the cognitive syn-
drome, its relationship to other events (such as a stroke, a
medical illness, or a surgical procedure), its mode of pro-
gression, the presence of fluctuations, REM sleep behavior
disorder, and so on. Subjects recruited from the commu-
nity typically are not accompanied by an informant, and
any available informant is unlikely to have the knowledge
or the motivation to provide the requisite information.
These issues can be problematic in clinical trials that
require independent assessments of the history and func-
tional status and clinical interview of the research subject
(usually performed by a physician) and the cognitive
assessment performed by a neuropsychologist. The indi-
vidual assessments of the patient are then reconciled by a
consensus process, which requires reconciliating discrep-
ancies between the diagnoses of the two assessments. The
thresholds used for distinguishing normal aging from
any form of MCI and MCI from mild dementia are arbi-
trary. Consensus diagnosis also can be time consuming
and labor intensive to produce, resulting in an increased
overall expense to the diagnostic process. The individual
views and the personality of a single clinician on a consen-
sus conference team may sway the consensus diagnosis in
a particular direction. Although the reliability of a con-
sensus diagnosis of dementia or MCI has been assessed
only infrequently (Hogervorst et al., 2003; Schafer et al.,
2004), in the few studies that have been done, the results
have not been impressive. To address these aforemen-
tioned issues, an algorithmic consensus diagnosis has
been proposed and used effectively to reconcile the differ-
ent perspectives of individual sources of data and to sys-
tematize the process of making the distinctions between
cognitively normal and MCI subjects and MCI and mild
dementia subjects (Duara et al., 2010).
After a global cognitive diagnosis of MCI or dementia
is determined, an etiologic diagnosis, which is based on
the same clinical, neuroimaging, and laboratory features
required to make a series of dementia diagnoses, may be
assigned. Examples of such MCI etiologic diagnoses are
MCI-AD (early AD), MCI-vascular or vascular cognitive
impairment (early vascular dementia), and MCI-LBD (early
Lewy body dementia), MCI-FTD (early frontotemporal
dementia). Cognitively impaired subjects seen in a mem-
ory disorder center are much more likely to have AD than
those recruited from a community study. Subjects found to
have cognitive impairment in a stroke clinic, a renal clinic, a

cancer center, or a sleep center are unlikely to be referred for
cognitive assessment because of the (often correct) assump-
tion that the cognitive impairment is associated with the
medical condition or its treatment at that clinic. Diagnos-
tic criteria for the individual causes of dementia generally
require the exclusion of all other identifiable neurologic,
psychiatric, and medical causes of dementia or cognitive
impairment. As such, the dominant medical illnesses pres-
ent in each individual should be emphasized as possible
etiologic factors for an MCI syndrome.
The methods that are available for making the diagno-
sis and the expertise of the diagnosticians at a particular
venue also determine the accuracy of the diagnosis. In
community practice, the time and expertise to adminis-
ter and even brief cognitive tests may not be available.
Culture, education, socioeconomic factors, and attitudes
regarding the aging process may determine the impor-
tance given to cognitive symptoms and the effort in diag-
nosing the cause of such symptoms. The availability of
neuropsychological evaluation, brain imaging, and CSF
evaluation may be determined by prevailing healthcare
regulations and regional biases toward the use of certain
tests. Diagnostic accuracy may also be influenced by the
specific tests used and how they are interpreted (e.g., cur-
rently only the exceptional radiologist assesses and com-
ments on the severity of medial temporal atrophy on a
magnetic resonance imaging (MRI) scan).
The challenge in assigning an etiologic diagnosis to an
MCI syndrome, especially in general practice, is that symp-
toms mimicking early dementia and performance on cog-
nitive tests may be related not only to a variety of medical
conditions or the effects of medications but also to psy-
chosocial factors, developmental cognitive disorders such
as attention deficit disorder and dyslexia, and psychiatric
conditions such as anxiety, depression, and personality dis-
orders (Budson and Price, 2005). The relationship between
depression and dementia is a complex one. The results of
some studies suggest that depression may often be a pro-
drome to AD. Other studies suggest that impaired atten-
tion and executive function are associated with geriatric
depression (Lockwood et al., 2002) and that these deficits
may persist even after successful treatment of depression.
Among 1777 subjects in the National Alzheimer Coor-
dinating Center (NACC) database (Beekly et al., 2004),
subjects with MCI who had prominent deficits in execu-
tive functioning were found to have greater severity of
depression (Rosenberg et al., 2011), but there was no
association between the presence of aMCI or naMCI and
depression. In another study, patients with four or more
neuropsychiatric symptoms were more likely to be diag-
nosed with aMCI, and patients diagnosed with aMCI were
more likely to exhibit depressive symptoms than other
symptoms and to have an increased risk of developing
dementia (Edwards et al., 2009). Although clinicians must
be aware that memory complaints may be symptomatic
Mild Cognitive Impairment 191
of underlying depression, it is especially important for
psychiatrists to be aware that depressive symptoms in an
individual who has demonstrable amnestic deficits often
suggests a diagnosis of an early form of dementia.
Pathology of MCI
The pathologic changes of AD may begin many years before
the patient is diagnosed with dementia (Crystal et al., 1988;
Braak and Braak, 1997; Silverman et al., 1997). The earliest
known event in the pathophysiology of AD is the deposi-
tion of amyloid beta protein in the neocortex (Oddo et al.,
2003). This, by itself, may result in subtle cognitive deficits
(Rentz et al., 2010). The neurodegenerative phase of AD
begins with selective involvement of the anterior aspects of
the transentorhinal and entorhinal cortex (ERC), the CA1
sector, and subiculum of the hippocampus (HP; Leverenz
and Raskind, 1998). About 30% of individuals who meet
neuropathologic criteria for AD and are classified as Braak
and Braak stage V or VI at autopsy remain nondemented
during life (Snowdon et al., 1997); this suggests that the
disease can reach a relatively advanced pathologic stage
without significant symptoms of dementia. Among elderly
clinically normal individuals (in the Mayo ADRC) who
have been classified pathologically as Braak and Braak
stage IV or less, amyloid or diffuse plaques are frequently
present, but neuritic plaques are rare (Jack et al., 2002).
Subjects diagnosed with MCI during life have greater
tau and neurofibrillary pathology (which correlates
closely with cognitive function) than cognitively normal
subjects but have cortical plaque densities that are similar
to those in patients with AD. Although AD pathology is
almost universally present among subjects classified clini-
cally to have MCI, about 30% also have other pathologies
such as Lewy bodies, argyrophilic grain disease, or hip-
pocampal sclerosis affecting the medial temporal lobe
(Forman et al., 2007). Biochemical alterations in corti-
cal tau, Aβ, and isoprostanes correlate with plaque and
tangle burden but do not distinguish MCI subjects from
those with clinical dementia. Markers of lipid peroxida-
tion, F2-isoprostanes (F2-IsoP), and F4-neuroprostanes
(F4-NP) have been found to be similar in the cerebral
cortex and hippocampus of MCI and AD subjects but are
elevated compared to normal controls. Cognitive function
has also been found to correlate with the loss of synaptic
markers and white matter pathology, even among normal
individuals (Markesbery et al., 2005).
Biomarkers in MCI
As described previously, the assessment of memory and
other cognitive deficits, typically affected by diseases such
as AD, may be influenced by a variety of demographic,
192 Neurologic Conditions in the Elderly
psychosocial, medical, and psychiatric factors, as well
as hearing and visual deficits (Lopez et al., 2000; Manly
et al., 2005; Acevedo et al., 2007; Dilworth-Anderson et al.,
2008). In contrast, such factors do not influence the accu-
racy of biomarkers for the detection and diagnosis of dis-
eases. In general, biomarkers become detectable years or
even decades preceding the onset of the clinical syndrome
of the disease in question. Biomarkers may be indices of
specific underlying pathologies such as the accumulation
of amyloid (Aβ1-42) in the brain (as indicated by low lev-
els of CSF Aβ1-42 or elevated levels of fibrillar amyloid
on amyloid positron emitting tomography (PET) scans).
Biomarkers may also be downstream indices of degenera-
tive changes in the brain (such as regional atrophy or syn-
aptic loss/dysfunction). Both specific and downstream
biomarkers are surrogates of underlying pathology and
can be used as aids in the diagnosis, potentially even in
the preclinical stage of diseases such as AD and FTLD.
They may also predict the rate of progression of the clini-
cal syndrome.
Alterations in the structure of the brain can be detected
and quantified by several structural imaging tech-
niques, including computed tomography (CT) and MRI,
especially in the medial temporal lobes, where AD and
FTLD-related degenerative pathology appear to be
most prominent early in the disease process. Functional
changes in the brain can be assessed with PET and single
photon emission computed tomography (SPECT), as well
as by functional MRI (fMRI). Amyloid deposition in the
brain can be detected using PET scans with either C-11
or F-18 labeled ligands that bind to fibrillar amyloid beta
protein. Genetic markers, such as APOE genotypes, can
identify subgroups of individuals who are at elevated risk
for cognitive decline and the development of AD pathol-
ogy (Cosentino et al., 2008).
Genetic markers for AD that are sensitive to autosomal-
dominant transmission include amyloid precursor pro-
tein (chromosome 21; onset at 40–65 years), presenilin 1
(chromosome 14; onset at 25–60 years), and presenilin 2
(chromosome 1; onset at 45–84 years). The most common
genetic risk factors for late-onset AD, the ApoE-e4 allele,
are associated with a greater prevalence and an earlier
age of onset of AD in most racial/ethnic groups. The
epsilon 4 allele for the apolipoprotein E (APOE) gene on
chromosome 19 is a risk factor that explains about 20%
of late-onset cases. Those heterozygous for the e4 allele
have increased risk for AD by two- to threefold, and those
homozygous for the e4 allele have 10- to 15-fold increased
risk for AD. The SORL1 gene on chromosome 11 and a
host of other candidate genes (see www.alzgene.org) also
explain small percentages of the variance with regard to
risk for AD. Relatively high prevalence of the APOE e4
allele, but with a lower risk for AD, has been reported
among nondemented African Americans (Kamboh et al.,
1989; Srinivasan et al., 1993), relative to non-demented
Hispanic, and even more so among non-Hispanic
Caucasian groups (Pablos-Mendez et al., 1997; Harwood
et al., 2004). The presence of the APOE e4 genotype com-
bined with clincal features has been used to increase the
predictive accuracy of the diagnosis AD, especially in its
predementia phase (Jobst et al., 1998; Visser et al., 2002).
Cerebrospinal fluid (CSF) biomarkers of AD pathol-
ogy are CSF Aβ1-42 (the 42 amino acid form of Aβ), as
an early marker of the amyloid phase of the disease; and
CSF total tau—that is, T-tau, phosphorylated tau associ-
ated with tangle formation phospho tau (P-Tau181P)—as
a marker of the later neurodegenerative phase of the dis-
ease associated with neuronal/axonal degeneration. Low
CSF Aβ42 has also been reported several years before
the onset of clinical symptoms, suggesting its poten-
tial utility for preclinical diagnosis (Fagan et al., 2007;
Stomrud et al., 2010). The CSF Aβ42/tau ratio differenti-
ated patients with subjective cognitive complaints, with
naMCI, and with aMCI from healthy controls (Visser
et al., 2009). Currently, the most promising biomarkers
that could assist in the diagnosis of early AD are the ratios
of CSF tau protein to CSF Aβ levels (Sunderland et al.,
2003) and CSF phosphotau-231 (ptau-231) (Buerger et al.,
2002, 2003, 2006; Hansson et al., 2006). CSF biomarkers
have been shown to have utility in predicting cognitive
decline in cognitively normal older adults (Fagan et al.,
2007) and progression to an MCI state (Li et al., 2007), as
well as progression of aMCI to AD (Li et al., 2007; Diniz
et al., 2008; Visser et al., 2009).
Using the US Alzheimer’s Disease Neuroimaging Ini-
tiative (ADNI) data set, a marked increase in CSF T-tau
and P-tau together with a marked decrease in CSF Aβ42
is found in AD (De Meyer et al., 2010), providing 85%
sensitivity at a specificity level of 90%. In this study, a
separate analysis derived an “AD signature” consisting of
specific ratios of CSF β-amyloid (1:42) to CSF phosphory-
lated tau181P. This signature was present among 90%
of AD patients, 72% of MCI subjects, and 36% of cogni-
tively normal elderly normal subjects. While the propor-
tion of cognitively normal subjects with the AD signature
was unexpectedly high, the APOE e4 allele frequency was
markedly increased in this subgroup of normal subjects
with the AD signature (De Meyer et al., 2010), suggest-
ing that the signature was able to detect preclinical AD.
A meta-analysis of the diagnostic and predictive utility of
CSF phosphorylated tau levels showed it was satisfactory
for diagnosing MCI and predicting progression of MCI
to dementia but was less capable of differentiating AD
from other types of dementia (Mitchell, 2009). In many
European specialty centers (which is the main location
for diagnosis and treatment of dementing diseases), lum-
bar puncture and CSF assays are performed routinely.
In countries where nonspecialists provide diagnosis and
treatment of dementia, CSF biomarkers are less likely to
become the prevailing standard for diagnosis of AD.

Structural neuroimaging is used routinely in the evalu-
ation of dementia/MCI, primarily for the purpose of
excluding conditions such as stroke, hydrocephalus, and
brain tumors. MRI is vastly superior to CT scanning as
a structural imaging technique, as it has greater resolu-
tion, provides far greater soft tissue contrast in the brain
and also has the advantage of avoiding ionizing radia-
tion. Assessment of hippocampal and entorhinal cortex
atrophy in structural brain images could be an inclusive
test for the diagnosis of prodromal and probable AD.
Entorhinal cortex and hippocampal volume loss on MRI
scans are highly correlated with the rate of progression
of MCI to AD. The presence of MCI or mild dementia
versus normal cognition has been associated specifi-
cally with atrophy of the left hippocampus, parahippo-
campal gyrus, and amygdala (Bobinski et al., 2000; Wolf
et al., 2001; Jarvenpaa et al., 2004; Salamon et al., 2004).
Smaller hippocampal and entorhinal cortical size on MRI
(de Leon et al., 1993, 1997) has been related to relatively
poor performance of memory function in normal aging
and future AD risk (Killiany et al., 2000; Xu et al., 2000).
The histopathologic correlate of these imaging findings
appears to be the accumulation of neurofibrillary tangles,
neuritic plaques, and the loss of neurons and dendritic
arbor in the transentorhinal cortex and the hippocampus
cortex (Bobinski et al., 1996, 2000; Gosche et al., 2002; Jack
et al., 2002; Burton et al., 2009). The presence of medial
temporal atrophy is not specific for AD, and conditions
such as FTLD, vascular dementia, and hippocampal
sclerosis may also demonstrate brain atrophy in these
regions. However, because of the high prevalence of AD
in the elderly, 85–90% of all degenerative pathology in
the medial temporal lobe in elderly subjects is AD pathol-
ogy (Barker et al., 2002), either alone or in combination
with other diseases. An early effort demonstrating the
importance of combining structural MRI with other risk
factors in the assessment of risk of progression of aMCI
to AD was the study by Petersen (2004). They found that,
among aMCI subjects, those who were APOE e4 allele
carriers had the greatest deficits on cued memory tasks
and reduced hippocampal volumes on structural MRI, as
well as the greatest risk for rapid progression to dementia.
Two functional imaging techniques, PET and SPECT,
are sensitive methods for providing quantitative evalu-
ation of physiologic functions, protein pharmacokinet-
ics, and distribution of receptors in the brain (Cedazo-
Minguez and Winblad, 2010). Radiolabeled glucose FDG
(fluoro-2-deoxy-d-glucose)-PET can be used to measure
cerebral glucose metabolism, which indirectly indicates
synaptic activity. Metabolic or perfusion deficits detected
on PET or SPECT scans in AD patients distinguish them
from normal control subjects and from patients with other
types of dementia and correlate with the severity of cog-
nitive impairment in MCI patients (Small et al., 2008).
Using FDG-PET, with an automated method of image
Mild Cognitive Impairment 193
analysis to study the medial temporal regions and hip-
pocampus, de Leon and colleagues showed that baseline
FDG-PET measures predicted decline from normal to
MCI or AD 6–7 years in advance of symptoms with 71%
and 81% accuracy, respectively. An extrapolation of these
results suggests that AD can be identified 12 years before
the patient is symptomatic.
A functional imaging technique (fMRI) can provide
measures of regional cerebral blood flow in various
brain areas with high temporal resolution, allowing
assessment of changes in blood flow in association with
a cognitive task. By using fMRI, Sperling (2007) studied
cognitive-behavioral functions in the early phases of neu-
rodegenerative disorders and identified neuroanatomic
networks affected by these diseases (Sperling, 2007). The
results of an fMRI study of verbal short-term memory
comparing healthy controls to AD patients showed that
alternate functional networks and greater overall activa-
tion occurred in AD patients during memory processing
(Peters et al., 2009).
Predictors of outcomes in MCI
The importance of recognizing individuals at high risk
for developing AD is based on the concept that such indi-
viduals may benefit from early therapeutic interventions
(Mosconi et al., 2007). The design of primary and second-
ary prevention trials and of pharmacologic and nonphar-
macologic treatment trials could be influenced by the
profile of neuropsychological, functional, and biomarker
tests that facilitate prediction of the rate at which individ-
ual MCI subjects will progress to dementia. By factoring
in these profiles and the predicted rates of decline with-
out any treatment for individual subjects participating in
a clinical trial, it may be possible to better determine the
effect of a specific intervention for a group of subjects.
In clinical settings, the rate of progression from aMCI
to dementia is generally 10–15% per year (Petersen et al.,
1999, 2001; Boyle et al., 2006). Morris et al. (2001) reported
that 100% subjects diagnosed with MCI (CDR score = 0.5)
progressed to dementia over a 9.5-year period, of which
84% received a neuropathologic diagnosis of probable
AD. Alexopoulos et al. (2006) found that 25% of subjects
with aMCI, 38% of subjects with naMCI, and 54% of indi-
viduals with mixed amnestic and nonamnestic impair-
ment progressed to dementia over a 3.5-year follow-up
period. On the other hand, Rountree et al. (2007) found no
differences in the rates of progression between those with
aMCI (56%) and those with naMCI (52%) over a 4-year
follow-up. The degree of impairment on both amnestic
and nonamnestic measures is associated with the likeli-
hood that individuals with MCI will progress to demen-
tia versus revert to a normal state over time (Loewenstein
et al., 2009). As might be expected, the prevalence rates
194 Neurologic Conditions in the Elderly
of MCI and the rates of progression to dementia among
subjects diagnosed in a community settings appear to be
considerably lower than for subjects seen in a clinical set-
ting (Larrieu et al., 2002; Ganguli et al., 2004).
Although aMCI and naMCI are generally diagnosed
on the basis of a cut-off point of 1.5 SD below age- and
education-corrected means on a single neuropsychologi-
cal test, it is apparent that, for aMCI, impairment in more
than one memory measure or a combination of deficits in
memory and nonmemory measures is much less suscep-
tible to reversion to a normal state and faster progression
to dementia than when only a single amnestic or non-
amnestic cognitive impairment is present (Manly et al.,
2005, 2008; Jak et al., 2009; Loewenstein et al., 2009; Brooks
and Loewenstein, 2010). Individual tests evaluate unique
aspects of cognitive function, and subjects with deficits on
multiple tests are likely to have more advanced or wide-
spread underlying pathology and be further along in the
disease process. As a result, it is not surprising that these
individuals progress to dementia at much greater rates
as well as show less reversion rates to a normal state of
cognition. Longitudinal studies suggest that patients with
naMCI are likely to have far more variability in terms of
symptomatology and progression to various forms of
dementia (such as frontotemporal dementia and primary
progressive aphasia; Nordlund et al., 2010; Ritchie and
Tuokko, 2010).
Non-neuropsychological measures that may predict a
high rate of progression of MCI to dementia include the
subjects’ age (older subjects are more likely to progress),
the presence of medial temporal lobe atrophy and white
matter hyperintensities on neuroimaging, low beta-amy-
loid, and high tau levels in the CSF. Abnormal neuropsy-
chiatric features including extrapyramidal signs, gait dis-
orders, and the presence of psychopathology also predict
the rate of progression of MCI to dementia (Kantarci et al.,
2008; Jack, 2010). A recent meta-analysis of approximately
50 different studies suggested that depression is a risk
factor for AD. However, while the presence of co-morbid
anxiety predicts progression to dementia (Edwards et al.,
2009), neither depression nor anxiety has been found to
predict the likelihood of reversion to a normal cognitive
state (Beekly et al., 2004; Budson and Price, 2005).
Visser et al. (2002) created the Predementia Alzheimer’s
Disease Scale (PAS) by combining demographic, cogni-
tive, and biomarker profiles and performing a multi-
variate analysis of various predictors of AD among clinic
patients diagnosed with MCI who were participants in a
large-scale European study. Variables shown to be asso-
ciated with an increased risk of progression from nor-
mal cognition to MCI in the PAS included age, memory
scores, hypertension, APOE e4 genotype, and presence
of hippocampal atrophy. The PAS was found to correlate
with beta amyloid levels in CSF (Schoonenboom et al.,
2005). In a retrospective validation study, the optimal cut
score of the PAS had a sensitivity of 82%, specificity of
85%, and positive predictive accuracy of 75% (Visser et al.,
2002) for predicting progression from MCI to AD over a
2–5-year follow-up period. The order in which the items
were included in the analysis of the PAS data (demo-
graphic, medical, cognitive, biomarker) reflected the
order used commonly in clinical practice.
Based on much of the afore-mentioned information,
guidelines for a diagnosis of AD in a predementia stage
have been proposed based on the PAS score (Dubois et al.,
2007, 2010). The “Dubois criteria” for “prodromal AD”
are based on criteria similar to those used for aMCI, with
the additional requirement that a positive biomarker be
present (medial temporal atrophy on MRI, parietotempo-
ral deficits of PET or SPECT scanning, or abnormal CSF
analysis of amyloid β or tau proteins. A more elaborate
classification of preclinical AD and MCI due to AD has
been proposed by workgroups convened by the National
Institute on Aging and the Alzheimer’s Association
(www.alz.org/research/diagnostic_criteria). They issued
their recommendations for new diagnostic criteria for AD
based on the following proposed clinicopathologic stages
of preclinical AD:
• Stage 1: asymptomatic cerebral amyloidosis. Evidence
of cerebral amyloid-β accumulation, by either low CSF
Aβ42 measures or elevated PET amyloid tracer retention,
with normal performance on all measures of cognitive
function.
• Stage 2: cerebral amyloidosis with evidence of early
neurodegeneration. Stage 1 plus evidence of an AD-like
pattern of abnormality on downstream markers of neu-
rodegeneration and synaptic dysfunction (increased CSF
tau or phospho tau, cortical volume loss, gray matter loss,
or thinning or hippocampal atrophy), with or without
normal cognition.
• Stage 3: cerebral amyloidosis with evidence of neuro-
degeneration plus subtle cognitive change. Stage 2 plus
definite evidence of subtle decline over time on standard
cognitive tests but not meeting criteria for MCI.
• Stage 4: cerebral amyloidosis with evidence of neuro-
degeneration plus evidence of MCI.
The workgroup developed the following criteria for a
diagnosis of MCI due to AD. These are similar but slightly
different from the original criteria for MCI because they
include intra-individual changes in cognition and function:
• Concern regarding a change in cognition. The patient,
an informant, or a skilled clinician can identify concern
about a change in cognition.
• Impairment in one or more cognitive domains. Per-
formance is lower than would be expected, considering
the patient’s age and education (impairment is typically
1–1.5 standard deviations below the mean of the individ-
ual, adjusted for age and education). Impairments may
present in more than one domain and may be amnestic or
nonamnestic.

• Preservation of independence in functional abilities.
The criterion allows mild problems with complex tasks
to be present, as long as independence of functions, such
as paying bills, preparing meals, and shopping, is main-
tained, albeit with minimal aids and assistance.
• Not demented. The cognitive changes should be suf-
ficiently mild that there is no evidence of impairment in
social or occupational function.
Using these criteria for MCI, the workgroup developed
the following criteria for a diagnosis of MCI due to AD.
Biomarkers classify MCI patients into three groups, with
increasing levels of certainty of underlying AD pathology:
• MCI of a neurodegenerative etiology. The patient
fulfills MCI criteria, but no biomarker evidence is pres-
ent (biomarkers may not have been tested—or, if tested,
results are ambiguous or negative).
• MCI of the Alzheimer type. The patient fulfills MCI
criteria and has positive findings from at least one “down-
stream” biomarker, such as MRI evidence of hippocampal
atrophy or FDG PET alterations.
• Prodromal Alzheimer’s dementia. The patient fulfills
MCI criteria and has positive biomarker evidence of amy-
loid accumulation in the brain, such as low CSF Aβ42, or
amyloid accumulation on PET imaging.
Treatment of MCI
Medications currently available for the cognitive treat-
ment of AD and other dementias, such as donepezil,
rivastigmine, and galantamine, have evidenced limited
or no effectiveness in their ability to improve cognitive
status in MCI or to decrease the rate of progression from
MCI to dementia (Farlow, 2009). The most rigorous of
these studies compared the use of donepezil, vitamin E
(2000 IU daily), and a placebo among more than 750 older
adults with aMCI over a 3-year period. Vitamin E showed
no benefit at all, but the subjects receiving donepezil had
a reduced risk of progressing to AD during the first year
of the trial. However, by the end of the 3-year study,
their risk was not statistically different from the risk of
those taking vitamin E or the placebo, although among
APOE e4 carriers, a statistically significant benefit was
found. However, these results were not considered strong
enough to support a clear recommendation to treat MCI
with donepezil (Petersen et al., 2005). It is unclear whether
the use of biomarkers such as apolipoprotein E (APOE4),
CSF Aβ1-42 and tau levels, and PIB positivity on brain
PET scans will identify subgroups of MCI subjects who
may respond more favorably to these medications. Nev-
ertheless, most physicians are likely to use cholinesterase
inhibitors for the treatment of patients with aMCI.
Nonpharmacologic approaches to MCI and early
dementia may have a useful and perhaps more effective
role in preventing progression of aMCI to dementia.
Mild Cognitive Impairment 195
For example, it is well known that epidemiologic stud-
ies have suggested that individuals who are engaged in
regular cognitive activity and physical exercise have a
lesser risk for MCI and dementia than their peers who are
not so engaged (Yaffe et al., 2001; Wilson et al., 2002). A
well-controlled clinical trial of physical exercise and cog-
nitive function among elderly normal subjects and those
with MCI suggests that exercise may enhance cognition
among these subjects (Lautenschlager et al., 2008). With
regard to cognitive rehabilitation, procedures such as
face–name association enhanced by spaced retrieval and
fading cues techniques can improve cognitive function.
Moreover, functional skills, such as making change for
a purchase, can be facilitated by using motor and proce-
dural learning techniques and paradigms that enhance
the speed of cognitive processing. All these techniques
make use of the family member as a therapy extender and
also employ memory notebooks as compensatory strate-
gies (Loewenstein et al., 2004). Reviews of nonpharma-
cologic interventions in MCI and early AD by Acevedo
and Loewenstein (2007) and Middleton and Yaffe (2009)
suggest that further studies of cognitive and physical
interventions are necessary because of their potential to
improve cognition or decrease cognitive decline through
either mechanisms of neuroplasticity, increased oxygen-
ation, or their effect on inflammatory markers.
Impact on society/ethical issues
An earlier diagnosis of AD allows the patient and family
members to address important medical, social, and finan-
cial management decisions sooner. However, although
there are obvious advantages to obtaining a diagnosis of
MCI, the potential negative consequences deserve seri-
ous consideration. Earlier diagnosis could be associated
with a higher error rate and mislabeling of individuals
who are disease free, especially because milder cases are
more likely to be misclassified as cognitively normal or
to have other potentially reversible or self-limiting dis-
orders. Among those who are correctly classified, a cer-
tain proportion of patients and their families may regard
the diagnosis as threatening, intrusive, and unwelcome,
regardless of any potential benefits of early intervention.
Cultural and individual attitudes toward conveying the
diagnosis of an incurable condition that afflicts the elderly
need to be assessed and balanced with the possible advan-
tages to be obtained by imparting a diagnosis of MCI to
a patient. A diagnosis of very early AD may result in
substantial and unnecessary curtailment of the patient’s
activities, freedom to make choices, social interactions;
loss of employment; inappropriate denial of health care,
long-term care, and life insurance; and social isolation.
The relatively modest attendant benefits of currently
available treatments may not be considered worth the
196 Neurologic Conditions in the Elderly
cost of the evaluations and treatments. When these
potential negative consequences are balanced against the
anticipated individual and societal benefits of making an
earlier diagnosis, the ultimate decision to proceed with an
earlier diagnosis of AD will most likely be influenced by
the patient, the physician, societal priorities, the setting
and culture in which care is delivered, and governmen-
tal healthcare policies. Acceptance of MCI as a diagnostic
entity requiring intervention will likely have an economic
impact on the healthcare systems of different countries.
The negative economic, ethical, social, and other effects
of revising AD criteria deserve serious consideration and
study.
Future directions
The progress being made in diagnosing AD and other
forms of dementing diseases in the earliest possible stages
will likely continue because it is generally agreed that ear-
lier identification and intervention in any of these diseases
will improve outcomes. The criteria for an earlier form of
MCI (early MCI or eMCI) have been outlined for ADNI-2,
and definitions for a pre-MCI entity have also been pro-
posed (Duara et al., 2011). Studies are currently underway
to define the rates of progression and reversal, as well
as the biomarker status for these diagnostic entities. The
two independent groups (Dubois et al., and the NIA/
Alzheimer’s Association Workgroups) that have proposed
new criteria for diagnosing prodromal (e.g., MCI) and pre-
clinical forms of AD in 2010 will likely be continuing stud-
ies to support or validate their proposed criteria.
Further optimization of information obtained from a
variety of biomarkers, such as amyloid load in the brain,
CSF proteins and specific patterns of brain atrophy in
medial temporal and other brain regions, glucose metabo-
lism, and blood flow, combined with neuropsychological
measures will allow these criteria to be refined. A grow-
ing database of studies on the natural history of aMCI
and the predictive accuracy of individual biomarkers and
combinations of biomarker tests for identifying individu-
als with aMCI who will progress to AD is now becom-
ing available. The ADNI-1 has already provided a host of
evidence in this regard (Jack et al., 2010). It is likely that
ADNI-2 as well as similar studies in Europe, Japan, and
Australia, which are currently in the planning or early
execution stages, will provide a wealth of data supporting
the use of particular combinations of tests or procedures.
This will be a valuable resource for developing practice
guidelines for the diagnosis of early AD in different set-
tings. The progression to dementia from preclinical and
prodromal stages of AD is a continuous process that may
be best predicted by multivariate algorithms, includ-
ing both neuropsychological variables and biomarkers.
However, factors that are predictive of the earliest mani-
festations of disease are not necessarily the same variables
that are sensitive to more rapid progression. In devising
treatments to be introduced in the earlier stages of AD,
these considerations are important. The welfare of the
patient is best served by focusing on how to prevent pro-
gression toward dementia from an early preclinical or
prodromal phase of AD.
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 Chapter 9.2
Alzheimer’s Disease
Martin R. Farlow
Introduction
Alzheimer’s disease (AD) is by far the most common
form of dementia in the United States. It currently affects
5.4 million people, the vast majority of whom are over the
age of 65 (Alzheimer Association, 2011). The prevalence of
this disease is 1–2% at age 65, doubling every 5 years and
reaching as high as 50% by age 85 (Alzheimer Association,
2011). It is estimated that the number of patients affected
will more than triple, from 16 to 80 million patients
worldwide, by 2050 (Alzheimer Association, 2011). The
incidence rate for AD in the United States was 454,000 in
2010. The cost of care in 2009 in the United States was esti-
mated to be $150 billion (Alzheimer Association, 2011).
Although 90% or more of clinically diagnosed patients
with dementia have AD, 50% or more of cases have mixed
etiologies for their dementia. The most frequent contrib-
uting causes are cerebrovascular disease and, almost as
common, diffuse Lewy body disease. This chapter briefly
reviews clinical features, evaluation, diagnostic criteria,
risk factors, and genetics for AD.
Clinical features and diagnostic
evaluation of AD
A detailed medical history and mental status examina-
tion in a patient with suspected AD is necessary to docu-
ment symptoms and their progression, including changes
in functioning in ADLs and behavior. New criteria allow
biomarkers to aid the diagnosis and separate AD from
reversible causes. Environmental risk factors can also be
assessed, including those for vascular disease, as well as
history for head trauma and family history of dementia.
Symptoms of AD
History taken from the patient with AD may be helpful
or misleading. Subjects often minimize or deny symptoms
either, from anosognosia (lack of cognitive awareness of
symptoms) or related to fear of the diagnosis, social stigma,
or loss of independence. It is almost always necessary to
obtain history from a spouse or other family member, a
knowledgeable friend, or a caregiver to confirm details of
this history, particularly regarding nature and history
of onset of cognitive symptoms, functioning in ADLs, or
other illness potentially affecting cognitive functioning.
200
Certainly, reliable history obtained confirming the
decline in episodic memory over time is essential to
evaluating and diagnosing AD in a cognitively impaired
patient. Also important is documenting deficits in some
other aspects of cognitive functioning such as language,
visuospatial functions, or executive function. Individuals
with the illness in early stages typically repeat themselves
in conversation with family and become less reliable in
scheduling activities such as appointments and/or daily
medication.
Patients may have poor recall of the day’s events as
seen on television or read in the newspaper. Typical clini-
cal features beyond memory impairment in an early stage
of the illness might include language difficulties, starting
with trouble remembering first names of acquaintances
and then names of family and close friends. They may
have difficulty coming up with the right word in con-
versation and might use more general phrasing or sub-
stitute similar but incorrect words. Fluency continuously
decreases as the illness progresses to simple phrases in the
severe stage; most individuals eventually become mute.
Visuospatial difficulties are common in AD, and many
patients get lost while driving or misplace personal
objects around the house. Difficulties with mathematical
calculations are such that an AD patient seen in the mild
stages of the illness no longer can balance a checkbook or
figure tips.
Executive functioning deficits also occur early in the ill-
ness, typically contributed to by short-term memory and
attention deficits. Patients may no longer keep track of
finances, be able to cook a meal from a recipe, or work
easily with a personal computer. As the AD dementing
process progresses, patients may also exhibit dyspraxia;
they may exhibit clumsiness in dressing and using uten-
sils, operate home appliances inappropriately, and even
have difficulty opening and closing doors.
Behavioral symptoms are common in AD and are part
of the core clinical criteria for dementia. In early stages of
dementia, patients exhibit apathy, with loss of drive
or interest in pursuing activities that previously were
important to them. This may be as disabling as short-term
memory problems. Significant depressive symptoms are
found in as many as 30% of mild-stage patients; typical
symptoms include loss of energy, appetite, and insomnia.
The differential for causes of insomnia in patients
with AD is much broader than depression. Apnea, sleep

myoclonus, and adverse effects of drugs (often cholines-
terase inhibitors) are frequent instigators. Anxiety also
often occurs in mild to moderate stages of the illness and
is a particular problem when patients leave the home
environment, travel outside the home, and/or are in large
groups of people. Disinhibition also may be present in
AD. Dementia patients may be inappropriately familiar
with strangers or, more disturbingly, may make inappro-
priate advances toward family members, strangers, or
even children.
As AD progresses to moderate to severe stages of the
illness, most instrumental ADLs are lost and patients
begin having difficulties with more basic activity, such
as dressing, hygiene, eating, and toileting. They may
fail to recognize family members and, for example,
may think a daughter is a wife. Patients may be irri-
table and resist participating in activities, particularly
bathing and, in the late stages, taking pills. Visual hal-
lucinations and paranoia also may occur. AD subjects
commonly believe strangers are in their house or room,
when none are present. Verbal or physical aggression
occurs commonly, with agitation eventually arising at
some point in as many as 75% of AD patients (Farlow,
2007).
Regarding medical history, the patient and/or infor-
mant should be questioned about risk factors for AD,
such as family history of the illness, head trauma, hyper-
tension, hyperlipidemia, diabetes, or insulin resistance.
Other causes of dementia, such as vascular dementia,
should be excluded by asking questions regarding a
previous stroke or TIAs and any associated cogni-
tive deterioration. Fluctuations in alertness and cogni-
tive functions, early onset visual hallucinations, and
Parkinson’s disease symptoms all suggest Lewy body
dementia. Personality change, executive dysfunction,
and language abnormalities suggest possible frontotem-
poral dementia (FTD). History of hypothyroidemia, B12
or folate deficiency, and especially past medications that
might alter cognitive functioning—such as anticholiner-
gics (typically used for bladder incontinence), pain med-
ications (narcotics such as oxycontin or fentanyl patch),
anticonvulsants, sedatives, and psychotropics—suggest
potential reversible etiologies. Certainly, the patient’s
history should rule out depression or a pseudodemen-
tia. Typically patients with pseudodementia complain of
memory loss and various other cognitive symptoms but
do not exhibit them, whereas dementia patients show
signs of dementia on examination but are less likely to
complain.
In summary, the history in a patient with suspected
AD should document symptoms and their progression,
including changes in functioning in ADLs and behavior.
Environmental risk factors should be assessed, includ-
ing those for vascular disease, as well as history for head
trauma and family history of dementia.
Alzheimer’s Disease 201
Neurologic examination
In evaluating the dementia patient with possible AD, the
physical and neurologic examinations assist diagnosis by
first looking for signs that suggest or support other types
of dementia. The examinations then document cogni-
tive and behavioral abnormalities that directly support
the clinical criteria for the illness. The examinations also
determine whether more extensive neuropsychologi-
cal testing is needed to clarify ambiguous results upon
clinical evaluation regarding mild cognitive impairment
(MCI) or AD. If dementia is clearly present, evaluation
results can begin staging the illness to guide recommen-
dations regarding prognosis, drug therapy, and support-
ive care.
The physical examination provides a brief screen for
organ system failure contributing to or causing cognitive
impairment (such as hepatic or renal encephalopathy).
The neurologic examination (aside from cognitive impair-
ment) in the early or middle stage of AD is often normal.
The presence of focal findings such as visual field defects,
spasticity, and weakness in an arm or leg suggests a poten-
tial vascular etiology for the cause of cognitive impair-
ment. Signs of Parkinson’s disease (bradykinesia, rigidity,
tremor, stooped and shuffling gait) suggest dementia
with Lewy bodies or dementia with Parkinson’s disease
in the cognitively impaired patient. Gait imbalance or fall-
ing might be seen in early stages of dementia with either
Parkinson’s dementia or subcortical vascular dementia.
If there is limited vertical eye movement or dysphasia,
the diagnosis of progressive supranuclear palsy should
be considered. If the gait instability is accompanied by a
history of urinary incontinence, normal pressure hydro-
cephalus needs to be excluded as a cause. However, in the
latter stages of AD, gait difficulties become quite common
and are less helpful in differential diagnosis: Myoclonic
jerks in early stages of dementia are uncommon in AD,
and their presence instead suggests an underlying met-
abolic abnormality or, more rarely, a prion disease such
as Creutzfeldt-Jakob disease. However, in the later, more
severe stages of AD, myoclonus may be seen in 5–10% of
patients, so this symptom again is less helpful in diagno-
sis. In general, specific neurologic signs, taken in the con-
text of dementia disease stage, may help guide additional
laboratory or imaging evaluations directed toward other
causes of cognitive impairment that may be acting in a
mixed fashion in a patient also afflicted with AD.
Mental status and brief clinical cognitive examinations
are valuable in both supporting the diagnosis of MCI or
AD and defining the disease stage with individual testing
assessments and tests. Chapter 4.1 describes commonly
used mental status tests and their role in aiding diagno-
sis. Typical tests used to evaluate the dementia patient
include Clock Drawing, Mini-Mental State Examination
(MMSE), Montreal Cognitive Assessment (MoCA), and
St. Louis University Mental Status (SLUMS) test.
202 Neurologic Conditions in the Elderly
In general, ethnicity, education, and familiarity with
the English language must be taken into consideration
when judging performance on the tests. Finally, questions
should be asked of accompanying family members or
caregivers regarding function in activities of daily living.
This can assist in documenting impairments that are sec-
ondary to the cognitive impairment, to support the diag-
nosis, stage the disease, and guide both supportive care
and therapeutic recommendation.
Laboratory studies
Laboratory studies in general clinical practice over the
last three decades have generally excluded other poten-
tially reversible and nonreversible causes of dementia.
Refer to Chapter 8 for more details.
A basic evaluation includes these components:
• Complete blood count (CBC)
• Metabolic panel, including electrolytes, creatinine, glu-
cose, and SGOT
• Thyroid function studies (TSH)
• B12 and folate levels
• Urinalysis
• Computerized tomography (CT) or magnetic reso-
nance imaging (MRI), to exclude structural concerns for
dementia, particularly normal pressure hydrocephalus
and vascular dementia
With the recent revision of AD criteria detailed in the
next section, structural MRI, positron emission tomogra-
phy (PET) amyloid imaging, and lumbar puncture with
analysis for amyloid β1–42, tau and/or pTau may be
more widely used in the future to increase specificity or
certainty of diagnosis.
Diagnostic criteria for AD
Historically, two sets of clinical criteria have been
widely used in both general practice and the research
communities to define AD over the last three decades.
The Diagnostic and Statistical Manual of Mental Disor-
ders, Fourth Edition (DSM-IV) (American Psychiatric
Association, 1994) is the broader of the two sets of cri-
teria. The DSM-IV criteria for AD require gradual and
continuing decline in memory, and another aspect of
cognitive functioning, that impair function in daily
activities, and that other potential causes have been
excluded. The consensus criteria developed by the
National Institute of Neurological and Communica-
tive Disorders and Stroke and Alzheimer’s Disease
and Related Disorders Association (NINCDS-ADRDA)
(McKhann et al., 1984) were originally developed in
1984 and have defined diagnosis of this illness (par-
ticularly for research purposes) without revision until
2011. The original NINCDS-ADRDA criteria for prob-
able AD required deficits in two or more areas of cogni-
tive functioning, with one of them being memory; pro-
gressive deterioration was confirmed by clinical and
neuropsychological evaluations, and no other central
nervous system or systemic illnesses could be identi-
fied as potential causes for the dementia.
The diagnosis is supported by impaired functioning in
activities of daily living and behavioral symptoms.
Both the original DSM-IV and NINCDS-ADRDA sets
of criteria relied heavily on clinical history and neurologic
evaluations, limiting their diagnostic specificity, and both
excluded broad populations of patients in earlier stages
of the illness, where disease mechanisms arguably may
be less well established and the potential to respond to
disease-modifying therapies may be greater.
These limitations were initially addressed by the pro-
posed Dubois Consensus Criteria (Dubois et al., 2007),
which modified the original NINCDS-ADRDA criteria and
effectively introduced an earlier predementia stage for AD.
This stage was defined by the following core features:
1 Gradual and progressive decline in memory function re-
ported by patients or informants for more than six months
2 Objective evidence of significantly impaired episodic
memory on testing, generally consisting of a recall deficit
that does not improve significantly or does not recover
with cues
3 Episodic memory problems that may be isolated or as-
sociated with other cognitive changes at onset or as the
disease process advances
These clinical criteria are supported by one or more of
the following objective assessments: medial temporal lobe
atrophy with volume loss of hippocampus, entorhinal cor-
tex, or amygdala on MRI; decreased amyloid β1–42 levels
in cerebrospinal fluid; tau or phosphotau levels in CSF; a
specific pattern of altered glucose metabolism on FDG-
PET known to be associated with AD; and the presence of
increased levels of cortical amyloid demonstrated by PIB
and or other amyloid binding ligands on Amyloid-PET.
The Dubois criteria define a more homogenous prodromal
stage for AD out of the broader previously defined MCI
population and have been employed in a limited num-
ber of recent drug trials. They have not been otherwise
broadly adopted in general clinical practice.
By 2009, it was recognized that the original NINCDS-
ADRDA criteria of 1984 often were not holding true. These
criteria assumed clinical–pathologic association between
amnesia progressing to dementia associated with corti-
cal amyloid plaques and neurofibrillary tangles. Amyloid
plaques and neurofibrillary tangles were acknowledged
to be present in cognitively normal individuals in 20–40%
of the elderly population. Furthermore, neuropathologic
studies demonstrated that many dementia patients who
had language or visual spatial deficits as predominant
clinical features at onset rather than episodic memory
loss displayed typical plaque and tangle AD pathology
at autopsy. Considerable advancement also was made in
general knowledge about the biologic processes under-
lying and associated with AD since the original clinical

criteria were previously established 25 years ago. For
these reasons, a broad consensus developed that the AD
diagnostic construct needed to be updated. The National
Institute of Aging and the Alzheimer’s Association
assembled three working groups to revise and extend the
original diagnostic criteria (Jack et al., 2011).
In 2011, new diagnostic criteria agreed to by these three
working groups greatly revised and broadened the origi-
nal NINCDS-ADRDA 1984 criteria (Albert et al., 2011;
McKhann et al., 2011; Sperling et al., 2011).
New consensus criteria were with the following changes:
1 New specific research criteria
2 A new prodromal stage, encompassing patients who
are biomarker positive and clinically asymptomatic, but
at risk for AD
3 Revised MCI criteria that employ biomarker changes
4 Better-defined Alzheimer’s dementia stage that recog-
nizes the spectrum of clinical symptom variation and em-
ploys biomarker criteria
Preclinical stage of AD criteria
The operational research criteria for the preclinical stage
of AD were proposed to better support longitudinal natu-
ral history studies to better determine the roles of various
biomarkers in developing various preclinical aspects of the
ongoing pathophysiologic disease process and to support
potential future disease-modifying therapeutics at a time
when such agents may be more effective. It has been recog-
nized that an underlying pathophysiologic cascade of pro-
cesses may begin decades before the onset of clinical symp-
toms and the later onset of dementia in the spectrum of
AD. Risk for the disease appears likely to be determined by
biomarkers that are still being validated regarding specific-
ity and sensitivity and eventual clinical utility. In various
populations of cognitively normal elderly patients studied,
β-amyloid deposits were detected in 20–40% of patients by
determining low levels of amyloid β1–42 protein in CSF or
by PET amyloid imaging. This amyloid appears to be a risk
factor for future deterioration in cognitive functioning and
MCI or eventual dementia. Nonetheless, many individuals
with decreased CSF amyloid β1–42 levels or positive amy-
loid imaging may never develop cognitive symptoms. The
biologic correlations and clinical meaningfulness for these
biomarkers are still being determined.
Figure 9.1 lists the proposed criteria for preclinical AD.
Three stages for preclinical AD are proposed. In Stage 1,
biomarker abnormalities are present related to amyloid
deposition and likely factor directly into an underlying risk
for the illness or disease process itself (Sperling et al., 2011).
In Stage 2, in addition to biomarker indications of amyloid
deposition, there is evidence of neuronal dysfunction or
neurodegeneration. Finally, in Stage 3, amyloid plus neuro-
nal loss progresses to subtle cognitive decline, insufficient
to meet the criteria for MCI or dementia. Clearly, these are
research criteria meant to facilitate further investigation and
Alzheimer’s Disease 203
STAGE 1
Asymptomatic amyloidosis
High PET amyloid tracer retention
Low CSF Aβ1–42
STAGE 2
Amyloidosis–neurodegeneration
Neuronal dysfunction on FDG-PET/fMRI
High CSF tau/p-tau
Cortical thinning/hippocampal atrophy on sMRI
STAGE 3
Amyloidosis–neurodegeneration and subtle cognitive decline
Evidence of subtle change from baseline level of cognition
Poor performance on more challenging cognitive tests
Does not yet meet criteria for MCI
MCI AD dementia
Figure 9.1 The 2011 criteria for preclinical AD.
are likely to be modified in the future to reflect future gains
in knowledge regarding biomarkers, pathophysiology, and
relevant associations and relationships between these fac-
tors and the development of future clinical symptoms.
Dementia due to AD diagnostic criteria
The revised guidelines retained the general framework of
the original NINCDS-ADRDA criteria for AD (1984). How-
ever, the working group for AD recognized that much has
been learned about the pathophysiologic processes under-
lying AD, the breadth of potential clinical symptoms at
onset, and the place of AD in the spectrum of other neuro-
degenerative illnesses that also cause dementia in adults.
Knowledge gained over the last 27 years includes:
1 Recognition that AD pathophysiologic process may be
found in MCI and even cognitively normal individuals
2 Broader characterization of the other dementias, such as
dementia with Lewy bodies and the various subtypes of FTD
3 Recognition that the primary cognitive deficits for AD
at onset may be visuospatial or aphasic rather than defi-
cits in episodic memory
4 Recognition of autosomal-dominant causative genes,
including primarily mutations in the genes for the amy-
loid precursor protein, presenilin 1 and 2 protein
5 Recognition of associated biomarkers (MRI, PET, CSF
analyses) that may aid diagnosis
6 Recognition that AD pathology and clinical symptoms
may occur in patients younger than 40 and older than 90
(McKhann et al., 2011)
204 Neurologic Conditions in the Elderly
Table 9.1 Core clinical criteria for dementia
Criteria for dementia
Interferes with function at work or daily activities
Decline in functional ability
Not delirium or major psychiatric disease
Cognitive impairment documented by informant and objective
clinical bedside assessment or neuropsychological testing
Cognitive and or behavioral impairments must include
two or more of the following
Impaired learning and short term memory deficits
Impaired reasoning, judgment, and handling of complex tasks
Impaired visual spatial abilities
Impaired language which may include speaking, reading, or writing
Change in personality, behavior—typical symptoms would
include apathy, obsessive compulsive behavior, agitation, socially
inappropriate behavior
With these facts in mind, the working group pro-
posed new core clinical criteria for all causes of dementia
(Table 9.1). These are similar to those previously described
in the original 1984 criteria.
The revised criteria for AD include core clinical crite-
ria for probable AD and for possible AD, and new cat-
egories for probable and possible AD (Table 9.2). New to
the core clinical criteria are explicit recognition of onset
with symptoms other than amnesia, including language
dysfunction, visual spatial dysfunction, and executive
functioning deficits. Also explicitly recognized under the
probable AD category are core clinical dementia criteria
associated with autosomal dominant causative mutations
(Table 9.3).
Criteria for probable AD dementia with evidence of AD
pathophysiologic process incorporate in a manner similar
to MCI criteria two classes of biomarkers: (1) indicators of
amyloid-β protein deposition in the brain (PET amyloid
imaging and low CSF amyloid β1–42 levels) and (2) indi-
cators of neuronal dysfunction or degeneration with
Table 9.3 AD dementia criteria incorporating biomarkers
Diagnostic category Aβ (PET or CSF)
Probable AD dementia
Based on clinical criteria Unavailable, conflicting,
or indeterminate
With three levels of evidence Unavailable or indeterminate
of AD pathophysiologic process
Positive
Positive
Possible AD dementia
Atypical clinical presentation
Based on clinical criteria Unavailable, conflicting,
or indeterminate
With evidence of AD Positive
pathophysiologic
Dementia unlikely due to AD Negative
Table 9.2 Clinical criteria for probable AD
Clinical criteria for probable AD
Meets criteria for dementia
Insidious onset with worsening cognition by report or observation
Most prominent clinical symptoms at onset include either:
Amnestic presentation, impaired learning, particularly of recently
learned information
Nonamnestic presentation with language dysfunction often word
finding or visuospatial deficits in spatial cognition such as object
agnosia, impaired face recognition, simultanagnosia and alexia or
executive function deficits such as impaired learning judgment,
problem solving
For both amnestic and nonamnestic presenters, other cognitive
deficits should be present
AD should not be diagnosed when there is evidence of stroke
temporally related to the cognitive deficit, multiple infarcts,
dementia with Lewy bodies or FTD or other neurologic or non-
neurologic illnesses that could impact cognitive function
Probable AD with increased certainty of diagnosis
Meets core clinical criteria for probable AD
Evidence of increasing progression in cognitive decline from informant
or by formal neuropsychological testing
Carries dementia-associated genetic mutations in APP, PSEN1, or PSEN2
decreased FDG uptake in temporal lobes on PET; atrophy
in medial, basal, and lateral temporal lobes and medial
parietal cortex on structural MRI sequences; and high
total tau and phosphorylated-Tau (pTau) levels in CSF
(Table 9.2) (McKhann et al., 2011). The major advantage
of incorporating these biomarkers is that they increase
the certainty of diagnosis, which may aid research stud-
ies, particularly clinical trials. Major limitations for these
biomarkers are that the methods of imaging, collecting,
and analyzing cerebrospinal fluid and interpretation of
the data are not fully standardized, and access of these
services may be limited at many healthcare sites. In
addition, cut points and practical clinical utility in real-
world settings remain to be demonstrated.
Neuronal injury (CSF tau, Biomarker probability
FDG-Pet, sMRI) of AD etiology
Unavailable, conflicting, Uninformative
or indeterminate
Positive Intermediate
Unavailable or indeterminate Intermediate
Positive High
Unavailable, conflicting, Uninformative
or indeterminate
Positive High but does not rule out
second etiology
Negative Lowest

Probable and possible AD dementia;
core clinical criteria
In the possible AD core clinical criteria, patients with
dementia who are atypical for meeting criteria for demen-
tia with Lewy bodies or FTD but who are positive for both
a biomarker associated with the amyloid B pathophysi-
ologic process and a biomarker associated with neuronal
degeneration would need criteria for possible AD.
Again, as more data and experience with these bio-
markers in association with clinical diagnoses become
available, there will likely be further modification in the
use of these criteria in aiding the diagnostic process, fur-
ther improving their validity and future diagnostic utility.
Table 9.3 lists levels of certainty in the research diagnosis
of AD incorporating various biomarkers (McKhann et al.,
2011).
Epidemiology
The major risk factors for AD are increased age and the
apolipoprotein E ε4 genotype (Farlow, 2007). Other poten-
tial clinical and demographic risk factors for developing
AD at an earlier age of onset identified over the last three
decades include depression, female gender, low levels of
education, smaller head circumference, and family history
of Down’s syndrome. History of head trauma, previous
exposure to anesthesia, and low levels of physical activity
have also been associated with increased risk for devel-
oping AD (Geldmacher, 2011). Over the last two decades,
increasing evidence suggests that vascular disease, such
as myocardial or cerebrovascular infarction, also is associ-
ated with increased risk for developing AD at an earlier
age (Dodge et al., 2011).
Vascular risk factors in general that are associated
with the metabolic syndrome, including increased body
weight (particularly abdominal adiposity), hyperten-
sion, diabetes mellitus, insulin resistance or predia-
betes, hypercholesteremia (high LDL levels, low HDL
levels), and hypertriglyceridemia (Martins et al., 2006),
are all associated with increased risk for AD. In addi-
tion, increased plasma levels of homocysteine associ-
ated with increased risk for vascular disease have been
associated with increased risk for AD (Shumaker et al.,
2003, 2004).
Epidemiologic studies have suggested that several
types of drugs may be protective or reduce risk for AD,
including estrogens, nonsteroidal anti-inflammatories,
and statins. However, none of these drugs have proven
to reduce risk in prospective double-blind, placebo-
controlled trials (Aisen et al., 2003; Espeland et al., 2004;
Maillard and Burnier, 2006). Estrogens, in particular, have
proven to increase rather than decrease risk for AD in
women over the age of 60 years (Craig et al., 2005).
Alzheimer’s Disease 205
Genetics
Family history of dementia affecting two or more first-
degree relatives is obtained in approximately 20% of indi-
viduals with AD, with the other 80% being of sporadic
occurrence (Alzheimer Association, 2011).
In families with early-onset AD under the age of 65,
mutations in a handful of genes have been identified
that are associated with autosomal-dominant inheri-
tance with high prevalence for dementia typically in the
fourth to seventh decades. The first causative mutation
described was in the amyloid precursor protein gene on
chromosome 21 in the region of the gene that codes for the
β-amyloid proteins that are deposited forming the cores
of amyloid plaques. More than a dozen mutations in this
region have now been associated with either dementia
or cerebral amyloid vasculopathy in two dozen families.
These mutations are thought to alter β-amyloid metabo-
lism and have been associated with chronically higher
levels of β-amyloid, potentially a key factor leading to
AD in these families. Duplication of the APP gene and
missense mutations (black box) in the APP gene cause
inherited forms of AD and cerebral amyloid angiopathy
(Goedert and Spillantini, 2006).
Other families with early-onset forms of the disease
have been found to have different mutations in the prese-
nilin 1 gene on chromosome 1 (a handful of mutations in a
few dozen families) and presenilin 2 gene on chromosome
14 (several hundred different mutations) (Goedert and
Spillantini, 2006; www.molgen.ua.ac.be/ADMutations/).
Presenilin 2 mutations are by far the most commonly
identified cause of presenile familial AD, but they still are
the cause for dementia in less than 10% of these families
and less than 0.5% of AD patients overall.
The presenilin proteins coded for by these genes oper-
ate in a complex with other proteins functionally acting
as gamma secretase, a key enzyme in one of the major
degradative pathways for the amyloid precursor pro-
tein that potentially is involved in the disease process
(De Strooper, 2003). Increased β-amyloid1–42 levels have
been found in association with almost all of the reported
presenilin 1 and 2 mutations (Citron et al., 1997). Clini-
cally, in addition to causing early onset of dementia, these
mutations have been associated with a variety of other
neurologic signs and pathologies, including spasticity,
seizures, extrapyramidal signs, and cortical hemorrhages
(Menendez, 2004).
Identifying mutations in at-risk members of families
with known genetically associated presenile forms of the
illness allows for potential genetic counseling by facili-
tating the identification of the at-risk gene carrier. In the
future, it may enable investigations of presymptomatic
therapeutic interventions.
However, the most significant impact of these genes
has been to speed clinical drug research by enabling the
206 Neurologic Conditions in the Elderly
development of animal models for AD. Hopefully this
will hasten preclinical testing of promising therapies.
The most significant genetic risk factor identified for AD
is inheritance of the apolipoprotein E ε4 genotype located
on chromosome 19. ApoE is one of the major lipid- and
cholesterol-carrying proteins in peripheral blood, and it
plays a similar role in the central nervous system, where
it is the major lipid transport protein and the predominant
transport protein for the soluble form of the β-amyloid
protein (Mayeux et al., 1998). Ninety-nine percent of the
general population carry three major genotypes—ε2, ε3,
and ε4—in different combinations. Approximately 1–2%
of people are homozygous for the ε4 genotype, and these
individuals have a 50% risk of developing AD by their mid-
to late 60s (Saunders et al., 1993). Approximately 15–20%
of the population carry one copy of the ε4 genotype and
have a 50% risk of developing AD by their mid- to late 70s.
Individuals with ε3 (the predominant genotype) are more
likely to develop AD later in their 80s or not at all. Inter-
estingly, evidence indicates that the ε2 genotype may be
protective, reducing overall risk for AD (Rebek et al., 2002)
while simultaneously conveying some increased risk for
cardiovascular disease. However, if an individual with one
or more copies of ε4 has remained cognitively normal into
the age range of significant dementia risk, there is evidence
that their future risk of dementia is no greater than that of a
non-ε4-carrying individual of the same age going forward.
Patients clinically diagnosed with AD in some series,
followed to autopsy, will be found in 20% of cases to have
other primary dementing illnesses and pathologies. ApoE
ε4 genotyping has been suggested to be potentially useful
as a diagnostic tool improving specificity for diagnosis of
AD in elderly patients with dementia. If ApoE ε4 geno-
typing is performed as a diagnostic adjuvant, the strong
association particularly for homozygotes to AD has in
some series strengthened post-mortem clinical pathologic
diagnostic correlations to 93% (Mayeux et al., 1998). How-
ever, given the great overlap of AD with vascular demen-
tia and the Lewy body dementias, and given the absence
of differential therapies to be more directly targeted by
more accurate diagnosis, the clinical utility of ApoE4
genotyping in the broad elderly dementia population is
questionable; however, it may be helpful in patients with
atypical clinical features such as rapid or slow course or
unusual clinical symptoms at onset.
ApoE genotyping in patients with MCI has demon-
strated that 40–50% of patients carry one or two copies
of  ε4. When followed for 3–4 years, these subjects are
much more likely to convert to AD than ε2 or ε3 geno-
types (Petersen et al., 1995). MCI subjects carrying ε4 are
also more likely to be responsive to cholinesterase inhibi-
tor therapy (Galasko et al., 2005; Feldman et al., 2007).
However, once AD is diagnosed, the ApoE genotype
through the different disease stages has not been demon-
strated to differentially affect rates of disease progression.
These data suggest that underlying disease mecha-
nisms at the MCI stage may be differentially affected
by ApoE proteins of different phenotype, but once the
various pathogenetic mechanisms underlying more full-
blown dementia become widespread, the difference in
ApoE genotype effects becomes less significant.
In the last 5 years, genome-wide association stud-
ies (GWAS) of progressively increasing size and power
have been undertaken in Europe and the United States in
elderly affected and unaffected members of families with
late-onset AD. These studies have employed gene chips
that screen for 100,000s of single nucleotide polymor-
phisms (SNPs) spanning the chromosomes. Using this
technology, new genetic polymorphisms associated with
late-onset AD have been identified and both confirmed
and reconfirmed; these include CLU, PICALM, and BIN-1
(Harold et al., 2009; Lambert et al., 2009; Seshadri et al.,
2010). Recently, a large GWA study combining multiple
large population data sets established ABCA7, MS4A/
MS4A6E, CD2UAP, CD33, and EPHA1 as additional genes
associated with AD (Schellenberg et al., 2011). It is impor-
tant to note that the magnitudes of increased risk associ-
ated with the inheritance of one or more of these polymor-
phisms are small and that the frequencies of some of these
associated polymorphisms are very low compared to the
much larger risk associated with inheritance of the ApoE
ε4 genotype. Nonetheless, they provide further valuable
clues regarding the complex disease mechanisms that
underlie AD and the factors that may influence risk for
and age of onset for dementia. Known general actions for
the proteins coded for by these genes include lipid metab-
olism, amyloid metabolism, chaperone proteins enhanc-
ing amyloid deposition, inflammation, and cellular main-
tenance mechanisms. Fuller understanding of how these
genes and their proteins interact with the environment is
the goal of ongoing active research and should aid future
diagnosis and therapy.
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 Chapter 9.3
Dementia with Lewy Bodies
Clive Ballard
Overview
Dementia with Lewy bodies (DLB) is a synucleinopathy
characterized by a progressive dementia syndrome that is
usually associated with parkinsonism and typically domi-
nated by attentional, visuospatial, and executive dysfunc-
tion and relatively preserved memory. Additional key
symptoms are visual hallucinations, cognitive fluctuations,
and sleep disturbances such as excessive daytime sleepiness
and REM-sleep behavioral disorder (McKeith et al., 2005).
Clinical profile
Similar to Alzheimer’s disease (AD), DLB results in a
dementia syndrome with progressive loss of cognition
and function. However, it is apparent that significant
components of functional disability in DLB derive from
associated motor and autonomic impairments and the
impairments of cognition. The profile of cognitive impair-
ment in DLB reflects a combination of cortical and sub-
cortical neuropsychological impairments with substantial
attentional deficits and prominent executive and visuo-
spatial dysfunction (Calderon et al., 2001; Collerton et
al., 2003). This profile may be harder to recognize later in
the disease when global cognitive difficulties obscure the
picture. It has been suggested that a “double discrimina-
tion” can help differentiate DLB from AD, with relative
preservation of short- and medium-term recall and rec-
ognition, and greater impairment on visual perception
and performance tasks (Walker et al., 1997). Compos-
ite global cognitive assessment tools, such as MMSE or
CAMCOG, do not distinguish DLB from other common
dementia syndromes. DLB patients with additional neo-
cortical tangle Alzheimer pathology often lack the typical
DLB cognitive profile (Ballard et al., 2004), showing pro-
nounced memory deficits and a clinical presentation more
characteristic of AD. Fluctuating attention, a key feature
of DLB, is not evident in patients with AD and is less pro-
nounced in DLB patients without parkinsonism (Ballard
et al., 2002). Visual hallucinations and delusions are much
more common in DLB than in AD, occurring in 60–70% of
patients with DLB (Klatka et al., 1996; Ballard et al., 1999).
REM-sleep behavior disorders are also substantially more
common in DLB than in AD and may actually precede the
dementia syndrome in many patients (Boeve et al., 2004).
Depression is common in most dementias, but it probably
208
has a higher frequency in DLB (Klatka et al., 1996; Bal-
lard et al., 1999) than in AD. From 60–80% of DLB patients
experience parkinsonian symptoms. These are generally
similar to the symptoms of Parkinson’s disease (PD), but
the tremor is often qualitatively different from that seen
in patients with PD, and the presentation is more likely
to be symmetrical. In addition, postural instability and
gait difficulties, predominantly mediated by nondopami-
nergic lesions, may be more pronounced in DLB patients
(Gnanalingham et al., 1997).
Neuropathology
Limbic and cortical Lewy bodies (LB) are the main sub-
strate of the clinical dementia syndrome in DLB (Harding
and Halliday, 2001; Aarsland et al., 2005a, 2005b; Tsuboi
and Dixon, 2005). The density of temporal lobe LB also
correlates with the early occurrence of the characteristic
well-formed visual hallucinations, and the overall sever-
ity of cortical LB pathology correlates with psychosis and
fluctuating cognition (Harding et al., 2002). In addition,
increasing LB densities in limbic and frontal cortices cor-
relates with the presence and severity of dementia in the
related condition of Parkinson’s disease dementia (PDD;
Samuel et al., 1996; Kovari et al., 2003).
The majority of DLB patients also have concur-
rent amyloid pathology, with a density of Aβ-positive
plaques in many DLB patients equivalent to that found
in AD, and 90% of DLB patients meet CERAD criteria
for probable AD (Hansen et al., 1990). The amount of
Aβ deposition also correlates with dementia severity
in DLB (Harding and Halliday, 2001). Although typi-
cally the density of neocortical plaques is similar to AD
(Hansen et al., 1990), the burden of tangles is less than in
“pure” AD (Hansen et al., 1990). For example, when LBs
occur in conjunction with Alzheimer’s pathology suf-
ficient to meet CERAD criteria for probable or definite
AD, neocortical neurofibrillary tangles are usually rare
or absent, and tangles in the entorhinal cortex and hip-
pocampus are intermediate between age-matched con-
trols and AD patients (Hansen et al., 1990). Fewer than
40% of DLB patients meet criteria for a Braak stage IV
or higher, although several recent studies indicate that
these patients are less likely to present with a “typical”
DLB profile and are less likely to meet consensus criteria
for probable DLB (Ballard et al., 2004).

α-Synuclein is the key constitutive protein of LB and
is also widely found in more diffuse cortical aggregates,
usually referred to as Lewy neurites, in DLB patients.
α-Synuclein is a cytosolic protein, enriched in presyn-
aptic terminals associated with synaptic vesicles. Three
known alternatively spliced isoforms of α-syn exist, full-
length, consisting of 140 amino acids and shorter isoforms
of 112 and 126 amino acids, respectively. In addition to
α-synuclein, β- and γ-synuclein are members of the pro-
tein family of synucleins. α- and β-synuclein proteins are
primarily found in brain tissue, and γ-synuclein predomi-
nantly is a protein of the peripheral nervous system. Recent
work has also begun to indicate that β-synuclein may play
an important pathological role as well (Fujita et al., 2009).
Findings of missense mutations in the gene encoding for
α-synuclein (Polymeropoulos, 1998) and multiplications of
the gene of α-synuclein SNCA in families with PD (Single-
ton et al., 2003) suggest that the conversion of α-synuclein
from soluble monomers to aggregated, insoluble forms
in the brain is an important event in the pathogenesis
synucleinopathies (Koprich et al., 2010). Truncated forms
of α-synuclein have been isolated from LBs, and several
studies have also shown that specific truncated forms of
α-synuclein have an increased tendency to form aggre-
gates (Murray et al., 2003). This tendency of truncated
α-synuclein species to rapidly aggregate suggests that
they may play a role in inducing LB formation.
In addition to the α-synuclein and concurrent AD
pathology, there is clear evidence of a loss of cortical
synapses, as observed by a loss of dendritic spines, dre-
brin, and synaptophysin in DLB (Kramer and Schulz-
Schaeffer, 2007).
Neurochemistry
The majority of neurochemical studies of DLB have
explored the dopamine and acetylcholine systems in neu-
ropathologic studies. One of the characteristic features
is the presence of marked cortical cholinergic deficits,
which are probably secondary to cell loss of forebrain
nuclei. These deficits are even more severe than in AD
(Bohnen et al., 2003) and are associated with decreased
performance on tests of attentional and executive func-
tioning (Bohnen et al., 2006). In DLB patients, there is also
a correlation between visual hallucinations and choliner-
gic deficits in the temporal cortex (Ballard et al., 2000).
These studies have also suggested an association between
delusions and up-regulation of muscarinic M1 receptors
in DLB patients (Ballard et al., 2000). In addition, there
is evidence linking cholinergic changes, particularly
nicotinic modulation of thalamo-cortical circuitry, with
the disturbed consciousness in patients with DLB (Pim-
lott et al., 2006). Neuroimaging studies using SPECT
ligands have also reported cholinergic receptor changes
Dementia with Lewy Bodies 209
in DLB, with increased muscarinic (Colloby et al., 2006)
and reduced nicotinergic binding in comparison to AD
(O’Brien et al., 2007).
Nigrostriatal dopamine changes are evident in DLB,
although there appears to be no associated post-synaptic
dopaminergic up-regulation in DLB patients, which may
partly explain the increased risk for neuroleptic sensitiv-
ity reactions in these individuals (Piggott et al., 1999).
Preliminary data from our group show a significant
increase in frontal 5-HT1A receptor-binding density in
DLB patients, which may be associated with mood disor-
ders (Sharp et al., 2008).
A preliminary post-mortem study has also reported
glutamatergic alterations in DLB, suggesting that group I
mGluR dysfunction may be implicated in the pathogene-
sis of cognitive impairment and dementia in the common
form of DLB (Dalfo et al., 2004).
Frequency
Dementia with Lewy bodies was first reported in the 1960s
(Woodard, 1962). Several small case series also emerged
from Japan in the 1960s, 1970s, and early 1980s (Okazaki et
al., 1962; Kosaka et al., 1984), before reports describing larger
groups of patients in the late 1980s and the early 1990s (Byrne
et al., 1989; Gibb et al., 1989; Hansen et al., 1990; Perry et al.,
1990; McKeith et al., 1992) began to highlight the frequency
of the syndrome and the characteristic clinical features.
However, not until the emergence of ubiquitin staining and
the later identification of α-synuclein as the fundamental
core pathologic hallmark, was the true extent of the pathol-
ogy and importance of the syndrome acknowledged.
A recent systematic review concluded that the proportion
of dementia patients fulfilling the clinical diagnostic criteria
for DLB in hospital-based single-center cohorts varied from
0% to 26% (Aarsland et al., 2008a, 2008b). Even among the
few community-based studies, the proportion varies mark-
edly from 0% to 30.5% (Aarsland et al., 2008a, 2008b). In two
more recent community-based studies with a specific focus
on DLB, the proportion of subjects with dementia with clini-
cal probable DLB was reported to be 10.9% in those 65 years
and older and 14.6% in those 75 years and older (Aarsland
et al., 2008a, 2008b). However, there has been some concern
that the limited sensitivity of the 1996 consensus diagnos-
tic criteria, upon which most clinical studies of prevalence
are based, may have led to an underestimation of frequency
(see the next section on diagnosis).
Diagnosis
Based initially on clinicopathologic studies, diagnostic
criteria were proposed by Byrne et al. (1991), and McKeith
et al. (1992), and were superseded by international
210 Neurologic Conditions in the Elderly

Table 9.4 Sensitivity, specificity, positive predictive value, and negative predictive value of the consensus criteria for probable DLB:
diagnostic validation studies

No. of cases Diagnosis Sensitivity Specificity PPV NPV

Retrospective
Mega et al. (1996) 24 AD, PD, PSP 0.4 1.0 1.0 0.93
Litvan et al. (1998) DLB, PS, PSP, CBD, MSA, FTD, 0.18 0.99 0.75 0.89
AD, CJD, VP
Luis et al. (1999) 56 DLB, AD, mixed DLB/AD 0.57 0.9 0.91 0.56
Lopez et al. (1999) 40 AD, PSP, FTD, DLB 0.34 0.94 – –
Verghese et al. (1999) 18 DLB 0.61 0.84 0.48 0.96

Prospective
Hohl et al. (2000) 10 AD, DLB, PSP 0.80 0.80 0.80 0.80
Holmes et al. (1999) 75 AD, VaD, DLB, mixed 0.22 1.0 1.0 0.91
McKeith et al. (2000) 50 DLB, AD, VaD 0.83 0.91 0.96 0.80
Lopez et al. (2002) 26 DLB, AD, mixed AD/VaD, PSP, 0.38 1.0 – –
CJD, FTD

AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; VaD, vascular dementia; PSP, progressive supranuclear palsy; CBD, cortico-basal
degeneration; MSA, multisystem atrophy; CJD, Creutzfeldt–Jakob disease; VP, vascular parkinsonism; PPV, positive predictive value; NPV, negative
predictive value.

consensus criteria (McKeith et al., 1996). In addition to the Fluctuating cognition

presence of a progressive dementia, the core diagnostic
criteria were described as fluctuating cognition, persis-
tent or recurrent visual hallucinations, and spontaneous
motor features of PD. Two of these three core features
were required for a diagnosis of probable DLB. A number
of validation studies of these criteria have been reported
(Table 9.4).
Although probable DLB was diagnosed with a
specificity of more than 80%, sensitivity was an issue,
and the diagnosis of DLB in patients with a concur-
rent cerebrovascular disease was problematic (McK-
eith et al., 2000). Importantly, diagnostic accuracy may
also vary with dementia severity; for example, Lopez
et al. (2002) compared 180 patients with AD alone to
60 patients with AD and concurrent DLB. In patients with
mild dementia, no specific clinical syndrome was asso-
ciated with concurrent LBs. Overall, the McKeith et al.
(1996) consensus criteria for DLB worked reasonably
well in clinical practice and in research studies, and
this was an important first step. However, refinement
of the criteria to improve sensitivity was clearly a
priority.
Approaches to improving diagnostic
accuracy
Although a great starting point, applying the consensus
criteria for DLB in clinical practice may not be sufficient.
In order to improve diagnostic accuracy, refinement of the
criteria may be needed to improve sensitivity. Additional
clinical markers and biomarkers such as dopamine trans-
porter SPECT may help make the diagnosis in selected
cases.
Fluctuating cognition was identified as one of the three
core diagnostic features of DLB, but accurately identi-
fying fluctuating cognition can be a major clinical chal-
lenge. For example, two inter-rater reliability studies
suggested poor agreement between different expert rat-
ers regarding the presence of fluctuating cognition in
individual patients (Mega et al., 1996; Litvan et al., 1998).
Subsequently, several validated clinical ratings scales
have been shown to substantially improve the recogni-
tion of fluctuating cognition. The Clinician Assessment
of Fluctuation Scale (Walker et al., 2000a, 2000b) uses two
screening questions about the presence of “fluctuating
confusion” or “impaired consciousness” and requires an
experienced clinician to judge its severity during the pre-
vious month. The semi-structured One Day Fluctuation
Assessment Scale (Walker et al., 2000a, 2000b), which can
be administered by less experienced health professionals
or research staff, generates a cut-off score that reportedly
distinguishes DLB from AD or VaD. The Mayo Fluctua-
tions Composite Scale (Ferman et al., 2004) requires three
or more “yes” responses from caregivers to structured
questions about the presence of daytime drowsiness
and lethargy, daytime sleep greater than two hours, long
periods of staring into space, or episodes of disorganized
speech, as suggestive of DLB rather than AD. Finally,
recording variation in attentional performance using
a computer-based test system offers an independent
method of measuring fluctuation that is also sensitive to
drug treatment effects (Walker et al., 2000a, 2000b).
REM sleep behavior disorder
RBD is manifested by vivid and frightening dreams dur-
ing REM sleep but without the muscle atonia that nor-
mally occurs. Patients therefore “act out their dreams,”

vocalizing and moving around the bed sometimes vio-
lently. Vivid visual images are often reported, although
the patient may have little recall of these episodes. The
history is obtained from the bed partner, who may report
many years of this sleep disorder before the onset of
dementia and parkinsonism (Boeve et al., 2004). Of par-
ticular importance, several cross-sectional studies have
identified RBD in 60% or more of people with DLB or
related synucleinopathies, and further reports indicate
that the clinical symptoms of idiopathic RBD precede the
onset of neurologic disease PD (Olson et al., 2000) and
DLB (Boeve, 1998) by 1–7 years in more than 60% of indi-
viduals (Olson et al., 2000). In a more recent prospective
study, Iranzo and coworkers (2006) assessed survivors of
44 patients with idiopathic RBD who had been diagnosed
5 years earlier. About 45% had developed a neurologic
disorder, usually of the α-synuclein type—such as PD,
DLB, or MSA—based on clinical evaluation. The find-
ings are also consistent with the current autopsy litera-
ture, which indicates that idiopathic RBD is underpinned
by α-synuclein pathology in all the cases reported (as
reviewed in Boeve et al., 2007). Screening questions about
the presence of daytime and nighttime sleep disturbance
should always be included and may be facilitated by the
use of sleep questionnaires. A history of RBD can be con-
firmed by polysomnography, when available.
Severe neuroleptic sensitivity
Approximately 25–50% of DLB patients receiving typical
or atypical antipsychotic agents experience severe neuro-
leptic sensitivity reactions (McKeith et al., 1992; Ballard
et al., 1998; Aarsland et al., 2005a, 2005b). Conversely, at
least 50% of individuals with DLB do not react adversely
to antipsychotics; therefore, a history of neuroleptic tol-
erance does not exclude a diagnosis of DLB. However,
a positive history of severe neuroleptic sensitivity is
strongly suggestive of DLB. Deliberate pharmacologic
challenge with D2 receptor-blocking agents should not be
used as a diagnostic strategy for DLB because of the high
morbidity and increased mortality associated with neu-
roleptic sensitivity reactions (McKeith et al., 1992); this is
why severe neuroleptic sensitivity reactions were omitted
from the original 1996 consensus criteria for DLB.
Dopamine transporter SPECT imaging
Imaging with specific single positron emission computer-
ized tomography ligands for DAT (FP-CIT, beta-CIT, IPT,
and TRODAT) provides a marker for presynaptic neuro-
nal degeneration. DAT imaging is abnormal in idiopathic
PD, MSA, and PSP and does not distinguish among these
disorders. Low striatal uptake has also been reported in
DLB and is normal in AD, making DAT scanning particu-
larly useful in this common clinical distinction (Walker
et al., 2002; O’Brien, 2004). Notably, a recent phase III mul-
ticenter study demonstrated a sensitivity and specificity
Dementia with Lewy Bodies 211
of abnormal DAT scans in diagnosing probable DLB from
AD of 75% and 90%, respectively (McKeith et al., 2007). A
similar degree of discrimination is evident between DLB
patients without parkinsonism and patients with AD.
The impact of concurrent vascular pathology striatal DAT
binding has not been determined (Brooks and Piccini,
2006). Despite this minor caveat and the limited diagnos-
tic potential to distinguish different synucleinopathies,
DAT scans clearly play a key role in the differential diag-
nosis of DLB and AD.
Revised consensus diagnostic criteria
To address some of the issues raised from validation stud-
ies of the McKeith et al. (1996) criteria and to enable new
developments to be incorporated, the consensus criteria
have subsequently been updated The core diagnostic cri-
teria remain the same—fluctuating cognition, recurrent
visual hallucinations, and spontaneous motor features of
PD—but the operationalization of these symptoms has
been refined. In addition, although the presence of two
of these features is still sufficient for a diagnosis of prob-
able DLB, probable DLB can also now be diagnosed if one
of these symptoms is present in combination with REM
sleep behavior disorder, severe neuroleptic sensitivity
(Aarsland et al., 2005a, 2005b), or low dopamine uptake
in the basal ganglia (as indicated by dopamine transport-
ers SPECT or PET scanning).
Do the revised criteria improve
case identification?
A Norwegian study examined whether the proportion of
patients diagnosed as having probable DLB is increased
by using the 2005 consensus criteria in comparison to the
1996 criteria. Only 25 (12.8%, CI 8.1–17.4) patients fulfilled
criteria for probable DLB using the 1996 criteria compared
to 31 (15.8%, CI 10.7–20.9) using the revised criteria, a 24%
(CI 18.0–30.0) increase in the frequency of probable DLB.
The transition from possible to probable DLB using the
revised criteria was due to RBD in four and a positive CIT
SPECT in two (Aarsland et al., 2008a, 2008b; Rongve et al.,
2010). Table 9.5 shows this information in more detail.
Although this study does suggest that the new criteria
improve case identification, more robust prospective vali-
dation against post-mortem diagnosis is needed.
Applying the operationalized consensus
criteria in clinical practice
Some useful clinical common-sense steps can be adopted
to try to improve the accuracy in everyday practice. For
example, visual hallucinations are much more indicative
of DLB if they initially arise in the relatively early stages
of the dementia and become more frequent in AD patients
during the moderate stages of the disease (Ballard et al.,
212 Neurologic Conditions in the Elderly

Table 9.5 Number of patients fulfilling the criteria of the old 1996 non-neurologic diseases—such as diabetes, myocardial
and the revised 2005 criteria for a clinical diagnosis of DLB infarction, ischemic heart disease, and cardiomyopathy—
Diagnosis Probable DLB Possible DLB that are common in older patients may damage the post-
ganglionic sympathetic neurons. More information is
Old/ New/ Old/ New/
Criteria McKeith 96 McKeith 05 McKeith 96 McKeith 05
needed about the impact of concurrent cardiac pathology
on the interpretation of the results. An abnormal profile
N 25 31 13 8
on MIBG scintigraphy is already highlighted in the con-
VH 24 25 3 2
sensus criteria as supportive of DLB, and it is likely to be
Parkinsonism 11 14 8 5
Fluctuations 17 18 3 2
adopted as a more important aspect of the criteria with
RBD – 10 – 0 further studies.
DATSCAN – 3 – 0
99mTc-HMPAO
Neuroleptic – 0 – 0 SPECT
sensitivity Loss of the 99mTc-HMPAO SPECT signal is observed in
the parietotemporal and frontal cortical regions in AD
(Colloby et al., 2002). By contrast in DLB, there are greater
parieto-occipital deficits, but temporal hypoperfusion
1999). Similarly, parkinsonian symptoms are a less use- is absent (Colloby et al., 2002). Differences in regional
ful discriminator in the more severe stages of the disease, cerebral blood flow (rCBF) visualized by 99mtechnetium-
when they become more frequent in the context of AD hexamethylpropylene amine oxime (99mTc-HMPAO)
(Lopez et al., 2002). In addition, we strongly recommend SPECT may therefore assist discrimination between DLB
using one of the standardized tools for assessing cogni- and AD (Colloby et al., 2002, 2004) in patients with charac-
tive fluctuation (see the previous section). teristic patterns, but the overall sensitivity and specificity of
this approach is much less impressive than for DAT scans.
Other potential investigations that may
contribute to improved diagnosis PET/SPECT imaging to monitor changes in
Additional biomarkers such as myocardial scintigraphy, nondopaminergic neurotransmitter systems
99mTc-HMPAO SPECT, structural MRI, and CSF biomark-
Dementia with Lewy bodies can potentially be distin-
ers are being investigated and eventually may contribute guished from other forms of dementia by measuring
in cases where diagnostic accuracy is low after using the changes in cortical cholinergic function (Perry et al., 1994;
established criteria. Lippa et al., 1999). For example, several studies have
shown alterations in uptake of SPECT tracers directed
Myocardial scintigraphy toward nicotinic and muscarinic acetylcholine (ACh)
It is important to note that LB pathology is also present in receptors (AChR) in DLB and AD patients (Colloby et al.,
the autonomic peripheral nervous system, affecting post- 2006, 2008; O’Brien et al., 2008). Analysis of nicotinic AChR
ganglionic sympathetic nerves (Orimo et al., 2005). For (nAChR) using (123)I-5-Iodo-3-[2(S)-2-azetidinylmethoxy]
example, cardiovascular autonomic dysfunction is par- pyridine (5IA-85380)-SPECT indicates decreased uptake
ticularly common in DLB (Allan et al., 2007). Myocardial in the frontal, temporal, and cingulate cortex, as well as
scintigraphy with 123I-MIBG is a common technique for the striatum in DLB patients, compared to healthy con-
the quantification of post-ganglionic cardiac sympathetic trols (O’Brien et al., 2008); in contrast, the study showed
innervation (Orimo et al., 2005). A number of studies decreased uptake in medial temporal lobe, frontal cortex,
using 123I-MIBG scintigraphy have shown reduced car- striatum, and pons, respectively, in AD patients (O’Brien
diac versus mediastinal uptake in DLB, compared to et al., 2007). In addition, investigations of differences in
AD and healthy controls (Watanabe et al., 2001; Yoshita the distribution of muscarinic AChR (mAChRs) using
et  al., 2001, 2006). Indeed, cardiac MIBG imaging was (R,R)-123I-iodo-quinuclidinyl-benzilate (QNB) suggest
able to distinguish between clinically diagnosed DLB and elevated binding in the occipital lobe of DLB patients
AD with high sensitivity and specificity in these studies (Colloby et al., 2006) but decreased tracer uptake in the
(Yoshita et al., 2006). Importantly, similar findings have hippocampus, temporal lobe, and frontal rectal gyrus in
been reported in DLB patients with no overt parkinson- patients with AD (Pakrasi et al., 2007). Although poten-
ism (Yoshita et al., 2006). Therefore, if these findings were tially interesting, further work is needed to determine the
to be replicated in multicenter studies with large patient diagnostic potential of these approaches.
groups, it could be suggested that MIBG scintigraphy may In addition, PD, DLB, and PDD patients have been
be a useful tool for the early discrimination of DLB from studied using objective measures of acetylcholinesterase
AD (Aarsland et al., 2008a, 2008b). However, it should (AChE) activity by N-[11C]-methyl-4-piperidyl acetate
be cautioned that pathologic MIBG scans are difficult to PET (Shimada et al., 2009). In these studies, AChE activ-
interpret (Aarsland et al., 2008a, 2008b). Moreover, other ity was clearly reduced in all patient groups and could

not reliably separate or distinguish among PD, DLB, and
PDD (Shimada et al., 2009). Whether there are differences
between DLB and AD patients and whether this tech-
nique can be used to objectively measure disease progres-
sion remain important questions.
A number of studies focusing on AD have now
imaged amyloid load using N-methyl-[11C]2-(4′-
methylaminophenyl)-6-hydroxybenzothiazole (Pittsburgh
compound B, PIB) PET, which binds β-amyloid plaques in
cortical association areas and diffuse amyloid deposits in
the striatum, with a twofold increase in uptake compared
to healthy controls (Klunk et al., 2003, 2004). Several stud-
ies utilizing 11C-PIB PET have now been undertaken in
DLB patients, suggesting that the majority of individuals
have raised amyloid load (Edison et al., 2008; Gomperts
et al., 2008; Maetzler et al., 2008). Further work is needed to
determine whether different magnitude of amyloid bind-
ing can be used to distinguish DLB and AD patients, and
whether this can be used as a reliable method of tracking
disease progression or treatment response.
Structural MRI
Building upon previous clinical studies (such as Barber
et al., 2000; Burton et al., 2002; Beyer et al., 2007), recent
data from a series of neuropathologically confirmed cases
with antemortem MRI indicated significantly greater
medial temporal lobe atrophy (MTA) in AD patients,
compared to those with DLB (Burton et al., 2009). How-
ever, it is still debatable whether the overall sensitivity
and specificity of these differences is sufficient to make
this useful as part of a diagnostic assessment.
Functional MRI (fMRI)—which measures alterations in
patterns of brain activation in response to a stimulus or task—
has also been compared between DLB and AD patients, high-
lighting potential differences in the occipitotemporal activa-
tion and default network deactivation in response to visual
color, face, or motion stimuli in the two conditions (Sauer et
al., 2006). However, further work is needed to understand
the potential significance of this finding.
Cerebrospinal fluid
Studies of CSF have consistently shown characteristic
changes of amyloid-beta and tau peptides in AD, but
Table 9.6 Lewy body pathology: a comparison of DLB and PDD
DLB (N = 29)
Age 79.9 ± 4.8
F gender 17
MMSE closest to death 9.6 ± 9.1
Duration of dementia 2.6 ± 1.8
Duration of parkinsonism 1.2 ± 1.4
Frontal LB density 1.2 ± 1.5
Transentorhinal LB density 3.8 ± 2.9
Anterior cingulate LB density 2.5 ± 2.4
Dementia with Lewy Bodies 213
the initial studies focusing on DLB have shown conflict-
ing results (reviewed by Aarsland et al., 2008a, 2008b).
α-Synculein is the pathologic hallmark of DLB and PDD
and appears to be the pathologic substrate most closely
related to progressive cognitive decline in these individu-
als. α-Synculein is therefore a potentially attractive bio-
marker, and although recent progress has been made on
the measurement of α-synculein in the CSF, the results are
highly conflicting (El Agnaf et al., 2003; Mollenhauer et al.,
2008; Ballard and Jones, 2010; Ballard et al., 2010). Recent
work does suggest that an increase in α-synculein dimers
in the CSF (Tokuda et al., 2010) may be more indicative of
DLB/PDD than alterations in total α-synculein.
The small number of studies and the absence of longi-
tudinal studies directly comparing CSF markers in DLB
and AD across the spectrum of disease severity make it
difficult to develop firm conclusions.
Spectrum of Lewy body dementias: relationship
of PDD to DLB
The distinction and overlap between DLB and PDD
has been controversial. There is a substantial overlap
in symptoms between the two conditions (reviewed by
Aarsland et al., 2004a, 2004b), probably reflecting a com-
mon underlying cortical molecular pathology, with corti-
cal LBs and more diffuse α-synuclein pathology as com-
mon diagnostic features of both conditions at autopsy.
More specifically, several studies have suggested that,
in many cortical regions, the amount of LB pathology
does not differentiate DLB from PDD or PD (Harding
and Halliday, 2001; Tsuboi and Dixon, 2005). In con-
trast, data from the Newcastle brain bank (see Table 9.6)
indicate more pronounced cortical LB pathology in DLB
compared to PDD in a range of cortical areas, although
the prolonged duration of PD prior to dementia in this
cohort may explain the magnitude of disparity in corti-
cal LB pathology. Other work has suggested a more spe-
cific regional pattern of differences in LB density, with
higher LB densities in parahippocampal and inferior
temporal cortices in DLB compared to PDD (Harding et
al., 2002). In both DLB and PDD, cortical LB pathology
impacts phenotype. For example, the density of tempo-
ral lobe LB in DLB correlates with the early occurrence
PDD (N = 11) Evaluations
74.2 ± 4.3 t = 3.3; p = 0.002
5 χ2 = 0.6; p = 0.46
12.2 ± 9.4 t = 0.7; p = 0.47
2.1 ± 1.3 t = 0.9; p = 0.35
9.9 ± 6.9 t = 6.5; p < 0.0001
0.4 ± 0.3 t = 2.5; p = 0.02
1.8 ± 1.0 t = 3.1; p = 0.004
1.4 ± 1.1 t = 2.0; p = 0.049
214 Neurologic Conditions in the Elderly
of the characteristic well-formed visual hallucinations,
and increasing LB densities in limbic and frontal cortices
in PDD correlate with the severity of dementia (Samuel
et al., 1996).
The density of amyloid plaques has generally been
reported to be higher in DLB than in PDD, with the
density of Aβ-positive plaques in many DLB patients
equivalent to that found in AD. Although the amount of
Aβ deposition and cortical LBs correlates with demen-
tia severity in DLB, this does not seem to be the case
in PDD (Harding and Halliday, 2001). Neurofibrillary
tangles are typically substantially less pronounced than
in AD, but they may influence the clinical phenotype,
particularly in DLB (Merdes et al., 2003; Ballard et al.,
2004).
One study reported a marked LB neurodegenera-
tion in the striatum in DLB but not PD. PDD patients
had striatal neurodegeneration intermediate between
PD and DLB (Duda et al., 2002). In contrast, an impor-
tant preliminary report focusing on striatal pathology
in 28  brains—including 7 PD, 7 PDD, and 14 DLB—
indicated that striatal α-synuclein pathology is similar
in PDD and DLB. Amyloid plaques were also similar in
severity in the striatum in the two conditions (Tsuboi
and Dickson, 2005).
Overall, studies consistently indicate higher amyloid
pathology in DLB than in PDD, but the literature is highly
variable, with marked discrepancies related to cortical
LB pathology and striatal pathology. One study from our
group, examining the relationship between LB pathology
and the number of years of PD prior to dementia as a spec-
trum, demonstrated substantially less cortical LB pathol-
ogy in patients with long-standing PD prior to dementia
than in DLB patients, but the differences were less pro-
nounced in patients with 1–5 years of PD before dementia
developed (Ballard et al., 2006). Importantly, this suggests
pronounced clinical heterogeneity within the two syn-
dromes and indicates that the differences within the PDD
group may be even more substantial than between PDD
and DLB. For example, some PD patients may develop
dementia early in the course of the disease, whereas oth-
ers remain cognitively intact or develop dementia late in
course (Aarsland et al., 2007a, 2007b). Studying the rela-
tionship between the time from onset of PD to demen-
tia, we found that those with early dementia (less than
10 years after onset of PD) had similar morphologic and
neurochemical changes as those with DLB, whereas PD
patients with late-onset dementia had less morphologic
cortical pathology (LBs, amyloid plaques, and neurofi-
brillary tangles) but more severe cholinergic deficit in
temporal cortex (Ballard et al., 2006). This study supports
the concept of a continuum of LB disease instead of two
distinct diseases, and the different duration of PDD in dif-
ferent studies may explain some of the discrepancies in
results.
Comparative studies of clinical features
in PDD and DLB
The overall profile of cognitive deficits is similar in the two
syndromes, with both PDD and DLB patients exhibiting
significantly more marked executive and attention defi-
cit, fluctuating attention, and less severe memory deficits
than those with AD (Aarsland et al., 2004a, 2004b). Some
studies have reported more pronounced executive dys-
function in DLB than in PDD, particularly in patients with
mild dementia (Downes et al., 1998; Aarsland et al., 2003).
Although studies based on group means provide impor-
tant information, comparison of group means may dis-
guise heterogeneity within the groups. Indeed, recent
evidence has demonstrated that in PD and PDD, sub-
groups with different cognitive profiles exist: The major-
ity of patients have an executive-visuospatial-dominant
profile, whereas others have a memory-dominant pro-
file (Foltynie et al., 2004; Janvin et al., 2006). Similarly,
some DLB patients, probably those with more abundant
Alzheimer-type changes, may lack the characteristic pat-
tern of neuropsychological deficits usually associated
with LB diseases.
The profile of neuropsychiatric symptoms is also similar
in DLB and PDD. Persistent visual hallucinations are the
most frequent psychiatric symptoms and are characteris-
tic of both dementias (Ballard et al., 1999; Aarsland and
Cummings, 2004). Although misidentification syndromes
and delusions are also frequent and have a similar phe-
nomenology in both DLB and PDD patients (Mosimann
et al., 2006), they may be more frequent in DLB than in
PDD, possibly due to morphologic or neurochemical dif-
ferences reported earlier.
A modest proportion of DLB patients do not have
parkinsonism, but in those who do have it, severity and
profile of parkinsonism is similar to the findings in PDD,
and parkinsonism is a key factor explaining the func-
tional impairment in DLB (McKeith et al., 2006). In the
most detailed comparative study of parkinsonism to date,
Burn et al. (2003) reported that DLB patients had less
severe parkinsonism than PDD but had a similar sever-
ity of motor deficits compared to PD patients without
dementia. Postural instability and gait difficulties, pre-
dominantly mediated by nondopaminergic lesions, were
more pronounced in DLB and PDD than in PD patients
without dementia, whereas the opposite was found for
tremor.
Genetic studies
In a systematic review of the available literature about
familial occurrence and genetics of dementia plus parkin-
sonism to explore the genetic evidence of PDD and DLB,
we found substantial coincidental familial occurrence of

dementia and parkinsonism in 24 families (Kurz et al.,
2006). In 12 families, the presentation of dementia and
parkinsonism fulfilled current criteria for DLB and PDD,
implying that the same mutation in different members
of the same family caused different clinical entities. This
demonstrates a substantial overlap between the entities
in at least a proportion of the cases, suggesting a shared
underlying pathophysiology of PDD and DLB. Further-
more, it implies that the arbitrary distinction between
PDD and DLB according to the relative timing of parkin-
sonism and dementia does not reflect the molecular biol-
ogy of the disease process. As this overlap is clearly evi-
dent in familial cases of PDD or DLB, the same will likely
be true in sporadic presentations. Interestingly, patients
with familial co-occurrence of dementia and parkinson-
ism either displayed mutations in the synuclein gene
or showed positive correlations with the APOE3/4 and
E4/4  allele. Consistent with these observations, a three-
generational Belgian family with different phenotypes
involving dementia and/or parkinsonism (Bogaerts et al.,
2007) was described, with significant linkage to 2q35-q36.
Together these reports support the hypothesis of a com-
mon genetic underpinning of DLB and PDD.
Treatment of DLB and PDD
Because there are relatively few treatment studies, a
number of the studies have included patients with DLB
and those with PDD. As presented earlier, the literature
strongly indicates that DLB and PDD are on a spectrum
instead of being completely distinct conditions. This sec-
tion focuses on the treatment of both DLB and PDD.
Given the complex combination of symptoms in people
with DLB and PDD, it is helpful to think about the dif-
ferent treatment targets. Ultimately, the goal is to iden-
tify therapies that fundamentally impact the disease
process. Some emerging evidence indicates that cholin-
esterase inhibitors (CHEIs) may reduce the accumula-
tion or impact of concurrent amyloid pathology (Ballard
et al., 2007) and points to a number of other potentially
exciting avenues of exploration, such as the relationship
between proteosome function and α-synuclein pathology
(MacInnes et al., 2008), the role of β-synuclein (Fujita et
al., 2009) and the impact of altered forms of α-synuclein
on the propensity to aggregate (Ballard and Jones, 2010).
However, these remain research questions, and clinical
management needs to focus on key symptoms.
DLB and PDD are both progressive neurodegenera-
tive dementias associated with global cognitive deterio-
ration and impairment of self-care and other activities of
daily living. As with all dementias, improving cognition
and stabilizing self-care skills are major treatment goals.
However, in DLB and PDD, prominent neuropsychiatric
symptoms, parkinsonism, falls, autonomic dysfunction,
Dementia with Lewy Bodies 215
or sleep disorders may be the most important symptoms
for a particular individual. It is therefore helpful to docu-
ment the symptoms that require assessment and treat-
ment in a therapeutic plan, based on a problem list of
key symptoms, prioritized in order of importance to the
patient. Caregiver opinion about the impact of particular
symptoms should also be inquired about, particularly
because some symptoms—such as sleep or behavioral
disturbances—may have the most impact upon them.
Before any pharmacologic intervention, it is helpful to
explain that improvements in one symptom domain may
lead to deterioration in others, and slow and careful titra-
tion of drug dose may help reduce this. Frequent monitor-
ing for response to treatment and adverse effects of medi-
cations is recommended.
Pharmacologic treatments for cognition and
function in DLB and PDD
The main evidence base for treating cognitive symp-
toms pertains to the use of acetyl CHEIs. The first trial
was a small open-label study of seven patients with PDD
treated with tacrine. They experienced improvement
in cognition (MMSE score) and visual hallucinations
and suggested that, contrary to previous concerns, par-
kinsonian symptoms actually improved. Although the
potential utility of tacrine is limited by the high risk of
hepatotoxicity, the trial was extremely important in high-
lighting the potential value of CHEI therapy (Hutchinson
and Fazzini, 1996). Aarsland et al. (2004a, 2004b) sum-
marized the literature and highlighted 14 small studies
focusing on CHEI treatment in patients with PD with
an open or randomized crossover design, including a
total of 144  patients and trials with tacrine, donepezil,
rivastigmine, and galantamine between 1996 and 2003.
Overall MMSE scores improved by approximately two
points, and more than 90% of patients had an improve-
ment in their visual hallucinations. Although the overall
balance of the literature did not support Hutchinson and
Fazzini (1996) in suggesting an improvement in motor
symptoms, only a modest proportion of individuals expe-
rienced a worsening of parkinsonism. The only large
parallel group, randomized, controlled trial of a CHEI in
PDD, published in 2004 (Emre et al., 2004), confirmed the
impression from the previous preliminary studies and
demonstrated that rivastigmine was significantly bet-
ter than a placebo during 24 weeks of treatment for 541
patients with PDD (allocated 2:1 rivastigmine : placebo).
During the treatment period, the rivastigmine-treated
patients had a one-point advantage on the MMSE, an
almost three-point advantage on the ADAS-COG, and
significant benefits on more specialized assessment of
attention and executive function. There were also sig-
nificant two-point advantages for rivastigmine-treated
patients on the ADCS activity of daily living scale and
the neuropsychiatric inventory. Although there was no
216 Neurologic Conditions in the Elderly
overall significant worsening of parkinsonism, there was
a significant increase of tremor as a reported adverse
event in the rivastigmine-treated patients. As expected,
the participants receiving rivastigmine were more likely
to experience nausea (29% vs. 11%) and vomiting (16.5%
vs. 2%), but there was no difference in falls, with 75% of
participants able to tolerate rivastigmine for the duration
of the study. Mortality rates were significantly lower in
the rivastigmine-treated patients (1.1% vs. 3.9%).
A similar evolution of studies was seen for DLB, with ini-
tial small case series (such as Kaufer et al., 1998; Shea et al.,
1998; Aarsland et al., 1999) indicating that about two-thirds
of patients experienced benefit from CHEI treatment, espe-
cially with respect to neuropsychiatric symptoms. Several
reports (such as Kaufer et al., 1998) highlighted improve-
ments in fluctuating confusion. In general, this literature
supports the conclusions of the treatment studies in PDD,
indicating that parkinsonian symptoms worsened in only
a minority of individuals; however, in one of the reports
(Shea et al., 1998), three of the nine patients experienced a
worsening of parkinsonism. Again, this literature empha-
sizes the need for a randomized, controlled clinical trial,
culminating in a multicenter, placebo-controlled trial
(McKeith et al., 2000) of 120 DLB patients treated with riv-
astigmine (mean dose 7 mg) or placebo for 2 weeks. The
primary outcome measure was 30% improvement in a
four-item subscore (delusions, hallucinations, apathy, and
depression), which was attained by 63% of people treated
with rivastigmine and 30% of people treated with pla-
cebo—a significant difference on the observed case analy-
sis. On the total NPI, there was a nonsignificant three-point
advantage to the rivastigmine-treated patients. However,
it should be emphasized that this difference was not evi-
dent at the 12-week assessment point, and the benefit
appeared to emerge between 12 and 20 weeks. The impact
on specific psychiatric symptoms and fluctuating cogni-
tion has been studied less. Significant improvements were
also seen in attentional performance, with a nonsignificant
one-point advantage to the rivastigmine-treated patients
on the MMSE. The reports of adverse events were similar
to those in the subsequent PDD trial.
The literature overall is extremely encouraging, with
evidence from two large RCTs supported by extensive
case series literature, indicating that rivastigmine is sig-
nificantly better than placebo for the treatment of cogni-
tive deficits and neuropsychiatric symptoms. Evidence
from the PDD study (Emre et al., 2004) also showed sig-
nificant advantages for activities of daily living.
Rivastigmine is well tolerated, with no significant exacer-
bation of parkinsonism, although nausea and vomiting can
be a problem. In addition, detrusor instability is common
in DLB patients, can occur early in the course of the illness
(Del-Ser et al., 1996), and may be exacerbated by CHEIs.
The RCTs in DLB and PDD were undertaken with the
rivastigmine capsule. More recently, a successful RCT in
AD has been completed with a rivastigmine transdermal
patch (REF), which appears to have a favorable side effect
profile compared to the capsule and is now widely licensed
for the treatment of AD. There have not yet been any RCTs
in PDD or DLB using the transdermal formulation.
The case series literature suggests that donepezil is
also an effective treatment for DLB and PDD (Aarsland
et al., 2004a, 2004b). More recent RCTs show more mixed
results. In a recent large placebo-controlled RCT showed
only limited benefits in comparison to a placebo (Dubois,
2009). In contrast, an RCT from Mori et al. (2012) indicated
significant advantages in comparison to placebo, with a
similar magnitude of benefit to that reported with riv-
astigmine. One large 2-year RCT comparing rivastigmine
and donepezil for the treatment of AD did suggest a mod-
est advantage for rivastigmine in the subgroup of patients
who met criteria for possible DLB, but the diagnostic
status of these patients is unclear (Bullock et al., 2005).
One small crossover study with donepezil in a combined
cohort of DLB and AD patients indicated a significant
exacerbation of syncope and carotid sinus hypersensitiv-
ity (CSH) and related falls in donepezil-treated patients
(McLaren et al., 2003). This is a real clinical concern, given
the high frequency of CSH and other aspects of autonomic
dysfunction in DLB and PDD patients, but it is unclear
whether the propensity to exacerbate these problems dif-
fers between the different CHEI. An ECG, assessment
of autonomic function and postural hypotension, and a
good clinical history to evaluate syncope should probably
be completed before instigating treatment. Any emergent
symptoms or features of autonomic dysfunction should
also be monitored carefully during therapy.
Studies of CHEI other than rivastigmine and donepezil
are limited.
Predictors of treatment response to CHEI
The presence of visual hallucinations or more severe
attentional impairments, probably both markers of more
severe cholinergic deficits, are both associated with pref-
erential treatment response (McKeith et al., 2004).
Memantine
Memantine is an N-methyl d-aspartate (NMDA) receptor
antagonist that affects glutamatergic neuronal transmis-
sion and prevents the toxic effects of raised concentrations
of the excitatory neurotransmitter glutamate. Memantine
has established efficacy as a treatment for AD. Of note,
altered glutamatergic markers have been identified in
patients with DLB (Dalfo et al., 2004).
Three RCTS have now been reported. Leroi and col-
leagues (2009) reported a 22-week placebo-controlled RCT
of 25 participants with PDD. Memantine was well toler-
ated by participants at 20 mg/day dosing, and no partici-
pants were withdrawn due to memantine-related adverse
events. The power of the study to detect clinical benefits

was limited, but the results suggested a benefit in global
clinical outcome. In another RCT, 72 patients (40  with
PDD and 32 with DLB) were randomized to memantine
or placebo for 24 weeks. Again, memantine conferred sig-
nificant benefit compared to placebo in global clinical out-
come, with a mean CGIC score in the memantine group
of 3.5 (SD 1.5; median 3.0), compared with 4.2 (1.2; 4.0) in
the placebo group. In the intention-to-treat analysis with
LOCF, the mean difference was 0.70 (95% CI 0.04–1.39;
p = 0.03), with an effect size of 0._52. A moderate or sub-
stantial clinical improvement was noted in eight (27%)
patients in the memantine group, compared with none
in the placebo group. There were also significant benefits
in cognition (as measured by the MMSE) but not in neu-
ropsychiatric symptoms (Aarsland et al., 2009). A further
paper based on secondary outcomes indicated additional
benefits with respect to sleep symptoms (Larsson et al.,
2010). Although the numbers are too small to permit a
detailed subanalysis, there was some suggestion that the
main benefits were evident in the PDD patients.
In the largest RCT, 195 patients (75 DLB and 120 PDD)
were randomly assigned to memantine or placebo treat-
ment (Emre et al., 2010). At week 24, patients with DLB
who received memantine showed greater improvement
in global clinical outcome (Clinical Global Impression
of Change) than did those who received placebo (mean
change from baseline 3.3 vs. 3.9, respectively, difference
−0.6 [95% CI −1.2 to −0.1]; p = 0.023). There was also a sig-
nificant improvement in neuropsychiatric symptoms but
not in cognition. The incidence of adverse events and num-
ber of discontinuations due to adverse events was similar
in the two groups. In contrast to the Aarsland et al. study,
the benefits were mainly evident in the DLB patients.
Overall, global clinical benefits and good tolerability
were reported in all three studies, indicating the poten-
tial value of memantine as a treatment for PDD and DLB
patients. However, the specific benefits with respect to
neuropsychiatric symptoms and cognition and the rela-
tive benefits conferred to DLB and PDD patients, respec-
tively, all require further clarification.
Neuropsychiatric symptoms
When assessing the treatment of these symptoms, it is
critical to determine whether there is any medical comor-
bidity, review potentially contributing medications, assess
relevant visual impairments, and determine the severity
of the symptoms and the level of distress caused to the
person and the caregiver. Particular attention should be
paid to the potential contributing role of antiparkinsonian
medications, and dose reduction or even discontinuation
of some antiparkinsonian medications may be indicated.
Nonpharmacologic interventions have been shown to
effectively ameliorate neuropsychiatric symptoms in peo-
ple with dementia, but they have not yet been systemati-
cally evaluated in DLB. Approaches vary in complexity,
Dementia with Lewy Bodies 217
from optimizing the care and support package and pro-
moting good communication and person-centered care,
to tailoring specific interventions involving the patient,
caregiver, or environment. If symptoms are not causing
enormous distress, nonpharmacologic treatments should
probably be the intervention of first choice, although
CHEIs prescribed as a more generic pharmacotherapy
may confer additional benefit.
When specific pharmacologic intervention is required
to treat neuropsychiatric symptoms in DLB or PDD, the
main options are CHEIs or atypical antipsychotic medi-
cations. Open-label and placebo-controlled studies have
suggested possible benefit with all three generally avail-
able CHEIs on visual hallucinations, delusions, and
associated agitation in DLB and PDD (Aarsland  et  al.,
2004a, 2004b), although this question has not been spe-
cifically addressed in RCTs. The RCTs in DLB and PDD
have compared rivastigmine to placebo and show a
general improvement in neuropsychiatric symptoms
(McKeith  et  al., 2000; Emre et al., 2004), but the specific
impact on visual hallucinations has not been reported
and the time to improvement appears to be 3–6 months.
Although there is some disparity between the case series
and the RCT data, a trial of a CHEI will give general ben-
efits, is well tolerated, and is the pharmacologic treatment
of first choice. No comparative data exists between the
CHEIs in PDD or DLB, although given the higher level
of evidence, rivastigmine is probably the treatment of
choice. Beneficial effects of CHEIs may be sustained for at
least 2 years of treatment (Grace et al., 2001), and sudden
withdrawal may precipitate marked deterioration in neu-
ropsychiatric symptoms (Minett et al., 2003). If symptoms
are particularly severe and distressing, the time frame of
response to CHEI therapy may be too slow.
The use of atypical neuroleptics creates a more diffi-
cult clinical dilemma because of the general potential for
adverse events and the specific risk of severe neuroleptic
sensitivity reactions in DLB and PDD patients. Widely
reported general side effects of neuroleptics include par-
kinsonism, drowsiness, dystonia, and abnormal involun-
tary movements (tardive dyskinesia) associated with long-
term treatment (with many agents also causing anticho-
linergic side effects, including delirium). In people with
AD, evolving evidence has also highlighted serious risks,
including cerebrovascular adverse events and increased
mortality (Ballard and Howard, 2006). In DLB and PDD,
there is the additional specific problem of severe neuro-
leptic sensitivity reactions (McKeith  et  al., 1992; Ballard
et al., 1998; Sadek and Rockwood, 2003; Aarsland et al.,
2005a, 2005b). McKeith et al. (1992) reported that 50% of
neuroleptic-treated patients with DLB experienced severe
drug sensitivity, with symptoms that included marked
extrapyramidal features, confusion, autonomic instability,
falls, and accelerated mortality. An accumulating litera-
ture of case reports and case series, as well as subsequent
218 Neurologic Conditions in the Elderly
larger and more systematic series, shows that severe sen-
sitivity reactions occur with a wide range of typical and
atypical antipsychotics, including clozapine, in DLB and
PDD patients (such as Aarsland et al., 2005a, 2005b). Fail-
ure of neuroleptic prescriptions to up-regulate dopamine
D2 receptors has been highlighted as a major contributing
factor to severe neuroleptic sensitivity (Piggott et al., 1998,
1999). However, the largest and most systematic study
suggested that the highest frequency of severe neurolep-
tic sensitivity reactions occurred in olanzapine-treated
patients (Aarsland et al., 2005a, 2005b), raising the possi-
bility that antimuscarinic properties may also be impor-
tant. Clinically, severe neuroleptic sensitivity reactions are
a major concern, as they can occur after only a few doses
(Ballard et al., 1998) or even single doses (Sadek and Rock-
wood, 2003) of neuroleptic. Clear evidence from RCT in
AD patients with behavioral and psychiatric symptoms
indicates that atypical neuroleptics are an effective treat-
ment for the short-term (6–12 weeks) treatment of aggres-
sion but with more marginal benefits for psychosis and
other symptoms of agitation (Ballard and Howard, 2006;
Schneider et al., 2006). There is only one RCT of an anti-
psychotic in DLB/PDD, which indicated that quetiapine
did not confer any benefit in the treatment of neuropsychi-
atric symptoms in these individuals (Kurlan et al., 2007).
Balancing the risks of therapy with atypical antipsy-
chotics and the limited specific evidence of benefit in
DLB and PDD, atypical antipsychotics should be used
for only extremely severe neuropsychiatric symptoms in
which there is extreme distress or risk to the patient or
others. If therapy is instigated, it should be undertaken
with extremely close monitoring during the first 2 weeks,
especially the first 2–3 days, so that any early indications
of severe neuroleptic sensitivity reactions or other major
adverse events can be identified and treatment can be dis-
continued as soon as possible.
In AD, some evidence from crossover studies and RCT
indicates that anticonvulsants, such as carbamazepine and
sodium valproate, and antidepressants, such as citalopram,
may improve some neuropsychiatric symptoms (Ballard
and Howard, 2006; Ballard et al., 2009). However, the evi-
dence is limited and mainly indicates potential benefit for
symptoms of agitation rather than psychotic symptoms.
There are no studies of these agents in people with DLB or
PDD, and the safety of these treatment approaches has not
been established in these individuals. Emerging data from
AD trials also suggests that memantine may confer benefit
in the treatment of neuropsychiatric symptoms, although
the evidence from the RCTs so far conducted with meman-
tine in DLB/PDD patients is contradictory between stud-
ies (see the previous section regarding treatment of cog-
nition and function). A recent placebo-controlled RCT of
the 5HT2C inverse agonist pimavanserin has indicated
significant benefit in the treatment of psychosis in people
with Parkinson’s disease, including the subgroup with
significant cognitive impairment. Tolerability was also
favorable (Cummings et al., 2013).
Mood disorders
Depression is common in both DLB and PDD, and there
have been no systematic studies of its management. Cur-
rently, SSRI and SNRIs are probably preferred pharmaco-
logic treatment, although studies of SSRIs in PD without
dementia have been disappointing (Zahodne and Fer-
nandez, 2008). Tricylic antidepressants and those with
anticholinergic properties should be avoided. Nonphar-
macologic interventions, such as activity programs and
exercise, have been shown to be effective for the treatment
of depression in AD (Teri et al., 1997, 2003) but have not
been evaluated in DLB. Anxiety is also frequent and may
be secondary to fluctuating confusion, psychotic features,
or depression. Treating the underlying neuropsychiatric
condition often results in resolution. However, there is
no specific evidence base to inform the treatment of more
severe or persistent symptoms. In studies of CHEIs in AD,
anxiety is often one of the symptoms that show a prefer-
ential response (Gauthier et al., 2002). Nonpharmacologic
interventions, similar to those utilized for depression, can
be helpful and SSRIs may be worth considering. Benzodi-
azepines should probably be avoided because of the risks
of worsening amnesia, decreased alertness, impairment
of motor function, and increased risk of falls.
Sleep disorders are also frequently seen in LB disease
and may be an early feature. RBD can be treated with
clonazepam (0.25 mg at bedtime), titrating slowly and
monitoring for both efficacy and side effects (Boeve et al.,
2004). CHEIs (Reading et al., 2001) and memantine
(Larsson et al., 2010) may also be helpful for disturbed
sleep. Apathy, often associated with attentional and exec-
utive impairments, is a common feature that often adds
to social and functional disability and generally responds
well to CHEIs (McKeith et al., 2000).
Fluctuating cognition is often a prominent and dis-
tressing symptom, which adds to impairment on every-
day activities and can create major practical problems for
planning an appropriate care package. Several case series
include patients whose fluctuating cognition improved
with CHEI therapy, but the data are less clear-cut from the
RCTs. In the McKeith et al. (2000) study, after adjusting
for overall improvement in attentional performance, there
was no specific improvement of fluctuation. Fluctuating
cognition is an important treatment target meriting further
research, but it may be improved by using CHEI treatment.
Parkinsonism
Motor symptoms contribute to the disability experienced
by DLB and PDD patients and are associated with an
increased risk of falls. l-Dopa can be used for the motor dis-
order of both DLB and PDD, but doses should be titrated
more carefully. l-Dopa is generally well tolerated but may

increase confusion in a small proportion of patients (Molloy
et al., 2005). Responsiveness to l-dopa is more limited in
both DLB and PDD patients, with significant improvement
of parkinsonism seen in approximately half of PDD patients
and a smaller proportion of individuals with DLB, although
falls may be reduced even in some patients without opti-
mal motor response (Molloy et al., 2005). Caution should
be exercised in adding other parkinsonian medications—
including selegeline, amantadine, COMT inhibitors, and
dopamine agonists—because of concerns about exacer-
bating confusion and psychosis (visual illusions, halluci-
nations, and delusions). Anticholinergics should also be
avoided in both DLB and PDD. Cognition and psychosis
should be monitored with standardized evaluations.
Motor disability, including parkinsonism and postural
instability, may also be improved by physiotherapy and
occupational therapy approaches. The unpredictable and
fluctuating nature of cognitive and motor impairments can
prove particularly frustrating to patients and caregivers.
Education, discussion, and reassurance on dealing with
variable performance can help both parties adopt a flexible
approach, depending upon the patient’s functional level.
Falls and dysautonomia
There is a high prevalence of falls in DLB and PDD, with
a considerable risk of related injuries. There is little direct
evidence from specific RCTs to inform clinical practice;
therefore, recommendations are based upon best practice
recommendations for the management of falls in older
people without dementia and some anecdotal clinical
experience in the management of these problems in people
with DLB and PDD. Falls prevention is therefore an impor-
tant management consideration. Falls are multifactorial
in dementia patients, with a number of factors including
parkinsonism (with or without postural instability), pos-
tural hypotension, muscle weakness, posture, confidence/
anxiety, medication, and the environment all contributing.
Therefore, a broad approach is needed that should include
an evaluation of the patient’s environment, the need for
walking devices, physiotherapy for gait training, and other
rehabilitation efforts. Blood pressure should be checked for
orthostatic BP, and minimization of cardiac medications
and benzodiazepines is recommended. Management of
postural hypotension includes removing medications that
may be causative or additive. If postural hypotension per-
sists following medication adjustment, potential additional
pharmacologic treatments could include fludrocortisone
and midodrine. Syncope may be an important attribut-
able cause of falls. If suggestive symptoms are apparent,
a detailed cardiovascular assessment is recommended,
including head-up tilt and carotid sinus massage in a spe-
cialist facility. From anecdotal experience, cardiac pacing
may be beneficial in some of these patients. Protective
underwear and careful attention to flooring may reduce
the risk of serious injury in patients at high risk of falling.
Dementia with Lewy Bodies 219
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 Chapter 9.4
Vascular Cognitive Impairment
Helena C. Chui and Freddi Segal-Gidan

In the United States, the second leading cause of dementia
is cerebrovascular disease (CVD), either alone or in com-
bination with Alzheimer’s disease (AD). In the Framing-
ham study, the lifetime risk for stroke was comparable to
that of AD (Seshadri et al., 2006). Because approximately
one-third of persons meet criteria for dementia following
stroke, these two statistics alone underscore the adverse
consequences of CVD for cognitive health. Stroke, how-
ever, is only the tip of the iceberg of vascular brain injury
(VBI; Sacco, 2007). VBI contributes additively to cognitive
impairment, and a surge in obesity and metabolic syn-
drome portend increasing risk of VBI. Although vascular
cognitive impairment (VCI) is potentially preventable,
recent increases in vascular risk factors warn that the fre-
quency of VCI may rise instead.
Vascular cognitive impairment is the nomenclature
currently employed to encompass all degrees of cogni-
tive impairment greater than expected for age caused by
CVD. In this chapter, the terms subclinical vascular brain
injury (subclinical VBI), vascular cognitive impairment not
demented (vascular CIND), and vascular dementia (VaD)
are used to denote the spectrum of cognitive impairment
encompassed by VCI. For a summary of terms and abbre-
viations used in this chapter, see Table 9.7.

Table 9.7 Glossary of terms and abbreviations

SYNDROMES
CIND Cognitive impairment not demented
MCI Mild cognitive impairment (cognitive impairment without significant compromise of instrumental or personal activities of
daily living)
MCI subtypes Amnestic, amnestic plus other cognitive domain, non-amnestic single domain, non-amnestic plus other cognitive
domains
Memory impairment Free recall is below expectations
Amnestic memory Free recall is below expectations and is not attributed to diminished attention or retrieval (i.e., is not improved
impairment significantly with cueing)
VCI Vascular cognitive impairment (cognitive impairment ascribed to vascular disease or vascular brain injury)
VaD Vascular dementia (dementia ascribed to vascular disease or vascular brain injury)
ALZHEIMER’S DISEASE
AD Alzheimer’s disease (refers to progressive cognitive decline associated with widespread neurofibrillary tangles and
neuritic amyloid plaques)
Clinically diagnosed AD Mild cognitive impairment or dementia ascribed to AD, without pathological data
CEREBROVASCULAR DISEASE
CAA Cerebral amyloid angiopathy
CVD Cerebrovascular disease (disease of blood vessels; e.g., atherosclerosis, arteriolosclerosis)
Atherosclerosis Disorder affecting endothelial and elastic lamina of larger arteries
Arteriolosclerosis Disorder affecting smooth muscle cell layer of arterioles
Arteriosclerosis Includes atherosclerosis and arteriolosclerosis
VASCULAR RISK FACTORS
VRF Vascular risk factors (refers to known risk factors for stroke; e.g., hypertension, hyperlipidemia, diabetes mellitus, atrial
fibrillation)
Vascular factors Includes VRF and CVD
VASCULAR BRAIN INJURY
Stroke Sudden onset neurological deficit ascribed to CVD
Subclinical VBI Evidence of vascular brain injury (e.g., WMH and SBI) in non-symptomatic individual
VBI Vascular brain injury (parenchymal brain injury ascribed to vascular disease)
MRI LESIONS
WMH White matter hyperintensity on MRI (synonyms include WML = white matter lesion, WMSH = white matter signal
hyperintensity, leukoaraiosis = rarefaction of white matter on CT)
SBI Silent brain infarct on MRI
SI Silent infarct on MRI
SL Silent lacune (may include infarcts and perivascular spaces)

224

History
During the past century, the relative gravitas assigned to
CVD and AD has swung back and forth like a pendulum.
As new knowledge accrues, the AD–CVD model is adjusted
and refined. It is now clear that CVD and AD are both
highly prevalent disorders in the elderly that have additive
but differential effects on cognitive health (Figure 9.2). In
the early to mid-twentieth century, “hardening of the arter-
ies” (arteriosclerosis) was thought to be the primary cause
of progressive loss of intellectual function in late life. Later,
widespread neurofibrillary tangles and senile plaques (as in
AD) were recognized as the predominant cause of demen-
tia (Tomlinson et al., 1970). Multi-infarct dementia fell to a
more distant second, requiring diagnosis of frank cerebral
infarction, usually symptomatic stroke, not merely the pres-
ence of CVD (Hachinski et al., 1974). Today the pendulum
has turned again, as neuroimaging and neuropathology
frequently reveal subclinical evidence of VBI (such as white
matter hyperintensities (WMH) and silent brain infarcts
(SBI)) alone or in combination with AD.
In the 1990s, the incorporation of structural imaging tech-
niques (CT and MRI) in large community-based studies
revealed evidence of widespread subclinical vascular
pathology in many elderly, asymptomatic individuals, lead-
ing to the resurgence of interest in CVD and VCI. Asymp-
tomatic WMH and SBI were identified by MRI in 20–30% of
nondemented, community-dwelling elderly (Longstreth et
al., 1996, 1998; Vermeer et al., 2003a, 2003b; see Figure 9.3).
The term vascular cognitive impairment was adopted to
emphasize recognition and treatment of early, subclinical
VBI, as well as mild cognitive changes not severe enough to
be classified as dementia. Later epidemiologic studies called
out associations between risk factors for stroke (hyperten-
sion, diabetes, hyperlipidemia) and clinically diagnosed AD
(cognitive impairment without frank stroke).
During the past 5 years, community-based autopsy stud-
ies have shown that mixed pathologies are common in older
CVD
AD
WMH Beta-amyloid
VCI
Brain Stroke
SBI Phosph-tau
injury
Impact on
cognition
Subclinical CIND Dementia
Spectrum of cognitive impairment
Figure 9.2 Evolving model: relative contributions of CVD and AD
to cognitive impairment.
Vascular Cognitive Impairment 225
Subcortical ischemic vascular disease
(SIVD, SVD)
Figure 9.3 Silent infarcts and white matter changes are found in
20–30% elderly persons.
persons with either dementia or mild cognitive impairment
(Schneider et al., 2007, 2009a, 2009b; White, 2009). Various
combinations of amyloid plaques/neurofibrillary tangles,
cerebral infarcts, and Lewy bodies are found in more than
half of dementia cases (Schneider et al., 2007). Moreover,
converging evidence from clinical–pathologic correla-
tions illustrate that infarcts and AD pathology contribute
additively to the risk of dementia (Schneider et al., 2004).
Although the mechanistic link between vascular factors and
type of neuropathology and the functional link between VBI
and cognition are still subject to debate, the importance of
vascular disease to brain health is incontrovertible.
Conceptual framework
VCI is not a disease, but a syndrome or phenotype, based
on cognitive impairment due to underlying VBI. The
model used in organizing this chapter identifies the blood
vessel pathology or CVD as the primary disease process.
It follows logically that primary prevention should be
directed at reducing CVD. This conceptual model of VCI
can be summarized as VRF ➡ CVD ➡ VBI ➡ VCI.
Underlying CVD results in VBI (such as cerebral isch-
emia, oxidative stress, infarcts, hemorrhage, and inflamma-
tion), which, in turn, leads to VCI. Many types of CVD exist,
including arteriosclerosis (atherosclerosis and arterioloscle-
rosis) and cerebral amyloid angiopathy (Table 9.8) (Grinberg
and Thal, 2010). Many types of risk factors are at work.
Well-known vascular risk factors for arteriosclerosis include
hypertension, diabetes mellitus, hyperlipidemia, and smok-
ing. The apolipoprotein E ε4 allele is a genetic risk factor for
cerebral amyloid angiopathy, increasing the accumulation
of β-amyloid in blood vessels as well as in the brain paren-
chyma as amyloid plaques. Genetic mutations give rise to
Cerebral autosomal dominant arteriopathy with subcorti-
cal infarcts and leukoencephalopathy (CADASIL), cerebral
autosomal recessive arteriopathy with subcortical infarcts
 226

Table 9.8 The pathogenetic spectrum of vascular cognitive impairment: RF → CVD → VBI → VCI
Mechanism of Brain pathology Clinical phenotype or
Risk factors Vascular phenotype: “CVD” Vascular distribution brain injury phenotype: VBI Location/neural network syndrome: “Stroke” VCI

Modifiable Cerebrovascular Single artery Ischemia Complete infarction Limbic-diencephalic memory system Multi-infarct dementia
Hypertension Atherosclerosis (large artery, small (symptomatic or silent) Multimodal association areas Strategic infarct
Acute
Neurologic Conditions in the Elderly

Hyperglycemia Arteriolosclerosis arteriole, capillary) Incomplete infarction Cortico-basal ganglia-thalamocortical loops dementia
Thrombosis
Hyperlipidemia Amyloid angiopathy (demyelination, selective Deep white matter connections Lacunar state
Border zone Embolism
(apolipoproteins) Vasculitis neuronal loss) (cingulum, superior frontal occipital SVD
(large arteries,
Smoking Tortuosity Chronic Hematoma fasciculus, superior longitudinal fasciculus) Binswanger syndrome
small arterioles,
Obesity Anomaly Hypoperfusion Microbleed
capillaries)
Neuronal loss with gliosis
Nonmodifiable Cardiac Hemorrhage
Vein
Age Atrial fibrillation Leaky BBB
Gender Endocarditis Anoxia
Race Myopathy
Heredity Mural thrombus
CADASIL
Blood content
CARASIL
Hypoglycemia
HCHWA-D
Hypoxemia
HCHWA-I
Hemoglobinopathy
Coagulopathy

BBB, blood–brain barrier; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL, cerebral autosomal recessive arteriopathy with
subcortical infarcts and leukoencephalopathy; HCHWA-D, hereditary cerebral hemorrhage with amyloidosis, Dutch type; HCHWA-I, hereditary cerebral hemorrhage with amyloidosis, Icelandic type.

and leukoencephalopathy (CARASIL), and hereditary cere-
bral hemorrhage with amyloidosis (HCHWA).
A variety of pathways can lead to the development of
VBI and the subsequent development of VCI. This results
from complex interactions between lesions that vary
depending on site, size, and number (Tomlinson et al.,
1970). It may involve a large number of lesions in various
locations throughout the cerebral cortex, or one or more
lesions strategically located within cognitive networks.
The relative impact of VBI on cognitive function ranges
widely, from mild effects on executive function or pro-
cessing speed to devastating hemispheric neurobehav-
ioral syndromes (refer to Figure 9.2).
Ergo, no singular behavioral phenotype or temporal
course for VCI exists. The major determinant of clini-
cal symptoms (such as aphasia, neglect, visual–spatial
impairment, and executive dysfunction) is the anatomic
location of VBI (e.g., dominant perisylvian cortex, non-
dominant parietal lobe, deep white matter). One of the
subtypes of VCI, namely subcortical vacular dementia due
to small vessel arteriolosclerosis is associated with greater
impairment of executive compared to memory function.
The pathophysiologic mechanism of VBI is a major deter-
minant of temporal course and clinical progression. For
example, embolization, thrombosis, and hemorrhage are
associated with abrupt onset or stepwise decline. In con-
trast, widespread small vessel disease may be associated
with slowly progressive decline (such as Binswanger syn-
drome). Mixed CVD/AD may be associated with a combi-
nation of stepwise and slowly progressive decline.
Epidemiology
VCI is a syndrome, not a disease, so there are many ways of
operationalizing the definition of vascular CIND and VaD
(see the upcoming section “Diagnostic criteria”). Differences
in severity and pattern of cognitive impairment, evidence of
vascular etiology, and inclusion or exclusion of mixed AD/
VCI cases affect epidemiologic estimates. In this section,
we review various estimates of VaD, vascular CIND, post-
stroke cognitive impairment, and preclinical VBI.
VCI is considered to be the second most common cause of
cognitive impairment in late life, after AD. Most epidemio-
logic data relate to VaD, with rates approximating half those
of AD. As with AD, the incidence of VaD increases exponen-
tially after 65 years of age. For persons older than age 65,
the overall rate is estimated to be 11 per 1000 person-years
(about 1% per year; Fitzpatrick et al., 2004; Ravaglia et al.,
2005). At age 80, the incident rates for VaD vary from 0.3%
to 1.9% (Rocca and Kokmen, 1999; Knopman et al., 2002). A
higher incidence rate for VaD in men than women has been
reported in some studies (Ruitenberg et al., 2001; Fitzpatrick
et al., 2004), but pooled analyses showed no significant dif-
ferences (Andersen et al., 1999). The Cardiovascular Health
Study reported twice as many African Americans with
Vascular Cognitive Impairment 227
incident VaD, compared to European Americans (Fitzpat-
rick et al., 2004). Several factors may contribute to apparent
differences in rates of VaD, including differences in defini-
tion, methodology, education, and socioeconomic status.
Far less data is available for vascular CIND. In the
Canadian Health & Aging Study, there were twice as
many prevalent cases with CIND (16%) as dementia (8%)
or stroke (8%) (Jin et al., 2006). Although the etiology of
CIND was not differentiated, CIND was associated with
increased risk of not only incident dementia, but also inci-
dent stroke. In the Religious Orders and Rush Memory and
Aging autopsies studies, macroscopic infarcts were com-
monly found in subjects with MCI (both amnestic (18.6%)
and nonamnestic (13.3%)) and dementia (Schneider et al.,
2009). The epidemiologic and pathologic data suggest that
CVD is an important contributing factor to CIND or MCI.
CIND and dementia are frequent sequelae of stroke.
Following a first stroke, one in three survivors experi-
ences cognitive impairment that meets criteria for demen-
tia (Tatemichi et al., 1992b; Henon et al., 2001). Stroke sur-
vivors who are not affected by dementia after their first
stroke are twice as likely to develop dementia in the fol-
lowing decade, compared to normal controls (Ivan et al.,
2004). The latter finding is consistent with the notion that
underlying CVD poses ongoing risk to cognitive health.
Silent brain infarcts are five times as common as symp-
tomatic infarcts. Estimates of the prevalence of SBI on MRI in
community-based samples have varied between 5.8% and
17.7%, depending on age, ethnicity, presence of comorbidi-
ties, and imaging techniques (Das et al., 2008). On average,
SBI is present in approximately 11% of individuals in middle
or late life. Most have a single lesion, and the infarcts are
most often located in the basal ganglia (52%), followed by
other subcortical (35%) and cortical areas (11%) (Das et al.,
2008). Risk factors for SBI are generally the same as those
for clinical stroke (Das et al., 2008; Prabhakaran et al., 2008).
WMH are often present in most individuals over 30
years of age ( Decarli et al., 2005), and increase steadily in
extent with advancing age. WMH also shares risk factors
with stroke, especially with hypertension and smoking
(Jeerakathil et al., 2004). Importantly, a semi-quantitative
rating of WMH has been developed (Longstreth et al.,
1996), with age-specific definitions of extensive WMH
(Massaro et al., 2004); this proves useful in defining risk
for VCI in a community cohort (Debette et al., 2010). The
data confirm the common prevalence of subclinical SBI
and WMH in older community samples.
Evaluation
In 2006, the National Institute for Neurological Disorders and
Stroke (NINDS) and the Canadian Stroke Network (CSN)
convened researchers in clinical diagnosis, epidemiology,
neuropsychology, brain imaging, neuropathology, experi-
mental models, biomarkers, genetics, and clinical trials to
228 Neurologic Conditions in the Elderly
recommend minimum, common, clinical, and research stan-
dards for the description and study of VCI (Hachinski et al.,
2006). As a clinical phenotype, VCI is inherently heteroge-
neous. Collection of common variables in a standardized
manner (harmonization) is greatly needed to reduce extra-
neous noise and improve understanding of brain-behavior
correlations, diagnosis, prognosis, and outcome.
The clinical evaluation for VCI, or VaD, follows the
established approach to the evaluation of cognitive
impairment: a thorough history (from both the patient
and a reliable informant); physical examination, includ-
ing a screening mental state examination, with emphasis
on complete neurologic (focal neurologic signs, gait dis-
turbance) and cardiovascular components (funduscopic
examination of retinal vessels, carotid bruit, and cardiac
arrhythmia); laboratory testing (left ventricular hyper-
trophy and renal insufficiency); and neuroimaging (brain
CT or MRI). Additional testing (such as comprehensive
neuropsychological, diffusion weighted MRI, and genetic
testing) should be done as indicated by the history and
presentation. Emphasis is placed on identification by his-
tory of vascular risk factors (hypertension, hyperlipid-
emia, diabetes, and heart disease), medical history, and
family history (stroke, TIA, MI) for risk reduction, and
on the pattern of cognitive and affective disturbance and
functional decline for symptomatic treatment, manage-
ment, and support.
Mental status examination
Mental status screening tests commonly employed for
dementia screening may underestimate VCI, especially
vascular CIND. The Folstein Mini-Mental State Exami-
nation (MMSE; Folstein et al., 1975) does not include
any measures of speed or executive function, which are
affected by WMH and SBI. The Modified MMSE (3MS;
Teng and Chui, 1987) and the Montreal Cognitive Assess-
ment (MoCA; Nasreddine et al., 2005) contain elements of
verbal fluency (semantic and phonemic list generation),
similarities, and cued recall that add to their utility in
cases of VaD, as well as other non-AD dementias.
Neuropsychological testing
Comprehensive neuropsychological testing may be utilized
in VCI to identify areas of cognitive decline, particularly in
the early stages of CIND. On neuropsychological testing, the
executive domain often shows the earliest impacts of small
vessel VBI. In particular, inclusion of Trails B, phonemic and
semantic fluency, clock drawing, and digit symbol substitu-
tion are recommended, along with tests sensitive to episodic
memory, language, and visual–spatial domains. The cognitive
deficits in VaD and VCI are characterized by the disturbance
of frontal functions, with less verbal memory impairment
(Sachdev et al., 2004a, 2004b). In contrast to AD, in which cat-
egory fluency is usually more impaired than verbal fluency,
both types of fluency are affected to a comparable degree in
VCI (Tierney et al., 2001). Recommendations for 5, 30, and
60 minutes of neuropsychological assessment have been
proposed (Hachinski et al., 2006).
Structural imaging
Brain imaging (preferably MRI) is an essential tool for the
clinical evaluation of VCI. Many types of VBI are visible on
structural neuroimaging studies, including infarcts, hem-
orrhages, SBI, dilated perivascular spaces, white matter
changes, and microbleeds. Semi-quantitative rating scales
are useful in describing the severity of white matter lesions
(Longstreth et al., 2005) and have been correlated with
volumetric measures (Gottesman et al., 2010). Microbleeds
appear as rounded hypointense foci, larger than 5 mm, on
T-2* weighted MRI and are associated with hypertension,
cerebral amyloid angiopathy, and CADASIL (Viswanathan
et al., 2007). At the present time, microinfarcts are too small
to be reliably detected by MRI and are found only upon
autopsy. Hippocampal volume is usually preserved in pure
VCI, in contrast to AD and hippocampal sclerosis (Zarow et
al., 2005). Diffuse cerebral cortical atrophy is a nonspecific
finding in many dementias, including VaD (Jagust et al.,
2008). Harmonization standards for MRI have been pro-
posed and include measures of brain atrophy, WMH, infarc-
tion, and hemorrhage (Hachinski et al., 2006).
Neuropathology
Neuropathologic examination post-mortem provides infor-
mation about the underlying nature and severity of CVD
(atherosclerosis, arteriosclerosis, and cerebral amyloid
angiopathy). Pathologic examination provides a measure-
ment of VBI that can confirm lesions identified by in vivo
neuroimaging; identify lesions not detectable by current
imaging techniques (microinfarcts and hippocampal scle-
rosis; Vinters et al., 2000; White et al., 2002); and deter-
mine the presence, distribution, and severity of other brain
pathology, such as neuritic plaques and neurofibrillary
tangles associated with AD. A number of recent studies
have shown that VBI and AD exert additive effects on risk
of dementia (Snowdon et al., 1997; Schneider et al., 2004;
White, 2009). An autopsy study of SIVD/AD suggested
that although silent VBI contributes to CIND, its effects are
comparatively dwarfed by those of AD and hippocampal
sclerosis in cases with dementia (Chui, 2007). Important
elements in the assessment of CVD (such as atherosclerosis,
arteriolosclerosis, and cerebral amyloid angiopathy), VBI,
leukoencephalopathy, hippocampal lesions, and associated
neurodegenerative lesions are outlined by the NINDS–
CSN Harmonization standards (Hachinski et al., 2006).
Diagnostic criteria
No well-established consensus guidelines exist for the
clinical diagnosis of vascular CIND or for the diagnosis
of mixed AD/VCI. On the other hand, numerous criteria
cover the clinical diagnosis of VaD (Table 9.9). In addition,
there are published criteria for two subtypes of VaD,
Table 9.9 Clinical criteria for VaD

Diagnostic criteria Dementia CVBI Evidence of causal relationship

Hachinski ischemic score
(0–17 points; Hachinski et al.,
1974)
HIS ≥7 suggests MID
HIS 5–6 suggests MIX
HIS ≤4 suggests AD
No specific criteria CVD risk factors (HTN, ASCVD) Not specifically required
Sudden onset
Stepwise progression
Focal neurologic signs and symptoms

DSM-IV (APA, 1994) Memory loss Stepwise deteriorating course, and “patchy” distribution of Evidence from the history, physical examination, or
Sufficient to interfere deficits, focal neurologic signs, and symptoms laboratory tests of significant CVD that is judged to be
No clouding of consciousness etiologically related to the disturbance

ICD-10 (WHO, 1993) Unequal distribution of deficits in Evidence of focal brain damage, which manifests as at least From the history, examination, or test, evidence of
higher cognitive functions, with one of the following: unilateral spastic weakness of the limbs, significant CVD, which may reasonably be judged to be
some affected and others relatively unilaterally increased tendon reflexes, an extensor plantar etiologically related to the dementia (history of stroke,
spared response, or pseudobulbar palsy evidence of cerebral infarction)

ADDTC (Chui Probable Multifaceted cognitive impairment Infarct outside cerebellum by imaging Two infarcts, or one infarct with temporal relationship
et al., 1992) sufficient to interfere with to onset of cognitive impairment
customary affairs of life

Possible One infarct outside cerebellum by imaging OR confluent white Not required
matter change

NINDS-AIREN Probable Memory loss plus impairment in Focal neuro signs Abrupt onset
(Roman et al., two other cognitive domains Imaging findings Stepwise progression
1993) Temporal relationship to onset of cognitive impairment

Possible Either imaging findings, abrupt onset, or stepwise OR temporal relationship

Vascular Cognitive Impairment
229
230 Neurologic Conditions in the Elderly
namely subcortical vascular dementia (SVD) (Erkinjuntti et
al., 2000) and Binswanger syndrome (Bennett et al., 1990).
In general, these criteria address three basic issues: (1) evi-
dence of cognitive impairment, (2) evidence of VBI (by neu-
rologic examination or neuroimaging study), and (3) likeli-
hood that cognitive impairment results from VBI. Memory
impairment, while included in several of the criteria, need
not be prominent and is generally not considered essential.
The Hachinski Ischemic score (Hachinski et al., 1975),
developed four decades ago, is still useful (Table 9.9). Under
this framework, 1 or 2 points are assigned to a list of risk
factors, signs, and symptoms associated with stroke (for
example, sudden onset, stepwise progression, and focal
neurologic symptoms and signs). A score of >7 is associ-
ated with a high likelihood, and a score of <4 is associated
with a low likelihood of vascular contribution to cognitive
decline. The Diagnostic and Statistical Manual IV (APA,
1994) and ICD-10 (WHO, 1993) leave the clinician to deter-
mine whether there exists “significant CVD that is judged to
be etiologically related to the disturbance.” Criteria devel-
oped by the Alzheimer’s Disease Diagnostic and Treatment
Centers (ADDTC; Chui et al., 1992) require neuroimaging
evidence of an infarct with a temporal relationship to the
onset of cognitive impairment or two infarcts outside the
cerebellum, with no requirement for prominent memory
disturbance or focal neurologic signs. The National Insti-
tute of Neurological Disorders and Stroke and Association
Internationale pour la Recherche et l’Enseignement en Neu-
rosciences (NINCDS–AIREN) criteria require (1) impair-
ment in memory plus two other cognitive domains, (2) focal
neurologic signs and infarcts or white matter changes on
neuroimaging, and (3) onset of dementia within 3 months
of stroke or stepwise progression (Roman et al., 1993). The
NINCDS–AIREN criteria are most conservative and have
been the most widely adopted for research studies, particu-
larly for pharmacologic drug trials.
Each of the diagnostic criteria provides a similar but not
identical or interchangeable approach to the clinical diag-
nosis of VCI/VaD. A patient who meets criteria for prob-
able or possible ischemic vascular dementia (IVD) under
ADDTC may not meet criteria for NINCDS–AIREN VaD
or DSM or ICD-10 criteria, and vice versa. The Cardiovas-
cular Health Study Cognition Study compared cases clas-
sified as probable VaD by ADDTC, NINDS–AIREN, and
DSM-IV and found significant differences, with almost
three times meeting ADDTC criteria (n = 117), compared
to NINDS–AIREN (n = 42; Lopez et al., 2005).
Pathologic examination remains the gold standard for
determining the underlying etiology of dementing dis-
orders, although biomarkers and amyloid imaging are
improving etiologic specificity for AD. Unlike AD, pres-
ently there are no established criteria for the pathologic
diagnosis of VCI/VaD. The current standard is based on
the identification of VBI in the neocortex, without requir-
ing specific linkage to clinical symptoms or presentation.
Gold et al. (2002) compared the sensitivity and specificity
of these clinical criteria for VaD against a pathologic refer-
ence standard (evidence of cortical ischemic brain injury).
They demonstrated that overall current clinical criteria for
VaD are highly specific (0.78–0.94), but lacked sensitivity
(0.20–0.70), suggesting that clinical criteria may underes-
timate the extent of ischemic brain injury. The accuracy of
various criteria for VaD has been reviewed (Chui, 2005).
Positive likelihood ratios generally fall in the range of 2–5,
which is associated with small but sometimes important
changes between pre- and post-test probability.
VCI subtypes
At present, no agreed-upon classification system
addresses the various presentations and underlying neu-
ropathologic changes in VCI. Several subgroups of VCI
commonly encountered in the literature are post-stroke
dementia (PSD), SVD, Binswanger syndrome, CADASIL,
and preclinical silent VBI.
Post-stroke dementia refers to the onset of cognitive
and functional impairment in a temporal association
with an acute stroke. Cross-sectional studies post-hospi-
talization have reported that approximately one-third of
first-stroke survivors (26–32%) meet criteria for dementia
3 months post-stroke (Tatemichi et al., 1993; Pohjasvaara
et al., 1999; Desmond et al., 2000; Henon et al., 2006).
In up to one-third of these cases, a history of cognitive
decline prior to the stroke suggests that underlying VCI
or neuropathologic changes of AD may play a contribut-
ing role (Henon et al., 2001). A history of stroke has been
reported to increase risk of dementia over 10 years (Ivan
et al., 2004), and at 5 years post-stroke, the incident of PSD
has been reported as high as 48% (Kokmen et al., 1996).
Even after adjusting for other risk factors (demographics,
cardiac disease, stroke severity, and stroke reoccurrence),
the long-term mortality has been reported to be two to six
times higher in patients with PSD (Leys et al., 2005).
Among neuroimaging findings, silent cerebral infarcts,
white matter changes, and global and medial temporal
lobe atrophy are associated with increased risk of PSD
(Leys et al., 2005). Left hemisphere, anterior and posterior
cerebral artery distribution, multiple infarcts, and strategic
infarcts have been associated with PSD in at least two stud-
ies. Based on small case studies, locations considered to
be “strategic” have traditionally included the left angular
gyrus, inferomesial temporal, mesial frontal, anterior and
dorsomedial thalamus, left capsular genu, and caudate
nuclei. The concept of strategic infarction, however, needs
to be re-examined in larger prospective MRI studies, with
the extent and location of VBI defined in relation to cogni-
tive networks (Mayda and DeCarli, 2009).
It is difficult to determine the extent to which cognitive
impairment may be due to stroke vs. concomitant AD.

Estimates of the proportion of PSD patients with presumed
AD vary widely between 19% and 61% (Leys et al., 2005).
About 15–30% of persons with PSD have a history of
dementia before stroke (Pohjasvaara et al., 1999; Cordoliani-
Mackowiak et al., 2003), and approximately one-third to
one-half have significant medial temporal atrophy (Henon
et al., 1998; Bastos-Leite et al., 2007). In the Lille study, the
incidence of dementia 3 years after stroke was significantly
greater in those patients with vs. without medial temporal
atrophy (81% vs. 58%; Cordoliani-Mackowiak et al., 2003).
It is plausible that the likelihood of AD is higher among
patients with cognitive impairment preceding stroke or with
MTA atrophy, but this remains conjectural in the absence of
neuropathologic confirmation.
Subcortical dementia refers to the accumulation of small
infarcts in the deep white and gray matter. SVD includes
lacunar state, strategic infarct dementia, and Binswanger’s
syndrome. Small vessel infarcts comprise approximately
25% of subjects hospitalized for strokes, but nearly 60% of
asymptomatic strokes in community-based studies (Vermeer
et al., 2002). A single infarct in a strategic location, such as the
anterior or dorso-medial nuclei of the thalamus, or the genu
of the internal capsule that disrupt frontal–subcortical loops,
can produce a dementia syndrome (see Figure 9.4; Tatemichi
et al., 1992a, 1992b, 1995; Carrera and Bogousslavsky, 2006).
Binswanger’s syndrome can be considered an extreme phe-
notype of SVD, which is clinically characterized by a slowly
progressive decline in cognition, gait apraxia, and urinary
incontinence (Roman, 1987; Bennett et al., 1990). This triad
presentation may be confused with normal pressure hydro-
cephalus (NPH) clinically, but on structural brain imag-
ing, there is diffuse cerebral atrophy and confluent deep
white matter changes. The SVD subtype of VCI has been
proposed, emphasizing slowing of cognition, executive
Prefrontal cortex
Anterior gentrum semiovale
Head of caudate
Anterior limb internal capsule
Globus pallidus
Capsular genu
Anterior and dorsomedial
thalamus
Figure 9.4 Subcortical vascular dementia prefrontal–subcortical
circuits.
Vascular Cognitive Impairment 231
dysfunction (impairment in select attention, abstract rea-
soning, and mental flexibility), depression, extrapyramidal
signs, and gait disturbance (Erkinjuntti et al., 2000). In an
autopsy-confirmed study, a “low executive” profile was 67%
sensitive and 86% specific in distinguishing SVD from AD
(positive likelihood ratio = 4.7; Reed, et al., 2007). Although
the sample size was relatively small, categorization based
on neuropathologic finding avoids circularity inherent in
purely clinical studies and suggests modest clinical utility of
the executive dysfunction profile for SVD.
Cerebral autosomal dominant arteriopathy with subcorti-
cal infarcts and leukoencephalopathy (CADASIL) is consid-
ered representative of “pure” SIVD. The disorder is caused
by a defect in the Notch3 gene on chromosome 19 and causes
progressive degeneration of vascular smooth muscle cells
(Tournier-Lasserve et al., 1993). It is estimated to be present
in 500 families worldwide, making this entity more common
than familial AD (FAD). Diagnosis can be confirmed by skin
biopsy or genetic testing, but no specific treatment is cur-
rently available. The MRI in CADASIL is characterized by
subcortical infarcts, severe confluent white matter changes,
and microbleeds (Lesnik Oberstein et al., 2001; O’Sullivan
et al., 2001). The involvement of frontal, parietal, and tem-
poral white matter, along with claustrum and corpus cal-
losum, distinguishes CADASIL from the frontoparietal
white matter changes associated with chronic hypertension.
Associated with CADASIL are recurrent migraine attacks,
ischemic events, and progressive subcortical dementia asso-
ciated with premature death (mean age 65 years; Dichgans
et al., 1998). The neuropsychological profile of CADASIL is
characterized by pronounced deficits in executive function
and processing speed (Peters et al., 2005).
The recognition of WMH and SBI as harbingers of future
cognitive impairment emerged from prospective, longitu-
dinal, community-based studies. In the Rotterdam Scan
Study, the presence of SBI at baseline more than doubled the
risk of dementia at 3.6 years and tripled the risk of stroke
at 4.2 years, even after adjustment for WMH and atrophy
(Vermeer et al., 2003a, 2003b). Progression of WMH and
incident SBI were associated with decline in overall cog-
nitive function, especially information processing speed,
but not with change in memory function (van Dijk et al.,
2008). With more than 5 years’ follow-up in the Cardiovas-
cular Health Study, incident SBI and worsening of WMH
grade predicted greater decline in the modified MMSE and
the digit symbol substitution test (Longstreth et al., 2002,
2005). In the Framingham Offspring Study of middle-aged
adults where AD pathology is likely to be low, SBI pre-
dicted increased risk of stroke and dementia, independent
of vascular risk factors (Debette et al., 2010). WMH also por-
tended increased risk of stroke, mild cognitive impairment,
dementia, and death, independent of vascular risk factors
and interim vascular events (Debette et al., 2010). The data
indicate the importance of SBI and WMH as preclinical
signs of VCI and important targets for risk reduction.
232 Neurologic Conditions in the Elderly
Treatment
The best approach to the treatment of VCI is prevention
through early identification and management of vascular
risk factors and CVD. The Framingham Stroke Risk Pro-
file is useful for estimating the 10-year risk for stroke in
men and women 55–80 years old. The risk profile weighs
age, systolic BP, diabetes, smoking, cardiovascular dis-
ease, atrial fibrillation, and left ventricular hypertrophy to
predict the future 10 years’ risk of stroke (Wolf et al., 1991;
D’Agostino et al., 1994). The benefit of treating vascular
risk factors for stroke prevention has been well estab-
lished by randomized clinical trials, and evidence-based
guidelines that incorporate these have been disseminated
for use in clinical practice (Goldstein et al., 2009). On the
other hand, there is still relatively little clinical trial data
demonstrating the effectiveness of vascular risk factor
reduction on cognitive outcome measures. Lack of evi-
dence, however, is not the same as negative evidence. To
demonstrate protective effects for cognition, clinical trials
may need to be started earlier in life, last much longer,
and use more sensitive cognitive measures.
Primary prevention: identification and
reduction of stroke risk factors
Primary or secondary prevention trials that include cog-
nitive outcome measures are more limited. Hypertension
control for the prevention of stroke is well-established and
accepted medical practice (see Table 9.10). By extension,
it is believed that hypertension control will reduce VCI,
but studies supporting this are limited. A follow-up of
the Systolic Hypertension in Europe Trial (Syst-Eur trial)
Table 9.10 Primary and secondary prevention antihypertensive trials with cognition outcome measure
Antihypertensive medication
Primary prevention
SHEP (1991) Diuretic (chlorthalidone) and/or beta
N = 4736 blocker (atenolol) or reserpine
Forette et al. (1998) Ca-channel blocker (dihydropyridine)
N = 2418 with or without beta blocker
(enalapril maleate) and/or diuretic
(hydrochlorothiazide)
Lithell et al. (2003) ARB (candesartan cilexetil) and/or
N = 4937 diuretics
Peters et al. (2008) Diuretic (indapamide) with or without
N = 3336 ACEI (perindopril)
Secondary prevention
Tzourio et al. (2003) ACEI (perindopril) with or without
N = 6104 diuretic (indapamide)
Diener et al. (2008) ARB (telmisartan)
N = 20,332
demonstrated that long-term antihypertensive therapy
(3.9 years) reduced the risk of dementia by 55% (43  vs.
21 cases, p < 0.001; Forette et al., 2002). Using this out-
come data, it is estimated that treating 1000 patients for
hypertension for 5 years can prevent 20 cases of dementia.
In the Systolic Hypertension in the Elderly (SHEP) trial,
hypertensive treatment was associated with a significant
reduction in stroke (36%; p = 0.0003) and a 16% reduc-
tion in dementia (nonsignificant; SHEP 1991). Initiating
hypertensive treatment early and maintaining optimal
blood pressure control over the years is believed not only
beneficial for reducing stroke and heart disease, but also
necessary to preserve cognitive function.
Diabetes is another well-recognized risk factor for
cardiovascular disease, due to accelerated atherosclero-
sis and arteriosclerosis. Thus, it is also thought to play a
role in the development of VCI. The Memory in Diabetes
(MIND) substudy of the Action to Control Cardiovascular
Risk in Diabetes (ACCORD) trial focuses on a random-
ized subset (2977) of the 10,251 individuals with estab-
lished type 2 diabetes whose screening A1C was ≥7.5%, to
specifically address whether interventions reduce cogni-
tive decline and structural brain changes. Baseline data
from ACCORD–MIND showed that higher A1C levels
were associated with lower MMSE scores and slowing on
the digit symbol substitution test (Cukierman-Yaffe et al.,
2009). With the growing epidemic of metabolic syndrome,
research is greatly needed to improve understanding and
treatment of diabetes and cognitive impairment.
The use of statins for primary prevention cognitive
impairment remains unproven. In the PROSPER study
(n = 5804; mean age = 75.3 ± 3.4 years), no difference in
Duration of
follow-up (years) Main results for dementia Significance
4.5 16% reduction in dementia n.s.
2.0 50% (0–76%) reduction in dementia p = 0.05
3.7 7% increased risk in active arm (but only p > 0.20
3.2/1.6 mmHg reduction in BP in treatment
vs. control arm)
2.2 14% (–9% to 23%) reduction in dementia p = 0.2
Trial stopped early because of significant
reduction in stroke and mortality
4.0 12% (–8% to 28%) reduction in dementia p = 0.2
2.4 No reduction of risk of dementia p = 0.48

cognitive decline was found in subjects treated with
pravastatin, compared to placebo (all p > 0.05; Trompet
et al., 2010). The MRC/MRC/BHF Heart Protection ran-
domized, controlled study of 20,536 high-risk individu-
als given 40 mg simvastatin daily demonstrated reduced
rates of myocardial infarction, stroke, and revasculariza-
tion by about one-quarter over 5 years (2002) but did
not include cognitive outcome measures. The size of the
benefit was related to the participants’ overall risk of
major vascular events rather than on their blood lipid
concentrations alone.
The use of antioxidants to preserve cognitive function has
been the subject of great public interest, leading research-
ers to investigate whether these claims have any validity.
In individuals with cardiovascular risk factors or disease,
there is no evidence that antioxidants preserve cognitive
function or reduce mortality. The Women’s Antioxidant
Cardiovascular Study (n = 2824), a trial of vitamin E, beta
carotene, and vitamin C, for the secondary prevention of
cardiovascular disease reported no slowing of cognitive
change among women with pre-existing cardiovascular
disease or cardiovascular disease risk factors (Kang et al.,
2009). In the MRC/BHF Heart Protection Study, antioxi-
dant treatment was not associated with any significant
differences in all-cause mortality, deaths due to vascular
or nonvascular causes, nonfatal myocardial infarction or
coronary death, nonfatal or fatal stroke, or coronary or
noncoronary revascularization (MRC/BHF, 2002).
Secondary prevention: recurrent stroke
and cognitive decline
The risk for subsequent stroke is known to increase after
an individual has had one or more TIAs or a stroke.
Whether the prevention of additional ischemic injury and
another stroke can prevent further cognitive decline has
not been proven. In the secondary prevention PROGRESS
trial (Tzourio et al., 2003), 6105 subjects with previous
stroke or TIA were randomized to perindopril plus or
minus indapamide vs. placebo and followed for 3.9 years.
Using the MMSE as an outcome measure, the treatment
group showed a 19% relative risk reduction vs. placebo
in cognitive decline and a 43% reduction in new WMH
on MRI imaging (Dufouil et al., 2005). In the secondary
prevention PRoFess trial, 20,332 subjects were random-
ized to two antiplatelet regimens, with one arm combined
with telmisartan vs. placebo. After 2.4 years of follow-up,
no differences were found in disability due to recurrent
stroke and cognitive decline (Diener et al., 2008).
Treatment of VaD
The basic principles and approach to dementia care,
emphasizing supportive care to optimize quality of life
and advance care planning, are similar and of equal
importance for patients and families with VCI and VaD
as they are for those with AD and other dementias.
Vascular Cognitive Impairment 233
Presently, there are no specific treatments for the cogni-
tive impairment associated with VCI or VaD, once devel-
oped. Although they do not have Food and Drug Admin-
istration (FDA) approval in the United States for VaD (or
other non-AD dementia), during the past decade, three
cholinesterase inhibitors have been studied in random-
ized, controlled trials of VaD. A vascular rationale for
cholinesterase inhibitors in VaD has been proposed based
on a study that showed galantamine increases cerebral
vascular reactivity in subjects with both AD and VaD
(Bar et al., 2007).
Mild benefits in the Alzheimer’s Disease Assessment
Scale, cognitive subscale (ADAS–-cog) have been reported
with use of galantamine and donepezil in subjects with
probable VaD (Erkinjuntti et al., 2002; Wilkinson  et al.,
2003; Auchus et al., 2007). Among subjects meeting
NINDS–AIREN criteria for probable or possible VaD,
over 24-week clinical trial periods, donepezil (5–10 mg)
was associated with an approximately 1- to 2-point dif-
ference in the ADAS-cog subscale, compared to placebo
(Black et al., 2003; Wilkinson et al., 2003; Roman et al.,
2010). Some caution is warranted, however, as increased
mortality has been noted in a meta-analysis of donepezil
in VaD (Kavirajan and Schneider, 2007) of unclear signifi-
cance (Figure 9.5). A small, randomized study of rivastig-
mine among patients with stroke and cognitive impair-
ment without dementia showed statistically significant
improvement in animal fluency in the treatment group
(n = 25), compared to controls (n = 25) (Narasimhalu
et  al., 2010). In a study of CADASIL, a relatively pure
example of VaD, no significant differences were noted in
the ADAS-cog between the treatment (n = 86) and placebo
(n = 82) groups (Dichgans et al., 2008). However, in this
relatively small study, treatment effects favoring donepe-
zil were observed for secondary executive outcome mea-
sures (Trails B time, Trails A time, and EXIT25).
Memantine has also been studied for the treatment
of VaD in randomized, clinical trials, with modest ben-
efits shown (Orgogozo et al., 2002; Wilcock et al., 2002;
Narasimhalu et al., 2010). A meta-analysis of randomized
clinical trials in VaD found favorable effects of cholin-
esterase inhibitors and memantine on cognition but not
global outcomes (Kavirajan and Schneider, 2007). VaD
has significant heterogeneity, such that subjects with
VaD enrolled across trials may have variable underly-
ing pathology (large vs. small vessel, mixed VaD/AD)
and severity of cognitive impairment. This confounds the
results, raising the possibility that certain VaD subgroups
may be more or less likely to benefit.
Treatment must also address the affective and behav-
ioral symptoms of VaD. Depressive symptomatology,
both dysphoria and depression meeting DSM criteria,
and apathy frequently accompany VCI and VaD. Treat-
ment with antidepressants is effective. Selective sero-
tonin reuptake inhibitors (SSRI) are the first choice in
234 Neurologic Conditions in the Elderly

Drug Placebo WMD WMD

n Mean (SD) n Mean (SD) (fixed; 95% CL) Weight (%) (fixed; 95% CL)
Donepezil 5 mg vs placebo
370 196 –0.96 (5.49) 194 0.72 (5.64) –1.68 (–2.78 to –0.58)
308 199 –1.75 (4.70) 180 –0.10 (5.36) –1.65 (–2.67 to –0.63)
319 648 –0.71 (5.18) 326 0.00 (5.18) –0.71 (–1.40 to –0.02)
Subtotal 1043 700 –1.15 (–1.65 to –0.64)
Test for heterogeneity: χ2=3.37; df2 (p=0.19); P=40.70%
Test for overall effect; p<0.00001
Donepezil 10 mg vs placebo
307 195 –1.52 (5.74) 194 0.72 (5.64) –2.24 (–3.37 to –1.11)
308 194 –2.19 (6.27) 180 –0.10 (5.36) –2.09 (–3.27 to –0.91)
Subtotal 389 374 –2.17 (–2.98 to –1.35)
Test for heterogeneity: χ2=0.03; df1 (p=0.86); P=0%
Test for overall effect: p<0.00001
Galantamine 24 mg vs placebo
GAL-INT-6 149 –2.00 (6.10) 77 0.00 (6.76) –2.00 (–3.80 to –0.20)
GAL-INT-26 367 –1.80 (5.94) 373 –0.30 (6.32) –1.50 (–2.38 to –0.62)
Subtotal 516 450 (–2.39 to –0.80)
2
Test for heterogeneity: χ =0.24; df1 (p=0.63); P=0%
Test for overall effect: p<0.0001
Rivastigmine 12 mg vs placebo
VantagE 360 –0.70 (7.21) 338 0.40 (6.99) –1.10 (–2.15 to –0.05)
Test for overall effect: p=0.04 –1.10 (–2.15 to –0.25)
Memantine 20 mg vs placebo
MMM300 147 –0.40 (5.70) 141 1.60 (6.10) –2.00 (–3.36 to –0.64)
MMM500 277 0.53 (7.02) 261 2.28 (7.77) –1.75 (–3.00 to –0.50)
Subtotal 424 402 1.86 (–2.79 to –0.94)
Test for heterogeneity: χ2=0.07; df1 (p=0.79); P=0%
Test for overall effect: p<0.0001

Favors drug Favors placebo

Figure 9.5 Meta-analysis of controlled trials of AchEI and memantine in VaD. Source: Kavirajan and Schneider (2007). Reproduced with
permission from Elsevier.

VaD. They are activating, helping to overcome the slow-
ness and apathy that is often associated with VaD, and
are well tolerated. The older tricyclic antidepressants can
be sedating and are less well tolerated due to their signif-
icant anticholinergic side effects. Disruptive behaviors,
agitation, delusions, and other psychotic symptoms are
much less common in VaD than AD. Antipsychotic medi-
cations for behavior management in VaD should be used
cautiously, particularly in VaD patients with extrapyra-
midal signs, as they may increase imbalance and the risk
of falls. If required, atypical antipsychotics (risperdone,
quetiapine, and olanzapine) have fewer side effects and
should be used for only a limited period of time; they
should be closely monitored and their ongoing need
reassessed frequently. These medications each carry a
“black box” warning due to the increased risk of sudden
death in older individuals. Benzodiazepines are sedat-
ing, increase confusion and the risk of fall, and should
be avoided in all older individuals, especially those with
dementia.
VaD patients often have one or more vascular risk fac-
tors (e.g., hypertension, diabetes, atrial fibrillation, and
hyperlipidemia) that require ongoing management. The
optimal control of these chronic medical conditions to
minimize vascular ischemia requires addressing the need
for supervision or assistance with medication manage-
ment early on. To be successful, a proactive, multidis-
ciplinary approach that is patient–family-centered and
addresses risk reduction, patient safety, advanced care
planning, and quality of life is required.
Prognosis/outcome
The two outcomes that have received the most attention
have been cognitive decline and mortality in VaD. The
prognosis and outcome for silent VBI—namely SBI and
WMH—have been discussed under subtypes of VCI. In
general, the rate of cognitive decline in VaD is believed
to be slower and more variable than AD. In placebo-
controlled drug trials for VaD, there was no significant
change in cognitive decline, as measured by ADAS-
cog, over 6–12  months (Erkinjuntti et al., 2002; Wilkin-
son et al., 2003). A 7-year study of elderly persons with
dementia in Sweden found that the average annual rate
of cognitive decline over 3 years was greater for those
with AD than VaD (Aguero-Torres et al., 1998a, 1998b).
In longitudinal studies of stroke survivors, the presence

of dementia or additional stroke was associated with
greater cognitive decline (Nyenhuis et al., 2002; Sachdev
et al., 2004a, 2004b). Multivariate analyses in a prospec-
tive, longitudinal MRI study of normal aging, subcortical
ischemic vascular disease, and AD showed higher mor-
tality rates in association with cognitive impairment, age,
male gender, depressed mood, and presence of lacunes
(Lavretsky et al., 2010). Participants with both lacunes
and depressed mood had the shortest survival among all
cognitive groups.
Not unexpected, given the close association with
known cardiovascular risk factors (hypertension,
diabetes, and hyperlipidemia), mortality is greater in
VaD than AD. A community-based study of people over
age 75 in Sweden reported a mean survival of 2.8 years
for VaD, compared to 3.1 years for AD (Aguero-Torres
et al., 1998a, 1998b). A retrospective study in Rochester,
Minnesota, found twice the mortality risk for VaD, com-
pared to AD (Knopman et al., 2003). On the other hand,
a more recent cohort study reported no difference in the
7-year survival rate among African Americans with AD,
VaD, or stroke without dementia (Freels et al., 2002).
Current clinical practice focused on earlier identification
and better control of vascular risk factors is based on the
belief that this will preserve cognitive function longer
and delay mortality.
Conclusion
The role of CVD in cognitive decline, especially in late
life, has received increased attention during the past
half-century. VCI is not a single entity, but a heteroge-
neous phenotype with differences in severity, underly-
ing pathophysiology, and symptomatology, depending
upon site(s), size, and sum of the underlying VBI. Emerg-
ing evidence from neuropathologic studies indicates that
cerebral infarcts contribute additively with AD pathol-
ogy to cognitive impairment. No agreed-upon clinical or
pathologic diagnostic criteria currently exist for vascular
CIND, mixed AD/VCI, or even VaD. Structural MRI cur-
rently provides the most sensitive and specific measure
of VBI. Many of the risk factors associated with VBI (e.g.,
hypertension, diabetes mellitus, and dyslipidemia) are
known, clinically identifiable, and modifiable with treat-
ment. Clinical trials to date, focusing primarily on stroke,
have often started too late, been too short in duration, or
lacked sufficiently sensitive cognitive outcome measures
to demonstrate an impact on cognitive function. Cur-
rently, no specific FDA-approved symptomatic treat-
ments address VCI. In the meantime, clinical care focus-
ing on reducing risk factors through early identification,
aggressive treatment, and close monitoring are essential
to minimize cognitive decline, impairment, and dementia
from underlying CVD.
Vascular Cognitive Impairment 235
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 Chapter 9.5
Frontotemporal Dementia
David Perry and Howard Rosen
Introduction and definition of terms
In 1892, Arnold Pick described a patient with progressive
behavior and language deterioration and left temporal lobe
atrophy. Based upon subsequent cases described by Pick
and pathologic findings described by Alois Alzheimer, the
entity of Pick’s disease was recognized (Pick, 1892, 1904;
Alzheimer, 1911). Although the terminology has changed
over the subsequent decades and the term frontotemporal
dementia (FTD) has gained favor, the hallmark features
of these disorders remain a progressive deterioration in
personality and behavior and/or language impairment.
Instead of being one homogeneous disorder, FTD is now
understood as including multiple distinct clinical subtypes
that can be caused by several pathologic processes. The
nomenclature in the field has been inconsistent and con-
fusing. In this chapter, the term frontotemporal dementia is
used as an overarching term to refer to any of the three
core clinical syndromes of FTD. These include the behav-
ioral variant of FTD (bvFTD), which presents primarily
with changes in personality and socioemotional function,
and two variants of primary progressive aphasia (PPA),
including the semantic variant (svPPA) and the nonflu-
ent/agrammatic variant (nfvPPA). The term frontotemporal
lobar degeneration (FTLD) is used to describe the associated
pathologic entities. Chapter 9.6 describes the clinical, imag-
ing, and pathologic features of PPA; this chapter focuses
on the clinical features of bvFTD and on FTLD as a whole,
along with its diverse clinical, pathologic, and genetic fea-
tures. Research in FTD has also identified links between
FTD and other neurologic syndromes, including cortico-
basal syndrome (CBS), progressive supranuclear palsy
(PSP), and motor neuron disease (MND), which are associ-
ated with FTLD pathology and are often considered as part
of the FTLD spectrum. PSP and CBS are discussed in detail
in other chapters of this volume, but the disorders are
reviewed here to highlight their relationships with FTD.
Epidemiology
Frontotemporal dementia was previously felt to be a rare
entity, but current data indicate that it is the third most com-
mon cause of dementia (Ratnavalli et al., 2002; Ikeda et al.,
2004a; Brunnstrom et al., 2009). Prevalence estimates have
varied, but in one study in the Netherlands, it was esti-
mated at 2.7/100,000 (Rosso et al., 2003). A study conducted
in Rochester, Minnesota, indicated that, in patients whose
dementia begins prior to age 60, FTD is as common as
Alzheimer’s disease (Knopman et al., 2004). Onset is most
commonly in the sixth decade but has been described as
early as the third decade and as late as the ninth (Rosso et al.,
2003; Mercy et al., 2008).
Survival from disease onset is shorter than in Alzheim-
er’s disease. The longest survival is in svPPA, at 11.9 years
from onset; the shortest is in patients with FTD and co-
existing MND (approximately 2 years). BvFTD and
nfvPPA are intermediate, at 8.7 years and 9.4 years,
respectively (Roberson et al., 2005).
Core FTD clinical syndromes
Behavioral variant of FTD (bvFTD)
Case 1
A 58-year-old right-handed accountant began to change
his performance at work 4 years before presentation. He
began to delay submission of his clients’ tax returns, say-
ing he was too busy to submit them and instead getting
extensions without their permission. He also began to
skip meetings with his partners. Because of his experience
and proficiency, he managed to keep his job. Two years
before presentation, however, he developed a gradual
change in personality. He began to swear at his clients
and colleagues and say inappropriate things to strangers,
including commenting on their weight and other physi-
cal characteristics and telling them dirty jokes or telling
them about personal problems he was experiencing with
his wife. He became less engaged in group activities and
was thought to be depressed. Over time, he started to
develop new habits, including monitoring the duration of
visits with family and friends, insisting that they leave at
exactly at the time they had planned. He began craving
sweet foods, eating whole bags of cookies in a sitting and
gaining 20 pounds, causing his wife to begin locking the
pantry. At a baseball game, he might eat food found on
the bleachers. One afternoon 6 months before presenta-
tion, his daughter called from a hospital to tell him that
she had been in a car accident; his wife was shocked when
he told their daughter to call when she needed a lift home
and then left the house to play his weekly round of golf.
He developed repetitive behaviors, involving pacing and
rubbing his arms and hair. He began to compulsively
arrange water bottles or papers to make certain they were
aligned with the edge of the desk.
239
240 Neurologic Conditions in the Elderly
On presentation to the clinic, he was asked why he
was visiting the clinic. He said, “I have some prob-
lems” but could not elaborate. He recognized that he
had lost his job but said it was because the partners at
work were jealous of his success. On examination, he
had increased speech output and asked repetitive ques-
tions, but his speech was fluent and sensible, and he fol-
lowed complex commands quickly and accurately. He
did not persist in following commands—for instance,
he would close his eyes when asked by the exam-
iner but repeatedly opened them immediately before
the examiner asked him to (motor impersistence). He
stared at the examiner for long periods of time, and
he interrupted the examination twice to tell off-color
jokes. The rest of the physical neurologic examination
was unremarkable.
On neuropsychological testing, he scored 26/30 on the
Mini–Mental State Examination (MMSE), had a flat learn-
ing curve on a test of verbal memory, and had particular
difficulty with the Stroop interference task and impaired
fluency, particularly phonemic fluency, as he named three
words beginning with the letter D in 1 minute.
His MRI scan (Figure 9.6) showed right greater than left
frontotemporal atrophy, with particular orbitofrontal and
caudate atrophy.
Symptoms in bvFTD
Sometimes referred to as frontal variant or simply as
FTD, bvFTD is the most common presentation of FTD,
comprising about 50% of cases, with svPPA and nfvPPA
making up the other 50% (Johnson et al., 2005). The
symptoms begin with insidious changes in behavior and
Figure 9.6 MRI axial, coronal, and sagittal T1 showing bifrontal atrophy, more on the right.
personality. Frequently, these are felt either to be psychi-
atric in nature or to represent a “midlife crisis” (Woolley
et al., 2011). Typical early symptoms include disinhibi-
tion, apathy, loss of empathy, changes in eating behaviors,
and compulsive behaviors. Patients with bvFTD often
have a lack of insight into their own symptoms. Disin-
hibited acts can include socially inappropriate behaviors,
involving touching strangers, displaying a lack of man-
ners or response to social cues, or carrying out impul-
sive or anti-social actions such as stealing. Symptoms of
apathy include a loss of interest or motivation, as well
as decreased initiation of behavior. A distinction between
a disinhibited subtype and an apathetic subtype has
been proposed (Neary et al., 1988), although they tend
to be coexistent. Affected patients are often described as
cold, unfeeling, and indifferent to the emotions of others,
which can be illustrated by dramatic examples such as
the one detailed in Case 1, in which the patient was inap-
propriately casual about his daughter’s accident. Typical
eating behaviors include both overeating and displaying
a change in food preference, with more consumption of
sweet or high-carbohydrate foods, and sometimes devel-
oping food fads, such as insisting on foods from certain
establishments or foods of a certain color. Repetitive
motor behaviors can be observed, including simple ste-
reotypic behaviors such as tapping or rubbing, or com-
pulsive behaviors such as hoarding, checking, cleaning,
and arranging.
Imaging
Both structural and functional brain imaging reveals
abnormalities that can help support a diagnosis. Structural

imaging with CT or MRI typically shows a pattern of
atrophy that corresponds with the affected systems.
Atrophy is generally most prominent in the frontal
and/or the anterior temporal lobes. If there is asymmetry,
the right hemisphere is often more affected (Fukui, 2000).
The earliest structures affected include the anterior insula,
anterior cingulate, and orbitofrontal cortices (Seeley et al.,
2008), which are much less severely affected in Alzheimer’s
disease (Liu et al., 2004). The reason for the selective vul-
nerability of these regions in FTD is not known, but it has
been noted that these regions are the only location of large
bipolar projection cells, called von Economo neurons (See-
ley et al., 2006). These neurons are found only in humans,
great apes, certain whales, dolphins, and elephants, and
are particularly targeted in FTD. It has been suggested
that the introduction of these phylogenetically new cells
into these brain regions may have induced some vul-
nerability (Seeley, 2008). The prominent involvement of
these paralimbic structures that are known to be involved
in emotional processing (Lane et al., 1998; Craig, 2003)
explains the prominence of socioemotional dysfunction in
FTD, as specific symptoms such as apathy, disinhibition,
and loss of empathy have been correlated with structural
atrophy in particular portions of this network (Rosen et al.,
2005; Rankin et al., 2006). Even some of the bizarre changes
in eating behavior, compulsions, and lack of self-aware-
ness have been linked to specific portions of this network
(Tonkonogy et al., 1994; Rosso et al., 2001; Snowden et al.,
2001; McMurtray et al., 2006; Whitwell et al., 2007; Woolley
et al., 2007; Josephs et al., 2008; Piguet et al., 2011).
While structural imaging usually demonstrates specific
patterns of regional atrophy in bvFTD, functional brain
imaging such as positron emission tomography using
flourodeoxyglucose (FDG–PET) and single photon emis-
sion computed tomography using Tc-hexamethylpropyle-
neamine oxime (HMPAO–SPECT), which images cerebral
perfusion, has been frequently used to identify frontotempo-
ral abnormalities in FTD (Ishii et al., 1998; Foster et al., 2007).
Neuropsychological testing
Early in the course of the disease, patients may perform
well on traditional neuropsychiatric measures (Greg-
ory et al., 1999), because most neuropsychological tasks
assess executive functions mediated by dorsolateral pre-
frontal cortex rather than the medial and orbital portions
of the frontal lobe (Krueger et al., 2011). Degeneration of
the regions affected in FTD results in deficits in social cog-
nition. Accordingly, research studies have demonstrated
that FTD patients are impaired at recognizing emotion
(Lough et al., 2006), recognizing sarcasm (Kosmidis et
al., 2008), and appreciating another’s point of view (The-
ory of Mind) (Gregory et al., 2002). Efforts are currently
being made to develop tasks that examine these abilities
into assessment tools that can be used in a clinic, with
appropriate norms. As FTD progresses to involve the
Frontotemporal Dementia 241
more dorsal and lateral frontal regions, patients develop
deficits in many traditional tests of frontal executive func-
tions. These include tests such as the Trails B task, which
assesses the ability to flexibly switch between two differ-
ent types of responses (Strauss et al., 2006); the Stroop
task, which assesses the ability to inhibit automatic or
“prepotent” responses (Strauss et al., 2006); and pho-
nemic fluency, which assess the ability to continually
generate novel responses (Henry and Crawford, 2004).
While everyday memory is often relatively spared in
FTD, performance on tests of verbal and visual memory
can be variable (Pasquier et al., 2001; Hornberger et al.,
2010). Similarly, visuospatial function is relatively spared,
although performance on tasks may be affected by poor
planning or organization (Kramer et al., 2003).
Primary progressive aphasia
The term primary progressive aphasia (PPA) refers to progres-
sive disorders in which language deterioration is the most
prominent symptom and the primary cause of a patient’s
impairment for the initial period of the illness (Weintraub
et al., 1990; Mesulam, 2001). This category includes three
syndromes: semantic variant PPA (previously referred
to as semantic dementia), nonfluent or agrammatic PPA
(also referred to as progressive nonfluent aphasia), and
logopenic progressive aphasia. The details of all these
syndromes are discussed in Chapter 9.6, so they are
briefly reviewed here. SvPPA is characterized by progres-
sive deterioration in knowledge about words and objects.
It begins with word finding and sometimes subtle word
recognition difficulties, and progresses to involve loss of
knowledge about objects and what they do. The disease
appears to begin in the left temporal pole, and often dra-
matic, asymmetric medial temporal atrophy can easily be
appreciated on MRI (Seeley et al., 2005). When the disease
begins on the right side, knowledge about faces can be an
early deficit, such as not recognizing famous faces of poli-
ticians or entertainers (Snowden et al., 2004). In addition,
patients with right temporal disease often present mainly
because of behavioral problems such as loss of empathy,
but at least some evidence of word finding and word rec-
ognition difficulties is often evident (Thompson et al.,
2003). Whether the disease begins on the right or left,
svPPA patients usually develop behavioral symptoms
typical of bvFTD within 3 or 4 years of onset, presumably
because of spread of the disease from temporal to frontal
structures (Seeley et al., 2005). NfvPPA is characterized by
slow, hesitant speech and difficulty with articulation and
agrammatism (decreased use of grammatical function
words) and is anatomically associated with atrophy and
hypometabolism in the left inferior frontal region (Gorno-
Tempini et al., 2004a; Josephs et al., 2006). Although
behavioral problems can develop over time in nfvPPA,
they have less of the dramatic change in socioemotional
function seen in bvFTD and svPPA (Rosen  et  al., 2006).
242 Neurologic Conditions in the Elderly
Logopenic aphasia is characterized by hesitant speech
and profound difficulty with word finding but relatively
preserved word comprehension. Imaging usually shows
left posterior temporal and parietal abnormalities. While
svPPA and nfvPPA are usually associated with FTLD
pathology, logopenic aphasia is usually associated with
underlying Alzheimer’s disease
Other clinical syndromes associated with FTD
Although bvFTD, svPPA, and nfvPPA represent the core
clinical syndromes of FTD, emerging research has demon-
strated that several other neurodegenerative syndromes
are associated with FTLD pathology at autopsy and have
overlapping clinical features. These syndromes are now
often included in discussions of FTD as “FTD-spectrum”
or “FTLD-spectrum.”
Frontotemporal dementia with motor
neuron disease (FTD-MND)
About 10–15% of patients with FTD also develop MND,
similar to what is seen in amyotrophic lateral sclerosis
(ALS, also known as Lou Gehrig’s disease) (Lomen-
Hoerth et al., 2002). This combination is associated
with the most rapid progression and shortest survival
(Roberson et al., 2005). MND may occur with any of
the three core FTD syndromes, but it is most likely to
occur with bvFTD. MND is characterized by muscular
weakness, atrophy, and fasciculations (twitching) due to
degeneration of anterior horn cells in the spinal cord, as
well as pyramidal signs such as spastic tone and hyper-
reflexia due to degeneration of neurons in the primary
motor cortex. The symptoms frequently involve the
bulbar muscles (tongue, face, those associated with
swallowing), and this is more common when MND is
associated with FTD. Either cognitive or motor symp-
toms may present first. When FTD is associated with
MND, patients may have strong, uncontrollable bursts
of laughing or crying, referred to as pseudobulbar affect
(PBA) (Chang et al., 2005), and symptoms of PBA in the
setting of FTD should prompt investigations for MND.
The behavioral symptoms in FTD-MND are similar to
those occurring in FTD without MND, although psy-
chotic symptoms are more common in FTD-MND (Lillo
et al., 2010). Imaging in FTD–MND can sometimes be
less dramatic than in FTD without MND. Although ALS
was traditionally thought to be associated with demen-
tia very rarely, the occurrence of MND in the setting of
FTD prompted researchers to examine patients with
ALS more closely. These studies revealed that a small
percentage of patients presenting to neuromuscular clin-
ics with only motor complaints actually have substan-
tial cognitive and behavioral problems consistent with
FTD (Murphy et al., 2007), and that up to 50% of ALS
patients have more subtle cognitive deficits detectable
using psychometric or quantitative assessment. These
findings further cemented the link between FTD and
ALS (Lomen-Hoerth et al., 2003; Murphy et al., 2007).
Progressive supranuclear palsy
Progressive supranuclear palsy has traditionally been
included in neurologic texts as an atypical form of par-
kinsonism. The disorder is characterized by progressive
difficulty with balance, resulting in falls; progressive stiff-
ness of the body and neck (called axial rigidity); and an
inability to voluntarily move the eyes (supranuclear gaze
palsy). In addition, many patients develop cognitive dif-
ficulties suggesting frontal lobe dysfunction, and they fre-
quently develop behavioral and or language symptoms
seen in bvFTD and nfvFTD. PSP patients can also initially
suffer from these cognitive or behavioral symptoms, with
minimal or very subtle motor difficulties, and only then
progress to develop the typical motor features of PSP. This
symptomatic overlap, along with the fact that PSP is asso-
ciated with the pathologic features of FTLD, has led to its
inclusion with FTD-spectrum disorders.
Corticobasal syndrome
Corticobasal syndrome is another atypical parkinsonian
disorder that shows symptomatic and pathologic over-
lap with FTD and is also a disorder in which the true
spectrum of clinical presentation is in flux. Traditionally,
CBS (often called corticobasal degeneration, or CBD) was
described as a cognitive and motor disorder with mark-
edly asymmetric movement difficulties, including tremor
and myoclonus (jerking), rigidity and dystonia, alien limb
(tendency for the limb to move on its own and sometimes
interfere with movements of other limbs), and asymmetric
sensory problems, suggesting dysfunction in the somato-
sensory cortex. Studies have also described language dif-
ficulties similar to nfvPPA or, less commonly, lvPPA, as
well as profound visuospatial disturbances and neglect of
the left side of space (Rebeiz et al., 1968; Gorno-Tempini
et al., 2004b). Recent studies have suggested that many
CBS patients, even with asymmetric motor symptoms,
have Alzheimer’s pathology (Boeve et al., 1999; Hu et al.,
2009) and those with AD pathology have more tempo-
roparietal atrophy (Whitwell et al., 2010). When CBD is
found pathologically, patients can present with the asym-
metrical motor symptoms or with cognitive and behav-
ioral deficits typical of frontal lobe dysfunction similar
to those seen in FTD, and they may not have significant
motor deficits (Lee et al., 2011).
Pathology
One of the challenges clinicians who see patients with
neurodegenerative disorders, face is translating the clini-
cal syndrome that a patient presents with into a predic-
tion of the underlying molecular and histopathology.
These correlations will be more relevant as treatments
are developed that target the molecular basis of disease.

Unfortunately, this prediction is made more complicated
by the fact that FTLD is associated with more than one
type of pathology.
All subtypes of FTLD pathology show gross frontal and
temporal lobe atrophy, as well as neuronal loss, variable
gliosis, and microvacuolation (Brun, 1987). Subtypes are
differentiated from each other by the types of neuronal
inclusions and other morphologic features. The earliest
reports of FTLD described Pick bodies (Alzheimer, 1911),
which were later recognized to contain hyperphosphory-
lated tau proteins. Subsequently, many cases of FTLD
were described with tau inclusions but not necessarily
Pick bodies; however, this still accounted for only about
half of cases of FTLD. The pathologic descriptions for the
other half have evolved over time, having been described
for many years as dementia lacking distinctive pathology
(Knopman et al., 1990). Subsequently, more careful stain-
ing demonstrated that many patients who would have
been described in this way actually show tau-negative
ubiquitinated inclusions, termed FTLD-U. In 2006, it was
discovered that the ubiquitinated protein in these cases is
the 43 kD TAR DNA binding protein (TDP-43) (Neumann
et al., 2006). Now it is recognized that these two patholo-
gies, tau inclusions or TDP-43 inclusions, are approxi-
mately found in equal frequencies in bvFTD and account
for the majority of cases (Snowden et al., 2007). Recently,
it was discovered that patients showing inclusions with
the fused in sarcoma (FUS) protein explain most of rest
of the cases.
Tau
The tau protein, which is also called microtubule associ-
ated protein tau (MAPT), is coded on chromosome 17
and is important for stabilizing microtubules; it sup-
ports molecular transport within neurons (Weingarten
et al., 1975). The protein exists in two forms created by
alternative splicing, which leads to a three amino acid
sequence repeat form (3R) and a four-repeat form (4R).
Both forms are present in normal cells, but some pathol-
ogies are associated predominantly with one form. Pick
bodies, the classic histopathology in FTLD, contain the
3R form of tau (Figure 9.8). Pick cells, or achromatic bal-
looned neurons, are associated with Pick bodies, and
many patients have Pick cells without Pick bodies. Other
pathologic settings dominated by tau pathology include
FTD with parkinsonism linked to chromosome 17, a
genetic form associated with mutations in the MAPT
gene; this is a mixture of 3R and 4R tau. The rarer tangle-
dominant dementia (TDD) and the Guam ALS Parkin-
son’s dementia complex are also 3R+4R mixtures. CBD
and PSP are both 4R tau forms. CBD is associated with
tau immunoreactive astrocytic plaques and glial threads
and coils. PSP is characterized by globose neurofibril-
lary tangles and tufted astrocytes (Cairns et al., 2007).
Argyrophilic grain disease (AGD) and multiple system
Frontotemporal Dementia 243
tauopathy with dementia are rarer 4R tau pathologies
(Cairns et al., 2007).
TDP-43
The functions of the TDP-43 protein are not completely
understood, but it is a normal constituent of neurons.
In these circumstances, staining is limited to the nuclei,
which is consistent with data indicating that TDP-43 is
a regulator of DNA transcription (Buratti and Baralle,
2008). In FTLD, TDP-43 inclusions are found in the cyto-
plasm, and various patterns of staining have been rec-
ognized based on whether the TDP-43 appears to be
collecting mostly in the cytoplasm of the neuronal bod-
ies, the dendrites, or both. This classification is impor-
tant because certain pathologic subtypes are associated
with specific clinical presentations. The Sampathu clas-
sification (Sampathu et al., 2006) recognizes four types
of TDP-43 pathology. Type I has long dystrophic neu-
rites in superficial layers and few neuronal cytoplasmic
inclusions. Type II has numerous neuronal cytoplasmic
inclusions in superficial and deep cortical layers with
infrequent neurites. Type III includes frequent small dys-
trophic neurites and neuronal cytoplasmic inclusions
and may have neuronal intranuclear inclusions. Type IV
is relatively rare and includes dystrophic neurites and
intranuclear inclusions. At the time that the link between
TDP-43 and FTLD was discovered, it was also found to
be present in the majority of patients with ALS, which
provides a pathologic basis for the clinical links between
ALS and FTD noted earlier (Neumann et al., 2006; Mack-
enzie et al., 2007).
FUS
Fused in sarcoma (FUS) pathology was initially discov-
ered in patients with familial ALS. Soon thereafter, it was
discovered in patients with FTD (Neumann et al., 2009a).
Basophilic inclusion body disease (BIBD) (Munoz et al.,
2009), neuronal intermediate filament disease (NIFID)
(Neumann et al., 2009b), and atypical FTLD-U (aFTLD-U)
are rare pathologies in the FTLD spectrum that are now
attributed to FUS pathology as well.
Other
Some cases still have no inclusions and thus “lack distinc-
tive histopathology.” Other cases, termed FTD-3, are dis-
cussed shortly with the corresponding genetic mutation.
Clinical–pathologic correlation
Overall, the relationship between the specific clinical
presentation and the molecular and histopathology is far
from a 1:1 correlation (Figures 9.7), but some clinical pre-
sentations are fairly predictive of specific pathologies.
SvPPA is usually caused by TDP-43 pathology, spe-
cifically Sampathu Type I (Gorno-Tempini et al., 2004a),
although it can also be caused by Alzheimer’s disease
244 Neurologic Conditions in the Elderly
PPA
PSP CBS bvFTD svPPA nfvPPA lvPPA
FTLD-TAU FTLD-FUS FTLD-TDP
and very rarely by tau pathology (Davies et al., 2005).
Nonfluent PPA is often caused by tau pathology, usu-
ally PSP or CBD (Josephs et al., 2006), although it can
be the result of other pathologies as well (Kertesz et al.,
2005). ALS, with or without FTD, is caused by Sympathu
Type II pathology. Type III pathology is seen in patients
with familial FTD associated with Progranulin muta-
tions and can cause multiple other sporadic FTD syn-
dromes. Type IV pathology is also associated with famil-
ial cases of FTD, inclusion body myositis, and Paget’s
disease of bone due to mutations in Valosin-containing
protein (VCP).
Clinically, patients with FUS pathology have a young
age of onset and often have a psychiatric presentation
Figure 9.8 Pick’s bodies detected in a 74-year-old woman with
progressive nonfluent aphasia due to Pick’s disease. A 3-repeat
tau antibody was applied to the dentate gyrus, where Pick bodies
can easily be detected due to the neuronal packing density of the
structure. Hematoxylin counterstain. Courtesy of W.W. Seeley,
University of California, San Francisco.
FTD-MND Figure 9.7 Clinical and pathologic correlates
between FTD spectrum syndromes and FTLD
pathologies. PSP, progressive supranuclear palsy;
CBS, corticobasal syndrome; bvFTD, behavioral
variant frontotemporal dementia; PPA, primary
progressive aphasia; svPPA, semantic variant primary
progressive aphasia; nfvPPA, nonfluent variant
primary progressive aphasia; lvPPA, logopenic
variant primary progressive aphasia; FTD-MND,
frontotemporal dementia with motor neuron disease;
FTLD-tau, frontotemporal lobar degeneration with
tau pathology; FTLD-TDP, FTLD with TAR DNA-
binding protein 43 (TDP-43) pathology; FTLD-FUS,
AD FTLD with fused in sarcoma (FUS) pathology;
AD, Alzheimer’s disease.
(Urwin et al., 2010). Their imaging is associated with more
caudate atrophy than other pathologies (Josephs et  al.,
2010).
While svPPA and nfvPPA are strongly associated with
specific pathologies, bvFTD is associated about equally
with tau or TDP-43 pathology, and no clinical features
are currently recognized as predicting the subtype. Some
patients with bvFTD show Alzheimer’s pathology. In
some cases, this is seen in addition to FTLD pathology,
but in many cases, Alzheimer’s pathology appears to be
the only cause.
When the supranuclear gaze difficulties characteristic
of PSP are present, PSP pathology is highly likely (Litvan
et al., 1996). As noted earlier, the clinical features of CBS
can be associated with various pathologies, including
Alzheimer’s disease, and the features predicting CBD
pathology are still being resolved.
Genetics
The majority of cases of FTD are sporadic and there is
no clear pattern of inheritance. About 10% are associated
with an autosomal dominant inheritance pattern. About
40% of patients have a family history of dementia or psy-
chiatric conditions but do not necessarily have a clear
inheritance pattern (Goldman et al., 2005). There are two
haplotypes of tau, H1 and H2, and the H1/H1 genotype
has been associated with an increased risk of developing
4R tau disorders, PSP or CBD (Baker et al., 1999; Houlden
et al., 2001).
MAPT
The MAPT gene, found on chromosome 17, contains more
than 40 different currently recognized disease-causing
mutations. Carriers of this gene develop symptoms at a
younger age than sporadic cases, and imaging reveals a
more symmetric pattern of atrophy, with more temporal
lobe atrophy than other cases (Whitwell et al., 2009b).

There is also some suggestion that different mutations
may be associated with different patterns of atrophy
(Whitwell et al., 2009a).
PGRN
Mutations in the progranulin gene (also on chromo-
some  17) can cause a wide variety of clinical presenta-
tions, including not only symptoms of bvFTD, but also
parkinsonism, memory impairment, hallucinations or
delusions, and a nonfluent aphasia, often without apraxia
of speech. The atrophy pattern tends to be more asym-
metric and more posterior than other forms of FTLD.
The mechanism by which PGRN mutations lead to TDP-
43 pathology is currently unclear. In contrast to MAPT,
mutations in PGRN lead to haploinsufficiency rather than
a toxic gain of function.
CHMP-2B
The gene CHMP-2B (charged multivesicular body pro-
tein 2B, also referred to as chromatin-modifying protein
2B) is found on chromosome 3. It encodes a component
of the endosomal sorting complex required for trans-
port III and causes the type of FTLD known as FTD-3.
It is not associated with tau, TDP-43, or FUS pathol-
ogy. It is extremely rare and described in only a few
families, with the original one being Danish (Gydesen
et al., 2002).
VCP
Valosin-containing protein mutations on chromosome 9
are associated most commonly with an inclusion body
myositis and, in some affected, individuals also with
symptoms of Paget’s disease of bone and FTD. VCP muta-
tions have also been associated with familial ALS.
Other
Some families show an autosomal dominant pattern of
inheritance of FTD without a known gene. It is consid-
ered likely that a gene resides on chromosome 9 that
is associated with FTD and MND (Morita et al., 2006;
Vance et al., 2006), but the gene itself has not yet been
discovered. Genome-wide association studies (GWAS)
have been performed to look for additional genes that
may confer risk. While variants in several genes have
been found to increase risk in single studies, none of
these results have yet been replicated. Mutations in the
TDP-43 and FUS genes have been found and linked
mostly to familial ALS, with rare associations with an
FTD presentation.
Diagnosis
Criteria published in 1994 (The Lund and Manchester
Groups, 1994) and 1998 (Neary et al., 1998) have been
used most commonly for diagnosis. These criteria have
proven difficult to use in clinical practice because not all
Frontotemporal Dementia 245
patients meet the major criteria, and many of the minor
criteria in these publications occur too inconsistently to
be clinically useful (Rascovsky et al., 2007). New, simpler
criteria have been proposed by an international consensus
panel and are being validated (Table 9.11). Whereas prior
criteria depended only on clinical features for diagnosis,
the new criteria make use of newer knowledge about
biomarkers to increase the certainty of diagnosis. Thus,
while clinical features can be used to make a diagnosis of
possible bvFTD, imaging findings consistent with FTD—
such as PET hypometabolism or atrophy in the frontal
lobes, or mutations associated with FTD—are necessary
to increase the certainty to a probable diagnosis. The use
of imaging is supported by studies showing that imaging
enhances the accuracy of diagnosis (Foster et al., 2007).
In fact, a subset of patients has been identified who meet
Table 9.11 Proposed international consensus criteria for bvFTD
I. Required criterion: Progressive deterioration of behavior and/or
cognition by observation or history
II. Possible bvFTD (three of six required)
A. Early behavioral disinhibition—socially inappropriate behavior, loss
of manners or decorum, or impulsive actions
B. Early apathy or inertia
C. Early loss of sympathy or empathy
D. Early perseverative, stereotyped, or compulsive/ritualistic behavior
E. Hyperorality and dietary changes
F. Neuropsychological profile: executive/generation deficits with
relative sparing of memory and visuospatial functions
III. Probable bvFTD (all of the following required)
A. Meets criteria for possible bvFTD
B. Significant functional decline
C. Imaging results consistent with bvFTD (frontal and/or anterior
temporal atrophy on CT or MRI or frontal hypoperfusion or
hypometabolism on SPECT or PET)
IV. bvFTD with definite FTLD pathology (one and either two or
three required)
A. Meets criteria for possible or probable bvFTD
B. Histopathologic evidence of FTLD on biopsy or at postmortem
C. Presence of a known pathogenic mutation
V. Exclusion criteria for bvFTD (criteria A and B must both be
answered negatively; criterion C can be positive for possible bvFTD
but must be negative for probable bvFTD)
A. Pattern of deficits is better accounted for by other nervous system
or medical disorders
B. Behavioral disturbance is better accounted for by a psychiatric
diagnosis
C. Biomarkers strongly indicative of Alzheimer’s disease or other
neurodegenerative process
Additional features
A. Onset before age 65
B. Presence of MND
C. Motor symptoms and signs similar to CBS and PSP
D. Impaired word and object knowledge
E. Motor speech deficits
F. Significant grammatical deficits
246 Neurologic Conditions in the Elderly
clinical criteria for bvFTD but either do not progress in
time or progress very slowly (Kipps et al., 2007). Imag-
ing and neuropsychological performance in this group is
normal. This group has been referred to as FTD pheno-
copy, implying that the etiology in these cases is not FTD,
although this has yet to be established, and the etiology of
clinical symptoms in these cases is not known. The reason
for lack of progression is unclear. Imaging studies tend to
be normal (Davies et al., 2006). Similarly, new knowledge
about the clinical and imaging features and of PPA has led
to new criteria for these disorders (Gorno-Tempini et al.,
2011).
The development of additional biomarkers to
identify the molecular subtype in each case of FTD is
currently of great interest. Some patients with clinical
features of FTD show AD pathology at autopsy, and
spinal fluid levels of tau and amyloid have shown
promise for discriminating between FTLD and AD
(Bian et al., 2008). PET ligands are also available for
detecting amyloid plaques in vivo, providing another
approach for making this distinction. Recent work
has suggested that it may be possible to distinguish
FTLD-tau from FTLD-TDP based on assaying multiple
specific CSF analytes (Hu et al., 2010). Low progranu-
lin levels measured in serum, plasma, and CSF have
been found in patients with progranulin mutations
(Coppola et al., 2008; Ghidoni et al., 2008; Finch et al.,
2009; Sleegers et al., 2009). One study suggested that
elevated serum TDP-43 levels might be useful (Foulds
et al., 2008). All these findings, however, must still be
considered preliminary.
Treatment
No medications are approved by the US FDA for the treat-
ment of FTD. Limited evidence exists regarding symp-
tomatic treatment. Treatments directed at specific molecu-
lar targets are currently being developed.
Symptomatic
Nonpharmacologic methods of dealing with behavioral
symptoms are important, particularly given the lack of
proven pharmacologic treatments. Caregiver education
regarding the effects of the disease and an approach of
ensuring safety while otherwise avoiding confrontation
may be helpful. It is important for caregivers to realize
that rational debate or argument may not be helpful in
modifying the patient’s behavior.
The pharmacologic agents used in AD are not neces-
sarily useful in FTD, which affects different neural net-
works. FTD is not associated with a cholinergic deficit,
and there is no strong evidence for the use of cholines-
terase inhibitors in FTD. In one open-label trial, donepe-
zil showed no beneficial cognitive effect and resulted in
worsening of behavior (Mendez et al., 2007). An open-
label study of rivastigmine showed improvement in
neuropsychiatric symptoms but not cognition (Moretti
et al., 2004), and another study of galantamine showed
a nonsignificant trend toward language improvement in
a cohort of PPA patients that may have included some
with lvPPA (Kertesz et al., 2008). Weak evidence sup-
ports the use of memantine. Two open-label studies
have shown that the medication is well tolerated (Diehl-
Schmid et al., 2008; Boxer et al., 2009). A double-blind,
placebo-controlled trial in France recently showed no
improvement with memantine after 1 year (Vercelletto
et al., 2011). Another study in the United States is cur-
rently underway.
Behavioral symptoms can be treated with antidepres-
sants, particularly serotonergic agents. Open-label studies
of fluoxetine, fluvoxemine, sertraline, and paroxetine have
shown efficacy in controlling behaviors (Swartz  et  al.,
1997; Ikeda et al., 2004b). Paroxetine was effective in a
placebo-controlled study (Moretti et al., 2003a), although
a separate, very brief randomized study of this drug
showed no effect (Deakin et al., 2004). Trazodone has also
been shown effective in one study (Lebert et al., 2004).
No evidence supports the use of mood-stabilizing agents.
Antipsychotic medications should be used with caution,
given the unfavorable side effect profile, and the US FDA
has advised extra caution in using these agents. Seroquel
has less D2 receptor antagonism, making it a more appeal-
ing choice for avoiding extrapyramidal side effects. Data
show benefit only for olanzapine (Moretti et  al., 2003b)
(one open-label study), ariprazole (Fellgiebel et al., 2007),
and risperidone (single-case reports) (Curtis and Resch,
2000).
Disease modifying
The ultimate goal of treatment is not to ameliorate
symptoms but to cure disease. Current efforts are
underway to develop medications to target tau and
TDP-43 pathology. Tau-active drugs in development
include those that prevent tau kinase activity to block
phosphorylation and those that clear tau aggregates,
microtubule stabilizers, and aggregation inhibitors. A
pilot study of one such drug has recently been com-
pleted in PSP, and a Phase III study is underway. Pro-
granulin mutations result in their deleterious effect
through haploinsufficiency, so treatments aimed at this
molecular pathology are intended to increase progran-
ulin levels.
Conclusion
The term frontotemporal dementia encompasses multiple
distinct clinical phenotypes with personality, behav-
ior, and language changes, as well as extrapyramidal

syndromes and MNDs. It is caused by multiple distinct
pathologies and, in some cases, genetic mutations. Treat-
ments are currently symptomatic, but molecular-based
treatments are in development.
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 Chapter 9.6
Primary Progressive Aphasia
Maya L. Henry, Stephen M. Wilson, and Steven Z. Rapcsak
Introduction
The term aphasia refers to impairments of spoken and
written language caused by neurologic disease or dam-
age. The fact that aphasia can be the initial and most
salient behavioral manifestation of a neurodegenerative
disorder has been known for more than 100 years (Pick,
1892; Serieux, 1893). In the modern era, interest in primary
progressive aphasia (PPA) was reignited by Mesulam’s
(1982) seminal report of six patients who presented
with slowly declining language function in the absence
of general cognitive impairment. Neuroimaging stud-
ies showed focal left-hemisphere atrophy involving the
perisylvian language areas. For the past three decades,
PPA has been the focus of intense study, leading to the
rapid accumulation of scientific information regarding
the clinical features and neurobiologic correlates of this
unique syndrome. In the course of these investigations,
it has become apparent that PPA is not a single, homo-
geneous entity. Patients may present with distinct lan-
guage profiles that, in turn, can provide important clues
regarding the anatomic distribution and possible etiology
of the underlying neuropathologic process. In particular,
the three PPA subtypes currently recognized (nonfluent/
agrammatic, semantic, and logopenic variants) demon-
strate a predilection for involving different functional
components of the left-hemisphere language network and
have different probabilities of association with patholo-
gies related to frontotemporal lobar degeneration (FTLD)
or Alzheimer’s disease (AD). In this chapter, we review
the clinical, neuroimaging, genetic, and neuropathologic
correlates of PPA, with the primary goal of outlining a
practical approach to diagnostic assessment. Accuracy in
predicting the underlying pathology based on in vivo cog-
nitive and neurologic evaluation is critical for identifying
individuals with PPA who might benefit from emerging
disease-modifying therapies.
Diagnosis of PPA
A diagnosis of PPA should be suspected in individuals
who present with gradual speech-language deteriora-
tion with early sparing of episodic memory, perceptual/
visuospatial processing, executive function, and social
behavior (Mesulam, 1982, 2001). It should be empha-
sized, however, that the sparing of nonverbal cognitive
functions is relative rather than absolute, and detailed
neuropsychological assessment may demonstrate mild
to moderate impairments outside the language domain.
In fact, certain nonverbal cognitive deficits are regularly
associated with specific PPA subtypes and thus may have
differential diagnostic value (such as impaired knowl-
edge of objects and people in the semantic variant of
PPA). At the same time, it is important to keep in mind
that language dysfunction can interfere with performance
on a variety of neuropsychological tests (due to a failure
to understand instructions or because of the requirement
for a verbal response) and, therefore, can artificially lower
scores on tests ostensibly measuring nonverbal cognitive
abilities. Despite these complexities, the diagnosis of PPA
is appropriate when language impairment is the domi-
nant behavioral abnormality at presentation and consti-
tutes the main functional impediment for the patient with
respect to activities of daily living (Mesulam, 1982, 2001).
Furthermore, even though other cognitive domains may
become increasingly compromised with disease progres-
sion, language function usually remains disproportion-
ately affected throughout the course of the illness.
The frequency of PPA is difficult to estimate, but it has
been suggested that approximately 20–40% of patients
with FTLD present with predominant language impair-
ment (Grossman, 2010). It is currently unknown what
percentage of patients with AD have aphasia as their
initial symptom, compared to the much more common
amnestic presentation of the disorder. However, some
autopsy series have reported that AD is the underlying
pathology in about 30% of patients with the clinical diag-
nosis of PPA (Knibb et al., 2006; Alladi et al., 2007). As a
general rule, patients with PPA are younger (often 55–65
years of age) than the characteristic age of onset for typi-
cal AD (>65). Although most cases appear to be sporadic,
familial PPA has been described in association with FTLD
spectrum pathology. The majority of these patients had
mutations of the progranulin (PGRN) gene on chromo-
some 17 (Snowden et al., 2006; Mesulam et al., 2007; Beck
et al., 2008). Although mutations of the microtubule-
associated protein-tau (MAPT) gene on chromosome 17
can also be associated with progressive language impair-
ment, these patients typically present with a behavioral/
social disorder (Snowden et al., 2006; Pickering-Brown
et al., 2008).
When the clinical diagnosis of PPA is established and
nondegenerative etiologies (such as stroke, tumor, and
251
252 Neurologic Conditions in the Elderly

Table 9.12 Consensus criteria for diagnosis of PPA variants

Speech–language-associated Predicted
Speech–language core characteristics characteristics Typical imaging findings neuropathology

Nonfluent One of the following must be present:
variant 1) Agrammatic production
2) Effortful, halting speech with speech
sound errors, including distortions,
deletions, insertions, substitutions,
transpositions (consistent with
apraxia of speech)
Semantic Both of the following must be present:
variant 1) Impaired confrontation naming
2) Impaired single word comprehension
Logopenic Both of the following must be present:
variant 1) Impaired word retrieval in
spontaneous speech and
confrontation naming
2) Poor repetition of sentences and
phrases
Two of the following must be present: Left anterior perisylvian/ FTLD-tau (Pick’s,
1) Agrammatic comprehension fronto-insular atrophy and/or CBD, PSP)
2) Spared single-word comprehension hypometabolism FTLD-TDP-43
3) Spared object knowledge
Three of the following must be present: Asymmetrical (L>R) anterior FTLD-TDP-43
1) Poor object knowledge temporal lobe atrophy and/
2) Surface dyslexia/dysgraphia or hypometabolism
3) Spared repetition
4) Spared grammar and motor speech
Three of the following must be present: Left posterior perisylvian/ Alzheimer’s
1) Phonologic errors in speech temporoparietal atrophy disease
2) Spared single-word comprehension and/or hypometabolism
and object knowledge
3) Spared motor speech
4) Absence of agrammatism

Source: Adapted from Gorno-Tempini et al. (2011) with permission from Lippincott Williams & Wilkins.

subdural hematoma) for the language disorder have been
successfully ruled out by routine imaging studies (CT/
MRI), an attempt should be made to determine the spe-
cific PPA phenotype (Gorno-Tempini et al., 2011). As noted
earlier, PPA is a heterogeneous syndrome comprising dis-
tinct variants that are associated with different underlying
pathologic processes. In clinical practice, the identification
of PPA subtypes is based primarily on precise character-
ization of the language phenotype supported by neuroim-
aging evidence of signature patterns of localized cortical
atrophy/hypometabolism within the left-hemisphere lan-
guage network. Additional diagnostic information can be
obtained from neuropsychological evaluation, molecular
imaging with Pittsburgh Compound B (PIB) that tags beta
amyloid deposits in the brain, genetic testing, and the use
of cerebrospinal fluid (CSF)/blood biomarkers. The high-
est accuracy in predicting the underlying brain pathology
will likely be achieved by combining information from
multiple sources (Wilson et al., 2009b; Hu et al., 2010).
Clinical features and neurobiologic
correlates of PPA subtypes
Behavioral profiles of individuals with PPA are often
categorized broadly into three subtypes or variants:
nonfluent/agrammatic, semantic, and logopenic. The
clinical classification of patients into one of these PPA
subgroups is based on identifying the unique combina-
tion of impaired and preserved language and cognitive
abilities that characterizes each phenotype. It should be
noted, however, that subtyping patients is not always a
straightforward exercise, as symptoms may overlap and
linguistic profiles may change as the disease evolves. For
instance, a number of researchers have commented that
the binary assignment of patients into nonfluent vs. flu-
ent subgroups can be problematic (Rogers and Alarcon,
1999; McNeil and Duffy, 2001), and Kertesz and col-
leagues (2003) suggested that fluency status in PPA may
be a function of disease progression rather than an indi-
cator of distinct syndromes. Nonetheless, diagnosis by
variant is viewed as an increasingly feasible and impor-
tant endeavor, as specific language phenotypes are pre-
dictive of patterns of brain atrophy/hypometabolism and
also provide clues about the underlying neuropathology.
An international group of experts recently put forth
a set of consensus criteria for identifying PPA variants
(Gorno-Tempini et al., 2011; Table 9.12), including both
core and supportive features, as well as criteria for imag-
ing- and pathology-supported diagnosis. This effort was
intended to streamline and standardize the diagnostic
process, in hopes of facilitating scientific exchange across
clinics and laboratories and furthering efforts to develop
appropriate selection criteria for entering patients into
therapeutic trials. It is acknowledged, however, that these
diagnostic criteria are most clearly applicable in the early
stages of the disease and that certain patients will not eas-
ily fit into any taxonomic category.
The nonfluent/agrammatic
variant of PPA
The nonfluent variant is clinically identified by
agrammatic language and halting, effortful speech
production with speech-sound errors as core features.

Variable pathologies may underlie nonfluent PPA such as
FTLD spectrum disorders, including tauopathies (Pick’s
disease, progressive supranuclear palsy (PSP), cortico-
basal degeneration (CBD)) and TDP-43 proteinopathies.
Speech–language profile
The current consensus criteria identify agrammatic lan-
guage and halting, effortful speech production with
speech-sound errors as core features in nonfluent PPA.
Either must be present for diagnosis (Gorno-Tempini
et al., 2011; Table 9.12). Speech is slow in rate (approxi-
mately 70% reduction in the number of words produced
per minute, compared to healthy controls; Ash et al.,
2010; Wilson et al., 2010b) and consists mostly of con-
tent words (nouns > verbs), with omission of function
words (articles, prepositions, and pronouns) and bound
grammatical morphemes (such as the past tense). Syn-
tactic structure is simplified, and grammatical errors
include noun–verb agreement violations (as in “The girl
are running”) and tense errors (as in “Tomorrow I ate
lunch”) (Grossman et al., 1996; Turner et al., 1996; Wil-
son et al., 2010b). Although frankly telegraphic speech
output is rare (Knibb et al., 2009), it may emerge with
disease progression. In general, however, agrammatism
in production is not as severe as that observed in patients
with Broca’s aphasia due to vascular pathology (Graham
et al., 2004). (See Box 1 for a sample of connected speech
from an individual with nonfluent PPA.) Comprehen-
sion deficits, particularly for complex syntactic struc-
tures, are also noted in nonfluent PPA, consistent with
a central syntactic deficit (Hodges and Patterson, 1996;
Gorno-Tempini et al., 2004a; Grossman and Moore, 2005;
Peelle et al., 2008).
Whereas initial characterizations of nonfluent PPA
emphasized agrammatism, motor speech impairment
is now viewed as an important feature of the syn-
drome and, in some cases, may be the presenting sign
(Ogar et  al., 2007). In these patients, speech produc-
tion is effortful, with prominent impairment of motor
planning or apraxia of speech (AOS); dysarthria may
also be present (Gorno-Tempini et al., 2004a; Josephs
et al., 2006a; Ogar et al., 2007; Rohrer et al., 2010b).
In severe cases, motor speech production deficits can
progress to complete mutism (Gorno-Tempini et al.,
2006). Ogar et al. (2007) examined speech errors in
18 individuals with nonfluent PPA and found that
7 patients demonstrated AOS without dysarthria, with
the remainder exhibiting both types of motor speech
deficits. Features of AOS included slow, halting speech
and effortful “groping” of the articulators, with incon-
sistent distortions, deletions, substitutions, insertions,
and transpositions of speech sounds. Dysarthria was
described as spastic, hypokinetic, or mixed spastic–
hypokinetic. Disturbances of speech prosody (melody
and intonation) were also common.
Primary Progressive Aphasia 253
Box 1. Connected speech samples from
each PPA variant. Patients are asked to
describe the “picnic scene” picture from
the Western Aphasia Battery
Nonfluent variant
Um the dinner the parents have the /tıknık/ and um the
car is the driving the driveway. The um the kid um boy
is crying (flying) it the. . . it’s the /klaıt/ flying. The dog
is the um. . . someone is fishing on the dock. It’s the. . .
another kid is um it’s the water . . . it’s the lake. And two
things um two things is uh sailboat on the water and um
flag is flying. The um parents have um all um /radi/
(radio) and it’s the um tree is shade and um it’s the home
and the back of the tree and the um father is um /bεlf t/
(barefoot) in the uh sand and uh he was reading and the
wife is um um trying to um drink. It’s the um coffee or
so and um. . . the um ball is the lake is the um it’s the um
sand is the /pll/ um pail . . . and sail boat.
Semantic variant
Well there’s a man and a lady that uh are close by . . .I
don’t know if they’re close by their house but they’re
close by the . . .water. Now, I say the water but I can’t
remember . . . I don’t remember what this (lake) is.
There’s a . . .there’s some people in the water that are
using their. . . I don’t remember that word. And um
there’s a person in the water and this is a . . . I don’t
remember. . . what’s the name (sailboat)? And this man
or boy has something up on the top (kite). There’s a
car in the house and there’s a tree. And these people. . .
this boy is reading something and she is eating. . . she is
drinking. And they probably have a . . . phone? No not
a phone. . .music (radio) here and probably some food
in there.
Logopenic variant
Ok looks. . .a. . . looks like a. . . a family having a picnic.
Dad is /dri/ uh. . .um. . . reading a book. He took his
foot. . .uh. . .shoes off and the uh. . . food is in that basket.
His. . .uh. . .wife is pouring a. . . drink for the. . .picnic. And
the r. . .radio is on. There’s a truck (car) over here behind
this tree. There’s a boy with a. . . kite. . . across the water.
There’s a dog. . .just one dog. There’s a man. . . off of the
dock. . .fishing. There’s a boy. . . playing in the sand. And
then there’s. . .a. . .uh. . .what is that? Oh a /t∫^k/ . . .no not
a /t∫^k/ . . .a shovel. . . and a. . .is that a. . . . . .pail? There’s
a. . .flag. . .on the pole.
Although the presence of speech-sound errors is a gen-
erally accepted feature of nonfluent PPA, the nature of
these errors is a matter of some debate. Some researchers
assert that speech-sound errors originate at a phonologic
rather than motoric or articulatory level (Mendez et al.,
2003). In particular, Ash et al. (2010), examined 16 individ-
uals with nonfluent PPA and concluded that the majority
254 Neurologic Conditions in the Elderly
of errors were phonemic (substitution of one well-formed
speech sound for another) rather than phonetic (a dis-
torted production of a speech sound, such as slurring a
consonant) and, thus, more consistent with a phonologic
than a motor speech deficit. This is in contrast to other
recent studies, which report that the majority of speech
production errors in nonfluent PPA are sound distortions
and, therefore, indicative of AOS (Wilson et al., 2010b).
Precise determination of the nature and origin of speech-
sound errors can be difficult, and errors should be eval-
uated in the broader context of the language profile. In
general, the presence of speech-sound errors (phonemic
or phonetic) in conjunction with agrammatism, reduced
utterance length, and a slow speech rate is strongly sug-
gestive of the diagnosis of nonfluent PPA.
Whereas syntax and speech production are typically
impaired in nonfluent PPA, single-word lexical com-
prehension and object knowledge are generally spared
(Gorno-Tempini et al., 2004a), even in patients with
severely reduced spontaneous language output. These
features, along with syntactic comprehension deficits,
are considered to be supportive of the clinical diagnosis
(Gorno-Tempini et al., 2011; also refer to Table 9.12) and
are important for distinguishing nonfluent PPA from
other variants (Mesulam et al., 2009), as in Figure 9.9. In
addition, some degree of anomia is typically observed
on tests of confrontation naming, and letter fluency
may be more impaired than category fluency (Gorno-
Tempini et al., 2004a). Although reading and spelling
impairments have been documented in nonfluent PPA,
the characteristic alexia/agraphia profile has not been
fully defined (Watt et al., 1997; Croot et al., 1998; Gra-
ham et al., 2004).
In summary, the linguistic profile of nonfluent PPA is
characterized by prominent impairments in the domains
of syntax, motor speech, and, by some accounts, phonol-
ogy, in the context of relatively preserved lexical-semantic
processing and object knowledge.
+naming impairment
=SV
=LV +single word comprehension impairment
=NFV = SV
-single word comprehension impairment
=LV +agrammatism OR effortful, halting
=NFV production, motor speech errors
=NFV
-agrammatism AND effortful, halting
production, motor speech errors
Figure 9.9 Decision tree for PPA diagnosis by variant: core features. SV, semantic variant; LV, logopenic variant; NFV, nonfluent variant.
Associated cognitive, behavioral, and
neurologic deficits
Impairment of frontal executive functions, specifically
working memory, has been noted in nonfluent PPA
(Libon et al., 2007). Buccofacial apraxia for nonverbal oral
movements may be present (Gorno-Tempini et al., 2004a;
Josephs et al., 2006a). Episodic memory for day-to-day
events is generally intact, but patients may experience
difficulty on formal memory tests using verbal materials.
Visuospatial processing is characteristically preserved.
Concomitant behavioral features may include apathy, agi-
tation, and depression (Rohrer and Warren, 2010).
Neurologic examination in patients with the language
profile of nonfluent PPA may reveal the presence of extra-
pyramidal signs, including an asymmetric akinetic-rigid
syndrome, limb apraxia, alien hand, dystonia, or myoc-
lonus suggestive of CBD. Other patients demonstrate
typical clinical findings associated with PSP, including
eye movement abnormalities (vertical gaze paralysis,
especially affecting downward gaze), axial/nuchal rigid-
ity, and severe postural instability, leading to frequent
falls. Finally, some individuals with nonfluent PPA show
neurologic signs consistent with motor neuron disease
(MND), including bulbar and limb weakness, muscle
wasting, and fasciculations.
Neuroimaging
Brain imaging can provide important diagnostic informa-
tion about the topographic distribution of the underlying
pathology in PPA. On structural imaging studies (CT/
MRI), nonfluent PPA is associated with anterior perisylvian
atrophy. There is prominent involvement of left inferior
frontal cortex (Gorno-Tempini et al., 2004a), with posterior
inferior frontal gyrus/operculum and the anterior insula
most severely affected (Figures 9.10 and 9.11). As the disease
progresses, atrophy is seen in the middle/superior frontal
cortex and the left superior temporal gyrus (Rohrer et al.,
2009). There is reduced volume of white matter underlying
+phrase/sentence repetition impairment
=LV

(a) Nonfluent variant
(b) Semantic variant
(c) Logopenic variant
(d) Normal control
Figure 9.10 MRI scans showing distinct patterns of focal left-
hemisphere cortical atrophy in patients with different PPA
subtypes. Atrophy predominantly involves left inferior frontal
cortex and insula in the nonfluent variant, left anterior temporal
cortex in the semantic variant, and temporoparietal cortex in
the logopenic variant (arrows). Source: Wilson et al. (2009b).
Reproduced with permission from Oxford University Press.
Figure 9.11 Voxel-based morphometry (VBM) demonstrating the
topographic distribution of left-hemisphere cortical atrophy in
three PPA cohorts (red = nonfluent/agrammatic, blue = semantic,
and green = logopenic). Courtesy of S.M. Wilson and M.L. Gorno-
Tempini. (For a color version, see the color plate section.)
Primary Progressive Aphasia 255
the frontal lobe (Wilson et al., 2010a), and diffusion tensor
imaging (DTI) has revealed abnormalities in the superior
longitudinal fasciculus (SLF; Whitwell et al., 2010). Damage
to this important white matter tract, which connects ante-
rior and posterior perisylvian language areas, may contrib-
ute to the syntactic and motor speech impairments seen in
nonfluent PPA.
Atrophy of distinct left frontal lobe regions has been
linked to specific speech/language deficits in nonfluent
PPA. In general, reduced fluency and syntactic production/
comprehension impairment (agrammatism) correlate with
volume loss in posterior inferior frontal cortex (Amici et al.,
2007a; Peelle et al., 2008; Ash et al., 2009; Gunawardena et al.,
2010; Wilson et al., 2010b), whereas motor speech deficits
(AOS, dysarthria) are associated with atrophy involving pre-
motor cortex/supplementary motor area (SMA), primary
motor cortex, insula, and basal ganglia (Gorno-Tempini et
al., 2006; Josephs et al., 2006a; Ogar et al., 2007).
Consistent with the pattern of atrophy observed on struc-
tural imaging studies, [18F] fluorodeoxyglucose(FDG)-
PET in nonfluent PPA shows left frontal lobe hypometab-
olism particularly severe in inferior frontal gyrus/oper-
culum and the anterior insula (Nestor et al., 2003; Josephs
et al., 2010). Patients with AOS may show evidence of
more superior frontal hypometabolism, including pre-
motor cortex/SMA, whereas in patients with nonfluent
PPA characterized by agrammatism and reduced speech
rate but no AOS, the most significantly affected region is
posterior inferior frontal gyrus/operculum (Josephs et
al., 2010). The left posterior inferior frontal cortex is also
functionally abnormal: the blood oxygen level-dependent
(BOLD) signal measured by fMRI is not modulated by
syntactic complexity as it typically is in healthy subjects
(Cooke et al., 2003; Wilson et al., 2010a).
To summarize, the distribution of the atrophy/hypo-
metabolism within the language network in nonfluent
PPA indicates a predilection of the pathologic process for
left frontal lobe regions implicated in syntactic process-
ing, phonology, motor speech control, and articulation.
Neuropathology
The most common pathologies underlying nonfluent
PPA are FTLD spectrum disorders, including tauopathies
(Pick’s disease, PSP, CBD) and TDP-43 proteinopathies
(Kertesz et al., 2005; Knopman et al., 2005; Josephs et al.,
2006b; Knibb et al., 2006; Snowden et al., 2007; Josephs,
2008; Mesulam et al., 2008; Deramecourt et al., 2010). AD
has been reported much less frequently (Kertesz et al.,
2005; Knibb et al., 2006; Alladi et al., 2007) and may some-
times reflect the inclusion of patients who might have
been diagnosed by other groups as logopenic PPA using
current consensus criteria. Consistent with the notion that
nonfluent PPA is predominantly associated with FTLD
rather than AD histopathology, patients with this variant
typically do not demonstrate increased PET uptake of the
256 Neurologic Conditions in the Elderly
Pittsburgh Compound B (PIB) that tags amyloid-β (Aβ)
(Rabinovici et al., 2008), and there is no evidence of an
increased frequency of the APOE-e4 genotype in this pop-
ulation (Gorno-Tempini et al., 2004a).
There is some indication that tauopathies, especially
PSP and CBD, are the most likely pathologies in patients
with nonfluent PPA characterized by prominent AOS or
motor speech impairment (Josephs et al., 2006a; Josephs
2008; Deramecourt et al., 2010). By contrast, in patients
with nonfluent agrammatic language but no AOS/motor
speech deficits, TDP-43 pathology is more common
(Josephs et al., 2006a; Snowden et al., 2007; Josephs 2008;
Deramecourt et al., 2010). TDP-43 is also the underlying
histopathology in patients with nonfluent PPA and evi-
dence of MND (FTLD/MND overlap syndrome; Snowden
et al., 2007; Josephs, 2008; Lillo and Hodges, 2009).
TDP-43 pathology in nonfluent PPA is almost always
Sampathu type 3 (dystrophic neurites, neuronal cytoplas-
mic, and intranuclear inclusions; Sampathu et al., 2006;
Snowden et al., 2007; Deramecourt et al., 2010). Many
nonfluent patients with type 3 TDP-43 pathology have
mutations of the progranulin (PGRN) gene; (Snowden
et al., 2006; Deramecourt et al., 2010). However, PGRN
mutations more commonly result in an initial behavioral
presentation (Beck et al., 2008), and nonfluent patients
with PGRN mutations often have concomitant behavioral
symptoms (Deramecourt et al., 2010). Nonfluent PPA in
the setting of FTLD/MND has been associated primar-
ily with Sampathu type 2 TDP-43 pathology (dystrophic
neurites and neuronal cytoplasmic inclusions; Snowden
et al., 2007; Josephs 2008; Lillo and Hodges, 2009).
Biofluid biomarkers may have some utility for antemor-
tem prediction of the underlying pathology in nonfluent
PPA. Although tau levels can be assayed in CSF, these
results must be interpreted cautiously because both reduced
and increased levels have been reported in patients with
FTLD (Arai et al., 1997; Grossman et al., 2005). However,
the CSF tau/Aβ42 ratio is significantly lower in patients
with FTLD, compared to patients with AD, suggesting that
this biomarker may be useful for discriminating between
these disorders (Bian et al., 2008). TDP-43 can be detected
in plasma (Foulds et al., 2008), and CSF (Steinacker et al.,
2008) and elevated levels may indicate TDP-43-related
pathology. Individuals with PGRN mutations have been
shown to have reduced PGRN levels in plasma (Ghidoni
et al., 2008). Biomarkers such as these may greatly aid PPA
diagnosis in the future, but much research is needed to
establish the sensitivity and specificity of these measures.
The semantic variant of PPA
In the semantic variant of PPA, the characteristic lan-
guage impairment reflects the gradual erosion of semantic
memory (Hodges and Patterson, 2007). Unlike episodic
memory, which stores information about personally expe-
rienced events, semantic memory refers to general knowl-
edge of facts, objects, people, and the meanings of words
(Tulving, 1995). Selective impairment of semantic mem-
ory was first documented by Warrington (1975), and the
term semantic dementia was later adopted or patients with
degradation of conceptual knowledge caused by neuro-
degenerative disease affecting the anterior temporal lobes
(Hodges et al., 1992).
Speech–language profile
In semantic variant PPA, speech output is fluent with
preserved phonology, syntax, and articulation, but there
is evidence of a reduction in expressive and receptive
vocabulary (Hodges and Patterson, 2007). (See Box 1 for a
sample of connected speech from an individual with the
semantic variant of PPA.) Early in the course of the dis-
ease, anomia is the most prominent feature and may be
the only obvious clinical sign. Word-finding difficulty is
usually apparent in conversational speech but tends to be
particularly severe on more constrained tests of confron-
tation or generative naming. During confrontation nam-
ing tasks, patients frequently produce coordinate seman-
tic errors (such as “chair” for sofa), superordinate errors
(such as “animal” for lion), or outright omissions (Hodges
et al., 1995; Hodges and Patterson, 2007). Phonemic cue-
ing is rarely of any benefit (Hodges et al., 1992). On gen-
erative naming tasks, category fluency is typically more
impaired than letter fluency, a pattern opposite to that
observed in patients with nonfluent PPA. Due to progres-
sive anomia, conversational language becomes increas-
ingly devoid of content, with patients using generic terms
such as thing in instances of lexical retrieval failure for
specific items.
Whereas anomia is the most salient early feature in
semantic variant PPA, lexical comprehension deficits
also become increasingly apparent, with patients often
questioning the meanings of words: “What is a ther-
mometer? I don’t know that one” (Kertesz et al., 2010).
These two features (impaired naming and single-word
comprehension deficits) represent the core diagnostic
characteristics according to consensus criteria (Gorno-
Tempini et al., 2011; Table 9.12). Both naming and word
comprehension deficits are frequency and familiarity
dependent, with worse performance on low-frequency
items that are less familiar to the patient (Bird et al.,
2000; Adlam et al., 2006). Other important variables
include typicality, with less accurate performance on
items that are atypical members of their class (such as
penguin vs. duck), and level of specificity, with dispro-
portionate difficulty on tasks probing subordinate rather
than basic category or superordinate knowledge (Adlam
et al., 2006; Hodges and Patterson, 2007). In particular,
with increasing disease severity, one often observes a
specific-to-general deterioration of semantic memory in

which knowledge about the distinctive semantic prop-
erties of objects is lost before information about shared
attributes of category members (Rogers and McClelland,
2004). Accordingly, patients may initially identify the
picture of a “beagle” as a “dog” and, later in the course
of their illness, as an “animal.”
It is important to emphasize that the degradation of
conceptual representations in semantic variant PPA gives
rise to multimodal deficits that are apparent on both ver-
bal and nonverbal tests of semantic knowledge. Thus,
patients not only fail to produce and comprehend the
names of objects, but they also exhibit parallel, though
typically less severe, impairments on nonverbal tests of
object knowledge (such as picture semantic association
tests or tests requiring matching of pictures of objects
with their characteristic colors, sounds, or functions;
Bozeat et al., 2000; Adlam et al., 2006; Hodges and Patter-
son, 2007). The multimodal semantic deficit also extends
to knowledge of familiar persons, manifested by a diffi-
culty in recognizing famous individuals from face, voice,
or name cues (Gainotti, 2007). Defective object and person
knowledge is an important diagnostic feature of semantic
variant PPA (Gorno-Tempini et al., 2011; see Table 9.12),
and appropriate tests for identifying impairments in these
domains should be incorporated into the cognitive assess-
ment battery.
In semantic variant PPA, performance on language
tasks that do not depend on semantic memory is char-
acteristically preserved. For instance, patients can often
correctly repeat low-frequency lexical items made up of
complex sound sequences (such as stethoscope) without
being able to comprehend these words, a pattern that
is the opposite of what is observed in individuals with
nonfluent PPA (Hodges et al., 2008). Sentence repetition
is also usually spared. Furthermore, patients may retain
the ability to produce and comprehend sentences con-
taining complex grammatical structures, attesting to the
relative preservation of syntactic processing (Hodges and
Patterson, 2007).
Patients with semantic variant PPA demonstrate a
characteristic pattern of reading and spelling deficits,
referred to as surface dyslexia and dysgraphia (Patterson
and Hodges, 1992; Graham et al., 2000; Woollams et al.,
2007; Table 9.12). The hallmark of this syndrome is the
disproportionate difficulty in reading/spelling irregular
words that contain exceptional or atypical spelling-sound
correspondences (such as choir). By contrast, reading/
spelling of regular words (such as start) and nonwords
(such as boke) that contain predictable phoneme–graph-
eme mappings is preserved. It has been proposed that
accurate reading/spelling of irregular words requires
semantic mediation, particularly when these items are of
low frequency (Woollams et al., 2007). With reduced input
from the semantic system, patients with semantic variant
PPA produce “regularization” errors on irregular words,
Primary Progressive Aphasia 257
reflecting an over-reliance on sublexical sound–letter con-
version rules (reading yacht as /jæt∫t/ or spelling tomb as
t-o-o-m).
In summary, semantic variant PPA is a distinct syn-
drome characterized by poor performance across a vari-
ety of language and nonverbal tasks tapping conceptual
knowledge/semantic memory. Distinguishing individu-
als with semantic variant from other PPA variants can be
accomplished based on the presence of a fluent language
profile with marked anomia and poor single-word com-
prehension. Supporting features, at least three of which
must be present to satisfy current diagnostic criteria,
include poor object knowledge, surface dyslexia/dys-
graphia, spared repetition, and preserved grammar and
motor speech (Gorno-Tempini et al., 2011).
Associated cognitive, behavioral, and
neurologic deficits
Patients with semantic variant PPA may remain oriented
and demonstrate preserved day-to-day episodic memory
for personal events. On formal testing, memory for verbal
materials is impaired, but nonverbal memory can be rela-
tively intact. Basic visuoperceptual and visuospatial skills
are unaffected, and patients may perform reasonably well
on tests of executive function and working memory.
Individuals with semantic variant PPA are more likely
than patients with other PPA variants to show abnormal
behavioral patterns, including apathy, emotional cold-
ness, disinhibition, irritability, obsessive–compulsive
rituals, rigidity, and eating disorders (Rosen et al., 2006;
Rohrer and Warren, 2010). Features reminiscent of the
Kluver–Bucy syndrome (hyperorality, hypersexuality)
have been observed (Hodges et al., 1992). These behav-
iors can be particularly striking and are early features in
individuals, with greater right than left temporal lobe
involvement (Gorno-Tempini et al., 2004b; Seeley et al.,
2005).
Neuroimaging
In semantic variant of PPA, the neurodegenerative pro-
cess has a predilection for anterior and inferior temporal
lobe regions, including temporal pole, middle/inferior
temporal gyri, and anterior fusiform gyrus. Atrophy is
typically bilateral but more extensive in the left hemi-
sphere. Medial temporal lobe regions are also affected,
including amygdala, hippocampus, and entorhinal/peri-
rhinal cortices (Mummery et al., 2000; Chan et al., 2001;
Galton et al., 2001; Rosen et al., 2002; Gorno-Tempini
et  al., 2004a). Temporal lobe atrophy can be extreme,
and it is not uncommon to see volume loss greater than
50%. Although hippocampal atrophy is often as marked
as it is in AD, semantic variant PPA differs from AD, in
that anterior parts are more affected than posterior areas
(Chan et al., 2002; Davies et al., 2004). As the disease pro-
gresses, atrophy extends to the contralateral hemisphere,
258 Neurologic Conditions in the Elderly
to ventromedial, insular, and to anterior cingulate regions
within the frontal lobes and caudally within the temporal
lobe (Brambati et al., 2007; Rohrer et al., 2009). In semantic
variant PPA, white matter abnormalities are most striking
in the inferior longitudinal fasciculus (ILF) and the unci-
nate fasciculus (UF), as revealed by DTI (Agosta et al.,
2010; Whitwell et al., 2010). The ILF connects occipital and
temporal lobe regions, and damage to this tract may con-
tribute to the object/person recognition, picture naming,
and reading impairments documented in these patients.
It has been suggested that damage to the UF that connects
frontal and temporal lobe regions may play a role in the
prominent behavioral abnormalities observed in semantic
variant PPA (Agosta et al., 2010; Whitwell et al., 2010).
The same anterior temporal and ventromedial frontal
lobe regions that are atrophic on structural imaging stud-
ies in semantic variant PPA are also hypometabolic on
FDG-PET (Diehl et al., 2004; Drzezga et al., 2008; Josephs
et al., 2010). Functional imaging studies (PET/fMRI)
have shown reduced activation in inferior temporal lobe
regions but preserved functionality of dorsolateral fronto-
parietal cortical networks on semantic and reading tasks
(Mummery et al., 1999; Wilson et al., 2009a).
Specific linguistic and cognitive impairments in seman-
tic variant PPA have been shown to correlate with left ante-
rior temporal lobe atrophy, including anomia and verbal/
nonverbal semantic deficits (Mummery et al., 2000; Galton
et al., 2001; Davies et al., 2004; Grossman et al., 2004; Wil-
liams et al., 2005; Adlam et al., 2006; Amici et al., 2007b),
poor reading of irregular words (Brambati et al., 2009),
and reduced use of low-frequency content words in con-
nected speech (Wilson et al., 2010b). Atrophy of the right
anterior temporal lobe has been linked to defective rec-
ognition of faces (Josephs et al., 2008b). Taken together,
these findings are consistent with the proposal that ante-
rior temporal cortex plays a critical role in semantic mem-
ory and may function as an amodal “semantic hub” that
binds and integrates information about the attributes of
objects, people, and words represented in sensory, motor,
and language-specific cortical regions (Patterson et al.,
2007).
Neuropathology
Semantic variant PPA is usually associated with TDP-43
FTLD pathology (Davies et al., 2005; Snowden et al., 2007).
TDP-43 histopathology is almost always Sampathu type 1,
characterized by a predominance of dystrophic neurites with
few or no neuronal inclusions. A minority of patients have
been found at autopsy to have Pick’s disease or AD (Knibb
et al., 2006; Alladi et al., 2007). Consistent with the predomi-
nance of FTLD pathology, PET Aβ molecular imaging with
PIB is usually negative in semantic variant PPA (Drzezga
et  al., 2008; Rabinovici et al., 2008), and the frequency of
the APOE-e4 genotype is not significantly increased in this
patient population (Gorno-Tempini et al., 2004a).
No genetic biomarkers for semantic variant PPA are
known, as aphasias due to PGRN mutations are typi-
cally nonfluent (Snowden et al., 2006). Some patients with
mutations of the MAPT gene, which encodes tau, have
semantic loss but always in the context of a behavioral
disorder (Snowden et al., 2006; Pickering-Brown et al.,
2008). TDP-43 can be detected in plasma and CSF (Foulds
et al., 2008; Steinacker et al., 2008), and this biomarker
may turn out to have diagnostic utility.
The logopenic variant of PPA
For more than two decades, individuals with PPA were
dichotomized broadly into two subgroups based on flu-
ency status (fluent vs. nonfluent). Ultimately, however,
it became apparent that not all patients fit neatly into a
binary classification scheme (Grossman and Ash, 2004).
A third variant of PPA was occasionally mentioned in the
literature (Kertesz et al., 2003) and, once fully character-
ized, was referred to as logopenic progressive aphasia
(LPA; Gorno-Tempini et al., 2004a, 2008) or, more recently,
the logopenic variant of PPA (Gorno-Tempini et al., 2011;
Henry and Gorno-Tempini, 2010).
Speech–language profile
Initial characterizations of the logopenic (from Greek,
meaning “lack of words”) variant of PPA described a
paucity of verbal output, with relative sparing of syn-
tactic, semantic, and articulatory aspects of speech and
language (Kertesz et al., 2003). Subsequent work has
refined this clinical picture, identifying a fluency pro-
file intermediate between patients with nonfluent and
semantic variants. Spoken language is slow in rate,
with frequent word-finding pauses but spared gram-
matical form (Gorno-Tempini et al., 2004a, 2008; see Box
1 for a sample of connected speech from an individual
with logopenic variant PPA). Confrontation naming is
impaired; however, single-word comprehension and
object knowledge are preserved. As a rule, the confron-
tation naming deficit in logopenic PPA is less severe than
in the semantic variant, and patients tend to produce
phonologic rather than semantic errors. An important
diagnostic feature of logopenic PPA is poor repetition of
sentences and phrases with relatively spared reproduc-
tion of short, single words, consistent with an impair-
ment of phonologic working memory (Gorno-Tempini
et al., 2004a, 2008). Careful evaluation of the function-
ality of the “phonological loop” component of working
memory has confirmed that this is a characteristic area of
deficit (patients have difficulty holding and rehearsing
verbal information in short-term memory). In particular,
span performance for digits and short words is limited to
approximately three items, and patients are often unable
to repeat more than a single long word (word length

effect; Gorno-Tempini et al., 2008). Attempts at sentence
repetition, particularly for low probability/uncommon
sentences may reveal a semantically appropriate yet
incorrect rendition, such as “The baker was happy” for
“The pastry cook was elated,” suggesting a semantic
rather than phonologic approach to the task. Phonologic
short-term memory impairment may also play a central
role in the sentence comprehension deficits documented
in this group of patients. Consistent with this hypothesis,
performance on sentence comprehension tasks in logo-
penic variant PPA is influenced more by the length and
probability of sentences than by their grammatical com-
plexity, a pattern opposite to that observed in patients
with nonfluent PPA (Gorno-Tempini et al., 2004a; Gross-
man and Moore 2005; Gorno-Tempini et al., 2008; Peelle
et al., 2008). A central phonologic deficit is also likely to
be responsible for the disproportionate impairment of
nonword reading in individuals with logopenic PPA, a
profile referred to as phonologic alexia (Brambati et al.,
2009; Rohrer et al., 2010a, 2010b, 2012). Unlike real words,
nonwords contain unfamiliar combinations of phono-
logic elements, and correct performance on these items
relies critically on the ability to identify, maintain, and
manipulate sublexical phonologic information (Rapcsak
et al., 2009). Spelling deficits have also been observed in
logopenic PPA (Sepelyak et al., 2011), but their precise
nature awaits further clarification.
Individuals with logopenic PPA can be distinguished
from semantic variant patients by spared performance
on lexical-semantic measures, such as single-word
comprehension (Mesulam et al., 2009) and, in spon-
taneous speech, by a slower overall speech rate, the
presence of phonologic paraphasias, and less severe
impairment of lexical retrieval (Wilson et al., 2010b).
Logopenic patients can be distinguished from nonflu-
ent PPA patients based on spared syntactic abilities on
formal testing (Mesulam et al., 2009) and, in spontane-
ous speech, by the absence of frankly agrammatic pro-
ductions (Wilson et al., 2010b) and the lack of motor
speech errors (AOS, dysarthria).
In conclusion, recent studies have provided compelling
support for the existence of a logopenic variant of PPA
with a language phenotype that is distinct from both the
nonfluent and semantic variants identified earlier. Core
diagnostic features include impaired single-word retrieval
in spontaneous speech and confrontation naming, and
poor repetition of sentences and phrases. Additional sup-
porting features, at least three of which must be present
for diagnosis, include phonologic errors in speech, spared
single-word comprehension and object knowledge, pres-
ervation of motor speech, and lack of agrammatic utter-
ances (Gorno-Tempini et al., 2011). Current evidence sug-
gests that the characteristic language profile in logopenic
PPA is attributable to an underlying deficit of phonologic
short-term memory.
Primary Progressive Aphasia 259
Associated cognitive, behavioral, and
neurologic deficits
In addition to the characteristic language impairment,
several associated cognitive and behavioral deficits
have been identified in individuals with logopenic PPA.
Relative to the other PPA variants, they often show diffi-
culty on tests of calculation (Gorno-Tempini et al., 2004a;
Amici et al., 2006; Rohrer et al., 2010a, 2012) and may
demonstrate worse performance on episodic memory
tasks (Mesulam et al., 2008; Rohrer et al., 2012). Limb
apraxia has also been noted in some individuals with
logopenic PPA (Rohrer et al., 2010a, 2010b, 2012), and
apathy, irritability, anxiety, and agitation may be associ-
ated behavioral features (Rosen et al., 2006; Rohrer and
Warren, 2010).
Neuroimaging
Structural imaging studies in logopenic PPA indicate
preferential involvement of left posterior perisylvian cor-
tex by the neurodegenerative process. Atrophy is most
prominent in the left temporoparietal region, specifi-
cally in the posterior portions of the superior and middle
temporal gyri, and in the inferior parietal lobule (Gorno-
Tempini et  al., 2004a, 2008; Rohrer et al., 2010a, 2010b,
2012). This pattern is similar to that observed in patients
with AD, particularly the early age of onset form (Frisoni
et al., 2007; Migliaccio et al., 2009) but with greater left-
hemisphere lateralization. In some logopenic patients,
atrophy extends into anterior temporal lobe regions, but
in comparison to semantic variant PPA, there is always
a more posterior temporoparietal predominance of the
gray matter volume loss. As the disease progresses, other
brain regions typically involved in AD are also impacted,
such as medial temporal lobe areas and posterior cingu-
late cortex (Rohrer et  al., 2012). DTI studies of logope-
nic patients suggest that the only abnormal tract is the
posterior indirect segment of the arcuate fasciculus (AF)
that connects the inferior parietal lobule to the posterior
temporal lobe (Galantucci et al., 2011). The temporopa-
rietal atrophy, as well as the structural abnormalities in
this important white matter tract that is part of the indi-
rect pathway connecting anterior and posterior perisyl-
vian language regions (Catani et al., 2005), is consistent
with the phonologic short-term memory and repetition
impairments documented in logopenic PPA. Vascular
patients with conduction aphasia, who exhibit a similar
profile of linguistic deficits, also have damage to poste-
rior temporoparietal cortex and/or underlying white
matter tracts (Hickok and Poeppel, 2004; Catani and
Mesulam, 2008).
The left temporoparietal regions that are atrophic on
structural imaging studies in patients with logopenic
PPA are also hypometabolic on FDG-PET (Rabinovici et
al., 2008; Josephs et al., 2010). There have been no pub-
lished functional MRI studies on specifically diagnosed
260 Neurologic Conditions in the Elderly
logopenic PPA patients, but a study on nonfluent patients
who appear to have been mostly of the logopenic vari-
ant revealed reduced network connectivity between
anterior and posterior perisylvian language areas (Sonty
et al., 2007).
Neuropathology
The most common pathology underlying logopenic PPA
is AD (Gorno-Tempini et al., 2004a, 2008; Josephs et al.,
2008a; Mesulam et al., 2008; Grossman 2010; Rohrer et al.,
2012). A few logopenic patients had TDP-43 pathology at
autopsy (Mesulam et al., 2008; Grossman 2010).
Consistent with the prevalence of AD pathology,
Rabinovici et al. (2008) reported that four of four
logopenic patients had evidence of increased cortical
amyloid binding on PIB-PET, in contrast to only one
of six nonfluent variant patients and one of five seman-
tic variant patients. The regional distribution of PIB
uptake in logopenic PPA does not mirror the focal left-
lateralized temporoparietal atrophy/hypometabolism
seen on structural imaging and FDG-PET studies, but
is diffuse, with greatest uptake in the frontal lobes, pos-
terior cingulate gyrus, parietal and anterolateral tem-
poral cortex, and striatum, similar to the pattern seen
in typical AD.
In patients with logopenic PPA, CSF biomarkers may
show a profile consistent with AD (increased tau, reduced
Aβ42, and an elevated tau/Aβ42 ratio), and there is evi-
dence of a higher-than-expected frequency of the APOE-e4
genotype in this population (Gorno-Tempini et al., 2004a,
2008; Migliaccio et  al., 2009; Henry and Gorno-Tempini
2010; Rohrer et al., 2010a, 2010b, 2012).
Assessment of speech–language
function in PPA
Although bedside testing may be sufficient for estab-
lishing the clinical diagnosis of aphasia, we recommend
formal assessment of linguistic function in PPA. A thor-
ough evaluation can substantially improve diagnostic
accuracy by allowing a more detailed characterization
of impaired and preserved speech–language abili-
ties, and it can also provide a quantitative measure of
aphasia severity that can be used to chart the progres-
sion of the disease and document potential treatment
benefits. Standard aphasia batteries such as the West-
ern Aphasia Battery (WAB; Kertesz, 1982) and Boston
Diagnostic Aphasia Examination (BDAE; Goodglass et
al., 2001) may be used to characterize overall language
profile and to provide a gross measure of aphasia sever-
ity in PPA. However, it is likely that these language
assessment batteries, which were designed for use in
individuals with vascular aphasias, may not be sensi-
tive to the subtle deficits observed in early PPA, and the
classification of aphasia by subtype (such as Broca’s or
Wernicke’s) is not relevant in this patient population.
Therefore, in addition to such general measures, spe-
cific tasks designed to assess spontaneous speech pro-
duction, confrontation and generative naming, motor
speech, repetition, single-word and sentence compre-
hension, nonverbal semantic processing, and written
language should be administered.
A simple picture description task (such as the
“Cookie Theft” picture from the BDAE or the “Picnic
Scene” from the WAB) can be used to assess fluency
(speech rate/length of utterance), grammatical com-
petence, lexical retrieval ability, and motor speech. In
fact, recent work has indicated that measures of speech
and language derived from such a sample can be help-
ful in discriminating among the PPA variants (Wilson
et al., 2010b).
Confrontation naming may be assessed using the
Boston Naming Test (Kaplan et al., 2001). Of particular
interest is not only the severity of the naming deficit,
but the nature of naming errors, which are likely to dif-
fer among the three PPA variants. Individuals with the
semantic variant are likely to fail to name all but the
highest frequency items and may make superordinate or
coordinate semantic errors. They are unlikely to be aided
by phonemic cues and may also do poorly when given
multiple-choice options. Individuals with nonfluent
PPA generally demonstrate less severe impairment of
lexical retrieval and are likely to show spared semantic
knowledge for pictured items (i.e., are able to describe
sensory/functional attributes or typical locations of the
objects they fail to name and correctly select the word
from a field of written choices). Naming errors may be
phonetic or phonemic in nature, and phonologic cues
may be beneficial. Finally, individuals with the logope-
nic variant are likely to have naming impairment less
severe than semantic variant patients but more severe
than nonfluent patients. Similar to nonfluent cases,
patients with logopenic PPA may demonstrate spared
semantic knowledge for items they cannot name and
may be aided by phonologic cues and multiple-choice
options. Phonemic errors on naming tasks are frequently
observed.
Motor speech may be evaluated using test batteries
such as those designed by Wertz and colleagues (1984) or
Duffy (1995). These batteries of tasks include diadocho-
kinetic measures (rapid repetition of alternating speech
sounds such as “puh-tuh-kuh”) and repetition of utter-
ances of increasing articulatory complexity, from single
sounds to long sentences, as well as multiple repetitions
of words containing difficult articulatory sequences, such
as artillery or catastrophe. Such an evaluation can reveal
the presence of subtle dysarthria or AOS, which may
not be apparent in conversational speech. Particular fac-
tors to attend to are rate and ease of articulation, voice

quality, and presence and nature of speech errors, as
motor speech deficits are characteristic features of non-
fluent PPA. Oral repetition of nonwords, words, phrases,
and sentences can also be used to identify impairments of
phonologic processing. Factors that influence repetition
accuracy include lexical status/familiarity (worse perfor-
mance on nonwords compared to real words), predict-
ability of the phrase, and sentence length. Poor repetition
of sentences may indicate phonologic working memory
deficits, which can be an important diagnostic feature in
identifying logopenic PPA patients.
Single-word comprehension can be assessed by spo-
ken/written word–picture matching tasks (PALPA sub-
tests 47 and 48; Kay et al., 1992). Impaired single-word
comprehension is a characteristic finding in patients with
semantic variant PPA. Sentence comprehension tasks
from standardized aphasia tests such as the WAB, BDAE,
or Curtiss–Yamada Comprehensive Language Evaluation
(CYCLE; Curtiss and Yamada, 1988) can be used to iden-
tify impairments of receptive syntax. Individuals with
nonfluent PPA often show deficits in comprehension of
syntactically complex sentences, such as constructions
featuring a subject-relative or object-relative embedded
clause (such as “The brown horse that the dog chased
was fast”), whereas individuals with logopenic PPA
may be impaired for sentences of increasing length and
decreasing familiarity/probability, regardless of syntactic
complexity.
Nonverbal semantic processing may be evaluated
with picture tests of object knowledge. Picture associa-
tion tests (such as the Pyramids and Palm Trees Test;
Howard and Patterson, 1992) and picture–sound or
object–function matching tests can be used. Knowledge
of people can be assessed by asking patients to iden-
tify photographs of famous individuals and celebri-
ties. Impairments on tests of object/person knowledge
are particularly sensitive for identifying patients with
semantic variant PPA.
Finally, assessments of written language at the single-
word and text level should be incorporated into the PPA
evaluation. Single-word assessments of reading and
spelling should examine the effects of word frequency,
regularity (with regular words, such as stop and irreg-
ular words, such as tomb), and lexical status (i.e., both
real words and phonologically plausible nonwords such
as flig should be included). Individuals with semantic
impairment are likely to have particular difficulty with
reading/spelling irregular words (profile of surface
dyslexia/dysgraphia), whereas those with phonologic
impairment, particularly logopenic patients, may show
disproportionate deficits in processing nonwords (pro-
file of phonologic dyslexia/dysgraphia). Text-level writ-
ing, such as picture description, can reveal agrammatism
that is not yet apparent in spoken discourse in individu-
als with nonfluent PPA.
Primary Progressive Aphasia 261
Treatment approaches in PPA
There are currently no proven pharmacologic treatments
for PPA caused by AD or FTLD. Behavioral speech-
language treatments, however, have been shown to result
in improved communication in domains such as naming,
sentence production, and written language.
Pharmacologic treatment
Successful pharmacologic treatment for PPA ultimately
depends on accurate antemortem prediction of the under-
lying pathologic substrate, given that the syndrome can
be caused both by FTLD spectrum disorders and by AD.
There has been a great deal of research examining phar-
macologic treatment of AD, and the FDA has approved
several drugs, including cholinesterase inhibitors (done-
pezil, galantamine, and rivastigmine) and an NMDA
receptor agonist (memantine), to treat cognitive symp-
toms associated with this disorder. However, no studies
to date have addressed the efficacy of these drugs in treat-
ment of atypical variants of AD, including logopenic PPA.
No FDA-approved treatments currently exist for FTLD
and its associated syndromes, including the nonfluent
and semantic variants of PPA. Acetylcholinesterase inhib-
itors and memantine have been administered in small
trials with mixed groups of PPA patients, with minimal
effects (Kertesz et al., 2008; Boxer et al., 2009; Johnson
et al., 2010); however, larger, randomized, controlled clin-
ical trials are warranted. Additional small studies have
examined effects of bromocriptine, a dopamine agonist,
in PPA. Treatment with bromocriptine had little effect on
cognitive-linguistic deficits in PPA patients (Reed et al.,
2004) and failed to provide enhanced benefit when com-
bined with language treatment (relative to behavioral
treatment alone) (McNeil et al., 1995).
Behavioral treatment for speech and
language deficits
Compared to individuals with vascular aphasia, patients
with PPA are under-referred for speech–language pathol-
ogy services (Taylor et al., 2009) and are far less likely to
be offered behavioral treatment, in part because referring
and treating clinicians lack knowledge about the disorder
and also because of negative assumptions with regard to
the feasibility and utility of treatment in patients with neu-
rodegenerative disease. The body of research literature
examining treatment in PPA continues to grow, including
restitutive treatments designed to rehabilitate impaired
language processes (McNeil et al., 1995; Schneider et al.,
1996; Murray, 1998; Graham et al., 1999; Graham, 2001;
Snowden and Neary, 2002; Frattali, 2004; Rapp et al.,
2005; Jokel et al., 2006, 2007; Dewar et al., 2008; Henry
et al., 2008; in press; Bier et al., 2009; Heredia et al., 2009;
Newhart et al., 2009; Rapp and Glucroft, 2009), augmenta-
tive/alternative approaches to treatment (Murray, 1998;
262 Neurologic Conditions in the Elderly
Cress and King, 1999; Pattee et al., 2006), and interventions
designed to address activity and participation limitations
(Croot et al., 2008). Restitutive treatments have addressed
word-finding deficits as well as sentence production
(Schneider et al., 1996) and written language impairments
(Rapp and Glucroft, 2009). At present, there is cause for
cautious optimism with regard to the utility of speech–
language treatment in PPA. Studies have reported gains
on language measures, which were largely restricted to
treated language domains, but which appeared to slow
the progression of language deficits for specifically trained
behaviors. Nonetheless, much remains to be learned with
regard to the nature of the behavioral impairments in PPA
and the types of treatment that may be beneficial for its
clinical variants and stages.
Conclusions
PPA has emerged as a unique syndrome of isolated
and gradual language deterioration caused by a neu-
rodegenerative disorder. PPA is a clinically and patho-
logically heterogeneous entity, and current classification
systems have distinguished three major variants or sub-
types: nonfluent/agrammatic, semantic, and logopenic.
The behavioral manifestations of these PPA variants are
determined primarily by the neuroanatomic distribution
rather than by the nature of the underlying pathologic
process, and the distinctive language profiles reflect the
preferential involvement of specific left-hemisphere cor-
tical regions dedicated to syntax, phonology, semantics,
and motor speech. In clinical practice, the identification
of PPA subtypes is based on detailed language assess-
ment and neurologic/neuropsychological examination,
supported by structural/functional imaging studies
demonstrating characteristic patterns of focal cortical
atrophy/hypometabolism. Molecular imaging (PIB-
PET), genetic testing, and CSF/blood biomarkers have
excellent potential for identifying the pathologic basis
of PPA during the patient’s lifetime, but these tech-
niques are not generally available or recommended for
routine clinical use at this time. Most patients with PPA
harbor pathology related to FTLD spectrum disorders
(tauopathies, TDP-43 proteinopathies) or AD. Probabi-
listic inferences about the underlying pathology are pos-
sible based on demonstrated associations between PPA
subtypes and specific disease etiologies. However, it is
important to keep in mind that the clinical diagnosis of
a PPA variant does not reliably indicate the presence of
a specific pathology in an individual patient; therefore,
the language phenotype cannot be considered diagnos-
tic of the underlying disease process (Grossman, 2010).
Despite these caveats, we expect that progress in clinical,
imaging and biomarker research will further improve
antemortem diagnostic accuracy in PPA and facilitate
the selection of appropriate patients for participation in
emerging etiology-specific therapeutic trials.
Acknowledgments
This work was supported by grants R01DC008286,
P30AG19610, F32DC010945, R03010878, R01NS050915,
P01AG019724, and P50AG023501.
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 Chapter 9.7
Prion Diseases
Michael D. Geschwind and Katherine Wong
Introduction
The most common causes of dementia in the elderly (over
age 65) are, in decreasing order, Alzheimer’s disease
(AD), vascular dementia (VaD), and, far behind, other
dementias. For earlier-onset dementia (under the age of
65), AD and VaD are still the most common, but other
dementias have higher prevalence. These include fronto-
temporal dementia (FTD), Lewy body dementias (LBDs),
metabolic dementias, Huntington’s disease (HD), and
assorted other etiologies, including prion diseases. Prion
(pronounced pree-ahn) diseases are a group of uniformly
fatal neurodegenerative diseases caused by the transfor-
mation of an endogenous protein, PrP (prion-related pro-
tein), into an abnormal conformation, called the prion.
Dr Stanley Prusiner and colleagues identified prions as
the cause of a family of diseases called transmissible
spongiform encephalopathies. The term prion is derived
from proteinaceous infectious particle (Prusiner, 1998). The
transmissibility of the diseases and the long incubation
period between exposure and symptom onset (Gajdusek
et al., 1977; Brown et al., 1986b) puzzled researchers for
some time and supported the erroneous theory that these
diseases were caused by a slow virus or other exogenous
infectious agents. Research by Prusiner and others, how-
ever, determined that the infectious agent did not contain
DNA or RNA, a component of viruses. In 1997, Stanley
B. Prusiner received the Nobel Prize in Physiology and
Medicine for this work (Prusiner, 1998). It is now well
established that prions are necessary and sufficient for
causing these diseases, although other proteins might
also play a role in the disease process. This has been
proven resolutely by animal models, identification of
prion gene mutations causing prion disease in humans,
and in vitro production of prions with transmissibility
(Mead, 2006; Kim et al., 2010; Makarava et al., 2010).
Although prion diseases occur in animals and humans,
this chapter focuses on human prion diseases and dis-
cusses prion diseases in animals only when relevant to
humans.
Overview of human prion diseases
Prion diseases can develop in three different ways in
humans: spontaneously (sporadic), genetically, and
through transmission (acquired) (Prusiner, 1998).
Approximately 85% of cases are sporadic, 15% are genetic,
and fewer than 1% are acquired (iatrogenic or variant).
Sporadic prion disease, or sporadic Jakob–Creutzfeldt
disease (sCJD), is thought to occur due to the spontaneous
transformation of the normal cellular prion protein (PrPC,
in which C stands for cellular) into the abnormally shaped,
disease-causing form, called the prion (PrPSc, in which Sc
stands for scrapie, the prion disease of sheep and goats).
Genetic prion diseases (gPrD) are caused by a mutation
in the prion protein gene, PRNP, which codes for the
prion protein, PrPC (Figure 9.12). Familial CJD (fCJD),
Gerstmann–Sträussler–Scheinker (GSS), and fatal famil-
ial insomnia (FFI) are the three major forms of gPrDs.
Acquired prion diseases are the least common form of
human prion disease, but they are perhaps the most noto-
rious, in part due to their occurrence through inadvertent
transmission of prions, such as by iatrogenic means or
from animals to humans, as in the case of BSE and human
vCJD epidemic in the United Kingdom. Genetic and
acquired forms of human prion disease are even less com-
mon in the geriatric population; therefore, the majority of
this chapter focuses on sporadic CJD (sCJD).
Epidemiology
The incidence of human prion diseases is about 1–1.5 per
million per year in most developed countries, with some
variability from year to year and between countries. This
incidence translates to approximately 6000 human prion
cases worldwide and 250–400 in the United States annu-
ally. The peak age of onset of sCJD occurs around a uni-
modal relatively narrow peak of about 68 years (Brown
et al., 1986a). Because sCJD tends to occur within a rela-
tively narrow age range, a person’s lifetime risk of dying
from sCJD is much higher than the prevalence and is
probably about one in tens of thousands.
History of CJD nomenclature
In 1921 and 1923, Alfons Jakob published four papers
describing five unusual cases of rapidly progressive
dementia (RPD). Dr Jakob felt his cases were nearly
identical to a case described in 1920 by his professor,
Hans Creutzfeldt. This disease was referred to for many
decades as Jakob’s or Jakob–Creutzfeldt disease until
267
268 Neurologic Conditions in the Elderly
(a) “Refolding” model
PrPC PrPSc
(b) “Seeding” model
PrPC PrPSc
Very, Rapid Rapid
very
slow
Figure 9.12 Models for the conformational conversion of PrPC to
PrPSc. (a) The “refolding” model. The conformational change is
kinetically controlled, a high-activation energy barrier preventing
spontaneous conversion at detectable rates. Interaction with
exogenously introduced PrPSc causes PrPC to undergo an
induced conformational change to yield PrPSc. This reaction
could be facilitated by an enzyme or chaperone. In the case of
certain mutations in PrPC, spontaneous conversion to PrPSc may
occur as a rare event, explaining why familial CJD or GSS arises
spontaneously, albeit late in life. Sporadic CJD may come about
when an extremely rare event (occurring in about one in a million
individuals per year) leads to spontaneous conversion of PrPC to
PrPSc. (b) The “seeding” model. PrPC and PrPSc (or a PrPSc-like
molecule, light) are in equilibrium, with PrPC strongly favored.
PrPSc is stabilized only when it adds onto a crystal-like seed or
aggregate of PrPSc (dark). Seed formation is rare; however, once
a seed is present, monomer addition ensues rapidly. To explain
exponential conversion rates, aggregates must be continuously
fragmented, generating increasing surfaces for accretion. (For
a color version, see the color plate section.) Reproduced from
Weissmann C et al. (2002).
Clarence J. Gibbs, a prominent researcher in the field,
started using the term Creutzfeldt–Jakob disease because
the acronym was closer to his own initials (Gibbs, 1992).
We now know from the pathology and records that
Creutzfeldt’s case not only was very different clinically
than Jakob’s cases but also did not have what we today
refer to as prion disease. The disease probably should be
called Jakob’s, or at least Jakob–Creutzfeldt, disease, cer-
tainly not Creutzfeldt–Jakob disease. Unfortunately, the
term JCD might confuse some with the JC virus. There-
fore, we use the term Jakob–Creutzfeldt disease, with the
acronym CJD. The term CJD is used sometimes to refer to
all human prion diseases and sometimes to refer to just
the classic or sporadic form, sCJD. In this chapter, CJD
refers to all human prion diseases, whereas sCJD refers
only to sCJD.
As mentioned, prion diseases historically have been
referred to as transmissible spongiform encephalopathies
(TSEs) due to two distinguishing characteristics of prion
disease. Yet some gPrDs might not be transmissible, and
not all human prion diseases have spongiform changes
(now called vacuolation, due to fluid-filled vesicles in the
dendrites) on pathology.
What are prions?
The normal prion protein (PrP or PrPC) is not pathogenic,
but it can change shape into an abnormal, infectious form
of PrP called PrPSc. PrPC and PrPSc have identical primary
structures (amino acid sequence) but have different ter-
tiary structures (3-D shape). Prions are characterized by
their infectious properties and by the intrinsic ability of
their structures to act as a template and convert the nor-
mal physiologic PrPC into the pathologic, disease-causing
form, PrPSc. It is thought that the accumulation of prions,
PrPSc, in the brain leads to nerve cell injury and death
(Prusiner, 1998; Prusiner and Bosque, 2001), although the
specific pathologic mechanism is debated (Mallucci et al.,
2007). Prions are thought to spread in the brain via either
a refolding mechanism or a seeding model, which are not
mutually exclusive (Figure 9.12).
The complete function of PrP is still not known
(Geschwind and Legname, 2008). It is coded for by the
PRNP gene located on the short arm of chromosome 20
(Oesch et al., 1985; Basler et al., 1986) and is a primar-
ily membrane-bound protein on nerve and other cells
(Figure 9.13). It is highly conserved evolutionarily, so it
presumably plays an important role in neuronal devel-
opment and/or function (Kanaani et al., 2005). Mice
that have had both copies of the open reading frame
(ORF) of their PrP gene, PRNP, deleted (PrP-/-) have
a normal lifespan and appearance (Bueler et al., 1992;
Manson et al., 1994). Conditional knockout mice, in
which the gene is not removed until after the mouse has
already developed, also appear normal and unaffected
by gene removal. Both mice have some subclinical defi-
cits found later on postmortem examination (Legname
et al., 2005).
PrPC interacts with many proteins and cellular constit-
uents. Animal and cell models have generated a variety
of possible functions of PrPC. Cell signaling, adhesion,
proliferation, differentiation, and growth have all been
identified as possible PrPC functions through animal and
cell models. Importantly, mice devoid of PrPC cannot
be infected with prions—nor can they replicate them—
providing strong evidence that PrPC is necessary for prion
disease (Bueler et al., 1993; Prusiner, 1993; Katamine et al.,
1998).
 Prion Diseases 269

PRNP –8 –M 129V E219K

(a) Codons 1 23 50 100 150 200 231 254

PrPC Protein
Cu2+ X Y
Y
αA αB αc

β1 β1 S-S GPI
(b)

PrPSC Type Type Protein

membrane
PrPSC 1 2 X Y
Y

Cell
82 97 αB αc

(c) S-S GPI

P1 D2L

(d)

Figure 9.13 The prion protein. (a) The prion protein gene (PRNP) is located on the short arm of the human chromosome 20. The
nonpathogenic polymorphism includes deletion of one of the octarepeat segments, methionine–valine polymorphism at the 129 position,
and glutamine–lysine polymorphism at position 219. (b) Post-translational modification truncates the cellular prion protein (PrPC) at
positions 23 and 231 and glycosylates (Y) at positions 181 and 197. The phosphatidylinositol glycolipid (GPI) attached to serine at position
231 anchors the C-terminus to the cellular membrane. The intracellular N-terminus contains five octarepeat segments, P(Q/H)GGG(G/-)
WGQ (blue blocks), that can bind copper ions. The central part of the protein contains one short α-helical segment (α-helix A encompassing
residues 144–157 [green block]), flanked by two short β-strands (red blocks): β1(129–131) and β2(161–163). The secondary structure of
the C-terminus is dominated by two long α-helical domains: α-helix B (residues 172–193) and α-helix C (residues 200–227), which are
connected by a disulfide bond. The blue arrows indicate binding sites of the protein X within α-helices B and C. The dashed frame marks a
segment between positions 90 and 150, which is crucial for the binding of PrPC to PrPSc. (c) PrPSc has increased β-sheet content (red dashed
block). (d) Unlike PrPSc, which is anchored to the membrane, GSS amyloidogenic peptides are truncated and excreted into the cellular
space, where they aggregate and fibrillize into GSS amyloid deposits. This example is an 8-kDa PrP fragment associated with the most
common GSS/P102L mutation. A synthetic form of this peptide (90–150 residues), exposed to acetonitrile treatment to increase β-sheet
content, is the only synthetically generated peptide that, when injected intracerebrally into P102L-transgenic mice, is able to induce the GSS
disease. Source: Geschwind (2011). Reproduced with permission from Elsevier. (For a color version, see the color plate section.)

Clinical aspects of human prion
diseases
Sporadic prion disease
Sporadic CJD is thought to occur spontaneously in the
brain either through random transformation of PrPC into
PrPSc or possibly through somatic mutations that accu-
mulate in the body (see Watts et al., 2006, for a discussion
on possible origins of sCJD). The course typically con-
stitutes a rapid disease with a median survival of about
7–8 months and mean survival of 4 months. More than
90% of patients die within 1 year of onset of symptoms
(Brown et al., 1986a, 2006) The mean age of onset is 68,
and the median age is in the early 60s, although the range
is from the 20s to the 80s (Table 9.13). Occurrence of sCJD
at young (from 20s to 40s) or old (>75) ages is uncommon
(Will, 2003).
A broad range of symptoms is associated with sCJD,
typically including cognitive changes (dementia),
behavioral and personality changes, difficulties with
movement and coordination, visual symptoms, and
constitutional symptoms (Brown et al., 1986a; Rabi-
novici et al., 2006). sCJD usually progresses rapidly
over weeks to months from the first obvious symptoms
to death, although some patients live for more than
1.5 years. Most patients die from aspiration pneumo-
nia preceded by a state of akinetic mutism. Cognitive
problems in sCJD typically include confusion, memory
loss, and difficulty concentrating, organizing, or plan-
ning. Motor manifestations of CJD include extrapy-
ramidal symptoms (bradykinesia, dystonia, tremor),
cerebellar symptoms (gait or limb ataxia), and, later in
the disease, myoclonus (sudden jerking movements).
Although myoclonus has traditionally been considered
270 Neurologic Conditions in the Elderly

Table 9.13 Clinical characteristics of most common types of human prion diseases

Characteristic sCJD vCJD fCJD iCJD FFI GSS Kuru

Average age at onset 67 28 Variable among All ages 50 40 All ages

(yr) kindreds 23–55
Average duration of 7 14 Variable among 12 18 60; variable 11
disease (mo.) kindreds 8–96 among kindreds
60–240
Average incubation N/A 17 yr (12–23 yr); — Neurosurgical N/A N/A 12 yr
periods (range) blood transfusion 18 mo. (12–28); (5–50 yr)
7 yr dura graft 6 yr
(1.5–23 yr); hGH
5 yr (4–36 yr)
Most prominent early Cognitive Psychiatric Cognitive and/ Cognitive Insomnia, Ataxia, tremor, Ataxia,
signs and/or abnormalities, or behavioral dysfunction, autonomic extrapyramidal tremor
behavioral sensory dysfunction ataxia instability symptoms
dysfunction symptoms (later
dementia, ataxia,
and other motor
symptoms)
Cerebellar >40 97 >40 >40 No 100 in P102L 100
dysfunction (%) mutation; much
less common in
other mutations
DWI/FLAIR MRI Yes, >92% Yes, pulvinar sign Yes for most Variable; some Unclear Variable; most N/A
positive mutations positive in negative
deep nuclei or
cerebellum
PSW on EEG Yes, 65% No (rarely at end Yes Yes No No N/A
stage)
Amyloidosis Sparse plaques Severe in all Sporadically seen Sporadically No Very severe 75% of
in 5–10% cases seen cases
Presence of PrPSc in No Yes No Yes No No Unlikely
the lymphoreticular
system

Source: Geschwind (2011). Reproduced with permission from Elsevier.

Parchi et al. (1999), Brown et al. (2000, 2006), Valleron et al. (2001), Huillard d’Aignaux et al. (2002), Collie et al. (2003), Will (2003), Kong et al. (2004),
Collinge et al. (2006), Collins et al. (2006), Lewis et al. (2006), Brandner et al. (2008), Vitali et al. (2008), and Heath et al. (2010).
CJD, Creutzfeldt–Jakob disease; EEG, electroencephalogram; FFI, familial fatal insomnia; GSS, Gerstmann–Sträussler–Scheinker syndrome; mo.,
months; N/A, not available or not applicable; PSW, paroxysmal sharp waves; yr, years.

a classical sign in CJD, this abnormality may also be
found in dementia with Lewy bodies, AD, and cortico-
basal degeneration.
Subtle behavioral and psychiatric changes and consti-
tutional symptoms (e.g., fatigue, malaise, headache, dry
cough, lightheadedness, vertigo) can also be seen early,
very subtle symptoms (irritability, anxiety, depression, or
other changes in personality) in the disease course. Pre-
liminary research at our center shows that sCJD presents
as prominently with behavioral symptoms as behavioral
variant FTD. These symptoms are often overlooked and
should be given more weight in the diagnosis of sCJD.
Problems processing visual information lead to
visual symptoms such as blurred or double vision,
cortical blindness, or other perceptual problems.
Such patients often are referred to ophthalmologists.
As the age of onset in sCJD is also the common age
for cataracts, many sCJD patients with visual symp-
toms have cataract operations, which, of course, do
not improve the visual symptoms that have brain
origin.
Less frequently, other symptoms, such as aphasia,
neglect, or apraxia (inability to do learned movements)
due to parietal dysfunction occur and can be presenting
features. Sensory symptoms such as numbness, tingling,
and/or pain are less well-recognized symptoms and are
probably under-reported, given the magnitude of the
other symptoms in sCJD (Geschwind and Jay, 2003; Will,
 Prion Diseases 271

2004; Lomen-Hoerth et al., 2010; Prusiner and Bosque,

2001).

Diagnosing sCJD
A diagnosis of sCJD can be considered definite, prob-
able, or possible based on level of certainty. Definite
criteria require pathologic evidence of PrPSc in brain
tissue (by biopsy or autopsy; Kretzschmar et al. 1996;
Budka, 2003). Several criteria exist for the diagnosis
of possible or probable sCJD. Unfortunately, most of
these criteria are geared toward the purpose of surveil-
lance and epidemiologic studies for patients who were
not definitely diagnosed pathologically and thus are
intended to catch most patients at the end of their dis-
ease course (Figure 9.14). Most of these criteria, there-
fore, are not very helpful when evaluating a patient
early in the disease course (Table 9.14). The most com-
monly used “probable” criteria are World Health Orga-
nization (WHO) Revised criteria (WHO, 1998). In the
criteria, pyramidal symptoms might include hyperre-
flexia, focal weakness, and a positive Babinski (exten-
sor) response. Extrapyramidal symptoms include rigid-
ity, slowed movement (bradykinesia), tremor, and dys-
tonia, for example. Akinetic mutism describes the state
when patients are without purposeful movement and
mute. Possible CJD criteria are the same as for prob-
able but do not require the ancillary testing (e.g., EEG
or CSF 14-3-3 tests; WHO, 1998). Many patients will Figure 9.14 Neuropathology of prion disease. (a) In sCJD, some
not meet revised WHO criteria for probable sCJD until brain areas may have no (hippocampal end plate, left), mild
(subiculum, middle), or severe (temporal cortex, right) spongiform
late in the disease course. UCSF criteria, utilizing brain
change. Haematoxylin and eosin (H&E) stain. (b) Cortical sections
MRI, were proposed in 2007 (Geschwind et al., 2007a);
immunostained for PrPSc in sCJD: synaptic (left), patchy/perivacuolar
in 2009, Modified European sCJD criteria also allowed (middle), or plaque type (right) patterns of PrPSc deposition. (c) Large
inclusion of brain MRI. Kuru-type plaque, H&E stain. (d) Typical “florid” plaques in vCJD,
H&E stain. Source: Budka (2003). Reproduced with permission from
Oxford University Press. (For a color version, see the color plate section.)

Table 9.14 Current diagnostic criteria for probable sCJD

WHO 1998 revised criteria
European criteria 2009a (Zerr et al., 2009) UCSF 2007 criteria (Geschwind et al., 2007a) (WHO, 1998)

1 Progressive dementia 1 RPD 1 Progressive dementia and/or

2 At least two of these four features: 2 At least two of the following: 2 At least two of the following four features:
Myoclonus Myoclonus Myoclonus
Visual or cerebellar disturbance Pyramidal/extrapyramidal Visual or cerebellar disturbance
Pyramidal/extrapyramidal signs Dysfunction Pyramidal/extrapyramidal signs
Akinetic mutism Visual disturbance Akinetic mutism
3 And one of more of the following: Cerebellar signs 3 PSWCs on the EEG and/or a positive 14-3-3
PSWCs on the EEG Akinetic mutism CSF assay and a clinical duration to death
A positive 14-3-3 CSF assay and a clinical duration Other higher focal cortical signb <2 years
to death <2 years 3 And a typical EEG or MRI 4 No alternative diagnosis on routine
High signal abnormalities in caudate nuclear and 4 No alternative diagnosis suggested by routine investigations
putamen or at least two cortical regions (temporal- investigations
parietal-occipital, but not frontal, cingulate, insular,
or hippocampal), in either DWI or FLAIR MRI
4 No alternative diagnosis on routine investigations

PSWCs, periodic sharp wave complexes.

aThere were errors in the table summarizing the criteria in the paper; criteria shown here are derived from the text of the paper.
bHigher focal cortical signs include such findings or symptoms as apraxia, neglect, acalculia, and aphasia.
272 Neurologic Conditions in the Elderly
Diagnostic tests for sCJD
EEG
The classic EEG finding in sCJD consists of sharp, or tri-
phasic, waves (periodic sharp wave complexes, or PSWCs)
occurring about once every second (Figure 9.15). This EEG
is found in only about two-thirds of sCJD patients, often
late in the disease. More commonly, sCJD patients pres-
ent with focal or diffuse slowing (Steinhoff et al., 2004).
Other diseases leading to cortical dysfunction such as AD,
Lewy body disease, toxic-metabolic and anoxic encepha-
lopathies, progressive multifocal leukoencephalopathy,
and Hashimoto’s encephalopathy, also can have PSWCs
on EEG (Seipelt et al., 1999; Tschampa et al., 2001).
CSF
Due to varying degrees of sensitivity and specificity around
the world, the clinical utility of CSF biomarkers is some-
what controversial. The 14-3-3 protein was one of the first
CSF proteins touted as a diagnostic marker for CJD, but it
has limited sensitivity and specificity (Chapman et al., 2000;
Figure 9.15 A typical EEG in a sCJD patient with diffuse slowing and 1 Hz periodic sharp waves complexes (PSWCs). Source: Geschwind
(2011). Reproduced with permission from Elsevier.
Geschwind et al., 2003), as it is found elevated in many non-
prion neurologic conditions (Satoh et al., 1999). When first
published, the 14-3-3 was reported to have 100% sensitiv-
ity and 96% specificity, but this study was limited by small
sample size and poor controls (Hsich et al., 1996). Subse-
quent larger European studies have found this protein to
have a sensitivity and specificity of about 85%, but control
patients were not sufficiently characterized in some of
these studies (Collins et al., 2006; Sanchez-Juan et al., 2006).
A more recent survey of the CSF results collected by the
UK CJD Surveillance Unit showed 14-3-3 sensitivity of 86%
and specificity of 74% in a pathologically confirmed sam-
ple (Chohan et al., 2010). Many feel that the 14-3-3 protein
is merely a marker of rapid neuronal injury and has little
specificity for sCJD (Satoh et al., 1999; Chapman et al., 2000;
Geschwind et al., 2003). Elevated CSF 14-3-3 protein may
be found in other neurologic conditions resulting in cortical
injury, including AD and stroke (Huang et al., 2003).
Total-tau (t-tau), neuron-specific enolase (NSE), and the
astrocytic protein S100β are also used as CSF biomark-
ers. The sensitivity and specificity of these biomarkers
 Prion Diseases 273

for sCJD vary greatly among studies. One large multi-
center European study recently examined the sensitivity
and specificity of four biomarkers: 14-3-3, t-tau, NSE, and
S100β. As not all patients underwent all four tests, nor
were they necessarily performed in the same CSF sam-
ples, this study did not allow for legitimate comparison
between biomarkers. Nevertheless, they found the sen-
sitivity and specificity of the 14-3-3 to be 85% and 84%,
t-tau (cut-off >1300 pg/mL) 86% and 88%, NSE 73% and
95%, and S100β 82% and 76%, respectively (Sanchez-Juan
et al., 2006). The same methodological problems were also
present in a more recent 2010 survey of the UK Surveil-
lance Center data. However, they did a separate analysis
of cases in which both 14-3-3 and t-tau protein were tested
in the same samples. The sensitivity and specificity for
14-3-3 and t-tau tested in the same samples were 85% and
74% for 14-3-3 and 81% and 85% for tau (Chohan et al.,
2010). The sensitivity and specificity of these tests in other
forms of prion disease, such as vCJD and gPrD, have con-
sistently been reported to be much lower than for sCJD.
MRI
MRI, particularly diffusion sequences, has higher sensitiv-
ity for sCJD than either EEG or 14-3-3 protein (Shiga et al.,
2004; Young et al., 2005; Zerr et al., 2009; Vitali et al., 2011).
Typical MRI abnormalities in CJD include T2-weighted
(including fluid attenuated inversion recovery [FLAIR]
sequences) and diffusion weighted imaging (DWI)
weighted hyperintensities in the deep nuclei (caudate,
putamen, and, less often, the thalamus) and cortical gyral
hyperintensities (cortical ribboning). DWI has higher sen-
sitivity than FLAIR for sCJD (Vitali et al., 2011).
When CJD is suspected, a brain MRI with DWI and
FLAIR sequences should be obtained (Vitali et al., 2011).
Figure 9.16 shows a typical MRI in sCJD. Even at major
medical centers, many radiologists are still not familiar

(a) (c) (e) (g)

(b) (d) (f) (h)

Figure 9.16 DWI and FLAIR MRI in sCJD and vCJD. Three common MRI patterns in sCJD: predominantly subcortical (a, b), both cortical and
subcortical (c, d), and predominantly cortical (e, f); also a patient with probable variant CJD (vCJD) (g, h). Note that, in sCJD, the abnormalities
are more evident on DWI (a, c, e) than on FLAIR (b, d, f) images. The three sCJD cases (a, b; c, d; e, f) are pathology proven. (a, b) A 52-year-old
woman with MRI showing strong hyperintensity in bilateral caudate (solid arrow) and putamen (dashed arrow) and slight hyperintensity in
bilateral mesial and posterior thalamus (dotted arrow). (c, d) A 68-year-old man with MRI showing hyperintensity in bilateral caudate and
putamen (note anteroposterior gradient in the putamen, which is commonly seen in CJD), thalamus, right insula (dotted arrow), anterior and
posterior cingulate gyrus (solid arrow, L>R), and left temporal–parietal–occipital junction (dashed arrow). (e, f) A 76-year-old woman with
MRI showing diffuse hyperintense signal mainly in bilateral temporoparietal (solid arrows) and occipital cortex (dotted arrow), right posterior
insula (dashed arrow), and left inferior frontal cortex (arrowhead), but no significant subcortical abnormalities. (g, h) A 21-year-old woman
with probable vCJD, with MRI showing bilateral thalamic hyperintensity in the mesial pars (mainly dorsomedian nucleus) and posterior pars
(pulvinar) of the thalamus, the so-called “double hockey stick sign.” Also note the “pulvinar sign,” with the posterior thalamus (pulvinar;
arrow) being more hyperintense than the anterior putamen. CJD, Creutzfeldt–Jakob disease; MRI, magnetic resonance imaging; DWI, diffusion-
weighted imaging; FLAIR, fluid-attenuated inversion recovery. Source: Geschwind (2011). Reproduced with permission from Elsevier.
274 Neurologic Conditions in the Elderly
with the MRI findings indicative of CJD, and a majority of
sCJD MRIs are misread (Geschwind et al., 2010; Carswell
et al., 2012). Diagnostic MRI criteria for sCJD have been
proposed. Some allow the use of FLAIR or DWI and do
not include abnormalities in the frontal lobes (Zerr et al.,
2009); others require diffusion abnormalities and do not
exclude frontal lobe involvement (Vitali et al., 2011).
Other laboratory testing
Basic laboratory studies, such as CBC, chemistry, liver func-
tion tests, ESR, and ANA, are generally unremarkable in
sCJD. CSF might show a mildly elevated protein (typically
less than 100 mg/dL) with normal glucose level. Red and
white blood cell counts usually are normal. Pleiocytosis, an
elevated IgG index, or increased oligoclonal bands rarely
occur in sCJD and should prompt evaluation for other con-
ditions, particularly infectious or autoimmune disorders. At
our center, we frequently rule out reversible causes of RPD
that sometimes mimic sCJD, including autoimmune para-
neoplastic (such as anti-Hu, anti-CV2, anti-Ma2, anti-Ri, and
anti-NMDA antibodies) and nonparaneoplastic diseases
(such as Hashimoto’s encephalopathy; antithyroid per-
oxidase and antithyroglobulin antibodies, and antivoltage
gated-associated encephalopathy (anti-VGKC antibodies).
Genetic prion disease
Mutations in the prion protein gene, PRNP, are responsible
for about 15% of all human prion disease cases. They are
always autosomal dominant, and most are 100% penetrant
(i.e., almost everyone with a mutation develops the disease
if they live a normal lifespan). More than 40  mutations,
including point mutations, stop codons, insertions, and
deletions, have been identified. Testing and diagnosis can
be achieved through DNA testing of blood while a patient is
alive or through autopsy tissue (Kong et al., 2004). Despite
the high penetrance, more than 60% of patients with gPrD
do not have a positive family history of prion disease. In
most of these cases, relatives were misdiagnosed with
other dementias, families hid their medical history, or there
was reduced mutation penetrance (Kovacs et al., 2005).
Based on clinical, genetic, and pathologic characteris-
tics, three forms of gPrDs have been identified: fCJD, GSS,
and FFI. This classification is not absolute, as some muta-
tions have features that blend fCJD and GSS.
Patients with gPrD typically have a younger age of onset
(typically from 40s to 60s), a slower progressive course, and
a longer lifespan (typically a few years) than sCJD patients.
Depending on the PRNP mutation and other genetic and
epigenetic factors, gPrDs often present identically (clini-
cally and pathologically) to sCJD with rapid onset of clini-
cal symptoms and short survival of weeks to months (Kong
et al., 2004). Common early symptoms include parkinson-
ism or ataxia with only mild personality or early cognitive
changes. Other mutations, such as those causing GSS, bring
about a slower illness, often with behavioral and motor
abnormalities early on and dementia later in the disease.
Some less common PRNP mutations result in an older age
of onset, in the 70s or 80s. There is often great variability in
presentation and disease course of the several mutations
causing gPrDs; in fact, even within the same family mem-
bers carrying the same mutation, there might be great clini-
cal variability. Polymorphism within PRNP, such as at codon
129, also alters the presentation of gPrDs (Kong et al., 2004).
It is generally thought that the mechanism for gPrDs
is that mutations in PRNP make PrPC more susceptible
to changing conformation into the abnormally shaped,
disease-causing form, PrPSc. It is thought that this confor-
mational change occurs throughout life but that these are
cleared by the cell; as one ages, the body’s ability to clear
abnormal proteins declines, leading to the accumulation of
PrPSc (Kong et al., 2004; van der Kamp and Daggett, 2010).
Familial CJD (fCJD)
More than 15 mutations are known to cause fCJD. Most
are point (missense) mutations, but some are insertion
mutations and a deletion (Kong et al., 2004; Meissner
et al., 2009). Most fCJD patients present similarly to sCJD,
with overlapping clinical MRI and EEG findings. The
most common fCJD mutation worldwide is E200K, found
most commonly among Libyan Jews and Slovakians.
Gerstmann–Sträussler–Scheinker (GSS)
Gerstmann-Sträussler-Scheinker is caused by at least 10
PRNP mutations, including several missense mutations, a
stop mutation, and insertion mutations (Kong et al., 2004).
The age of onset for GSS mutations is often under the age
of 65, typically in the 50s or younger, so we will not delve
into too much detail, as the likelihood of a geriatric presen-
tation is low. GSS often presents as a slowly progressive
ataxic and/or parkinsonian disorder. Cognitive impair-
ment often comes only later, although some mutations are
present with early dementia and/or behavioral abnormali-
ties. However, considerable phenotypic variability exists
within and between mutations and families (Kong et al.,
2004; Giovagnoli et al., 2008; Webb et al., 2008). Due to the
slow course (up to several years), persons with GSS can be
mistaken to have other neurodegenerative conditions, such
as multiple-system atrophy, spinocerebellar ataxias, idio-
pathic Parkinson’s disease, AD, or HD (refer to Table 9.13).
Fatal familial insomnia
Fatal familial insomnia is one of the rarest gPrDs and
is caused by a single PRNP point mutation, D178N,
with codon 129 having methionine (129M) on the same

30
MM blood
25
MV primary
Number of deaths
20 Untyped primary
MM primary
15
10
5 As prions are proteins, typical sterilization methods do
0 1987b; Prusiner, 1998); inactivation requires other meth-
1995 1997 1999 2001 2003 2005 2007
Year
Figure 9.17 Times series of observed vCJD cases in the United
Kingdom by genotype and presumed transmission route.
Bar graph depicting number of deaths from vCJD per year in
the United Kingdom through 2009. Bars refer to codon 129
polymorphism of decedent and their method of infection,
primary, through consumption of BSE, or blood, through
blood transfusion. Three persons, all codon 129 MM, died from
vCJD from blood transfusion (black bars). One probable vCJD
subject who died in 2009 (lighter bar) was codon 129MV and
had primary infection. The number of deaths from vCJD has
been relatively stable over the past five years. but it is not clear
whether there will be another rise in the number of cases. Source:
Garske and Ghani (2010). Reproduced with permission from
Public Library of Science.
chromosome (cis; see Figure 9.17). Patients with D178N but
cis valine at codon 129 (129V) usually present with fCJD,
clinically more similar to sCJD than FFI. FFI usually at a
mean age of 49 (range 20–72) presents with progressive,
severe insomnia and dysautonomia (tachycardia, hyper-
hydrosis, and hyperpyrexia), with motor and cognitive
problems appearing later in the course. Most FFI patients
survive slightly longer than sCJD patients, about one and
a half years. Although brain MRI is usually normal, FDG–
PET imaging reveals thalamic and cingulate hypometabo-
lism, often even before disease onset (Kong et al., 2004).
Confirming a PRNP mutation by DNA extraction is
important in diagnosing a gPrD, as pathology alone
often cannot confirm a genetic etiology. As many gPrDs
appear similar to sCJD and can have obscured family
histories, this testing is important after the appropri-
ate genetic counseling (Huntington’s Disease Society of
America, 1994).
Acquired CJD
Acquired forms of CJD occur because prions are transmis-
sible and infectious. A relatively large number of prions
(estimated several thousand proteins) probably are nec-
essary to transmit prion disease, so they are not highly
infectious or contagious.
Prion Diseases 275
Acquired prion diseases include Kuru (now essentially
extinct, occurring in the Fore tribe in Papua New Guinea
due to endocannibalism); iatrogenic CJD (iCJD); and the
highly publicized vCJD, occurring primarily in the United
Kingdom and France, caused by consumption of bovine
spongiform encephalopathy (BSE or mad cow disease),
contaminated beef (Will et al., 2000; Prusiner and Bosque,
2001; Will, 2003; Collinge et al., 2006), and, in a few cases,
blood transfusion.
not render them inactive (Bellinger-Kawahara et al., 1987a,
2009
ods or longer times at higher pressure and temperatures
than typically used for standard sterilization (Peretz et al.,
2006). This difficulty has led to approximately 400 cases of
iCJD, from the use of cadaveric-derived human pituitary
hormones, dura mater grafts, corneal transplants, the reuse
of cleaned and sterilized EEG depth electrodes implanted
directly into the brain and other neurosurgical equipment,
and blood transfusion (Brown et al., 2000; Will, 2003).
Most of the pituitary-derived (human grown hormone
[hGH] and gonadotrophin) cases occurred from contami-
nated batches in France, the United Kingdom, and the
United States. Methods have since been instituted to pre-
vent prion transmission through such hormones (Brown
et al., 2006). Thankfully, it appears that the number of iCJD
cases is declining. Despite WHO recommended practices,
however, for managing potential prion-contamination tis-
sues (WHO, 1999, 2003), this still occurs and leaves patients
at risk for iCJD. As most persons treated with these materi-
als were children and incubation period is from one year
at the shortest and up to one to two decades, such cases of
iCJD do not occur in the geriatric population.
The most notorious form of CJD is vCJD, first identi-
fied in 1995 (Will et al., 1996). It is caused by inadvertent
ingestion of BSE (mad cow disease) or, in a few cases,
blood transfusion from asymptomatic patients who were
unknowing carriers of vCJD (Zou et al., 2008). Cattle are
thought to have contracted BSE from being fed scrapie-
infected sheep products used as feed (Bruce et al., 1997;
Scott et al., 1999). Differing from sCJD, patients with vCJD
are generally younger, with a median age of around 27
(range 12–74), and almost all cases have occurred in per-
sons younger than 50. The mean disease duration is lon-
ger, about 14.5 months, versus about 7 months for sCJD.
Early psychiatric symptoms are more characteristic in
vCJD as compared to sCJD (Wall et al., 2005; Rabinovici et
al., 2006) and might occur several months before obvious
neurologic symptoms begin. Painful paresthesias, rela-
tively persistent through the disease course, often occur in
vCJD, although such pain rarely is seen in other prion dis-
eases. The EEG does not show the classic periodic sharp
wave complexes, except in rare cases at the end of the dis-
ease (Binelli et al., 2006). The best diagnostic marker cur-
rently is the brain MRI that usually shows the “pulvinar
sign,” in which the pulvinar (posterior thalamus) is
276 Neurologic Conditions in the Elderly
brighter than the anterior putamen on T2-weighted or
DWI MRI (refer to Figure 9.17; Collie et al., 2003); this MRI
pattern is very rare in the other prion diseases (Petzold
et al., 2004). More specific tests, including detecting vCJD
prions in the CSF, are under development. The younger
age of onset, MRI findings, prominent early psychiatric
features, persistent painful sensory symptoms, and cho-
rea help differentiate vCJD from sCJD. As with sCJD,
definitive diagnosis of vCJD is based on pathologic evi-
dence of PrPSc in brain biopsy or autopsy. As the prions
in vCJD are present in high numbers in the lymphoreticu-
lar system (unlike other human prion diseases, in which
there are high prion numbers only in the central nervous
system), tonsils and other lymphoid tissue can also be
used for pathologic diagnosis.
As of November 2013, approximately 225 cases of prob-
able or definite cases of vCJD have been documented,
mostly in the United Kingdom, and no cases of vCJD
have been acquired in the Western Hemisphere, including
the United States or Canada (three patients in the United
States and two in Canada have been diagnosed with
vCJD, but those cases are thought to have been acquired
elsewhere; CDC, 2006; UK National CJD Surveillance
Unit, 2013). Following the United Kingdom, France has
the second highest number of vCJD cases, which prob-
ably have the same origin as those in the United Kingdom
(Brandel et al., 2009). The height of the vCJD epidemic
passed in 2000. Experts fear that there may be further
peaks due to people with different genetic susceptibility
who were infected at the same time or the continuing risk
of iatrogenic spread of vCJD (Andrews, 2010). One Brit-
ish study found vCJD prions in three of 11,246 appendix
samples collected from 1995 to 2000 by immunostaining.
Another similar study, the National Anonymous Tonsil
Archive, found one positive sample among a subset of
10,000 tested (Garske and Ghani, 2010). Thus, some peo-
ple in the population are not sick and carry variant pri-
ons, but the risk is unclear. These asymptomatic carriers
of vCJD might pose the greatest risk for spread of vCJD,
through transfusion of blood products or invasive proce-
dures. Most alarmingly, it seems that infected asymptom-
atic vCJD donors are capable of transmitting the disease
1.5–6 years before they became symptomatic (Health Pro-
tection Agency, 2007). As of December 2010, four patients
have acquired vCJD through non-leukodepleted (white
blood cells removed) blood transfusions received before
1999 (Health Protection Agency, 2007). Figure 9.18 graphs
presumed vCJD cases in the United Kingdom.
Prion decontamination
Decontamination of prions requires methods that will
denature proteins, as prions resist normal inactiva-
tion methods used to kill viruses and bacteria. Some
recommended methods for prion decontamination
include very high temperatures with steam and caustic
denaturing agents—methods that often damage equip-
ment and instrumentation (WHO, 2003). Due to the risk
of transmission to subsequent patients, some medical cen-
ters opt for the more secure method of preventing iCJD by
destroying neurosurgical equipment (through incinera-
tion) rather than attempting to decontaminate and reuse.
Research into improved methods of decontamination of
prions is ongoing (Peretz et al., 2006).
Animal prion diseases
In addition to BSE as a cause of acquired human CJD,
a relatively new animal form of prion disease is rais-
ing similar concerns in North America: chronic wast-
ing disease (CWD). CWD is a prion disease of mule
deer, white-tailed deer, elk, and moose. The first clini-
cal cases were recognized in the late 1960s in North
America. The disease primarily has been reported in
the United States and Canada, with the highest con-
centrations occurring in the Central Mountain region
of the United States, especially Colorado and Montana,
as well as the Canadian provinces of Saskatchewan and
Alberta. Figure 9.18 shows the distribution of CWD in
North America. A most concerning aspect of CWD is its
Chronic wasting disease
in North America
Areas with CWD
infected cervid populations
States/provinces where
CWD has been found
incaptive populations
Figure 9.18 Map of the distribution of CWD in North America.
Darkest areas denotes areas where wild populations have been
infected. Medium dark denotes states and provinces with captive
herds contaminated with CWD. Reproduced from Chronic
Wasting Disease Alliance (www.cwd-info.org) with permission.

ease of horizontal transmission between cervids. This
might be in part due to the fact that CWD appears to be
transmittable through blood, urine, and saliva (Haley
et al., 2009). This feature makes it difficult to prevent
spread of the disease in free-ranging cervid popula-
tions (Williams, 2005). It still is not clear whether CWD
can spread to humans or whether there is a species bar-
rier, but there has been no reported increase in human
prion cases in states where CWD rates have been high-
est (Sigurdson et al., 2009).
Molecular and pathologic findings of
human prion diseases
The key pathologic features of sCJD are the presence of
PrPSc deposition (by either immunohistochemistry or
Western blot), neuronal loss, gliosis (proliferation of astro-
cytes), and vacuolation (spongiform changes; see Figure
9.15). We now know that the spongiform changes are due
to fluid-filled vesicles formed in distal dendrites near syn-
apses and are not air-filled holes (as in a sponge), so the
term vacuolation probably is more appropriate than spon-
giform.
GSS has a distinct neuropathology from most other
prion diseases, with large unicentric or multicentric
plaques of PrPSc amyloid the unicentric plaques, how-
ever, also are seen in a minority of sCJD cases, whereas
the multicentric plaques are more specific for GSS. Neuro-
pathology of FFI includes profound thalamic gliosis and
neuronal loss, causing atrophy. Involvement of regions
outside the thalamus is greater in FFI with codon 129 MV
than MM (Cortelli et al., 1997, 2006; Budka, 2003).
Because vCJD is typically acquired peripherally, PrPSc
can be found in the lymphoreticular system, including
tonsillar tissue (Will, 2004). Brain pathology of vCJD
shows abundant PrPSc deposition, particularly multiple
fibrillary PrP plaques surrounded by a halo of spongiform
vacuoles (“florid” plaques) and other PrP plaques, and
amorphous pericellular and perivascular PrP deposits,
especially prominent in the cerebellar molecular layer; the
pathognomonic plaques in vCJD are called florid because
they have the appearance of a flower with a dense cen-
ter and surrounding ring of vacuoles (refer to Figure 9.15;
Budka, 2003). The Western blot characteristics of vCJD
PrPSc also are different from those seen in other forms of
prion disease (Will et al., 2000; Will, 2003, 2004).
Molecular classification of sCJD
Sporadic Jakob–Creutzfeldt disease has been divided
into approximately six molecular subtypes based on
the genetic polymorphism at codon 129 in the prion
gene and the type of protease-resistant prion (type 1
Prion Diseases 277
Table 9.15 Distribution of PRNP codon 129 polymorphism in
normal population and several human prion diseases
MV (%) MM (%) VV (%)
Normal population 51 37 12
sCJD 12–17 ~66 to 72 17
iCJD 20 57 23
vCJDa 0 100 0
Source: Reproduced from Geschwind (2011) with permission from
Elsevier.
sCJD, sporadic Jakob-Creutzfeldt disease; iCJD, iatrogenic CJD; vCJD,
variant CJD.
a
All but one clinical case of vCJD have been MM; one probable vCJD
case was codon 129 MV, and some subclinical cases with vCJD
prions in the lymphoreticular system have been identified (Parchi
et al., 1999; Brown et al., 2000; Collins et al., 2006; Garske and Ghani,
2010; Peden et al., 2010).
or 2). Codon 129 polymorphisms are comprised of dif-
ferent combinations of either methionine (M) or valine
(V) at location 129 of PRNP (e.g., MM, MV, or VV; see
Table 9.15 and Figure 9.18). Additionally, upon extrac-
tion from the brain and partial digestion with protein-
ase, PrPSc may be cleaved at two possible sites (codon
82 or 97; refer to Figure 9.14), resulting in either a lon-
ger, 21 kDa (type 1) or a shorter, 19 kDa (type 2) pep-
tide on a Western blot. To some extent, this classification
separates sCJD cases based on their clincopathologic
features. MM1 and MV1 are the most common forms
(70%) and present as classic sCJD, with RPD and a dura-
tion of just a few months. VV2 (16%) starts with ataxia,
later-onset dementia, and a short duration. The remain-
ing four types, MV2 (9%), MM2-thalamic (2%), MM2-
cortical (2%), and VV1 (1%), have a duration of about
1–1.5 years. MV2 presents similarly to VV2 with ataxia,
but these cases have focal amyloid kuru plaques in the
cerebellum. MM2-thalamic presents often with insom-
nia, followed later by ataxia and dementia, with most
pathology confined to the thalamus and inferior olives
with very little vacuolation; some call this form sporadic
fatal insomnia (sFI) because it presents similarly to the
genetic prion disease, FFI. MM2-cortical patients have
progressive dementia with large confluent vacuoles in
all cortical layers. sCJD patients with VV1 also present
with progressive dementia, but these cases have severe
cortical and striatal pathology, with sparing of the brain-
stem nuclei and cerebellum. Unlike with MM2-cortical,
sCJD VV1 patients do not have large confluent vacuoles,
but there is faint synaptic PrPSc staining (Parchi et al.,
1999). Curiously, as shown in Table 9.15, heterozygosity
at codon 129 in the prion gene, PRNP, is somewhat pro-
tective against prion disease. Recently, however, it has
been found that many sCJD patients have a mix of both
type 1 and type 2 prions (Kobayashi et al., 2011), so this
classification scheme must be revised.
278 Neurologic Conditions in the Elderly
Proteinase-sensitive proteinopathy
(PSPr): a new form of sCJD
Until recently, one marker of prion disease has been the
resistance of PrPSc to proteases, enzymes that digest pro-
teins. A new form of sCJD has recently been identified in
which the vast majority of patients’ PrPSc is protease sensi-
tive. Thus, standard immunohistochemical techniques that
depend on identifying protease-resistant PrPSc for diagno-
sis are now considered insufficient. These subjects had a
different clinical phenotype based on their codon 129 geno-
type (VV, MV, and MV). These cases presented with psy-
chiatric symptoms and a frontal dementia syndrome (with
predominant behavioral symptoms and executive deficits),
and most had negative ancillary tests (MRIs, EEGs, and
14-3-3). Although their mean age was commensurate with
classic sCJD (late 60s), their mean disease duration was
much longer, at 2.5 years (Zou et al., 2010).
Treatments of human prion diseases
Human prion diseases have no known cure or disease-
modifying treatment. All cases are uniformly fatal. Some
hypothetical mechanisms for treating prion diseases include
removing or reducing the endogenous substrate, PrPC;
blocking the interaction of PrPC with PrPSc; and removing
PrPSc or blocking its toxicity (Korth and Peters, 2006). An
immunotherapy approach to treating prion diseases is cur-
rently under investigation, and it may be that some antibod-
ies that are effective against prions could be useful in other
neurodegenerative diseases as well (Freir et al., 2011). Sev-
eral medicines have been used to treat human prion disease,
but only flupirtine, quinacrine and doxycycline, given orally,
have been tested in randomized, double-blinded, placebo-
controlled trials. None were effective in prolonging survival
(Korth and Peters, 2006; Geschwind et al., 2013). Intraven-
tricular pentosan polysulfate has been used on a compas-
sionate basis in the United Kingdom, Japan, and a few other
countries, but observational data suggest that it does not
affect survival. The doxycycline treatment trial for human
prion disease in Italy and France completed in 2013 and did
not show any positive effect in survival or other outcomes.
(www.agenziafarmaco.it/en). Other drugs will likely be
tested in the near future (Stewart et al., 2008). Several labo-
ratories around the world are screening drug libraries and
using medicinal chemistry to identify and develop antiprion
therapies. In the absence of any curative treatments, man-
agement of prion diseases involves treating symptoms as
they arise and providing comfort care.
Differential diagnosis
The differential of prion diseases includes RPDs
(Geschwind et al., 2007b) and other slower, more common
neurodegenerative diseases, such as AD and Lewy body
disease (Tschampa et al., 2001). A useful mnemonic to
use when evaluating a patient with an RPD or suspected
prion disease is VITAMINS, for vascular, infectious, toxic-
metabolic, autoimmune, metastatic-metabolic, iatrogenic,
neurodegenerative-neoplastic, and systemic etiologies
(Geschwind et al., 2007b, 2008; Vernino et al., 2007).
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 Chapter 9.8
Normal Pressure Hydrocephalus
Norman R. Relkin
Introduction
Normal pressure hydrocephalus (NPH) is a chronic neu-
rologic disorder in older adults characterized by enlarge-
ment of the cerebral ventricles and progressive distur-
bances of gait, urinary continence, and cognition. Hakim
and Adams first described the classic symptom triad of
shuffling gait, urinary incontinence, and dementia in
1965 and identified NPH as a surgically treatable condi-
tion (Hakim and Adams, 1965). NPH is now widely rec-
ognized as a potentially reversible cause of physical dis-
ability and cognitive impairment in the elderly.
Classification of hydrocephalus
The term hydrocephalus is used to describe a number of
pathologic conditions in which the size of the cerebral
ventricles is increased. NPH is a particular type of hydro-
cephalus with certain distinguishing features:
• NPH is a “communicating” form of hydrocephalus be-
cause it develops chronically in the absence of a mac-
roscopic obstruction to the flow of cerebrospinal fluid
(CSF). This distinguishes NPH from acute, obstructive
forms of hydrocephalus that result from lesions such as
brain tumors and intracerebral hematomas. NPH can
occur in the aftermath of conditions such as intracrani-
al hemorrhage, meningitis, or head trauma. Such cases
are called secondary NPH (sNPH) because hydroceph-
alus arises as the distal consequences of a brain insult
rather than from an obstructive mass lesion. When
there is no identifiable antecedent cause for adult hy-
drocephalus, it is called idiopathic NPH (iNPH).
• Enlargement of the ventricles in NPH is not exclusively
the result of brain atrophy (so-called hydrocephalus ex
vacuo). In practice, differentiating NPH from ex vacuo
enlargement of the ventricles can be challenging. The
current approach involves subjective judgment of the
extent to which ventricular enlargement is dispropor-
tionate brain atrophy as assessed from signs such as the
degree of sulcal widening on brain imaging. Other po-
tentially distinguishing signs have been identified (see
the upcoming section “Neuroimaging”).
• NPH is a different disorder than hydrocephalus in
neonates and children. However, possible links be-
tween certain types of childhood hydrocephalus and
NPH have been identified. According to the so-called
“two hit” hypothesis of NPH, benign congenital ex-
ternal hydrocephalus combined with the develop-
ment of deep white matter ischemia later in life may
lead to NPH in older adults (Bradley et al., 2006). Be-
cause skull size becomes fixed after the fontanelles
close in early childhood, this could help explain why
head circumference is significantly increased in a
subset of patients with NPH (Krefft et al., 2004). An-
other NPH-like syndrome related to childhood hy-
drocephalus is called longstanding overt ventriculo-
megaly in adults (LOVA) (Kiefer et al., 2002). LOVA is
thought to begin with childhood hydrocephalus that
is initially compensated but progresses later in life
to cause symptoms. Associated findings include an
enlarged head circumference and, in some cases, an
empty sella turcica.
• Aqueductal stenosis (AS) can closely resemble NPH
but differs in cause and treatment. In AS, congenital or
acquired narrowing of the aqueduct of Silvius leads to
ventricular enlargement and symptoms quite similar to
those of NPH. Stenosis of the aqueduct can be identi-
fied on a midsagittal MRI scan and by flow-sensitive
MRI techniques that document diminished CSF flow
rates.
Demographics
Idiopathic NPH most commonly affects persons over
40  years of age and may occur alone or in combina-
tion with Alzheimer’s disease, Parkinson’s disease, and
other age-related disorders. NPH occurs in males and
females in roughly equal proportions. Familial associa-
tion has been anecdotally reported but is only rarely
encountered in practice. The precise incidence and
prevalence of NPH has not been rigorously determined.
A Norwegian study in over 200,00 subjects estimated
the incidence of NPH at 5.5 per 100,000 population and
estimated prevalence at 21.9 per 100,000 population
(Brean and Eide, 2008).
Pathophysiology
Not surprisingly, the most consistent finding in NPH
patients at autopsy is enlargement of the cerebral ventri-
cles. Pathologic studies have failed to identify lesions at
281
282 Neurologic Conditions in the Elderly
the gross or molecular levels that are universally diagnos-
tic of NPH or unequivocally explain its etiology. Increased
resistance to the clearance of CSF has been documented
in some cases, but its cause has yet to be determined.
Likewise, it remains unclear how disturbances in the CSF
compartment translate into brain dysfunction and clinical
symptoms in NPH. Intracranial pressure is only mildly ele-
vated in NPH, typically to 130 mm H2O or slightly higher.
Although this pressure is inadequate to cause cerebral
dysfunction in normals, it has been argued that the effects
are multiplied by the expanded ventricular surface over
which it is exerted in NPH. Ventricular expansion, tran-
sependymal fluid movement, and age-associated reduc-
tions in cerebral compliance may make the brain more
susceptible to the repeated impact of the CSF pulsations. A
provocative hypothesis has been recently forwarded that
implicates disturbances in CSF pulsatility in the pathogen-
esis of NPH (Bateman, 2008) According to this hypothe-
sis, altered brain compliance and CSF pulsatility leads to
cyclical compression of the tributary veins that empty into
the sagittal sinus, resulting in increased resistance to CSF
outflow (Ro). “Hydrodynamic” interference in CSF clear-
ance could explain the increased Ro documented by CSF
infusion studies in many NPH patients, in the absence of
an identifiable obstruction of CSF flow.
Physical distortion of neurons and their processes
caused by ventricular enlargement has been hypothe-
sized to delay or disrupt neuronal transmission in NPH.
However, motor-evoked response studies have failed to
show alterations in central conduction latencies, as would
be expected if physical stretching were the cause of cere-
bral dysfunction in NPH (Zaaroor et al., 1997). Reduced
cerebral blood flow has also been reported in NPH, but
brain perfusion is not universally compromised, nor is
it consistently improved after treatment. Small-vessel
ischemic cerebrovascular disease has been linked to pro-
gression of NPH. As the burden of cerebrovascular dis-
ease increases, NPH generally becomes more refractory
to treatment. In chronically untreated cases, small-vessel
infarction occurs throughout the periventricular region,
giving rise to a condition that is indistinguishable from
Binswanger’s disease.
Neuroimaging
A brain imaging study is necessary to identify ventricular
enlargement in NPH. However, diagnosis also requires
documentation of appropriate clinical findings. X-ray
computed tomography (CT) or nuclear medicine scans
such as cisternography can be used for this purpose, but
MRI is the preferred modality for evaluating NPH. The
use of MRI is limited by contraindications such as pace-
makers, metallic implants, and claustrophobia, as well as
in some venues by cost and availability. A T1-weighted
or other MRI pulse sequence that highlights ventricular
and cortical anatomy can readily be used for this purpose.
The Evans’ index, a measure of ventricular size calculated
from the ratio of the diameter of the skull to the diameter
of the lateral ventricle at its widest point, is 0.3 or greater
in NPH.
Because ventricular enlargement also occurs in aging
and neurodegenerative diseases, evaluation of possible
NPH requires determining whether the enlargement of
the ventricles is disproportionate to cerebral atrophy.
This is currently accomplished by visual inspection of
brain images to identify widened sulcal markings as
proxy measures of brain atrophy. This method is highly
subjective and may soon be supplanted by quantitative
MRI volumetric techniques that provide more accurate
measures of cortical atrophy. Advances in MRI methods
and other imaging techniques are likely to contribute to
improved differential diagnosis of NPH in the future.
Imaging can also be useful for verifying whether there
is any obstruction to CSF flow. In some cases, imaging
of the spine is useful for identifying obstructive causes
for hydrocephalus. Inspection of a midline sagittal
T1-weighted image is recommended for examining the
patency of the cerebral aqueduct and fourth ventricle.
In equivocal cases, a phase contrast CSF flow study can
provide useful information about CSF movement. Aque-
ductal flow rates are low or undetectable in aqueductal
stenosis, while in NPH, normal or increased (hyperdy-
namic) flow is observed. Hyperdynamic flow can some-
times be identified as a fourth ventricular flow void on
proton density images or nonwater-suppressed echo
planar images. Other structural findings associated with
NPH that can be identified on CT scans or MRIs include
enlargement of the temporal horns of the lateral ventricles
not attributable to hippocampal atrophy, upward doming
of the roof of the body of lateral ventricles, enlargement
of the Sylvian fissure, and compression of the paramedian
sulci of the frontoparietal region near the cranial convex-
ity (see Figure 9.20).
Symptoms
Although NPH is associated with gait ataxia, urinary
incontinence, and dementia, symptoms fall on a contin-
uum from very mild to severe and are not limited to those
of the classic triad. Symptoms are stage dependent and
may be minimal early in the disease or confined to just
one or two domains. It is therefore important for clini-
cians to become familiar with the full spectrum of presen-
tations and stages of NPH:
• Gait and balance: Impairments of walking and balance
are the most readily observed symptoms of NPH and
the most reliably reversed by treatment. The charac-
teristic gait disturbance in NPH is often described as

(a)
Figure 9.20 Midsagittal MRIs taken 5 years
apart in a patient with Alzheimer’s disease
who subsequently developed symptoms
of NPH. Note the expansion of ventricles
without a commensurate increase in sulcal
markings, and the apparent narrowing of
sulci at the parietal convexity. (a) Initial
presentation of AD. (b) Five years later,
coincident with onset of NPH symptoms.
“shuffling” or “magnetic.” Patients with NPH typi-
cally show a reduced foot–floor clearance and a wid-
ened base, walking in short steps with their toes point
outward. There is reduced counter-rotation of the hips
and shoulders while walking. Accelerometer studies
show an increased tendency to sway while walking
and while standing in place. There may be a prolonged
latency when starting ambulation or stopping. Tandem
gait is frequently disturbed. It takes symptomatic NPH
patients longer than normal to rise from a chair and to
walk a short distance. The number of steps required to
cover a given distance is also increased. Patients with
NPH frequently retropulse, either spontaneously or as
a consequence of being pulled backward on the “Pull
Test.” Turning in place may require multiple small
steps, so-called “en-bloc” turning. NPH patients fre-
quently fall directly forward or backward when bend-
ing or on uneven terrain but may fall in any direction.
Parkinsonism may be present in NPH patients either as
a comorbid illness or as a consequence of NPH itself.
Parkinsonism secondary to NPH is less responsive to
treatment with dopamine precursors or agonists than
idiopathic Parkinson’s disease. A timed walking test
is an inexpensive and sensitive method for identifying
and following the gait disturbances in NPH. Clinical
gait scales such as the one published by Boon and col-
leagues (Boon, 1971) can be useful for rating the full
range of associated gait and balance disturbances.
• Control of urination: The most common urinary symp-
toms associated with NPH are urinary frequency,
urgency, and nocturia. These early stage symptoms
may progress to urinary incontinence as the disease
progresses. In most cases, incontinence is confined to
micturition, but in advanced stages, defecation may
be involved as well. NPH patients are often aware of
their urinary symptoms and embarrassed when incon-
tinence develops. With progression of the disease, and
particularly with advancing dementia, they may de-
velop indifference to incontinence. Asking subjects or
spouses to keep a bladder diary indicating frequency/
Normal Pressure Hydrocephalus 283
(b)
urgency of urination and incidents of incontinence can
provide useful diagnostic information. Urologic evalu-
ation is recommended to rule out other causes of uri-
nary dysfunction. Urodynamic studies in NPH patients
tend to show a neurogenic-type pattern and may re-
veal an increased post-void residual. Persons with un-
treated NPH may be at increased risk of urinary tract
infections (UTIs), owing to incomplete voiding. Those
with recurrent UTIs may benefit from an antimicrobial
prophylaxis.
• Cognition: The cognitive profile of NPH is typically
subcortical with frontally weighted deficits and rela-
tive sparing of language function. Not infrequently,
NPH occurs in combination with diseases such as
Alzheimer’s which may add elements of cortical, limbic,
and paralimbic disturbances to the profile of cognitive
dysfunction. Cognitive impairments in NPH usually
manifest as disturbances of executive function, includ-
ing difficulties carrying out multistep tasks, multitask-
ing, formulating abstractions, and dividing attention.
Memory can fail secondary to impaired information re-
trieval. Recognition memory is relatively preserved, as
evidenced by performance improving with cues or mul-
tiple choice. This contrasts with Alzheimer’s disease,
in which the information is rapidly lost from memory
and may be neither recalled nor recognized. Language
ability usually remains intact, although phonemic (let-
ter) fluency and confrontational naming are decreased
in conjunction with frontal systems deficits. Ideomotor
praxis may be preserved, but some patients with NPH
have difficulty transitioning from a standing to recum-
bent position, such as on an examining table.
Screening tests such as the Folstein Minimental
State examination may not be sufficiently sensitive to
detect subtle frontal systems deficits in NPH. Timed
performance-based tasks and tasks with frontal weight-
ings are recommended to assess impairments in sus-
pected cases of NPH. Tests such as Trails A and B, The
Digit-Symbol test, tend to be sensitive to NPH-related
deficits and improve with treatment. Certain tests of
284 Neurologic Conditions in the Elderly
upper extremity function (Maze Drawing and Serial Dot-
ting) have recently been found sensitive to impairments
in NPH and are responsive to CSF drainage (Tsakanikas
et al., 2009). Neuropsychological testing can be useful in
documenting subtle cognitive dysfunction in mild stages
of NPH and for tracking response to treatment.
• Other findings: A variety of psychiatric disturbances
ranging from psychosis and agitation to depression
and anxiety disorders have been reported in association
with NPH, either as exacerbation of pre-existing condi-
tions or arising de novo. In some cases, psychiatric symp-
toms are responsive to treatment of hydrocephalus.
Recent onset of hypertension has been reported in an
unexpected fraction of patients with newly diagnosed
NPH, leading to the speculation of a possible causal re-
lationship. Decreased hearing and frank deafness have
been rarely associated with NPH, but primarily in the
aftermath of shunt placement instead of as a presenting
symptom. The same is true of epilepsy, which may oc-
cur in as many as 10% of shunted NH patients.
Diagnostic criteria
International consensus criteria for the diagnosis of
iNPH were published in 2005 (Relkin et al., 2005). These
evidence-based guidelines divide NPH into probable and
possible subcategories, to reflect the level of certainty
about the diagnosis. The guidelines also identify shunt-
responsive NPH as the subset of cases that have a positive
outcome from treatment.
Differential diagnosis
The symptoms of NPH overlap those of several conditions
that are common in elderly individuals. Alzheimer’s dis-
ease, Parkinson’s disease, and other neurodegenerative
conditions can manifest similar symptoms and may occur
comorbidly with NPH. Spinal stenosis, arthritic condi-
tions, and orthopedic disorders can cause gait and balance
disturbances resembling those of NPH. Prostatic enlarge-
ment and a number of other urologic conditions can give
rise to the urgency, frequency, and incontinence that is also
associated with NPH. Differential diagnosis of NPH there-
fore requires careful exclusion of other conditions, and, in
the cases with comorbidities, a determination of the extent
to which symptoms are attributable to NPH.
Prognostication
Some generalizations can be made about the likeli-
hood of a positive response to shunt treatment based on
demographic and medical history, and additional prog-
nostication can be made on the basis of clinical tests:
• Prognosis for a positive response to neurosurgical
treatment in NPH is better for patients aged 75 years or
less, with duration of symptoms less than 2 years and a
lack of serious medical comorbidities. A less favorable
prognosis is associated with atypical presentations, ad-
vanced dementia, longstanding symptoms, confluent
subcortical cerebrovascular changes, and concomitant
anticoagulation therapy.
• Several tests have been developed to estimate the like-
lihood that a person with NPH will respond positive-
ly to a shunt. These include techniques high volume
(30–50 cc) lumbar puncture (LP) “tap tests,” 24- to 72-
hour external lumbar or ventricular catheter drainage,
CSF dynamics studies, MRI CSF flow measurements,
B-wave monitoring, radionuclide cisternography, and
others. Positive results on these tests can indicate a
more favorable prognosis for shunt response, but nega-
tive outcomes do not preclude benefit from a shunt. For
that reason, these tests tend to be used selectively when
the decision about whether to proceed to shunt must
be balanced against increased risks. The likelihood of
shunt responsiveness can be determined with up to
90% accuracy when prognostic tests are positive (Mar-
marou et al., 2005).
Treatment
A distinctive feature of NPH is that its symptoms can be
rapidly reversed by procedures that divert CSF out of
the central nervous system. Temporary improvements
can occur after LP, external lumbar drainage (ELD), and
ventriculostomy. Lasting reversal of symptoms follows
neurosurgical implantation of a ventricular shunt. Shunt
placement is the standard of care for NPH and fosters
excellent recovery in well-selected patients.
Shunts are permanent implanted devices that serve
as an alternative physical conduit for the outflow of
CSF from the central nervous system. Shunts have
many different designs and configurations, the full
scope of which is beyond the scope of this chapter. The
most basic configuration is a tube running from the
cerebral ventricles to another location in the body in
which drainage occurs by gravity. In most cases, how-
ever, a shunt valve is introduced between the two ends
to control the rate and volume of drainage of CSF as
the position of the head relative to the rest of the body
changes. The most common types of shunts in use
today are differential pressure valves that open when a
certain pressure difference exists between the ventricu-
lar side of the shunt and its distal end, which is most
often placed intra-abdominally. The shunt valve may
be supplemented by an antisiphon device that prevents
the valve from remaining open when gravity induces a
rapid flow (siphon) effect.

Until the 1990s, most shunt valves had fixed open-
ing pressures (low, medium, and high). An important
innovation that changed the management of NPH was the
advent of programmable valves that can be noninvasively
adjusted post-operatively. Present-day programmable
valves can be adjusted by magnetic or electromagnetic
programming devices and can be set noninvasively to a
wide range of opening pressures. This provides an oppor-
tunity to optimize the shunt function in individual cases
and a way to adjust the extent of drainage. The settings
of a programmable shunt can be interrogated by vari-
ous means that are valve dependent, including magnetic
compass devices, acoustic devices, and X-rays. The value
of programmable shunts relative to reduction of shunt
morbidity compared to fixed-pressure shunts has not
been conclusively established, but they have given NPH
patients and their physicians greater latitude to manage
symptoms that would otherwise require repeated surgery.
Although shunts can provide relief to well-chosen sur-
gical candidates that persist for several years, the outcome
of shunt placement is not uniformly positive. Shunts fail
to provide improvement in some cases and are associated
with operative and post-operative morbidity rates rang-
ing from 10% to 80% in different case series (Bergsneider
et al., 2005). Complications such as subdural hematomas,
infections, and shunt blockage take a devastating toll
on frail, elderly NPH patients and dramatically increase
the costs of NPH care. Maximizing successful treatment
of NPH requires accurate diagnosis and skillful clinical
management by specifically trained healthcare profes-
sionals.
LOVA may be treatable by endoscopic third ventricu-
lostomy (ETV), a procedure that creates an alternative
conduit for CSF flow through the floor of the third ven-
tricle. ETV may be associated with lower morbidity than
using a shunt to treat NPH, but it does not reverse symp-
toms in all cases. AS can also be treated by ETV instead
of a shunt, making it an important condition to recognize
and distinguish from NPH.
Nonsurgical aspects of management are also extremely
important for the care of patients with NPH. In both the
pre- and post-surgical periods, vulnerability to falling
is increased and appropriate steps should be taken to
reduce fall risk. This can be promoted by prescription of
a cane, walker, or, when appropriate, wheelchair. Modifi-
cations to the household should be considered for safety
purposes, including but not limited to installation of grab
bars in the bathroom and handrails on ramps and stair-
wells. Suitable candidates should be referred for physical
therapy. A program of scheduled toileting may help those
prone to UTIs or daytime incontinence, and prescription
of prophylaxis against UTIs should be considered in some
cases. Medications such as cholinesterase inhibitors that
are approved to treat Alzheimer’s disease and dementia
in Parkinson’s disease have not been formally evaluated
Normal Pressure Hydrocephalus 285
in NPH but may have adjunct therapeutic value in some
patients. The same may be said about dopamine precur-
sors such as levodopa. Focal or generalized seizure may
emerge after shunt surgery and should be addressed
with antiepileptic medication if recurrent. Depression
and other behavioral disturbances also occur in the NPH
population and may require medication and/or psycho-
therapy. In patients with advanced symptoms or those
who are not candidates for surgery, a home health aide
or even institutionalization may become necessary. This is
particularly the case for individuals who live alone or are
more physically frail or severely demented.
Summary
• NPH is a chronic form of adult hydrocephalus that is
treatable and sometimes reversible. Idiopathic and sec-
ondary forms exist. Pathophysiology is incompletely
understood.
• Diagnosis of NPH requires evidence of ventricular en-
largement disproportionate to cerebral atrophy on a
brain imaging study and impairment in gait, balance,
continence, and/or cognition. MRI or another brain
imaging study is required. Clinical assessment must
include appropriate history and physical examination.
• The classic triad of gait ataxia, incontinence, and de-
mentia is sometimes, but not always, present in NPH
patients and can occur in other disorders. Impairments
may be mild and/or in a single domain. Symptoms
of NPH may overlap those of Parkinson’s disease,
Alzheimer’s disease, and other disorders even when
NPH occurs in isolation.
• The cognitive profile of NPH is typically subcortical
with predominant frontally weighted deficits. Not in-
frequently, NPH occurs in combination with diseases
such as Alzheimer’s, which may add elements of corti-
cal, limbic, and paralimbic disturbances to the cogni-
tive profile.
• Gait disturbance tends to be the most responsive to
treatment. Balance, control of urination, and cognition
follow, respectively, in terms of likelihood and time to
improvement.
• Invasive examinations such as lumbar drainage, infu-
sion tests, and ICP monitoring may add to diagnostic
and prognostic certainty but are not required in every
case.
• Neurosurgical placement of a shunt that diverts CSF
away from the brain in a controlled fashion is the cur-
rent treatment of choice for NPH. Ventriculoperitoneal
shunt is the most common configuration. Shunt valves
may be fixed- or adjustable-pressure types. Success rate
can be as high as 90% but varies across centers. ETV, de-
vices to alter CSF pulsatility, and medications are under
study by are not of proven value in NPH.
286 Neurologic Conditions in the Elderly
• Although mortality attributable to shunt surgery is
generally low, post-operative morbidity from shunts is
10–15% or higher. Subdural hematomas and effusions are
common complications. Seizures, infections, and shunt
failures are among other serious adverse consequences.
Factors such as advanced age, multiple medical comor-
bidities, extreme frailty, anticoagulation, and severe de-
mentia increase the risk of adverse outcomes from shunt
surgery. Accurate diagnosis, skilled surgical intervention,
and careful long-term management are required to mini-
mize morbidity and treat NPH successfully.
References
Bateman, G. (2008) The pathophysiology of idiopathic normal
pressure hydrocephalus: cerebral ischemia or altered venous
hemodynamics? Am J Neuroradiol, 29: 198–203.
Bergsneider, M., Black, P.M., Klinge, P., et al. (2005) Surgical man-
agement of idiopathic normal-pressure hydrocephalus. Neuro-
surgery, 57 (Suppl. 3): S29–S39.
Boon, W. (1971) Steplength measurement for the objective evalu-
ation of the pathological gait. Proc K Ned Akad Wet C, 74 (5):
444–448.
Bradley, W., Bahl, G., and Alksne, J. (2006) Idiopathic normal pres-
sure hydrocephalus may be a “two hit” disease: benign external
hydrocephalus in infancy followed by deep white matter isch-
emia in late adulthood. J Magn Reson Imaging, 24 (4): 747–755.
Brean, A. and Eide, P.K. (2008) Prevalence of probable idiopathic
normal pressure hydrocephalus in a Norwegian population.
Acta Neurol Scand, 118 (1): 48–53.
Hakim, S. and Adams, R.D. (1965) The special clinical problem of
symptomatic hydrocephalus with normal cerebrospinal fluid
pressure: observations on cerebrospinal fluid hydrodynamics. J
Neurol Sci, 2 (4): 307–327.
Kiefer, M., Eymann, R., and Steudel, W.I. (2002) LOVA hydroceph-
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Krefft, T., Graff-Radford, N., Lucas, J., and Mortimer, J. (2004) Nor-
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Marmarou, A., Bergsneider, M., Klinge, P., et al. (2005) The value of
supplemental prognostic tests for the preoperative assessment
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(3): S17–S28.
Relkin, N., Marmarou, A., Klinge, P., et al. (2005) Diagnsosing
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Tsakanikas, D., Katzen, H., Ravdin, L., and Relkin, N. (2009)
Upper extremity motor measures of tap test response in nor-
mal pressure hydrocephalus. Clin Neurol Neurosurg, 111 (9):
752–757.
Zaaroor, M., Bleich, N., Chistyakov, A., et al. (1997) Motor evoked
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62 (5): 517–521.
 Chapter 10
Depression in the Elderly: Interactions with
Aging, Stress, Chronic Pain, Inflammation,
and Neurodegenerative Disorders
Douglas F. Watt
Department of Neuropsychology, Cambridge City Hospital, Harvard Medical School and Alzheimer’s Disease Center/Clinic
for Cognitive Disorders, Quincy Medical Center, Quincy, MA, USA

Summary
• The separation-distress hypothesis of depression suggests that depression reflects a conserved neurobiological
mechanism to terminate protracted separation distress.
• Evolutionary perspectives also suggest that depressive withdrawal may have been selected to protect organisms from
intrinsically unreachable goals, particularly, potentially fatal dominance conflicts and terminating other maladaptive
forms of motivation and goal seeking.
• Depressive illness may reflect hypertrophy and disinhibition of basic depressive shutdown mechanisms and/or
disturbance of mechanisms that normally terminate depression upon social re-immersion.
• DSM-IV criteria for depression emphasize a depressed mood (which is a fundamentally circular criterion) along with
loss of interest and pleasure.
• Chronic stresses of wide varieties but, most particularly, chronic forms of separation distress, chronic pain, or other
chronic social stressors are potent depressogenic stimuli. Chronic pain combined with virtually any kind of chronic
separation distress results in an extremely high incidence of depression.
• The elderly are at elevated risk for depression due to their increased exposure to chronic pain, cognitive decline, loss of
social supports, and other prototype stressors for depression.
• Although SSRIs and other aminergic pharmacology are regarded as first-line treatments and are often times the only
treatment patients receive, they are modestly effective at best, while individual psychotherapy, social support, and reduction
of social isolation and other forms of chronic stress are underutilized and underappreciated as antidepressant interventions.

The heart asks pleasure first

And then, excuse from pain -
And then, those little anodynes
That deaden suffering;

And then, to go to sleep;

And then, if it should be
The will of its Inquisitor,
The liberty to die.
Emily Dickenson

Introduction and overview: the problem
space of depression
Depression is our most common mental health condi-
tion, yet its fundamental underpinnings remain myste-
rious. It is also a condition to which the elderly may be
exposed disproportionately, perhaps for many reasons.
Factors may include increasing exposure to multiple and
profound social losses, increased psychosocial isolation,
the stress of multiple age-related chronic and more acute
illnesses, chronic pain syndromes, increased financial
stress, and perhaps even just the intrinsic degradations
and humiliations of aging itself.
The biology of depression also appears to interdigitate
with many other comorbidities of aging, including an
intrinsic upregulation of inflammation (“inflammaging”)

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

287
288 Neurologic Conditions in the Elderly
and multiple neurodegenerative disorders, notably
Alzheimer’s disease, a major comorbidity of depression
in the elderly.
A basic organizing hypothesis of this review is that
depression reflects an evolutionarily conserved mecha-
nism in mammalian brains, selected as a shutdown mecha-
nism to terminate protracted separation distress, which, if
sustained, would be dangerous for infant mammals. This
fundamental shutdown mechanism remains available to
more mature mammalian and human brains, particularly,
those with certain polymorphisms in genetic endowment,
early loss/separation trauma, or other predisposing fac-
tors, which can promote reactivation in relationship to
almost any chronic stressor. Although depression must
have an adaptive and evolutionary basis (or else it surely
could not be so ubiquitous), depressive shutdown mecha-
nisms can become “hypertrophied” and released from
normal control mechanisms in vulnerable individuals to
potentially yield the full spectrum of depressive illness,
which is not adaptive.
The neurobiology of depression remains a challenging
puzzle box of correlates, involving changes in many bio-
genic amine and neuropeptide systems and alterations
in neuroendocrine and immune function. We suggest
that core factors form an interactive and even synergistic
“depressive matrix,” arguing against any “single-factor”
theory. We review core contributions to the biology of
depression from stress cascades, inflammation, and altera-
tions in multiple neuropeptide and monoamine systems.
In contrast to single-factor theories, this review suggests
synergisms between core neurobiological factors, as well
as a recursive (looping) control architecture regulating
both entry to and exit from depression. Such an interac-
tive matrix of factors may help explain why such an enor-
mous multiplicity of potential treatments are antidepres-
sant, ranging from psychotherapy and exercise to multiple
drugs, vagal and deep brain stimulation, and electrocon-
vulsive therapy (ECT). Unfortunately, traditional biologi-
cal psychiatric perspectives are almost totally “bottom
up” (neglecting relationships between depression and
social isolation and stress) and typically cannot explain
why depression is such a pervasive problem or why evo-
lution could have ever selected for such a mechanism. This
hypothesis suggests, in practical terms, that a primary
reduction of social isolation and increased social support
might be a fundamental and highly cost-effective preven-
tative measure in elderly at-risk populations. Exercise and
diet may also have protective and preventative effects.
Depression in the elderly must be understood in the
context of the problem of depression in general. In addi-
tion, we must appreciate the unique constellation of fac-
tors that might promote depression in late life. Depres-
sion is surely an ancient issue for human beings at vir-
tually every stage of the lifecycle, with references to
depression appearing in many classical sources onward
from the earliest recorded human history. Depression
may be both our most common and our most “mysti-
fied” emotional condition bringing patients into clinical
contact with a health professional, not just in this coun-
try, but in most, if not all, Western technologic societies.
Not only is it the most common emotional issue bring-
ing patients to physicians and mental health profession-
als, but it is also probably substantially underdiagnosed
(Lecrubier, 2007), with the true epidemiologic incidence
of depression poorly charted, due to significant underre-
porting bias. According to the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (DSM-IV;
American Psychiatric Association [APA], 1994), lifetime
risk for major depression is roughly 10–25% for women
and 5–12% for men; given the many who never seek
treatment and have highly motivated underreporting,
however, these numbers are probably serious underesti-
mates. If one were to include its milder forms or briefer
depressive episodes, the lifetime incidence of some form
of depressive-spectrum disorder would likely be much
higher, perhaps as high as 80% or more. For unknown
reasons, there is perhaps a twofold higher prevalence in
females, potentially indicating that their emotional sys-
tems are more sensitive or more affected by the abundant
stressors that promote depression. From a societal per-
spective, depression may exact a staggering human and
economic cost—recent estimates place major depression
as the third leading cause of disability worldwide and,
overall, the single most expensive disorder confronting West-
ern societies (including both the costs of treatment and lost
productivity; World Psychiatric Association [WPA], 2002).
Because depression may worsen many other medical con-
ditions (Kessler et al., 2003), including being a significant
risk factor for cardiac disease, immune dysregulation,
obesity, and addiction, to name a few, the total human and
economic costs associated with depression may be larger than
what have yet been estimated.
Although the popular media typically conceptualize
depression as an “illness caused by a chemical imbal-
ance,” with major pharmaceutical firms highly motivated
to advance similar notions, most scientific literature sug-
gests that depression should be treated as a syndrome and
not as a distinct illness. Additionally, popular depictions
of depression as “a chemical imbalance” are trivial, with-
out a concurrent functional–psychological analysis, as all
biologic conditions, including death, are accompanied by
“chemical imbalances.” The “illness” categorization also
begs the question of why evolution might have permit-
ted, or even selected for, such a common process in the
first place, a question rarely asked due to the equation of
depression with maladaptive behavior. Equating clinical
depression with maladaptation (implying that no selec-
tion processes would be involved), while understand-
able, is scientifically problematic if two core questions
are thereby obscured: (1) Why is depression so common?

(2) What evolutionarily conserved brain mechanisms pro-
mote depression? The neglect of such evolutionary per-
spectives may reflect, in part, psychiatry’s attempt to map
psychiatric syndromes directly onto brain mechanisms
while simultaneously ignoring the intervening neural
systems that generate the core prototype emotional states
in mammalian brains. (For a summary of these core affec-
tive processes, including fear, rage, playfulness, separa-
tion distress, lust, and maternal care, see Panksepp, 1998.)
Curiously, this long-standing neglect of potential relation-
ships between depression and mammalian-brain emo-
tional systems exists side-by-side with vigorous ongoing
efforts to develop and use multiple animal models in pre-
clinical antidepressant drug discovery and testing.
Although it is frequently presented in almost exclu-
sively molecular and reductionist terms in mainstream
psychiatry, evidence suggests that depression is a con-
served mammalian brain process, with correspondingly
ancient origins, possibly emerging concomitant with
many other aspects of a highly social brain (Insel and
Young, 2001; Baron-Cohen, 1999; Watt, 2007; Watt and
Panksepp, 2009). It indeed may reflect an intrinsic and
dark vulnerability in all highly social brains. Such consid-
erations suggest a possible logic to the greater incidence
of depression in females, as several authors have sug-
gested that the female brain is intrinsically more social.
It has already been argued that depression may represent
a conserved mechanism to terminate protracted separa-
tion distress (Watt and Panksepp, 2009), a potentially fatal
state for infant mammals separated from their conspecif-
ics. It may also serve additional adaptive purposes in
adult mammals, as a mechanism to withdraw from and
terminate potentially fatal dominance conflicts (Neese,
2000).
Our lack of an integrated picture of depression is evi-
dent in the dozens of neurobiologic correlates for depres-
sion presented in a voluminous literature, yet without any
clearly defined mechanistic integration that might allow
clinicians and researchers to link disparate facts to central
generative mechanisms. So far, candidate “driving” mech-
anisms in depression are envisioned largely in neuromod-
ulatory and biochemical terms, including some form of
monoamine deficiency (Schildkraut, 1965), cholinergic
overactivity (Janowsky et al., 1972), hypothalamic-pitu-
itary-adrenal (HPA) stress axis alterations (Holsboer, 2000;
de Kloet et al., 2005) that promote atrophic change in the
hippocampus (Dranovsky and Hen, 2006), potential defi-
cits in neuronal growth factors (Duman and Monteggia,
2006), and associated alterations in corticotropin-releasing
factor (CRF), glucocorticoid receptor function, and brain-
derived neurotrophic factor (BDNF). A recent reappraisal
of the role played by stress cascades has emphasized fun-
damental changes in the hippocampus associated with
cortisol, effects countered by BDNF (Holsboer, 2000),
coincident with the finding that antidepressants promote
Depression in the Elderly 289
or restore neuronal proliferation and neuroplasticity in
this brain region. Additionally, more recent ideas empha-
size multiple alterations in other neuropeptide systems
besides CRF, especially substance P, opioids, and oxyto-
cin (Holsboer, 2003), as well as upregulation of dynorphin
(the “dysphoric” or “paradoxical” opioid), which modu-
lates the nucleus accumbens (Todtenkopf et al., 2004) and
decreases motivation to seek rewards.
There is also evidence for significant functional altera-
tions in both glutamate and γ-aminobutyric acid (GABA),
with evidence for both GABAergic downregulation and
glutamatergic upregulation. However, the basis for these
changes in both GABA and glutamate is unclear. Glu-
tamatergic changes may be driven in part by possible
upregulation of quinolinic acid, which acts as an N-methyl-
D-aspartate (NMDA) agonist, due to alterations in path-
ways associated with upregulated pro-inflammatory
cytokines (for review, see Muller and Schwartz, 2007).
Because of the prolific roles in all brain functions of GABA
and glutamate, so far with limited therapeutic implication
for depression (Matsumoto, Puia, Dong, and Pinna, 2007)
except for the mood-stabilizing ability of certain anti-
epileptic agents that inhibit excitatory drive/processes
(such as affecting sodium channels), we note only the
most promising new lines of evidence in this enormous
field of research. Because of preclinical reports suggest-
ing that blockade of glutamate might have antidepressant
effects, recent clinical reports have now indicated that
intravenous administration of ketamine, which blocks
one of the glutamatergic receptors (the NMDA receptor),
yields robust and rapid (within 2 hours, after a short dis-
sociative effect) antidepressant effects that could last for
several days to a week (Zarate et al., 2006). This study is
part of a larger body of work suggesting that, in a variety
of preclinical models, metabotropic glutamate receptor
(mGluR1 and mGluR5) antagonists, as well as agonists at
alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic
acid (AMPA) receptors, have antidepressant-like activ-
ity. Of course, how this antidepressant effect from NMDA
antagonism is transduced in the brain remains uncertain,
but it must be noted that glutamatergic stimulation of
many subcortical brain sites can produce strong negative
emotional arousals (Panksepp, 1998).
In short, there is a complex panoply of neuromodulatory
changes in depression, with very uncertain leading versus
trailing edges, particularly given the enormous (and still
incompletely mapped) interactions between many modu-
latory systems. In contrast with any simplistic notion about
a primary “chemical imbalance” in depression, virtually
every modulatory system that has been closely studied
shows complex alterations in depression. A “prime mover”
in this complex symphony of changes remains elusive.
In addition to these traditional bottom-up neuro-
chemical/neuromodulatory perspectives, there has been
increasing evidence that depression involves fundamental
290 Neurologic Conditions in the Elderly
changes in large-scale corticolimbic emotional networks
(particularly, hyperactivity in Brodmann’s area 25, the sub-
callosal cingulate, particularly, in severe refractory depres-
sions; Mayberg et al., 2005), along with shifts in baseline
activation of a wide variety of corticolimbic systems, some
appearing upregulated and some, downregulated.
However, any putative functional integration of all
these disparate candidate mechanisms is rarely, if ever,
evident in the currently available literature. Might a more
concerted focus on conserved mammalian emotional
systems potentially coordinate many disparate and other-
wise fragmented lines of biologic thinking about depres-
sion? If so, such approaches may eventually significantly
improve biologic treatments of depression and better clar-
ify and refine psychotherapeutic practices as well. It may
also help eventually coordinate the growing numbers of
putative neurochemical correlates and causes into a more
coherent theoretical framework than presently exists.
A multifaceted separation-distress
hypothesis of depression
The many brain changes in depression may be differen-
tial manifestations—different “faces”—of a fundamental
shutdown process, reflecting ancient and evolutionarily
conserved mammalian brain mechanisms aimed at the
termination of separation-distress responses (see Watt and
Panksepp, 2009 for a comprehensive review). In Bowlby’s
(1980) terms, the shift from a “protest” to a “despair”
phase following social losses suggests a conserved psy-
chobehavioral shutdown mechanism that may initiate and
promote depression. The evolutionary adaptation (“pur-
pose”) of such a shutdown mechanism may have been the
benefits of terminating protracted separation distress, par-
ticularly in younger and infant mammals. Sustained sepa-
ration distress (crying) would likely prove fatal, either by
alerting predators to prey availability or by metabolically
exhausting small infants if they remained in a protracted
panic phase. Analogously, the protest that follows the loss
of other rewards, as well as other homeostatic losses (such
as illness and chronic pain), may also engender depres-
sive shutdown. Depression is fundamentally connected to
social attachment, social status, and comfort and its many
vicissitudes. This is not a new idea, but the possibility that
the fundamental neuroscience of depression could be bet-
ter integrated under this affective neuroscience umbrella
is a relatively novel idea within biologic psychiatry.
One could contrast this potential social biology view of
depression with classic molecular reductionism and argue
that mere “brute-force” cataloging of dozens of neurochem-
ical changes is not optimally heuristic or integrative. The
prevailing radical reductionism in mainstream psychiatry
still envisions that one can jump from molecules and simi-
lar brain details all the way to highly complex psychiatric
diagnostic categories and organized behavior, with no psy-
chologically meaningful or evolutionarily grounded neu-
roscience of emotions in between, almost as if the psycho-
logical properties of the brain and its adaptive mandates
are irrelevant to the predominantly molecular analysis.
Previous evolutionary views
of depression
Evolutionary perspectives on depression have not been
prominently featured in mainline psychiatric journals.
The first major volley occurred at the beginning of this
new century. Neese (2000) argued that depression might
serve several adaptive purposes, including communicat-
ing a need for help, as well as signaling submission in
social hierarchy conflicts, where one has little chance of
winning and considerable chance of losing and being seri-
ously injured or even killed (Malatynska et al., 2005). Thus,
depression might provide a mechanism for disengaging
from unreachable goals and for regulating patterns of maladap-
tive emotional investment and motivation. The idea that social
loss leads to depression was perhaps first articulated in
the 1970s and 1980s (Bowlby, 1980; Reite et al., 1981), but it
remained without substantive neuroscientific foundations
until fairly recently. Since then, several other contributions,
following themes advanced by Nesse, have emphasized
that brain mechanisms promoting depressive states must
have an evolutionary basis; otherwise, they could not exist.
More recently, Keller and Nesse (2006) have argued that
not only was there selection for depressive mood, but also
that depression may come in subtypes according to the par-
ticular type of adaptive challenges for which an organism
has no viable solution to cope with, especially when sus-
tained efforts to pursue difficult goals may result in dan-
ger, loss, injury, or wasted effort. In such situations, depres-
sive “pessimism” and lack of motivation may provide a
fitness advantage by virtue of inhibiting actions when one
has inadequate resources or plans, particularly when chal-
lenges to dominant figures may be hazardous. Depression
could thus confer a significant fitness advantage by termi-
nating risky or damaging dominance conflicts.
These arguments are complementary to our main hypoth-
esis, which focuses on the adaptive value of terminating
protracted separation distress, especially for young and
vulnerable infants. Separation distress is indeed intimately
coordinated with the generalized HPA stress response that
has been a mainstay of depression research, in humans as
well as animal models (Henn and Vollmayr, 2005; Keck et
al., 2005; Maier and Watkins, 2005). Shutdown mechanisms
activated in early-life separation-distress episodes could be
recruited later in life in relation to social losses experienced
in dominance–hierarchy conflicts. Indeed, it seems more
likely that evolution would select a mechanism if it could
“kill several birds with one stone,” so to speak.

A critical review of DSM-IV criteria
for major depressive episode
As with every syndrome in DSM-IV (APA, 1994), there
are no objective or laboratory diagnostic tests for the pres-
ence of depression, even though biomarkers—abundant
brain abnormalities—have been demonstrated at both
structural and biochemical levels. Indeed, given the lack
of bona fide objective tests for depression beyond a com-
pilation of symptoms approach favored in DSM-IV, there
is probably no absolutely clear line distinguishing some-
one with a mild form of clinical depression from those
who are simply having a difficult time in the course of
day-to-day existence and are simply mildly to moderately
dysphoric. This may further underline the ubiquitous
nature of depressive-spectrum phenomena. The DSM-IV
criteria for a major depressive episode are the following:
(a) Five (or more) of the following symptoms have been
present during the same 2-week period and represent
a change. At least one of the symptoms is either (1) de-
pressed mood or (2) loss of interest or pleasure.
1 Depressed mood most of the day, nearly every day
(NED), as indicated by either subjective report (feels sad
or empty) or observation made by others (appears tear-
ful). Note: In children and adolescents, it can be irritable
mood.
2 Markedly diminished interest or pleasure in all, or
almost all, activities most of the day, NED (as indicated
by subjective account or observation).
3 Significant weight loss when not dieting or weight gain
(a change of more than 5% of body weight in a month),
or decrease or increase in appetite NED. Note: In children,
consider failure to make expected weight gains.
4 Insomnia or hypersomnia nearly every day.
5 Psychomotor agitation or retardation NED (observable).
6 Fatigue or loss of energy NED.
7 Feelings of worthlessness or excessive or inappropri-
ate guilt (may be delusional) (not merely self-reproach
or guilt about being sick) NED.
8 Diminished ability to think or concentrate, or inde-
cisiveness NED (either by subjective account or as ob-
served by others).
9 Recurrent thoughts of death (not just fear of dying),
recurrent suicidal ideation without a plan, or a suicide
attempt or a specific plan for committing suicide.
(b) The symptoms do not meet criteria for a mixed
episode.
(c) The symptoms cause clinically significant distress or
impairment in social, occupational, or other important ar-
eas of functioning.
(d) The symptoms are not due to the direct physiologic eff-
ects of a substance (such as a drug of abuse or a medication)
or a general medical condition (such as hypothyroidism).
(e) The symptoms are not better accounted for by be-
reavement (APA, 1994).
Depression in the Elderly 291
Several issues are worth noting in regard to these criteria.
First, the criteria cut across the entire hierarchy of functional
domains of the brain (cognition, emotion, and homeostasis)
and involve cognitive disruption (especially criteria 8 and,
to a lesser extent, 9), obvious changes in emotion/mood
(criteria 1, 2, 7, and 9), and altered homeostasis (criteria
3–6), with sleep and appetite typically disrupted, but also
sexual functioning, endocrine status, and, more recently
appreciated, immune status, all altered in depression.
Core criteria emphasize either (1) depressed mood or
(2) loss of interest or pleasure as required for a diagnosis of
major depression. Unfortunately, the notion of a “depressed
mood” as a central diagnostic criterion for depression is strik-
ingly circular, a circularity rarely commented on or even
acknowledged in psychiatric circles. Also, unfortunately,
the criteria fail to make a careful distinction between sad-
ness and depression, using them as rough synonyms, a
recurrent problem in the psychiatric literature. We argue
instead that these states have to be viewed as quite dis-
tinct, albeit potentially related. They are commonly con-
flated in part because they are found together, in many
instances. In other words, patients are simultaneously both
sad and depressed, a coincidence of states underlining that
depressions are often reactions to losses; many depres-
sions, however, especially retarded and more severe ones,
show no sadness whatsoever, suggesting that sadness is
actually terminated by deepening depression and supporting
our core hypothesis. Additionally, we argue that the core
criteria of depressed mood necessarily indexes a funda-
mental loss of hopefulness—in other words, “depressed
mood” means an intrinsically less hopeful mood and orienta-
tion. Depression means that we no longer anticipate or expect
good things to happen. Indeed, in our judgment, it is a curi-
ous omission that hopelessness is not specified at all in
the DSM-IV criteria, even though despair and loss of hope
probably have a quite fundamental connection to suicidal
ideation and wishes to die. Earlier, DSM II and DSM III
criteria did reference hopelessness, but for uncertain rea-
sons, this notion has been pulled out of the more recent
versions of DSM diagnostic criteria.
Although “hopefulness” is not easily defined and
operationalized (perhaps leading recent revisers of DSM
to drop hopelessness as a criterion), hopefulness is tradi-
tionally contrasted with its antonyms, hopelessness and
despair. Although depression is, in a sense, more complex
than simple despair, these considerations suggest intrinsi-
cally close linkages between loss of hope and depression.
Perhaps one of the clearest operational indices of hopeful-
ness may be an organism’s willingness to struggle with adver-
sity. Indeed, this ability to struggle with adversity without
giving up the pursuit of rewarding activities or abandon-
ing our social connections may directly index a fundamental
emotional resilience and resistance to depression. This intrin-
sic connection between hopefulness and a willingness to
struggle is implicit in one of the most important behavioral
292 Neurologic Conditions in the Elderly
tests frequently used to evaluate potential antidepressants
in the animal literature—the “forced swim test.” In this very
important sense, depressed individuals lose their funda-
mental willingness and ability to struggle with challeng-
ing circumstances and basically give up. This “giving up”
of core organism goals is a fundamental dimension to depres-
sion that any candidate theory must at least attempt to explain,
and it certainly suggests that depression must have fundamen-
tal inhibitory effects on basic motivational systems in the brain,
especially the complex brain network “energized” by the
ventral tegmental mesolimbic dopamine system (concep-
tualized in Panksepp, 1998 as a generalized motivational
arousal, or “seeking” system). Indeed, if our core hypoth-
esis about depression is correct—namely, that it emerges
from an evolutionarily selected mechanism to terminate
protracted separation distress—such a putative shut-
down mechanism would have to negatively feed back
on central motivational arousal mechanisms in the brain
and attenuate the ability of those mechanisms to energize
behavior. Dynophin appears ideally positioned between
chronic stress and VTA modulation to help achieve such a
shutdown of motivational machinery.
The second core criterion in DSM-IV for major depres-
sion (after depressed mood) is anhedonia and loss of
interest. Interest in a wide variety of stimuli and pur-
suits in the world, and the anticipation of reward, may
be intrinsically related both to the operation of the ven-
tral tegmental mesolimbic–mesocortical “seeking” sys-
tem (Panksepp, 1998) and to social rewards garnered in
individuals with low activity in separation-distress sys-
tems and high activity in maternal care and “play” sys-
tems. Taken together, this suggests that depression may
fundamentally disrupt both the anticipation and the
pursuit of rewards (“interest”), along with a diminished
ability to experience pleasure, even when rewards are
available and obtained. We argue that this loss of interest
and anhedonia are also fundamental phenomena that any
heuristic theory must attempt to explain. Although loss
of interest and loss of pleasure are treated as one homoge-
neous entity in this important criterion, evidence suggests
that these are probably separate issues, with loss of interest
more dopamine-related and loss of pleasure more opioider-
gic (for a thorough review, see Berridge, 2004).
None of the subsequent seven criteria after these
first two are necessarily required for the diagnosis of
depression, but one must have at least four of the other
“subordinate” criteria and either depressed mood or
loss of interest/pleasure to meet diagnostic criteria. This
approach (“at least one from column A” and “at least four
from column B”), with two core criteria and seven sec-
ondary criteria, allows the DSM-IV diagnostic criteria to
at least partially cover the challenging heterogeneity of
depression, without prematurely committing to a sub-
typing paradigm (when subtypes are still not completely
understood or extensively validated in the literature).
A brief neuroscientific overview
of depression
Due to space considerations, in-depth coverage of neu-
robiologic work on depression is not feasible. We instead
emphasize heuristic (“big picture”) summation, particu-
larly how multiple neurobiologic processes may interdigitate
and form recursive and looping control factors that regulate
both entry into and exit from depressive states.
Aside from the general acceptance that severe life
stress is a prominent factor in the genesis of depression
(see Holsboer, 2000; Vollmayr and Henn, 2003), the larg-
est “bin” in the neurobiology of depression “box” would
clearly be classic neurotransmitter perspectives. Clas-
sically, the earliest hypotheses about depression cen-
tered on the first three monoamines characterized in the
brain—norepinephrine, serotonin, and dopamine—along
with the first transmitter discovered in the brain, in the
1920s, acetylcholine. The monoamine deficiency hypoth-
esis, with a focus on norepinephrine deficits, is the oldest
neurochemical hypothesis about depression (Schildkraut,
1965; for an update of the classic monoamine hypothesis,
see Harro and Oreland, 2001). However, simple aminer-
gic deficiency as an explanatory hypothesis has fallen by
the wayside and been largely discredited, in the context
of enormous evidence that depression is significantly
more complicated than a simple “deficiency” state in any
monoaminergic system, singly or even collectively (for a
summary of the history, see Healy, 1997). The strongest
data points against a simple noradrenergic (NE)/seroto-
nergic (5-HT) deficiency hypothesis are: (1) the failure of
norepinephrine or serotonin synthesis inhibition to create
depressive symptoms in normal individuals, even though
it can diminish mood in recently depressed individuals
(Delgado et al., 1990); and (2) the lack of rapid ameliora-
tion of depression following the rapid onset of reuptake
inhibition of various noradrenergic and serotonergic anti-
depressant drugs, resulting in significantly more synaptic
availability of biogenic amines in forebrain areas within
hours of ingestion (Delgado, 2000, 2004). Antidepressant
efficacy for these classic amine facilitators occurs weeks
later. Although the classical viewpoint has been that the
therapeutic effects are associated with an active down-
regulation of receptors and/or their active pruning in the
forebrain, more recent hypotheses have focused on a vari-
ety of neuronal growth and neuroplasticity factors modu-
lated by aminergic tone (Stone et al., 2003, 2008).
In addition to older hypotheses emphasizing the role
of norepinephrine and serotonin, more recently, mono-
amine perspectives have increasingly focused on dopa-
mine as well, particularly given its superordinate role in
motivated behavior (Panksepp, 1998; Ikemoto and Pank-
sepp, 1999; Alcaro, Huber, and Panksepp, 2007; Berridge,
2007). Also, mounting evidence now indicates that mul-
tiple other neurotransmitter systems, including GABA,

glutamate, and multiple neuropeptides (CRF, substance
P, cholecystokinin, dynorphin and other opioids, and
oxytocin), may also be centrally involved in depression.
Many aminergic and peptidergic neurotransmitter sys-
tems intimately coregulate each other in ways still incom-
pletely understood, adding layers of complexity to any
purely ‘modulator-centric’ neuroscientific understanding
and treatment of depression (Wong and Licinio, 2001;
Norman and Burrows, 2007; Stone et al., 2008). Addition-
ally, much thinking about depression has been guided
by depression’s intimate connection to alterations of the
HPA axis (for example, hypercortisolemia promoting hip-
pocampal atrophy; McEwen, 2004; Warner-Schmidt and
Duman, 2006; Drew and Hen, 2007). Moreover, increas-
ing evidence argues for an important role for pro-inflam-
matory cytokines in the modulation of mood and for a
primary role in depression, including critical effects on
the HPA axis that prevent hypercortisolemia from re-
normalizing the stress axis by negative feedback on CRF
(Leonard, 2006).
In addition to these more traditional bottom-up neu-
romodulatory perspectives, the neuroscientific and clini-
cal literature on depression has increasingly focused on
the possibility that depression may reflect some kind of
fundamental alteration in corticolimbic networks. Recent
work suggests that mood and self-related emotional infor-
mation processing probably reflect changes and dynamics
within highly distributed medial subcortical–cortical net-
works (Northoff and Panksepp, 2008). Regions of interest
in such distributed network formulations would centrally
include the prefrontal systems, the hippocampus, the
ventral or limbic stratum, and particularly the shell of the
nucleus accumbens/olfactory tubercle, along with sev-
eral other subcortical limbic and paleocortical paralimbic
structures, including periaqueductal gray (PAG) (Watt,
2000; Liotti and Panksepp, 2004; Northoff et  al., 2006).
Such a distributed network effect is seen when stress
reduces reward-seeking through a global reduction of
mesolimbic dopamine transmission, partly by the capac-
ity of upregulated dynorphin to make this whole hedonic
network less responsive (Nestler and Carlezon, 2006).
Considered jointly, these distributed network and neu-
romodulatory perspectives suggest that depression may
reflect global changes in large-scale reticular-limbic–
cortical networks critical to “seeking” (basic motivational
arousal) and associated exploratory behavior. Therefore,
they would also be critical to energizing primary attach-
ment behavior. Attachment behaviors centrally involve
the seeking of proximity to objects of attachment and
an associated pursuit of multiple rewarding of positive
affective states in the context of those social connections,
particularly the rewards of playfulness and affection, and
the seeking of comfort when distressed. All of these fun-
damental aspects of social seeking and attachment are
shut down, if not profoundly unavailable, to depressed
Depression in the Elderly 293
individuals (but not to individuals who are merely sad,
underlining this distinction). Basic neurobiologic perspec-
tives emerging from our current penchant for molecular
reductionism must be integrated with the long-standing
intuitive insight that depression is fundamentally related
to the brain’s reaction to emotional/social loss. This is par-
ticularly noteworthy when the subject feels a keen help-
lessness to mitigate the loss or when the loss is especially
penetrating and hurtful. This is not to suggest that molec-
ular perspectives and a view of depression as related to
the vicissitudes of attachment are in any way mutually
exclusive. On the contrary, we believe that this more
social view of depression, in which depression becomes a
dark vulnerability of a highly pro-social brain, dependent
on intimate social connection for its fundamental sense of
well-being, may eventually better integrate an enormous
amount of molecular data.
The challenging multifactorial nature
of depression: depression and the
social brain
Although play, empathy, social bonding, contagion (the
social  “infectiousness” of prototype emotions), and
separation distress are all largely viewed as discrete
processes in neuroscience and investigated quite inde-
pendent of one another, we argue that these putatively
disparate phenomena could be considered interlock-
ing threads, somehow jointly forming the full fabric of
a deeply social brain. Therefore, it seems reasonable to
us that these processes were selected in an integrated
manner by related evolutionary pressures. Each of these
phenomena is part and parcel of a truly social brain, in
which the pleasures of social connection and the pains of
social loss are all first-rank motivators. Consistent with
this viewpoint emphasizing the multicomponent nature
of a highly social brain, one might suggest that a vul-
nerability to depression is probably intrinsic within this
complex multidimensional fabric of a social brain. Some
social brains are clearly more vulnerable to this; some
are more resilient and resistant. Individuals with fortu-
nate genetic endowments and supportive and loving
upbringings may have intrinsic and robust protection
against depression, but even those with more resilient genetic
endowments and environmental good fortunes are never
totally or permanently protected from the reach of intrin-
sic depressive mechanisms. At least some degree of
depression lies only a major catastrophe away for almost
everyone.
At present, where radical reductionism and individual
neurochemical vectors are receiving primary attention in
psychiatry, more integrated (big-picture) psychobiologic
views of depression are badly needed. However, typical
modes of scientific analysis are obviously not well suited
294 Neurologic Conditions in the Elderly

for conducting the massive multifactorial studies that
such integration would require. Thus, we are left to patch
together more holistic levels of understanding from the
many factual parts that scientific empirical treatments can
spew out in abundance. However, the current tendency
to de-emphasize possible primary psychological dimen-
sions in depression within much of molecular psychiatry
is, in our estimation, not as likely to lead to a satisfactory
integration of all the available pieces of this challenging
puzzle. Future work will need to better integrate the many
factors that have been identified by existing molecular
approaches, summarized earlier and encompassing three
monoamine systems: the cholinergic system, multiple
neuropeptide systems including multiple opioid systems,
the neuroendocrine/stress axes, and immune/cytokine
issues. Although it is easy to assume by the current state
of the art that these factors constitute all the important
pieces of the puzzle, further research may underline that
even this impressive collection of factors falls well short
of a complete story.
This brings us to another touchstone concept.
Attempting to delineate unitary “first causes” or “prime
movers” in a system as massively recursive and inter-
active as the brain may be a mostly doomed enterprise.
From this perspective, the potential interactions between
factors has received overall far less “air time” in the history
of writings on depression than the many proposals promot-
ing single- or primary-factor theories. In general, however,
recent work seems more open to multifactorial points of
view. Instead, it may be more heuristic and much more
practical to think in terms of an interactive matrix of fac-
tors that can lead to depression, but where individual
variability might map to differential loading of various
core factors (suggesting, among other things, that future
optimal treatment of depression may require individually
tuned multidimensional approaches). As Table 10.1 delin-
eates, these presumed core neurobiologic factors regu-
late and massively influence one another. This suggests
that any individual mind “lurches,” in a sense, some-
times rather unpredictably through a complex trajectory
of neurochemical–neurodynamic space as these factors
cascade and reverberate in one direction or another, in
any particular instance of depression. This multifacto-
rial nature may also help to explain why so many differ-
ent therapies, ranging from exercise and psychotherapy
to ECT and deep brain stimulation, are antidepressant.
Although we are a long way from being able to explain
why one antidepressant therapy works in one depressed
individual and not in another, we suspect that an answer
to this also lies somewhere in a deeper understanding of
the dynamic relationships between these primary core
factors in a depressive matrix. Although it has been long

Table 10.1 Neurobiologic factors: an interactive depressive matrix

Depressive factor Driven by Producing Behaviorial and symptomatic correlates

Increased CRF, Multifactorial limbic influences
hypercortisolemia, on paraventricular nucleus,
choleocystokinin, and promoting activation of HPA
reduced BDNF stress axis
Increased acetylcholine Reduction of social and other
rewards, opioid withdrawal, and
any other social punishment
Decreased μ-opioids Separation distress and other
and oxytocin stressors, including physical
illness and pain
Increased dynorphin in Stress cascades
accumbens/VTA
Increased cytokines Acute but probably not chronic
stress, acute reduction of opioids
Reduced serotonergic Stress, increased corticosteroids,
drive/vulnerability cytokines, decreased μ-opioids
Diminished Constitutional vulnerability, stress
catecholaminergic and poor reward availability
(DA and NE) tone
Increased dynorphin, decreased 5-HT,
reduced neuroplasticity/HC atrophy,
intensification of separation distress,
disrupted ventral HC feedback on core
affective regions
Facilitation of separation distress
circuitry and other negative emotions,
effects on other core variables
Disinhibition/release of stress cascades,
decreased 5-HT and DA, overdriven NE,
promotion of cytokine generation
Downregulation of VTA and mesolimbic
DA system
Promotion of stress cascades,
decreased serotonergic and increased
glutamatergic tone, impairment of HPA
axis negative feedback
Lowered dopaminergic and increased
noradrenergic drive, less functional
segregation among brain systems
Reduced “signal-to-noise” processing
in all sensory–perceptual and motor/
executive systems
Dysphoria, sleep and appetite loss,
reduced short-term memory, and other
cognitive deficits
Negative affect and excess attention to
negativistic perceptions and thoughts
Anhedonia and sadness, reduced
positive affect, reduced sense of
connection, suicidality
Anhedonia, dysphoria, loss of
motivation
Fatigue, malaise, and appetitive
losses; increased cognitive disruption;
anhedonia
Poor affective regulation, impulsivity,
obsessive thoughts, possible
disinhibition of suicidality
Fatigue, diminished psychic “energy,”
appetitive sluggishness, dysphoria,
impaired coordination of cognitive and
emotional information processing

HC, hippocampus; 5-HT, serotonin; NE, noradrenergic; DA, dopamine; VTA, ventral tegmental area.

thought in psychopharmacology that everyone’s chemo-
architecture is different, interactions between these core
factors in a depressive matrix may also be differentially
“gated” across different individuals. This may eventually
allow us to answer the long-standing question of why, in
an individual clinical instance, one treatment works and
another does not.
This review underscores an oft-neglected relevance of
opioids and oxytocin for understanding depressive cas-
cades, as critical modulators for social connection and
social bonding, and how a strong social connection protects
brains against depression-generating chronic stress states.
Table 10.1 underlines what we consider to be the hand-
ful of core factors constituting this “depressive matrix.”
Core factors may consist of (1) diminished tone in opioid
and oxytocin systems associated with separation distress;
(2) altered and chronic stress neurophysiology promoting
upregulation of CRF and hypercortisolemia, leading to
hippocampal atrophy and the failure of negative feedback
on the stress axis; (3) alterations in numerous amine as
well as peptidergic neuromodulatory systems, and cho-
leocystokinin- and dynorphin-induced negative affects,
creating inhibitory feedback on the ventral tegmental
system dopamine and other catecholamine systems that
sustain “energized,” goal-directed bodily and mental
activities; (4) a critical role played by the immune system,
specifically pro-inflammatory cytokines, which appear
synergistic with stress cascades. Cytokines may directly
or indirectly promote glutamatergic overdrive and con-
tribute to a hypotonic serotonin system as well (Muller
and Schwartz, 2007); they further promote withdrawal,
fatigue, and behavioral and affective shutdown, impair-
ing HPA axis regulation by disrupting negative feedback
inhibition of CRF (Schiepers et al., 2005). Evidence indi-
cates that social disconnection and separation distress
(associated with changes in both μ- and κ-opioid systems)
result in potentiated stress cascades and increased cyto-
kine generation (Hennessy et al., 2001). We believe that
these interlocking pieces of a puzzle fit together, as dif-
ferential facets of a basic depressive cascade, although the
seams between the pieces cannot be completely stitched
together at this time.
This view of depression emphasizes the critical impor-
tance of social support, in both the long-term protection
against depression and its more acute and subacute
therapeutic management. Our perspective underlines
that social relations have a close relationship to the neu-
robiology of depression due to their intrinsic connections
of social biology to the stress axis, cytokine promotion,
modulation of critical growth and neurotrophic factors,
and modulation of multiple neuropeptide and amine
systems. We believe that the current treatment climate
in psychiatry could significantly benefit from such an
adjustment in emphasis. Psychotherapy and social sup-
port have fallen off the radar in the treatment of many
Depression in the Elderly 295
patients with depression, due to a largely bottom-up neu-
rochemical view of both etiology and treatment, often to
the detriment of basic patient care (Rush, 2007); many
patients with depression receive only psychopharmacol-
ogy, with classic aminergic agents often being modestly
effective, at best (see the section “Treatment algorithms in
relationship to depression in the elderly”).
Opioids and oxytocin, maintained tonically in securely
attached creatures, exercise a powerfully inhibitory effect
on basic stress cascades. The protracted downregulation
of these systems in the context of protracted separation
distress may tonically facilitate stress responsivity. The
promotion of CRF and the downregulation of opioids and
oxytocin may rapidly shift the affective state of the brain
from a more euthymic to a more dysthymic one. The older
view of stress cascades failed to adequately credit their
role in affective changes, viewing changes in the HPA axis
as if they were just physiologic changes instead of ones
that created psychological change. For a long time, there
has been comparative neglect of factors known to regu-
late separation distress and social attachments, namely
opioids and oxytocin systems, in preference for noradren-
ergic- and serotonergic-centered viewpoints. Also gen-
erally neglected until recently within the overall puzzle
were peptidergic variables most intimately and directly
related to mood (μ- and κ-opioids, cannabinoids, chole-
cystokinin, CRF, dynorphin, and oxytocin).
Protracted stress, the most prototypical being separa-
tion distress arising from social loss, may create an altered
balance in μ-, δ-, and κ-opioids and oxytocin. Promo-
tion of dynorphin and cholecystokinin tone, especially
in the nucleus accumbens and VTA, and the resulting
loss of motivation, including centrally the inhibition of
attachment-related needs/drives, potentially transform
separation distress from an acute (protest) phase to a sus-
tained chronic (despair) phase. This shutdown is assisted
by the potential fatigue/sickness-promoting effects of
pro-inflammatory cytokines. These parallel changes drive
global inhibition of many specific motivations, from food
appetite to erotic pursuits, generating a generalized anhe-
donia (with active dysphoria) and, thereby, loss of a more
hopeful orientation toward life opportunities and nor-
mal reward seeking. Altered homeostasis, particularly
sleep and appetite, may be caused not only by elevated
CRF effects on several homeostatic and circadian hypo-
thalamic systems, but also by the diminished influence
of prosocial neuropeptides. Such a sustained dysthymic
mood may promote negative cognition (which, in turn,
may help sustain negative mood via positive feedback
effects of sustained ruminations). The hypofunction in
prefrontal and hippocampal systems, perhaps associ-
ated with several neuromodulatory shifts and the effects
of excessive cortisol, results in the characteristic atten-
tional, executive, and mildly amnestic cognitive deficits
of depression. Thus, even the most generous allowance
296 Neurologic Conditions in the Elderly
for the causal role of a single factor may not come close
to explaining all the changes that constitute a full-blown
depressive episode.
The variety of brain–mind factors that can contribute to
depressive affect also underscores that surely not every
depression is precipitated simply by attachment losses,
or even by symbolic (such as social status) losses. Anhe-
donia and dysphoria can have various causes, including
endogenous neurochemical imbalances of the brain and
withdrawal from various drugs of abuse. Polymorphisms
of multiple genes involved in the neurochemical under-
pinnings of affective homeostasis can also presumably
modify the thresholds for the induction of the various
stress and affective cascades. However, it is now also clear
that early separation distress can promote lifelong dys-
regulation of hedonic homeostasis, leading to the disinhi-
bition of negative affective processes and stress cascades.
This combination of incompletely mapped genetic and
somewhat better understood early environmental factors
results in the potentiation of future depressive processes
more easily triggered by any severe chronic form of stress,
besides the classic precipitation by various forms of sepa-
ration distress. In fully considering the long-term conse-
quences of early stress, we can envision how the whole
system of regulatory controls over intrinsic depressive
mechanisms becomes epigenetically more fragile over
the entire lifespan (Mann and Courier, 2010). The pre-
cise manner in which that happens remains important
chapters for both future animal-brain and human devel-
opmental research. Of course, due to the challenging het-
erogeneity of depression (and virtually every other Axis
I condition in psychiatry), we must remain open to the
possibility of several distinct types of unipolar depres-
sion that we cannot yet clearly differentiate unambigu-
ously, either with differential symptom clusters or with
biomarkers.
Just as the neurobiologic correlates of depression
appear very multifactorial, developmental issues con-
tributing to lifetime vulnerability in depression appear
equally so. Recent developmental modeling (Kendler
et al., 2006) confirms this multifactorial nature of devel-
opmental pathways into depression, outlining a host of
“outside the skin” factors that presumably interact with
multiple “inside the skin” neurobiologic variables in a
fashion still poorly plotted. Kendler et al. (2006), found,
using a sophisticated statistical algorithm, that roughly
half of the variance for major depression in males can
be explained by 18 factors and their interactions: genetic
risk, low parental warmth, childhood sexual abuse, and
parental loss (early childhood factors); neuroticism, low
self-esteem, early-onset anxiety, and conduct disorder
(early adolescence factors); low educational achieve-
ment, lifetime traumas, low social support, and sub-
stance misuse/abuse (late adolescence factors); history of
divorce and past history of major depression (adult fac-
tors); and factors taking place in the last year (last-year
marital problems, other personal difficulties, and stress-
ful life events). How these factors might intersect in the
brain remains uncertain. Similar modeling was done for
females in an earlier study, with slightly more than 50%
of the variance explainable in terms of a similar complex
of factors (Kendler et al., 2002). Given that even with such
a complex matrix of predisposing variables, they could
explain only slightly less than 50% of the variance further
underlines the challenging heterogeneity of depression
in terms of its multifactorial developmental pathways.
In addition to the risk factors outlined in these models, it
seems obvious that chronic pain and perhaps numerous
other chronic illnesses can be powerfully depressogenic,
by virtue of chronic activation of stress and immuno-
logic/cytokine cascades and relative hypoactivation of
μ-opioid systems that may require not just social comfort
and secure attachment, but also general physical wellness
for their maximum tonic promotion (Panksepp, 1998).
Implications for an understanding of
common factors promoting late-life
depression
Such a pleiotropic view of depression suggests several
potential bridges to the problem of depression in the
elderly. Elderly women again show a greater incidence of
depression than elderly men, consistent with the greater
penetration of this syndrome in females throughout the
entire lifecycle. The elderly who undergo loss of loved
ones (especially spouses), increased social isolation due
to loss of friends or other social supports, loss of meaning-
ful and rewarding activities (often due to illness or dis-
ability), or virtually any major health problem (Kaji et al.,
2010) appear most at risk overall.
Most obviously and probably most importantly, many
elderly are exposed to severe and even catastrophic social
losses, in terms of the death of their spouses and friends.
In our view, this is a primary and powerful trigger for
depressive episodes. Many elderly must deal with pri-
mary losses of critical attachment figures, which then leads
to significantly increased social isolation, and from there,
to significantly increased risk of depression (Cacioppo
et al., 2010). Evidence indicates that social isolation also
increases the risk for acute medical illness, with acute ill-
ness representing an additional pro-depressive stressor
to which the elderly are differentially exposed, relative to
younger adults (Kaji et al., 2010; Molloy et al., 2010.)
An additional major point of intersection between
aging and depression may rest in extensive comorbidi-
ties between pain and depression. Recent work shows
that chronic pain syndromes, recently found to be the
most common degrading influence in overall health
status and sense of well-being in the elderly over 75 (at

least in Europe—this has not yet been replicated in the
United States), are a powerful pro-depressive influence to
which the elderly are differentially exposed (Konig et al.,
2010). Comorbidity of depression with chronic pain has
been associated with both poorer prognosis and greater
functional impairment, compared with those suffering
from each illness separately (Arnow et al., 2006). Rates
of depression in patients with chronic pain have been
reported to range from 30% to 60% (Miller and Cano,
2009), many times higher than incidence in the general
population. More severe and persistent pain also increases
the incidence of more severe depression and, not surpris-
ingly, is concomitant, with a stronger association toward
suicidality (Fishbain et al., 1997). Depressed patients have
a four times greater risk of chronic pain, compared with
nondepressed patients (Simon et al., 1999). Chronic pain is
a risk factor for subsequent development of major depres-
sion, while depression is a risk factor for the development
of chronic pain (Maletic and Raison, 2009).
These fundamental intersections between pain and
depression are still incompletely understood but may rest
in significant neuromodulatory, stress axis, neural net-
work, and even genetic factors that overlap between the
two conditions. Both depression and pain are associated
with key alterations in opioid and other neuropeptide
systems; increased stress axis activation; changes in dopa-
mine, serotonin, and glutamate systems; and promotion
of cytokine/inflammatory processes. Both conditions
also recruit functional changes in similar distributed cor-
ticolimbic networks (involving prefrontal, medial frontal,
insular, and several classic limbic system structures such
as hippocampus, amygdala, and nucleus accumbens; see
Narasimhan and Campbell, 2010 for a detailed review).
In relation to the most immediately relevant neuromodu-
latory system, that of μ-opioids, both pain and depression
might reflect low ebbs in complex subcortical/paleocorti-
cal opioidergic systems, signaling basic homeostatic well-
ness (see de Kloet et al., 2005 for confirmation of primary
opioidergic involvement in sadness and separation dis-
tress). An intriguing hypothesis about an evolutionary
continuity between pain and depression is suggested by
the hypothesis that separation distress may have emerged
from pain systems (Panksepp, 1998). If our earlier evolu-
tionary hypothesis is correct (that depression was selected
as a way of terminating protracted separation distress),
pain, as an evolutionary antecedent to separation dis-
tress, might constitute a potential primary trigger for
depression. Of course, much work remains to clarify (or
falsify) such intriguing hypotheses, yet the importance of
the common clinical comorbidity of pain and depression
cannot be denied, however incompletely we may under-
stand their intersection. An additional nontrivial point of
intersection is that both conditions are probably signifi-
cantly underdiagnosed and all too frequently missed in
primary care.
Depression in the Elderly 297
Additionally, given the relationship between depres-
sion and pro-inflammatory signaling cited earlier (also
see Pasco et al., 2010), the increased level of inflammatory
“tone,” thought to be possibly intrinsic to aging (“inflam-
maging”; Franceschi et al., 2007), suggests another impor-
tant potential relationship between aging and increased
intrinsic vulnerability to depression. Pro-inflammatory
cytokines can function as regulatory signals, with a sub-
stantial inhibitory effect on various hormones and neural
growth factors, many thought to sustain neuroplasticity
and mood. Sustained pro-inflammatory activity has been
thought to be a potential pathologic factor in the devel-
opment of many diseases of aging, including IBS (inflam-
matory bowel disease), type II diabetes, cardiovascular
and cerebrovascular diseases, rheumatoid arthritis and
osteoarthritis, major depression, Alzheimer’s disease,
and even aging itself (Franceschi et al., 2007). Addition-
ally, recent work shows that classic growth factors (such
as Insulin like growth factor [IGF]) and pro-inflamma-
tory cytokines have mutually inhibitory influences on
one another and can even induce resistance to the effects
of one another (O’Connor et al., 2008). O’Connor et al.,
hypothesized that a balance between these inflammatory
and growth factor processes is essential to optimal aging,
with growth factors generally declining and inflamma-
tion increasing. This suggests that anti-inflammatory
lifestyle variables, such as exercise; a diet rich in poly-
phenols, fiber, and an adequate ω-3/ω-6 ratio (an “anti-
inflammatory diet”); adequate sleep; positive social
engagement (which has been shown to promote growth
factors); and not too much stress especially chronic stress,
are all likely to help retain an adaptive balance between
pro-inflammatory and growth factor signaling.
Additionally, there are potential relationships between
dementing disorders and depression, particularly
Alzheimer’s disease. Although it has been long known
that recurrent major depression is a risk factor for
Alzheimer’s disease, recent work suggests a reciprocal
relationship, with Alzheimer’s disease also constituting
a risk factor for depression (Aznar and Knudsen, 2011).
The basis for this association remains to be fully clarified,
but evidence indicates that Alzheimer’s disease intrinsi-
cally deteriorates affective regulation (Nash et al., 2007),
a critical capacity in the resistance to depression in the
face of life stresses. Alzheimer’s disease also promotes
pro-inflammatory signaling and inhibits neuroplasti-
city, which has critical links to mood regulation (McE-
wen, 2004). Comorbidities may also exist between other
dementing disorders and depression, although these have
been less closely studied. Frontotemporal dementia may
predispose to more primary apathy states, frequently
misdiagnosed as depression, but also may predispose to
depression as well (Chow et al., 2009; Huang et al., 2010).
Last, but certainly not least, both acute medical illnesses
and more chronic diseases of aging (heart disease, cancer,
298 Neurologic Conditions in the Elderly
diabetes, arthritis, and all neurodegenerative disorders)
have been found to be significant risk factors for depres-
sion, perhaps particularly when combined with financial
and socioeconomic stress (Almeida et al., 2010; Baldwin,
2010; Kaji et al., 2010).
Treatment algorithms in relationship
to depression in the elderly
A comprehensive presentation of research into treatment
of depression is well beyond the scope of this brief chapter
summary. However, outside of paying particular atten-
tion to the unique lifestyle and developmental/adaptive
challenges facing the elderly, and addressing and mitigat-
ing the unique set of stresses that contribute to the risk for
depression in the elderly, there is no systematic evidence
that either the prevention or the treatment of depression
in the elderly is necessarily substantively different from
those considerations in a younger adult (although medi-
cine interactions can be significantly more challenging,
given that many elderly patients are often on multiple
medicines that can interact with psychotropic medicines
in a variety of ways).
In general, we argue that social support (particularly
including reduction of social isolation), both psychody-
namically oriented and cognitive behavioral psycho-
therapy, and careful attention to precipitating stressors
(helping patients to generate more adaptive behaviors in
response to those stresses) are often neglected in primary
care interventions with depressed elderly; often physi-
cians simply hand out a prescription for the latest selec-
tive serotonin reuptake inhibitors (SSRI). Current research
suggests that psychopharmacology alone is not nearly as
effective as a combination of psychopharmacology and
psychotherapy (STAR D work—see Rush, 2007). In gen-
eral, psychopharmacology of depression works best with
adopting a flexible empiricism and fitting patient char-
acteristics and symptomatology to drug effect profiles. A
detailed review of these issues is well beyond the scope of
this chapter, and clinicians looking for a review of specific
approaches to the psychopharmacology of depression
should consult standard texts (such as APA Publishing
Textbook of Psychopharmacology).
Recently, published work has suggested that big
pharma may have deliberately exaggerated effect sizes for
classic aminergic antidepressants. A recent meta-analysis
in the New England Journal of Medicine (Turner et al., 2008)
suggested widespread exaggeration of effect sizes in rela-
tion to many blockbuster (billion-dollar) antidepressant
compounds. It further stated that with the inclusion of
previously suppressed negative trials, effect sizes for pop-
ular antidepressant drugs are significantly less impres-
sive than initially reported. According to the published
studies, roughly 94% of the trials conducted on mainline
antidepressant drugs showed positive results. However,
if one included unpublished studies in the analysis, only
51% of the trials were positive. Separate meta-analyses of
the Federal Drug Administration (FDA) and journal data
sets demonstrated an increase in effect size from 11% to
69% for individual drugs, with a 32% overall inflation
of effect size across all studies. This recalibration shows
that effect sizes for many antidepressant drugs may be
relatively modest (0.31 on average, where a 0.5 effect size
might be the threshold for a clinically important effective-
ness, according to a meta-analysis by Ioannidis (2008).
This suggests that the current practice trends, particularly
within primary care of an exclusive reliance on popular
SSRIs and other related aminergic agents (selective nor-
adrenergic reuptake inhibitors [SNRI] and mixed sero-
tonergic noradrenergic drugs), may have a substantially
weaker evidence base than most medical practitioners
generally assume.
In an insightful study emphasizing a multivariate
view of depression and practical ability to predict risk in
patient populations, Almeida et al. (2010) showed that
a matrix of risk factors predicted a likelihood of minor
to major depression. A multivariate logistic regression
showed depression was “independently associated with
age older than 75 years, childhood adverse experiences,
adverse lifestyle practices (smoking, alcohol use, physical
inactivity), intermediate health hazards (obesity, diabetes
and hypertension), comorbid medical conditions (clinical
history of coronary heart disease, stroke, asthma, chronic
obstructive pulmonary disease, emphysema, or cancers),
as well as social or financial strain.” The authors stratified
the risk factors to build a predictive matrix demonstrat-
ing a probability of depression increasing progressively
with an accumulation of risk factors, from less than 3%
for those with no adverse factors to more than 80% for
people reporting the maximum number of risk factors.
Primary care physicians and other clinicians dealing with
the elderly might be able to more accurately gauge the
total level of biologic stress, determine the subsequent
risk for depression in their patients, and identify the need
for early and potentially mitigating, if not completely
preventative, interventions. In terms of common lifestyle
variables that might prevent depression, fish consump-
tion (Lin et al., 2010), vitamin D levels (Milaneschi et al.,
2010; Stewart and Hirani, 2010), and regular aerobic exer-
cise (Cotman et al., 2007; Bots et. al., 2008) appear to have
the best empirical support, but conclusive data is still
lacking. Unfortunately, systematic studies into prevent-
ing late-life depression have been relatively modest, at
best (Baldwin, 2010). Hyperhomocysteinemia, an inflam-
matory marker increasingly viewed as a risk factor for all
diseases of aging, and contributing to increased oxidative
stress in aging (Wu, 2007), may be a meaningful target for
prevention/reduction of systemic inflammation, multiple
diseases of aging, and depression as well (Almeida et al.,

2008). Vitamin D deficiency, sedentary lifestyles, obesity,
and sleep deprivation, all risk factors for inflammatory
diseases and other diseases of aging, may also be useful
prevention targets for delimiting penetration of depres-
sive disorders. Additional prevention targets may include
improved management of chronic pain and, of course,
reduction of social isolation.
Existential aspects of aging and their
impact on mood
Although it has not been systematically studied to our
knowledge, one might suspect that intrinsic features of
aging pose “depressogenic” challenges for many individ-
uals with less than optimal family and social histories.
Older individuals face the shrinking sense of any future
or substantial time to make up for previous mistakes, dis-
appointments, and lost opportunities, while often strug-
gling with an existential awareness of the inevitability
of death and physical decline. In contrast, in individuals
who have been most successfully and securely socially
connected, and for whom life has presented ample
opportunities for both social and work-related rewards,
these intrinsic challenges of mortality and aging are sub-
stantially buffered by an ongoing affirmation of deep ties
to spouses, friends, and other loved ones; devotion to
children and grandchildren; and continuing involvement
in a cultural and intellectual heritage to which one feels
connected and may have substantially contributed in the
past. Those without such resources, and lacking success-
ful social and work histories, may inevitably face what
Erik Erikson (1950) called, in his eighth stage of life, the
crisis of “integrity versus despair.” Instead of having an
accumulated wisdom and a reverence for life despite all
its many painful limitations, individuals who have not
successfully negotiated previous developmental chal-
lenges enter the final stage of life with conflicted, trau-
matic, or simply absent relationships. Instead of affir-
mation of continuing social, professional, and cultural
connections, they may feel a keen sense of despair over
their failures and multiple losses, and regret the absence
of youthful opportunities for substantially mitigating a
negative past. This suggests that, in old age, those who
have failed to achieve a secure sense of self-esteem and
associated social connection are particularly disadvan-
taged, as they face their own mortality and, inevitably,
declining health and function, intrinsically difficult chal-
lenges for even the most resilient elders. Such self-esteem
and chronic psychosocial and characterologic deficits in
these less fortunate individuals pose enormous burdens
on mood and mood regulation in the context of these
existential challenges of aging and form a critical and
often underappreciated vulnerability to depression in all
its forms.
Depression in the Elderly 299
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 Chapter 11
Cerebrovascular Diseases in Geriatrics
Patrick Lyden, Khalil Amir, and Ilana Tidus
Department of Neurology, Cedars-Sinai Medical Centre, Los Angeles, CA, USA

Summary
• Aging is influenced by diet, environment, personal habits, and genetic factors. Abrupt decline in any system or function
is always due to disease and is not considered “normal aging.”
• Symptoms of atypical aging include incontinence, memory disturbance or intellectual impairment, immobility and falls,
and instability.
• Delirium is defined as an acute decline in attention and cognition and requires the presence of acute onset and
fluctuating course, inattention and disorganized thinking, or altered level of consciousness.
• Stroke pathology includes cerebral infarction, primary intracerebral hemorrhage, and subarachnoid hemorrhage.
National Institutes of Health Stroke Scale (NIHSS) indicates stroke severity with a score more than 24, indicating severe
stroke.
• In previous studies, carotid endarterectomy (CEA) has been known to reduce the risk of recurrent disabling stroke or
death in patients with severe ipsilateral internal carotid artery stenosis.
• Biologic therapies, multimodality neuroprotection therapies, therapeutic hypothermia, and sonothrombolysis may
possibly help stroke treatment in the future.
• Cerebrovascular risk factors (CVRFs) predispose the patient to stroke or heart attack and are more likely to cause
depressive symptoms after stroke.

“Care of the elderly” arbitrarily refers to patients older
than 65 years of age. The clinical approach to the elderly
person is much different than the medical evaluation
of a younger adult person. These important differences
have many implications for correct diagnoses, appropri-
ate investigations, clinical outcome measures, quality of
care, hospital length of stay (LOS), and cost to health care
and the general public. Several physiologic and biologic
changes take place during aging that have implications
for medication-related adverse effects, atypical disease
presentations, and the way the aging body responds to
stress.
Other important factors to consider in the care of the
elderly are high prevalence of comorbidities, multiple
coexisting and interacting chronic diseases (such as dia-
betes, ischemic heart disease, heart failure, arthritis,
dementia, cerebrovascular and cardiovascular diseases,
social isolation, and polypharmacy). As a result of these
complex and interactive factors and biologic changes
with associated features, the manifestations of diseases
are more subtle and present with atypical and nonspecific
features. Barriers to physical examinations exist, as do
limitations in the correct diagnostic and prognostic tests
and therapeutic interventions. The other important vari-
able is the current and future demographic changes that
are more pronounced in the older population, particularly
with a significant increase in those 85 years and older.
All these changes, whether biologic, iatrogenic, or
demographic, have a direct impact on health-related
outcomes, quality of life, cost of health care, rate of hos-
pitalizations, the patient, families and caregivers, and
medical staff satisfaction. They also impact morbidity
and mortality (Warshaw, et al., 1982; Hirsch et al., 1990;
Inouye et al., 1993; Brennan et al., 1991).
Biologic changes with aging
Physiologically, human aging is characterized by a pro-
gressive constriction of the homeostatic reserve of every
organ system, called homeostenosis. Evident by the third
decade, it is gradual and progressive, but the extent of
decline may vary. It is also influenced by diet, environ-
ment, personal habits, and genetic factors.
Individuals become more dissimilar as they age, bely-
ing any stereotype of aging. In addition, it is important to
note that an abrupt decline in any system or function is
always due to disease, not to “normal aging.” “Normal
aging” can be attenuated by modifying risk factors (such
as hypertension, smoking, and exercise).

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

302

Generally, as one ages, the relative total body fat
increases and the total body water decreases. This has a
direct relationship to the volume of distribution (VD) for
fat-soluble and water-soluble medications. It increases
the VD for fat-soluble medications (such as benzodiaz-
epines and many other cardiac or central nervous system
(CNS)-acting drugs), hence increases the half-life and side
effects, and decreases the VD for water-soluble medica-
tions (such as alcohol, digoxin, and theophylline), with
increased concentrations and toxic effects.
In terms of cardiac and central nervous systems, sev-
eral neuroendocrine metabolites are altered such as with a
decrease in brain catecholamine synthesis and decreased
dopaminergic synthesis, among others, causing stiffer
gait, increased body sway, early wakening insomnia, and
decreased resting temperatures.
In the cardiovascular system, there is decreased arterial
compliance, increased systolic blood pressure, decreased
β-adrenergic responsiveness, decreased baroreceptor sen-
sitivity, and decreased sinoatrial node automaticity. These,
in turn, can cause reduced response to volume depletion,
decreased cardiac output and heart rate because of stress,
and impaired BP response to standing (Kasper et al., 2005;
Evans et al., 2000).
Clinical presentations in the elderly
“Healthy old age” is not an oxymoron. In fact, in the
absence of diseases, the decline in homeostatic reserve
causes no symptoms and imposes few restrictions on
activities of daily living (ADL), regardless of age.
However, as individuals age, they are more likely
to suffer from disease, disability, and the side effects of
drugs. When combined with the decrease in physiologic
reserves, these compounded factors can make the older
person more vulnerable to environmental, pathologic,
and pharmacologic challenges. Therefore, managing
elder patients involves distinct considerations.
In caring for geriatric patients, one typically manages
multiple chronic conditions. Similarly, more of an empha-
sis falls on care versus cure. Coupled with comprehensive
geriatric assessment (CGA), dealing with a whole patient
rather than disease specifics and using a team approach
with coordinated care across multiple sites is essential for
continuity of care (Kasper et al., 2005; Evans et al., 2000).
General approach to hospitalized
elderly patients
Although only 13% of the American population is elderly,
they account for 38% of all discharges and 46% of all hos-
pital inpatient days. This means longer hospital stays,
greater costs, and more adverse outcomes. Basically, acute
Cerebrovascular Diseases in Geriatrics 303
care is geriatric care (Kozak et al., 2004, 2005; Warshaw
et al., 1982; Hirsch et al., 1990).
Atypical presentations in the elderly
As mentioned earlier, care of the elderly involves atypical
and different clinical presentations. For example, simple
and mild hyperthyroidism can present with confusion,
atrial fibrillation, depression, syncope, and weakness—all
at the same time.
In addition, a limited number of symptoms predominates
because of the “weakest link” phenomenon. These include
confusion, depression, incontinence, falls, and syncope.
What constitutes geriatric giants is as follows:
• Incontinence (made worse by urinary tract infections,
immobility, diuretics, and many other disease processes)
• Memory disturbance or intellectual impairment (affect-
ed by many disorders such as stroke, Parkinson’s disease
(PD), delirium, and medication-related adverse effects)
• Immobility and falls (affected by arthritis, postural hy-
potension, osteoporosis, stroke, PD, Alzheimer’s disease
(AD), and medication)
• Instability (such as with decreased muscle mass and
visual impairment)
Other important and complicating factors in terms of
the clinical evaluation of an elderly person are that the
general rules of clinical approach may not strictly apply.
For example, an organ system-related symptom is less
likely to be the source of that symptom. Likewise, a clini-
cal depression is not likely strictly due to a psychiatric ill-
ness, as would probably be the case for a younger adult
with major depression.
Similarly, an acute confusional state or delirium would
likely not be the result of a new CNS lesion. More likely,
the problem is multifactorial, perhaps a contributing risk
factor with causative agents playing the major role.
Another example of atypical clinical presentation in the
elderly is that an older person who presents with syncope
or a brief period of loss of consciousness is unlikely to
have the illness due to a structural heart disease, unlike
a younger adult. It may well be due to postural hypoten-
sion, compounded by medication-related adverse effects
such as the simple antihistamine, anticholinergic medica-
tion diphenhydramine.
It is crucial that a clinician’s approach to older patients
be proactive and preventative in nature. Because elder
persons have decreased physiologic reserves, they can
have earlier presentations and manifestations of their
illness. An illustration is clinical congestive heart fail-
ure exacerbated or caused by mild hyperthyroidism.
In addition, a cognitive dysfunction may be related to
mild hyperparathyroidism or related to increased drug
side effects. For example, diphenhydramine may cause
confusion, digoxin may contribute to depression, and
304 Neurologic Conditions in the Elderly
much-overlooked over-the-counter sympathomimetics
can cause urinary retention.
Knowing these factors can reduce unnecessary
investigations and invasive or risky procedures. Correctly
identifying the risk factors and properly diagnosing the
clinical condition helps determine appropriate manage-
ment strategies. All of these are related to improved
outcomes, improved quality of life, and decreased mor-
bidity and mortality. In addition, this has cost savings
implications and results in improved satisfaction for the
patients, their caregivers, and staff.
Care of the elderly also involves multiple abnormali-
ties, but small improvements in each may yield dramatic
benefits overall.
Another aspect of care of the elderly in general involves
the theory that there is no anemia, impotence, depression,
or confusion of old age. The diagnostic “law of parsi-
mony” often does not apply. As an example, imagine that
a patient is admitted to the hospital with a constellation
of signs and symptoms consisting of fever, anemia, retinal
emboli, and heart murmur. In a young person, this would
indicate endocarditis. However, in an elderly person, it
could be an aspirin side effect, cholesterol emboli, aortic
sclerosis, or simply a viral illness. Even if the correct diag-
nosis is made, treating a single disease is unlikely to result
in a cure or a better outcome. Therefore, the “whole per-
son” approach is much more important than the disease-
specific approach because it addresses other issues related
to the care of the elderly (Kasper et al., 2004; Evanse et al.,
2000; Kozak et al., 2004, 2005).
Hospitalization of elderly patients
We know that hospitalization contributes to a decline
in the older patient’s functional status or the ability to
function independently in the physical, mental, and
social activities of daily life. These include bathing,
dressing, toileting, continence, and instrumental activi-
ties of daily life (shopping, housekeeping, preparing
meals, taking medications, using public transportation,
and so on). Therefore, older patients are more likely to
depend on ADLs at admission and to suffer functional
decline.
As we discussed, the elderly have diminished homeo-
static reserves and can have multiple comorbid conditions,
decreased muscle mass, and strength. This is further
compromised by sustained bed rest. Moreover, indepen-
dent self-care is further threatened in patients with cog-
nitive impairment, stroke, PD, arthritis, and heart and
respiratory failure.
Studies show that 25–60% of elderly hospitalized
patients experience loss of independent function during
hospitalization. This increases LOS, nursing home place-
ment, and mortality, with associated high cost.
Table 11.1 Geriatric principles of geriatric medicine
Primum non nocere (first, do no harm)
Pay attention
Avoid causing discomfort or indignity
Use meticulous clinical observations and proper technique
Actively search for signs and symptoms of dysfunction and disability
Evaluate the whole person, including physical, mental, and social
functions
Emphasize prevention, rehabilitation, and enhanced quality of life
Eliminate iatrogenic causes
Maintain function and independence at all times
Source: Courtesy of Professor Mark E. Williams (with minor
modifications).
In summary, the current hospital model can be a restric-
tive, unfamiliar, and threatening environment, particularly
for a patient with mild dementia, poor mobility, decreased
hearing, or visual disturbances. In addition, there is signifi-
cant iatrogenesis, and unnecessary tests and procedures are
carried out with related adverse outcomes. The prescrip-
tion of inappropriate medications in hospitalized elderly is
well documented and, again, is related to increased hospi-
tal LOS, increased cost, and negative outcomes.
To improve all outcomes for elderly hospitalized
patients, we can turn to several effective models of
care that have been shown to improve morbidity,
improve mortality, be cost-effective, reduce LOS, and
improve patient and staff satisfaction.
These comprehensive models are run with a multidis-
ciplinary team approach and care pathways geared to the
care of the elderly. Examples are stroke units, acute care
of the elderly (ACE) units, program of all-inclusive care
of the elderly (PACE), delirium preventions intervention,
and multidisciplinary falls and fracture prevention mod-
els (Warshaw et al., 1982; Hirsch et al., 1990; Inouye et al.,
1993; Brennan et al., 1991; Landefeld et al., 1995).
I want to specifically highlight the geriatric principles
in Table 11.1, which I adopted from one of my mentors
and role models in the care of the elderly at the University
of Virginia in Charlottesville, Virginia.
Specific diseases
Several issues need to be addressed while dealing with
specific disease, particularly considering the increasing
aging population and the high prevalence of delirium in
hospitalized elderly patients with associated increased
morbidity, mortality, increased LOS, increased cost, patient
and caregiver grief, and increased institutionalization.
Delirium or acute confessional state
Delirium is defined as an acute decline in attention and
cognition. Delirium is often underdiagnosed, has serious
implications, and is preventable.

The key features of delirium are as follows:
• Acute onset and fluctuating course
• Inattention
• Disorganized thinking
• Altered level of consciousness
The Confusion Assessment Method (CAM) has been
well validated and is used for rapid assessment and detec-
tion of delirium. It has a sensitivity of 94–100% and speci-
ficity of 90–95%, and uses the four criteria given below.
1 Acute onset and fluctuating course
2 Inattention
3 Disorganized thinking
4 Altered level of consciousness
The diagnosis of delirium requires the presence of cri-
teria 1, 2, and 3, or 4.
As we discussed, the prevalence of delirium ranges (on
admission) between 10% and 40%, with an incidence (in
hospital) of 25–60%. This is associated with significant
hospital mortality between 10% and 65% and annual
health-care expenditures of more than $8 billion.
Clinically, many risk factors predispose older patients
to developing delirium. These have been well validated
in studies and include the following:
• Cognitive impairment
• Sleep deprivation
• Immobilization
• Vision impairment
• Hearing impairment
• Dehydration
Recognizing these risk factors and being alert about them,
upon admission, enables health-care professionals to inter-
vene early in each of these steps and potentially prevent
delirium. Interventions may include reality orientations,
nonpharmacologic sleep protocols, early mobilization pro-
tocols, vision aids, amplifying devices (hearing aids), and
appropriate hydration.
Apart from the previously mentioned risk factors, sev-
eral etiologies for delirium exist. The pneumonic delirium
can be useful.
Dementia
Electrolyte abnormalities
Lungs, liver, heart, kidney, brain
Infection
Rx
Injury, pain, stress
Unfamiliar environment
Metabolic
In particular, the list of medications causing delirium
is large and important. Some culprits include benzodiaz-
epines, anticholinergics, antihistamines, antidepressants,
and many cardiac medications.
In terms of management, once risk factors or causative
agents are identified, emphasis should be on prevention,
risk factor evaluation on admission, and early intervention.
Cerebrovascular Diseases in Geriatrics 305
Generally, treatment is geared toward eliminating these
etiologies and treating the underlying condition.
A good clinical history including a medication list,
a thorough physical examination, a targeted metabolic
panel, and a search for occult infection, may be all that is
required and will have the greatest yield, as opposed to
EEG and CT/MRI–brain.
Emphasis is on nonpharmacologic approaches and less
invasive investigations. However, low doses of haloperi-
dol (0.5–1.0 mg IM/PO, with a maximum dose of 3–5 mg)
or short-acting benzodiazepines (such as lorazepam) can
be useful in alleviating symptoms.
In summary, delirium should be considered a medical
emergency and must be coupled with a thorough his-
tory and physical examination. Emphasis should be put
on early prevention and risk evaluation and less invasive
tests or investigations. Treatment must focus on eliminat-
ing the causative agents and using fewer pharmacologic
agents (Inouye et al., 1990, 1993,1999a,1999b; Inouye and
Charpentier, 1996; Cole et al., 2002; Francis et al., 1990).
Stroke
It is suggested and widely believed, though no concrete
evidence exists, that Hippocrates may have defined stroke
2400 years ago as apoplexy (struck down by violence),
although the term was used for different conditions.
Stroke is a clinical syndrome characterized by rapidly
developing clinical symptoms or signs of focal—and, at
times, global—loss of cerebral function; symptoms last
more than 24 hours or lead to death, with no apparent
cause other than that of vascular origin.
Not long ago, patients with stroke were either treated
at home or admitted for compassionate observation.
Doctors made an effort to localize lesions and describe
vascular syndromes and pathology. An aura of thera-
peutic hopelessness surrounded stroke care. Fortunately,
those days are over and optimism about the benefits of
treatment (stroke care units (SCUs) and thrombolysis),
coupled with a sense of urgency in dealing quickly with
every patient with acute stroke, has swept away that
nihilism (Barnett et al., 2000; Lyden 2008, 2009).
Risk factors for stroke
The risk factors for stroke are the usual suspects. Such
modifiable risks include hypertension, diabetes mel-
litus, tobacco abuse, hyperlipidemia, atrial fibrillation,
transient ischemic attack (TIA), certain medications and
recreational drugs, and alcohol. Other risks include non-
modifiable risks such as age, sex, and genetics.
Importantly and interestingly, when compared to the
risk identification for stroke, only 60% of the time-specific
risk factors are identified in stroke versus 90% in ischemic
heart disease (Whisnant, 1997; Yusuf et al., 2004).
306 Neurologic Conditions in the Elderly

Stroke classifications nosis among patients admitted to the hospital with an

admission diagnosis of stroke.
Stroke is classified pathologically, clinically, or by etiology. A retrospective study by Hemmen et al. (2008) reviewed
Pathology/subtypes are as follows: the discharge diagnoses of all patients who presented to
• Cerebral infarction the emergency department as a code stroke (411 patients).
• Primary intracerebral hemorrhage A patient was considered a stroke mimic, if a code stroke
• Subarachnoid hemorrhage (Warlow et al., 2003) was activated, but none of the first three International
Classification of Diseases, Ninth Revision codes on dis-
Etiology charge were related to TIA or ischemic stroke.
In all, 104 patients (25.3%) were discharged without a
The etiologic classification of ischemic stroke, which is some- diagnosis of stroke or TIA. The diagnoses in this group
times referred to as the Trial of Org 10172 in Acute Stroke were intracranial hemorrhage (19 patients), subarachnoid
Treatment (TOAST) classification, includes the following: hemorrhage (6), subdural hematoma (3), old deficit (11),
• Atherosclerotic hypotension (11), seizure (10), intoxication (8), hypogly-
• Cardioembolic cemia (7), mass lesion (6), migraine (5), and others (18).
• Small vessel thrombotic In all, 33 of 307 eligible patients (10.7%) were treated
• Other pathology (vasculitis, hypercoagulable state) with tissue-type plasminogen activator. None of the
• Undetermined cause patients with a stroke mimic received tissue-type plasmin-
Strokes can be classified into four clinical subtypes ogen activator. In 44 of 104 stroke mimics (42.3%), the acute
according to the (Bamford) Oxfordshire Community disease was caused by a severe neurologic condition other
Stroke Project (OCSP) classification (Table 11.2). than ischemic cerebrovascular disease. Only 60 of 411 code
Other causes of stroke and differential diagnosis strokes (14.6%) were initiated for patients without a severe
include the following: and acute neurologic condition. The study concluded that,
• Migraine in their community, 25.5% of all code strokes were initiated
• Seizure disorder/postictal for stroke mimics. Most mimic patients had an illness likely
• GA/TA to benefit from urgent neurologic evaluation (Adams et al.,
• Intracranial structural lesions 1993; Bamford et al., 1991).
• Tumor
• Aneurysm
Bottom of form
• Arteriovenous malformation
• Chronic subdural hematoma
Another study by Nor et al. (2005) showed the percentages
• Head injury
of final diagnosis of patients admitted with an admission
• Encephalitis
diagnosis of stroke.
• Cerebral abscess
• Multiple sclerosis Seizure disorder (24%)
• Labyrinthine disorder Sepsis (23%)
• Metabolic disturbance Migraine (10%)
• Hypoglycemia Somatization (6%)
• Hyponatremia Labyrinthitis/vestibulitis/vertigo (5%)
• Hypocalcemia Metabolic disorder (4%)
• Alcohol and drugs Brain tumor (4%)
• Myasthenia gravis Dementia (3%)
• Psychological cause Encephalopathy (2%)
• Panic Neuropathy/radiculopathy (1%)
• Hyperventilation Transient global amnesia (1%)
• Somatization disorder
Again, similar to the study by Hemmen et al., none
Another important clinical aspect of stroke is ruling
of these patients received thrombolysis (Nor et al., 2005;
out stroke mimics. This differentiation was illustrated in
Hemmen et al., 2008).
separate studies that showed an alternative final diag-

Table 11.2 Stroke clinical subtypes Stroke care

1 Total anterior circulation syndrome (TACS)
2 Partial anterior circulation syndrome (PACS)
3 Posterior circulation syndrome (POCS)
4 Lacunar syndrome (LACS)
Stroke care is a true interdisciplinary and multidisciplinary
approach that has shown to be effective and improve out-
comes of stroke, including reducing mortality. It involves

the patient, the community, the family, general and family
practitioners, emergency response services, the emergency
department, geriatricians, neurologists, general physi-
cians, psychologists, nurses, and the rehabilitation team.
The interdisciplinary team consists of the following:
• Physiotherapist
• Occupational therapist
• Speech and language therapist
• Dietician
• Pharmacist
• Social worker
• Bed manager
• Coordinator
The diagnosis of stroke is clinical and several aids can
help with the diagnosis, the severity of stroke, and func-
tional outcomes or prognosis.
• Clinical history and examination
• Los Angeles Pre Stroke Scale (LAPSS)
• Cincinnati Stroke Scale
• Face, Arm, Speech Test (FAST)
• Recognition of Stroke in the Emergency Room (ROS-
IER)
• Modified Rankin Scale (mRS)
• National Institutes of Health Stroke Scale (NIHSS)
• Scandinavian Stroke Scale (SSS)
• Barthel Index (BI)
• Glasgow Coma Scale (GCS)
NIHSS, a serial measure of neurologic deficit, is a
42-point scale that quantifies neurologic deficits in 11 cat-
egories. Normal function without a neurologic deficit is
scored as 0, and the scale is repeated at regular intervals.
The NIH designed the NIHSS; the National Institute
of Neurological Disorders and Stroke (NINDS), with
Dr Patrick D Lyden as one of its leaders, developed the
video materials it uses. It is quick (can be done in less than
7 minutes), has good interobserver reliability, and can be
administered by non-neurologists.
An NIHSS score of more than 24 indicates a severe
stroke; a score of less than 4 denotes a mild stroke. Both of
these scores are relative contraindications for thrombolysis.
The NIHSS has 11 parts as given below.
• Level of consciousness (1a, b, c)
• Best gaze and vision (2, 3)
• Facial palsy (4)
• Motor arm and legs (5a, b; 6a, b)
• Limb ataxia (7)
• Sensory (8)
• Language and dysarthria (9, 10)
• Extinction/neglect and inattention (11)
The mRS is a simplified overall assessment of function
that has been widely accepted as an outcome measure in
stroke studies. A score of 0 indicates the absence of symp-
toms, a score of 5 indicates severe disability, and a score of
6 indicates that the patient is dead.
Table 11.3 describes the scores for the mRS.
Cerebrovascular Diseases in Geriatrics 307
Table 11.3 Modified rankin scale
Score Measurement
0 No symptoms
1 No significant disability, despite symptoms; able to carry
out all usual duties and activities
2 Slight disability; unable to carry out all previous activities,
but able to look after own affairs without assistance
3 Moderate disability; requires some help, but able to walk
without assistance
4 Moderately severe disability; unable to walk without
assistance and unable to attend to own bodily needs
without assistance
5 Severe disability; bedridden, incontinent, and requires
constant nursing care and attention
6 Dead
The BI is a simple index of independence to score the
ability of a patient with a neuromuscular or musculoskel-
etal disorder to care for him- or herself and, by repeating
the test periodically, to assess improvement.
A patient scoring 100 BI is continent; eats, dresses, and
bathes independently; gets up out of bed and chairs; walks
at least a block; and can ascend and descend stairs. This does
not mean that the person is able to live alone. He or she may
not be able to cook, keep house, or meet the public, although
he or she is able to get along without attendant care.
As with the mRS, the advantage of the BI is its simplicity.
It is useful in evaluating a patient’s state of independence
before treatment, progress while undergoing treatment,
and status at maximum benefit. It can easily be under-
stood by all who work with the patient and anyone who
adheres to the definitions of the items listed, can quickly
and accurately score it. The total score is not as significant
or meaningful as the breakdown into individual items,
because these indicate where the deficiencies are.
Management goals for stroke are as follows:
• Minimize brain injury
• Maximize patient recovery
• Improve mortality
• Improve functional independence
• Increase patient, family, and staff satisfaction
• Prevent complications
Best practices, recommendations, and full guidelines
for stroke care are available from the American Heart
Association (AHA)/American Stroke Association (ASA)
and many other stroke organizations online (Stroke Unit
Trialists’ Collaboration, 2007; Brott, 1989; Bonita and
Beaglehole 1988; Van Swieten et al., 1988; Mahoney and
Barthel, 1965; Wade and Collin, 1988; Granger et al., 1979;
Shah et al., 1989; Sulter et al., 1999).
Stroke outcome data
Thrombolysis
The original NINDS rt-PA Stroke Study Group study was
a randomized controlled trial (RCT) that administered t-PA
308 Neurologic Conditions in the Elderly
0.9 mg/kg within 3 hours versus placebo, with strict inclu-
sion and exclusion criteria. The primary outcome measures
were functional independence as measured by mRS.
It showed a 32% relative risk reduction (RRR) and a
12% absolute risk reduction (ARR) at 90 days, with mini-
mal or no disability as per mRS. The number needed to
treat (NNT) was 8 to prevent one bad outcome. The odds
ratio (OR) for improvement was 2 (95% CI 1.3–3.1). It also
showed that at 1 year, 30% were more likely to have a favor-
able outcome. Mortality was the same, even though the risk
of symptomatic intracranial hemorrhage (sICH) was much
higher in the intervention group (6.4% vs. 0.6% in placebo).
The European Cooperative Acute Stroke Study (ECASS)
3 was a similar, recently published study that increased the
timeline from within 3 hours to within 4.5 hours. The RRR
was 16% (CI 1.01–1.34); p = 0.04 and 7.2% ARR at 90 days
with minimal or no disability as per mRS. The NNT was
14 and OR for improvement was 1.34 (95% CI 1.02–1.76; p =
0.04). Mortality was the same (7.7% vs. 8.4%; p = 0.68), and
sICH was 2.4% vs. 0.2% (p = 0.008). For every 100 patients
treated, 14 additional patients have a favorable outcome
(The National Institute of Neurological Disorders and Stroke
rt-PA Stroke Study Group, 1995; Hacke et al., 2004, 2008).
Stroke care units
The Cochrane Review under Stroke Unit Trialists’ con-
ducted a meta-analysis of more than 3500 patients in
20 trials. Outcome measures were of patients in stroke
units versus general units, with reduction in death OR
0.83 (95% CI 0.71–0.87), reduction in death and depen-
dency OR 0.77 (95% CI 0.65–0.87), ARR 5.6%, and NNT 18.
Similarly, other studies showed stroke unit care versus
medical ward was associated with reduced mortality at
30 days (39% vs. 63%; p = 0.007) and at 1 year (52% vs.
69%; p = 0.013). Organized inpatient MDT rehabilitation
was associated with reduced odds of death OR 0.66 (95%
CI 0.49–0.88; p = 0.01) and reduced death of dependency
OR 0.65 (95% CI 0.50–0.85; p = 0.001).
Patients who were treated in SCU versus general medi-
cal wards were discharged home versus NH (47% vs. 19%;
p <0.01). The Ottawa Panel showed acute stroke rehabili-
tation and MDT reduced death and dependency and LOS
(OR 0.56). Scientifically, all patients benefited from SCU,
regardless of the severity (Stroke Unit Trialists’ Collabora-
tion, 2007; Rønning et al., 2001; Langhorne and Duncan,
2001; Crome and Kalra, 1993; Kalra et al, 1995; Ottawa
Panel et al., 2006).
Anti-platelet therapy in acute stroke
Systematic reviews of aspirin (ASA) in 41,000 patients tak-
ing 160–300 mg within 48 hours of stroke and followed up
for 6 months showed a decrease in death and dependency
OR = 0.94, CI 0.91–0.98. There were two SICH for every 1000
treated, which was offset by seven with less recurrence of
ischemia and pulmonary emboli. Furthermore, treatment
increased the odds of making a complete recovery from the
stroke (OR 1.06; 95% CI 1.01–1.11): 10 more patients made
a complete recovery for every 1,000 patients treated. In
absolute terms, 13 more patients were alive and independent
at the end of follow-up for every 1,000 patients treated (Inter-
national-Stroke-Trial-Collaborative-Group, 1997; CAST- Col-
laborative-Group, 1997).
Hypertension therapy
A meta-analysis of seven RCTs showed that antihyperten-
sive drugs reduced stroke recurrence after stroke or TIA
(RR 0.76; 95% CI 0.63–0.92), regardless of BP and the type
of stroke. Therefore, BP should be lowered and monitored
indefinitely after stroke or TIA (Rashid et al., 2003; PATS
Collaborating Group, 1995; Yusuf et al., 2000; Bosch et al.,
2002; PROGRESS collaborative group, 2001).
Hyperlipidemia management
In the SPARCL (Stroke Prevention by Aggressive Reduc-
tion in Cholesterol Levels) trial, statin therapy with ator-
vastatin reduced stroke recurrence (HR 0.84; 95% CI
0.71–0.99). Similarly, the Heart Protection Study with sim-
vastatin reduced vascular events in patients with prior
stroke and reduced stroke in patients with other vascular
diseases (RR 0.76). The risk of hemorrhagic stroke was
slightly increased in both trials. The ARR achieved with
statin therapy was NNT 112–143 for 1 year. Statin with-
drawal at the acute stage of stroke may be associated with
an increased risk of death or dependency, and no recom-
mendation was made to start statins in the acute stroke
setting. Guidelines recommend continuing with the statin
therapy if the patient is already on it (Amarenco et al.,
2006; Heart Protection Study Collaborative Group, 2002).
Carotid surgery, carotid endarterectomy,
and carotid artery stenting after stroke
or transient ischemic attack
The grading of stenosis should be performed according to
the North American Symptomatic Carotid Endarterectomy
Trial (NASCET) criteria. Although the European Carotid
Surgery Trialists (ECST) and NASCET use different meth-
ods of measurement, it is possible to convert the percentage
stenosis derived by one method to the other. Carotid end-
arterectomy (CEA) reduces the risk of recurrent disabling
stroke or death (RR 0.52) in patients with severe (70–99%)
ipsilateral internal carotid artery stenosis. Patients with less
severe ipsilateral carotid stenosis (50–69%) also benefit.
CEA should be performed only in centers with a periop-
erative complication rate (all strokes and death) of less than
6% and should be performed as soon as possible after the
last ischemic event (ideally, within 2 weeks).
A recent study published by Brott et al., the Carotid
Revascularization Endarterectomy Versus Stenting Trial

(CREST) showed similar outcomes with carotid artery
stenting (CAS) and CEA for the treatment of carotid ste-
nosis. CREST is the largest prospective randomized trial
to date that compared these two interventions, enrolling
2502 patients from 117 US and Canadian centers.
On the composite primary endpoint of any stroke,
myocardial infarction (MI), or death during the peripro-
cedural period or ipsilateral stroke on follow-up, stent-
ing was associated with a 7.2% rate of these events versus
6.8% with surgery, a nonsignificant difference.
However, individual risks varied. At 30 days, the rate of
stroke was significantly higher with stenting, at 4.1% ver-
sus 2.3% with surgery, although among those with major
stroke, it was no different, at less than 1% in both groups.
Conversely, MI was higher with CEA, at 2.3% versus
1.1% with stenting, again, a statistically significant differ-
ence. Patients who had an MI, however, reported a better
quality of life after recovery than those who had a stroke,
the study authors noted.
Rates of ipsilateral stroke during a mean follow-up of
2.5 years were equal between groups, at 2% for stenting
and 2.4% with surgery. The investigators also reported an
effect of age, with younger patients having slightly fewer
events with CAS than CEA and older patients having
fewer events with surgery.
The study was supported by the National Institute of
Neurological Disorders and Stroke, with supplemental
funding by Abbott (Cina et al., 2000; Inzitari et al., 2000;
Rothwell et al., 2003; European Carotid Surgery Trialists’
Collaborative Group, 1996; Brott et al., 2010).
Novel therapies
Some novel therapies, such as biologic therapies, multi-
modality neuroprotection therapies, therapeutic hypo-
thermia, and sonothrombolysis, are currently under inves-
tigation and may play a future role in stroke treatment.
As clinicians, we need to be aware of important and
relevant issues regarding demographics that have direct
relation to increasing health-care cost, hospital admission
rates, LOS, nursing home placement, and quality of life
for older people.
The US Census Bureau in 2000 reported that an esti-
mated 35 million (12.4%) people were aged 65 and over
and about 25% of these groups were also caregivers for
their grandchildren. The demographic data from 2007
showed about 38 million people aged 65 and over, with
an average life expectancy of 17 years for men at 65 years
and 19.7 years for women at 65 years.
Hospital discharges and inpatient care was $13 mil-
lion for elderly patients 65 years and older; average LOS
was 5.5 days. Mortality for this patient population was
1,759,423 and the highest mortality was for 85 years of age
and over. The three leading causes of death were heart
disease, cancer, and stroke.
Cerebrovascular Diseases in Geriatrics 309
From a cerebrovascular disease point of view, each year
800,000 people experience stroke (either new or recur-
rent). An estimated 81 million adult Americans have one
or more types of cardiovascular and cerebrovascular dis-
ease. Of these, 38 million are estimated to be 60 years or
older. About 6.5 million people have had a stroke; it is the
third most common cause of death in the United States,
behind heart disease (with which it is closely linked) and
cancer, and it affects more than 700,000 individuals annu-
ally in the United States (approximately one person every
45 seconds). About 500,000 of these are first attacks, and
200,000 are recurrent attacks. In other words, someone in
the United States dies every 3.3 minutes from stroke, and
it is the leading cause of disability among adults in the
United States.
More than four million people in the United States have
survived a stroke or brain attack and are living with the
aftereffects. Four out of five families will be somehow
affected by stroke over the course of a lifetime.
In terms of recovery, 10% of stroke victims recover
almost completely, 25% of stroke victims recover with
minor impairments, and 40% of stroke victims experience
moderate-to-severe impairments requiring special care.
Another 10% of stroke victims require care in a nursing
home or other long-term care facility, and 15% die shortly
after the stroke. Mortality is different in different types of
stroke, with 7.6% of ischemic strokes and 37.5% of hemor-
rhagic strokes resulting in death within 30 days. The out-
comes for men and women are roughly the same, with
22% of men and 25% of women dying within a year of
their first stroke.
TIA should be taken seriously, as 14% of people who
have a stroke or TIA will have another within a year and
about 25% of stroke victims will have another within
5 years. The ABCD2 score system can be a helpful tool
in assessing patients with TIA and a risk of developing
future strokes.
Cost to health care and the country is another major
issue regarding stroke care. The total cost of stroke to the
United States is estimated at $43 billion per year, and the
direct costs of medical care and therapy are estimated at
$28 billion per year. Indirect costs from lost productivity
and other factors are estimated at $15 million per year,
and average cost of care for a patient up to 90 days after
stroke is $15,000. For 10% of patients, the cost of care for
the first 90 days after a stroke is $35,000.
Table 11.4 gives the percentage breakdown of the direct
costs of care for the first 90 days after a stroke.
Table 11.4 Breakdown of costs in first 90 days following stroke
Initial hospitalization 43%
Rehabilitation 16%
Physician costs 14%
Hospital readmission 14%
Medications and other expenses 13%
310 Neurologic Conditions in the Elderly
In terms of overall population, especially older persons,
the demographics are changing with the rapid growth
in older population. The US population is projected to
increase to an estimated 403 million by the year 2050, an
increase by 47% from the year 2000—and, more impor-
tantly, with a significant increase in persons 65 years
and older. The number of people 65 years and older will
increase from an estimated 35 million to about 80 million
(135% change); among these, people 85 years and older
will increase from about 4 million to 20 million (a change
of 350%). These staggering statistics will have many
important implications in our society and for the future
medically, socially, financially, and politically, affecting all
aspects of our daily lives (CDC).
The good news is that, as a result of new interven-
tions (such as stroke units and ACE units), therapeutic
advances, and novel models for the care of the elderly
and for stroke and other cerebrovascular disease/cardio-
vascular diseases, the cerebrovascular disease and related
outcomes have significantly improved.
However, considering the striking statistics, there
is a universal consensus that these issues are not being
addressed with urgency from a public health or clinical
(primary and secondary prevention) point of view.
Much more needs to be done to address healthy aging,
reduce disparity in health-related outcomes, emphasize
rehabilitation and exercise programs, and improve the
quality of life for our older population (Rothwell et al.,
2005; Centers for Disease Control and Prevention; US
census bureau; National Institutes of Health; National
Institute of Neurological Disorders and Stroke; American
Heart Association; American Stroke Association).
Vascular depression
The vascular depression hypothesis states that cerebro-
vascular diseases may predispose or perpetuate depres-
sive moods in geriatric patients (Alexopoulos et al., 1997).
Cerebrovascular risk factors (CVRFs) are pre-existing medi-
cal conditions that predispose the patient to stroke or heart
attack. These risk factors include diabetes, hypertension, a
history of TIA, high cholesterol, obesity or lack of exercise,
pregnancy and childbirth, trauma to the brain, alcohol and
drug abuse, smoking, and carotid or other arterial diseases.
In stroke survivors who suffer from any of those risk factors,
a large percentage reported depressive symptoms.
In many stroke survivors, structural abnormalities have
been discovered in the prefrontal cortex. This includes dif-
ferences in the bilateral gray matter in separate regions,
including the gyrus rectus and anterior cingulated, where
differences in the white matter and cerebrospinal fluid
(CSF) volume have also been marked in depressed geriat-
ric patients (Alexopoulos et al., 1997). A correlation between
CVRFs and these lesions has been reported, which is under-
standable because the risk factors for subcortical ischemic
diseases are the same as those for stroke (Steffens et al., 2003).
Patients who suffer from multiple CVRFs tend to have more
severe lesions and are five times more likely to demonstrate
depressive symptoms 6–18 months after stroke than those
with fewer CVRFs (Mast et al., 2004). What is unknown is
whether these lesions were caused by the actual stroke or
preceded it and are the result of the CVRFs.
It is difficult to determine what the depression, com-
monly seen in stroke patients, is actually due to. The rea-
soning behind the depressive symptoms could be simply
that the patient is experiencing fear and stress from being at
a higher risk of a life-threatening illness, or they could arise
because the CVRFs potentially change the actual physical
makeup and chemistry of the brain. It has been found that
depression can take two paths in the elderly. It can be caused
by high-intensity lesions produced by medical comorbidity
or through a series of interconnected neurobiologic events
that change frontal volumes (Alexopoulos, et al., 1997). Due
to this uncertainty of cause, treating the depression in these
patients is difficult. Each antidepressant regime must be tai-
lored to the patient, due to the potential differences in cause
and the other medications the patient may be taking.
A national survey in Sweden found that one in seven
stroke victims experienced depressive symptoms after
their first stroke. After stroke, 12.4% of male patients, 22.5%
of whom used antidepressant medication, and 16.4% of
female patients, 28.1% of whom used antidepressant medi-
cation, reported depressive symptoms almost every day. Of
those using antidepressants, 67.5% reported no appearance
of depressive symptoms while on the medication (Eriksson
et al., 2004). This, along with other case studies (Steffens
et al., 2003), has shown that the use of antidepressants in
stroke survivors can be highly beneficial, although drug
interactions must be taken into consideration. Because the
vascular depression hypothesis has not yet been proven
or disproven, the best antidepressants for stroke survivors
are believed to also target ischemic lesions and improve
neurologic recovery in the region of those lesions (Alexo-
poulos et al., 1997). According to the Sertraline Antidepres-
sant Heart Attack Trial (SADHART) despite the potential
interactions, antidepressants have proven to be helpful in
treating major depression in the context of medical illness
(Steffens et al., 2003).
Further resources
For further information about cerebrovascular disease,
refer to the following sources:
http://learn.heart.org/ihtml/application/student/
interface.heart2/nihss.html
www.NIHSS.com
www.strokecenter.org/trials/scales/scales-overview.
html
http://stroke.ahajournals.org

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 Chapter 12
Movement Disorders
12.1 Parkinson’s Disease
Robert Fekete1 and Joseph Jankovic2

12.2 Essential Tremor and Other Tremor Disorders

Holly Shill3

12.3 Progressive Supranuclear Palsy

Virgilio Gerald H. Evidente4

12.4 Corticobasal Degeneration

Katrina Gwinn5

1 Department
of Neurology, New York Medical College, Valhalla, NY, USA
2 Parkinson’s
Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine,
Houston, TX, USA
3 Banner Sun Health Research Institute, Sun City, AZ, USA
4 Movement Disorders Center of Arizona, Ironwood Square Drive, Scottsdale, AZ, USA
5 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

Summary
Parkinson’s Disease
• Hallmarks of Parkinson’s disease (PD) pathology include the presence of Lewy bodies with alpha-synuclein aggregates,
and a loss of dopamine-producing, melanin-containing neurons in the substantia nigra. This results in dopaminergic
deficiency in the striatum.
• Resting tremors, rigidity, akinesia/bradykinesia, and postural instability are all common precursors to PD.
• PD patients also exhibit neuropsychiatric symptoms such as hallucinations, delusions, agitation, depression, irritability,
anxiety, and apathy.
• Patients with cognitive dysfunction preceding the development of motor symptoms of PD are said to have diffuse
Lewy body disease (DLB), while dementia that develops post motor symptoms is classified as PD dementia (PDD).
• Mild symptoms are treated with monoamine oxidase (MAO) inhibitors and dopamine agonists. More severe symptoms
require levodopa to treat motor dysfunctions. Dopamine-blocking agents help control hallucinations. Surgical lesioning
procedures have been phased out in favor of deep brain stimulation (DBS). DBS helps treat OFF symptoms and is an
important therapeutic option for motor fluctuations.

Essential Tremor and Other Tremor Disorders

• Typical tremors in clinical practice include resting tremor, postural tremor, and kinetic/action tremor. Task-specific tremor
and orthostatic tremor are seen in essential tremor (ET) patients.
• ET is a monosymptomatic, bilateral, relatively symmetrical postural and kinetic tremor of the hands.
• Magnetic resonance spectroscopy and blood flow imaging show abnormalities in cerebellar circuitry with overactivity in
the cerebellar-thalamo-cortical loop.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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314 Neurologic Conditions in the Elderly

• Primidone and propranolol are medications most commonly used to treat ET. Gabapentin, topiramate, and pregabalin
are also used. No therapy other than thalamic deep brain stimulation (DBS) has been approved for this condition. DBS
is especially effective in drug-resistant patients.
• Other types of tremors include parkinsonian, primary writing, orthostatic, drug-induced, cerebellar, neuropathic, and
psychogenic tremors.

Progressive Supranuclear Palsy

• Clinical hallmarks of progressive supranuclear palsy (PSP) include supranuclear vertical gaze palsy, pseudobulbar palsy,
axial rigidity, and cognitive impairment.
• NINDS-SPSP clinical criteria classified cases into three categories: possible, probable, and definite PSP for clinical
diagnosis.
• Macroscopic pathology includes atrophy in precentral gyrus, midbrain tectum, substantia nigra, pons, superior
cerebellar peduncle (SCP), and cerebellar dentate nucleus. Neuronal loss, gliosis, and neurofibrillary tangles (NFTs)
affecting the basal ganglia, diencephalon, and brainstem are the typical microscopic findings in PSP.
• It is proposed a “penguin silhouette” sign, as observed in all PSP patients on midsagittal magnetic resonance imagings
(MRIs) is diagnostic feature.
• A poor or absent response to levodopa has been published as one of the diagnostic criteria for PSP. Treatment is largely
symptomatic but not very helpful.

Corticobasal Degeneration
• Initial symptoms of corticobasal degeneration (CBD) usually include asymmetric rigidity, bradykinesis, and dysmetria.
Asymmetrical limb dystonia is seen in almost all patients with CBD. Ideomotor apraxia is another abnormality seen
in CBD.
• The standard for CBD diagnosis is neuropathologic. Magnetic resonance imaging (MRI), SPECT, and DAT scanning are
sometimes used.
• There is no treatment to slow the course of CBD and symptoms usually resist therapy.
• An important part of neuropathology is that CBD results from the pathologic aggregation of tau protein as does
frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP).
 Chapter 12.1
Parkinson’s Disease
Robert Fekete and Joseph Jankovic
Introduction
James Parkinson described the disorder that now bears
his name in his “Essay on Shaking Palsy” (Parkinson,
2002). He described six cases exhibiting symptoms of the
disorder, including fatigue, stooped posture, difficulty
initiating ambulation, gait with short steps, hypersaliva-
tion, and constipation. He drew attention to rest tremor,
“agitation,” which stopped with “sudden” or “violent”
action and started over in a crescendo manner up to a min-
ute later. Although Parkinson did not emphasize rigidity,
he described manual dexterity leading to difficulty with
handwriting and using utensils while eating. He named
the disorder paralysis agitans, or shaking palsy. Parkinson
predicted success in developing disease-modifying treat-
ment “by which, at least, the progress of the disease may
be stopped” but, unfortunately, that promise has not yet
been realized (Parkinson, 2002). Prior reports of individual
clinical features of the disorder exist, but Parkinson was
the first to report the features as a coherent clinical entity.
For example, Sauvages de la Croix, Carguet, and Gaubius
previously noted scelotyrbe festinans (“hastening” or festi-
nating gait) but did not connect it to other clinical features.
Festinare means “to hurry” in Latin, and the authors were
referring to “walking with a quick and hastened step, as if
hurried along against their will” (Parkinson, 2002).
Jean Martin Charcot, professor at the famous Salpêtrière
Hospital in Paris, considered by many as the founder of
modern neurology, gave Parkinson credit by naming the
disorder Parkinson’s disease (PD). In his Leçons sur Les
Malades du Système Nerveux of 1877, he further discussed
propulsion and retropulsion, with the “individual being
apparently forced to follow a particular center of grav-
ity” (Pearce, 1989). He also described rigidity and distin-
guished rest tremor, which he likened to “spinning wool”
or “crumbling bread,” from the action tremor associated
with multiple sclerosis (Pearce, 1989).
Epidemiology
The frequency of PD varies depending on the diagnostic
criteria, study population, and epidemiologic methods
used, although the prevalence is generally thought to be
about 0.3% in the general population and 1% in people
over the age 60 years; the reported incidence figures have
ranged from 8 to 18 per 100,000 person-years (deLau and
Breteler, 2006). An estimated 5 million people have PD
worldwide. One study showed that the world’s high-
est prevalence of PD may be among the Amish in the
northeastern United States. The prevalence of PD was
5703 per 100,000 (nearly 6%) of people 60 years old or
older, more than three times the prevalence for the rest
of United States (Racette et al., 2009). One reason for the
wide variation in prevalence is difficulties differentiating
between PD and essential tremor (ET), a much more com-
mon disorder whose clinical (and pathologic) features
often overlap with PD (Fekete and Jankovic, 2011). Most
studies have demonstrated about 3:2 male preponder-
ance. In one of the largest prospective studies involving
142,902 professionals and nurses, the incidence rate was
estimated to be 18.6/100,000 person-years (43.2 for males
and 10.7 for females, respectively) (Chen et al., 2003).
Furthermore, there appears to be a decreased incidence
of PD in black populations, and some have postulated
that melanin may have a neuroprotective function. Inter-
estingly, PD patients are more likely to have melanoma,
and melanoma patients have a higher risk for PD (Inzel-
berg and Jankovic, 2007; Pan et al., 2011). Many studies
have found that living in rural areas, drinking well water,
being exposed to pesticide, and holding certain occupa-
tions, such as physicians, dentists, scientists, farmers,
teachers, and lawyers, are associated with increased risk
of PD (Tanner et al., 2009). In contrast, smoking, caffeine
intake, and exercise are associated with reduced risk of
PD (Chen et al., 2010).
Pathogenesis
PD is classified as a synucleinopathy along with dif-
fuse Lewy body disease (DLB), multiple system atrophy
(MSA), and pure autonomic failure (PAF). The hallmarks
of PD pathology are the presence of Lewy bodies with
alpha-synuclein aggregates, as well as loss of dopamine-
producing, melanin-containing neurons in the part of
the midbrain called the substantia nigra pars compacta
(Braak, 2002). This results in dopaminergic deficiency in
the striatum, particularly the putamen. However, evi-
dence suggests that nondopaminergic and autonomic
systems may be involved long before the degeneration
of substantia nigra, and some have suggested that PD is
315
316 Neurologic Conditions in the Elderly
a developmental disorder with onset as early as in the
perinatal period (Le et al., 2009; Mostile and Jankovic,
2009). In contrast to the traditional notion that PD starts
in the substantia nigra, Braak et al., provided evidence
that Lewy body pathology starts more caudally, in the
medullary nuclei (2004). Lesion experiments in cats and
other studies have linked locus ceruleus area to rapid eye
movement sleep without atonia (RSWA) and other sleep
and autonomic disorders, which could explain both the
dysautonomic and rapid eye movement sleep behavior
disorder (RBD) prodromes (Mostile and Jankovic, 2009).
Involvement then progresses to the midbrain, followed
by the temporal mesocortex and allocortex and, finally,
the neocortex (Braak, 2002; Hawkes et al., 2010).
Models of PD, such as the 6-hydroxydopamine lesion,
point to an increase in oxidative stress as a possible mecha-
nism of neurodegeneration. In addition, there is a sugges-
tion of changes in 5-hydroxytryptophan metabolism in
early disease that may contribute to affective symptoms
(Branchi et al., 2010). Functional imaging shows changes of
the PD motor-related pattern (PDRP) network that precede
the onset of motor symptoms by 2 years (Tang et al., 2010).
The majority of the patients in the geriatric age group
have idiopathic PD, as opposed to genetic PD, which
tends to have an earlier age at onset. Mutation in the gene
coding for alpha-synuclein is associated with autosomal
dominant inheritance of PD (Polymeropoulos et al., 1997;
Irvine et al., 2008), as well as DLB (Zarranz et al., 2004).
Mutations in the Parkin gene are an important cause of
early-onset autosomal recessive PD (Lücking et al., 2000;
Dawson and Dawson, 2003). The E3 ubiquitin ligase func-
tion of Parkin specifically targets proteins for degradation
via the proteosome (Zhang et al., 2000; Dawson and Daw-
son, 2003). Loss of this function may potentially allow the
accumulation of aggregation-prone proteins. Parkin itself
may be subject to post-translational regulation affecting
its activity (Yamamoto et al., 2005; Rubio de la Torre et al.,
2009), for example, by c-Abl-mediated tyrosine phosphory-
lation (Imam et al., 2011). In addition to Parkin, DJ-1 as well
as PTEN-induced kinase 1 (PINK1) mutations have been
recognized as causes of autosomal recessive PD. PINK1 is
thought to be a mitochondrial protein kinase (Silvestri et al.,
2005). It has been suggested that PINK1 recruits Parkin from
the cytoplasm into damaged mitochondria, where the ubiq-
uitin ligase function of wild-type Parkin initiates mitochon-
drial degradation (Matsuda et al., 2010). Leucine-rich repeat
serine/threonine protein kinase 2 (LRRK2) mutations are
an important cause of autosomal-dominant PD. Inves-
tigation of the mechanism of LRRK2 mutation revealed
involvement in cellular signaling pathways (Berwick and
Harvey, 2011). Further research is needed to elucidate the
pathogenic mechanism underlying genetic forms of PD.
Vascular parkinsonism is clinically manifested pre-
dominantly by slow, broad-based, shuffling and freezing
gait without much involvement of the upper body, hence
the term “lower body parkinsonism” (Winikates and
Jankovic, 1999; Kalra, et al., 2010). These patients have
risk factors for cerebrovascular disease and have evidence
of multiple vascular insults in the basal ganglia or white
matter on neuroimaging studies or at autopsy. Although
up to half of the patients with vascular parkinsonism
improve with levodopa, the response is rarely dramatic;
if it is robust, it suggests coexistent PD (Tzen, 2001).
Clinical features
Although at least 60% of these neurons are already lost
or damaged by the time the patient first develops the
cardinal motor features of PD—tremor, rigidity, akinesia
(bradykinesia), and postural instability (TRAP)—many
nonmotor features of PD may manifest long before the
motor symptoms (Jankovic, 2008). For example, depres-
sion and anxiety have been noted to precede develop-
ment of PD (Shiba et al., 2000). Retrospective studies
identified certain personality traits that may be associated
with PD, but prospective studies are needed to under-
stand this association further (Ishihara, 2006). Rigid, ner-
vous, cautious, conventional, and introverted personality
traits were reported (Ishihara, 2006). Constipation has
also been reported as preceding the development of PD
(Abbott et al., 2001). Other autonomic dysfunction such as
orthostatic hypotension (OH), sialorrhea, dysphagia, sex-
ual dysfunction, and respiratory problems (Mostile and
Jankovic, 2009; Mehanna and Jankovic, 2010) may also
precede the onset of cardinal motor symptoms for several
years or decades. RSWA associated with dream enact-
ment behavior not caused by medication or substance
use, called RBD, may precede the onset of motor symp-
toms not just in PD, but also in DLB and MSA, long before
other symptoms emerge. In one study, 38% of patients
with isolated RBD reportedly developed a parkinsonian
disorder after 12.7 years ( Schenck, Bundlie and Mahow-
ald, 1996). Some authors have reported a range of 15–50
years (mean 25 years) between the onset of RBD and PD,
DLB, or MSA (Claassen et al., 2010). Two cases of RBD
without additional neurologic symptoms were shown to
have Lewy body pathology on autopsy, suggesting that
this sleep disorder may be viewed as a form of synucle-
inopathy (Mahowald et al., 2010), although it may also be
seen in disorders other than synucleinopathies (Mahow-
ald, 2006). Although a “prodromal phase,” during which
these behavioral and autonomic symptoms are present,
has been suggested to last an average of 4–6 years, some
have suggested that it may last much longer and may
even have its onset in the perinatal period (Le et al., 2009;
Mahowald et al., 2010; Wu, et al., 2011).
The rest tremor is 4–6 Hz, tends to have a pronating/
supinating component, and has classically been described
as “pill rolling.” Lip, chin, or jaw tremor may be present
 Parkinson’s Disease 317

as well. PD patients may also have an action tremor (Sha-

hed and Jankovic, 2007). Rest tremor may become more
prominent while the patient is walking or performing
calculations (Raethjen et al., 2008). As only a few cases
of head tremor have been described in PD, the presence
of head tremor may signify concurrent ET (Shahed and
Jankovic, 2007). Bradykinesia causes impairment of fine
motor movements, as initially exhibited by a patient’s
difficulty with buttoning a shirt or tying shoelaces. Gait
in PD is described as “shuffling” with small steps and
reduced arm swing. Difficulty with initiation of gait (start
hesitation) and other forms of freezing of gait may be
present. Some patients also exhibit involuntary hastening
of gait, termed festination (Knuttson, 1972). “Freezing”
or arrest of gait may be present especially in tight spaces Figure 12.2 Foot dystonia.
such as elevators and doorways and when performing
turns. Freezing of gait early in the course of the disease drop (Figure 12.3; Jankovic, 2010). Camptocormia is a
is suspicious for vascular parkinsonism or early stages of severe, involuntary flexion of the trunk (Figure 12.4). The
progressive supranuclear palsy. The various classical fea- patient with camptocormia is able to straighten the back
tures of PD can be objectively assessed by various clini- in the supine position or when performing the “climbing
cal rating scales, including the Unified Parkinson Disease on the wall” maneuver (Jankovic, 2010).
Rating Scale (UPDRS), which has been recently modified PD may be classified into different subtypes, such as
as the Movement Disorder Society (MDS)-UPDRS (Goetz young onset versus late onset and familial versus spo-
et al., 2007; Jankovic, 2008). radic, and also may be classified according to its clinical
In addition to the classic PD symptoms (TRAP), many presentation; tremor dominant and postural instability
patients with PD gradually develop flexed posture and gait disorder (PIGD) are major subtypes (Jankovic et al.,
other neck, trunk, or joint deformities, so-called stria- 1990). The tremor-dominant subtype has been associ-
tal deformities, often wrongly attributed to “arthritis” ated with a more favorable prognosis (Jankovic, 2005).
(Ashour and Jankovic, 2006; Jankovic, 2010). These Although tremor is the most classic hyperkinetic disor-
include striatal hand (Figure 12.1) and foot (Figure 12.2) der associated with PD, many PD patients also exhibit
deformities. Other features that may be present include abnormal involuntary movements, called dyskinesia, as
stooped posture, scoliosis, “Pisa syndrome,” and head an adverse effect of levodopa. These dyskinesias may

Figure 12.1 Striatal hand deformity.

318 Neurologic Conditions in the Elderly
Figure 12.3 Bent spine deformity.
occur as repetitive, coordinated movements (stereoty-
pies), jerk-like movements that move randomly from
one body part to another (chorea), or more sustained,
patterned muscle contractions causing abnormal pos-
tures (dystonia; Jankovic, 2002). These dyskinesias not
only may impair motor functioning and interfere with
balance and activities of daily living, but also may
impair other functions, including respiration (Mehanna
and Jankovic, 2010).
Figure 12.4 Camptocormia.
Neuropsychiatric manifestations
Patients with PD display a range of neuropsychiatric
symptoms, including hallucinations, delusions, agitation,
depression, irritability, anxiety, and apathy (Aarsland,
1999). As apathy is associated with executive dysfunction
and depression in PD, it may be due to dysfunction of
frontal lobe systems (Aarsland, 1999).
Visual hallucinations (VH) may affect up to 50% of PD
patients and 73% of patients with DLB (Williams and
Lees, 2005). They may take the shape of persons, animals,
or objects (Meppelink et al., 2009). They are traditionally
thought of as effects of dopaminergic treatment, but a
challenge with high-dose intravenous levodopa in con-
tinuous or pulse infusion did not produce hallucinations,
even though dyskinesias worsened (Goetz et al., 1998). On
functional MRI, PD patients with VH were found to have
impaired processing in occipital and temporal extrastriate
visual cortices (Meppelink et al., 2009).
Symptoms of depression and anxiety may be present
for years preceding the development of motor symp-
toms of PD (Shiba et al., 2000). A study of consecutive
outpatient clinic PD patients found comorbid mood and
anxiety disorders in 19.3% of PD patients versus 8.6% of
age- and sex-matched controls (Nuti et al., 2004). Another
study found current and lifetime prevalence of at least
one anxiety disorder diagnosis among PD patients to be
43% and 49%, respectively (Pontone et al., 2009). Dysthy-
mia and depression, possible nonmotor manifestations of
dopamine deficiency among PD patients, can lead to mild
immediate reward-seeking behavior (Wolters et al., 2008).
Impulse-control disorders are thought to be extrin-
sic and related to dopamine-replacement therapy, espe-
cially administration of dopamine agonists (Wolters et al.,
2008). These include compulsive gambling, shopping,
binge eating, hypersexuality, hoarding, compulsive skin
picking, and pathologic Internet use (Wolters et al., 2008;
O’Sullivan, et al., 2010). Even impulsive smoking associ-
ated with increased dopamine agonist administration has
been reported (Bienfait et al., 2010). Treatment consists of
lowering the dosage of the offending dopaminergic agent,
switching from dopamine agonist to levodopa therapy,
and engaging in family or psychiatric counseling.
Punding is a stereotypic motor behavior associated
with levodopa use that involves repetitive handling,
examining, or dismantling of objects (Fernandez et al.,
1999). Similar behaviors are observed in patients who
abuse amphetamine and cocaine and are associated with
a sense of relief in that group; however, no relief or plea-
surable sensation is associated with these activities in the
PD group (Fernandez and Friedman, 1999).
Patients with cognitive dysfunction, particularly if
accompanied by hallucinations, preceding the develop-
ment of motor symptoms of PD are classified as having
DLB. Dementia that develops after motor symptoms of

PD is called PD dementia (PDD). DLB subjects tend to
have more conceptual and attentional errors than PDD
subjects, even after controlling for dementia severity
(Aarsland et al., 2003). Neuropathologically, DLB has
been shown to have widespread alpha-synucleinopathy
and Lewy bodies (Lippa et al., 2007). Considerable con-
troversy exists concerning whether PD, DLB, and PDD
represent related or independent disease entities.
Nonmotor features of Parkinson’s
disease
Nocturnal nonmotor symptoms play an important role
in affecting the quality of life of PD patients. Sleep frag-
mentation, vivid dreams, and nightmares may be present
(Goetz et al., 2010). Obstructive sleep apnea and hypop-
nea is common in the PD population (Mahowald and
Schenck, 2010). Sleep disruption contributes to exces-
sive daytime somnolence (Ray Chaudhuri, 2006). Rapid
transition from wakefulness to stage 2 sleep may cause
sudden sleep attacks (Rye and Jankovic, 2002). Dream
enactment behavior in RBD may be relatively benign
and limited to vocalizations (Ray Chaudhuri, 2006), or it
may develop into behaviors that have potentially danger-
ous consequences. Choking of the bed partner, dives out
of the bed, and near defenestration have been reported
(Schenck et al., 2009; Mahowald and Schenck, 2010).
Gradual weight loss is also commonly present in PD,
although other causes should be investigated if the weight
loss is abrupt and severe (Jankovic et al., 1992; Bachmann
and Trenkwalder, 2006).
OH has been reported in 47% of a community-based
cohort (Allcock et al., 2004; Mostile and Jankovic, 2009).
Cardiac denervation can precede the onset of motor symp-
toms of PD (Goldstein et al., 2007). Patients with PD–OH
have cardiac and extracardiac noradrenergic sympathetic
denervation (Sharabi et al., 2008). Even PD patients with-
out OH have cardiac sympathetic denervation (Goldstein
et al., 2000) Cardiac sympathetic denervation can precede
the onset of motor symptoms of PD (Milazzo et al., 2012).
A subset of PD patients present early in the disease
course with profound autonomic failure (AF-PD). The
symptoms may include OH and postprandial hypoten-
sion, in addition to urinary frequency, constipation, and
denervation supersensitivity to norepinephrine infusion
(Niimi et al., 1999; Mostile and Jankovic, 2009). Sympa-
thetic ganglionic and postganglionic nerves are involved
in AF-PD.
Olfactory dysfunction is also present almost univer-
sally in PD. It includes deficits in odor identification and
odor discrimination (Boesveldt et al., 2008). Odor identi-
fication deficit is independent of disease progression, but
impairment in odor discrimination increases with disease
duration (Boesveldt et al., 2008).
Parkinson’s Disease 319
Treatment
Treatment of PD depends on the severity of the disease, as
well as the subtype.
For early, mildly symptomatic disease, monoamine oxi-
dase (MAO) inhibitors such as rasagiline and selegiline
may be used. In addition to this mild symptomatic benefit,
rasagiline may have a disease-modifying quality and delay
the worsening of motor symptoms. Dopamine agonists
ropinirole and pramipexole can be initiated once stronger
symptomatic relief of loss of manual dexterity, rest tremor,
rigidity, or gait disturbance is required. Although early
introduction of dopamine agonists may delay the onset
of levodopa related motor complications, no disease-
modifying effects have been demonstrated with these
drugs (Schapira et al., 2013a). These agents are carefully
titrated to a dose providing optimum relief. Extended-
release versions of both medications are available, which
permits simplification of the dosing regimen. Care should
be taken to ask the patients about complications of dopa-
mine agonist therapy, which include sudden sleep attacks
and extrinsic impulse-control disorders, including patho-
logic gambling, compulsive shopping, binge eating, and
hypersexuality (Wolters et al., 2008).
As the disorder progresses, the addition of levodopa is
required for treatment of troublesome motor symptoms.
This can be done in conjunction with dopamine agonists.
Historically, the racemic mixture of dextro- (D) and levoro-
tatory (L) isomers of 3,4-dihydroxyphenylalanine (DOPA)
caused more nausea than the current L-DOPA (levodopa)
formulation (Pearce, 1989). The enzyme DOPA decarbox-
ylase, discovered in 1938, converts DOPA into dopamine
(Hornykiewicz, 2002). Nausea and lightheadedness from
peripheral conversion of dopamine is counteracted by
peripherally acting DOPA decarboxylase inhibitor such
as carbidopa or benserazide, which is not approved in the
United States. The medullary vomiting center is not pro-
tected by the blood–brain barrier, which allows peripher-
ally acting DOPA decarboxylase inhibitors to exert their
effect on this center (Jankovic, 2002). Additional carbi-
dopa (marketed under the trade name Lodosyn) can be
utilized for treatment of nausea. Trimethobenzamide has
also successfully been used for nausea. The peripheral D2
dopamine receptor blocking agent domperidone is not
available in the United States (Jankovic, 2002). Selective
5-HT3 receptor antagonists ondansetron or granisetron
may also be useful for this purpose (Jankovic, 2002).
Motor fluctuations include OFF phenomena and dyski-
nesias. Adding entacapone, a catechol-O-methyl transfer-
ase (COMT) inhibitor, to the levodopa regimen prolongs
the effective duration of each levodopa dosage (Merello et
al., 1994). Entacapone’s potential side effects include diar-
rhea, worsening or dyskinesias, and orange urine discolor-
ation. MAO inhibitors such as selegeline can also be used
for this purpose. After prolonged treatment with levodopa,
320 Neurologic Conditions in the Elderly
dyskinesias that are hyperkinetic, choreiform movements
can present. Dyskinesias may occur at the peak of each dose
of levodopa therapy or in a diphasic manner (Jankovic,
2002). Avoiding sustained-release formulations of levodopa
is recommended in this case, as uneven plasma levodopa
levels can contribute to dyskinesias. The total daily dose of
levodopa can be divided into smaller and more frequent
doses, to avoid the high peak plasma levels involved with
peak-dose dyskinesias. Novel delivery strategies, including
continuous intestinal infusion of levodopa gel (duodopa)
are increasingly utilized to smooth out motor fluctuations
(Fernandez et al., 2013). In addition, further analysis of data
from the Stalevo Reduction in Dyskinesia Evaluation in
Parkinson’s disease (STRIDE-PD) study showed that risk of
dyskinesia or wearing off increased with higher levodopa
dosages (Olanow et al., 2013). Addition of amantadine may
be beneficial for control of dyskinesia (Verhagen Metman
et al., 1998; Pereira da Silva-Junior et al., 2005). Anticholin-
ergics such as trihexyphenidyl historically were used for the
treatment of PD prior to the development of levodopa, but
these drugs are used only rarely today, as they effectively
treat only tremor and are associated with a variety of cogni-
tive, urinary, and other side effects (Pearce, 1989).
Tremor-dominant subtype of PD may benefit from uti-
lizing additional medications that have been traditionally
used to treat ET, including beta-blockers, topiramate, and
zonisamide. As mentioned earlier, potential worsening
of cognitive status may occur. Higher doses of levodopa
may be needed for this subtype as well. See Figure 12.5 for
a summary of therapeutic approaches to PD.
PARKINSON'S DISEASE
Therapeutic Strategies
Behavioral
Motor
Cognitive
MAO inhibitors Quetiapine for
initially hallucinations and
(rasagiline) psychosis
Clozapine for
Dopamine
hallucinations and
agonists
psychosis
Acetylcholinesterase
Levodopa inhibitors for cognitive
and memory issues
Figure 12.5 Treatment algorithm in PD.
PIGD subtype patients need assistive devices earlier in
the course of PD. Frequent falls are a source of morbid-
ity, resulting in hospitalizations and associated complica-
tions, as well as admission to assisted living facilities.
For patients with PD who exhibit AF-PD, treatment of
OH is an important consideration. Orthostasis may be
improved with pressure support stockings, increased fluid
intake, and medications such as midodrine and fludrocor-
tisone. L-threo-dihydroxyphenylserine (droxidopa) is cur-
rently being tested for treatment of OH. A potential side
effect of these medications is supine hypertension, which
may necessitate sleeping in a position with the patient’s
head elevated.
Hallucinations can be controlled with dopamine-
blocking agents. The challenge is to select an agent that
will least interfere with levodopa therapy. Clozapine, a
relatively specific D4 receptor antagonist, can effectively
control hallucinations in PD patients without causing
worsening of parkinsonian symptoms. Clozapine use is
limited by the requirement of weekly blood draws due
to risk of agranulocytosis (Jankovic, 2002). Quetiapine,
which blocks D1, D2, 5-HT1A, and 5-HT2 receptors, also
has a benefit on hallucinations in PD patients (Fernandez
and Friedman, 1999). Furthermore, pimavanserin, a selec-
tive serotonin 5-HT2A inverse agonist, has been shown in
phase 3 clinical trial to provide benefit to PD patients who
experience psychosis (Cummings et al., 2013).
Treatment of constipation includes typical over-the-
counter agents. Lubiprostone and linaclotide also may be
helpful for the treatment of constipation in PD patients.
Other Non-Motor Levodopa-Related
Symptoms Complications
Amantadine for
Melatonin for RBD
dyskinesias
Entacapone to
Clonazepam for RBD
reduce OFF time
Midodrine or
STN or GPi
fludrocortisone for
Deep brain
orthostatic
stimulation
hypotension

Depression is common with PD and can be treated with
selective serotonin reuptake inhibitors (SSRI) or tricyclic
antidepressants. SSRI may worsen tremor, which is a con-
sideration in tremor-dominant PD patients.
Rapid eye movement (REM) behavior disorder may
be treated with melatonin or benzodiazepines if dream-
enacting behavior becomes injurious to the patient or bed
companion (Aurora et al., 2010). Dihydropyridine L-type
calcium channel blockers that traverse the blood–brain
barrier have been shown to be potentially neuroprotective
(Ritz et al., 2010). Due to this potential effect, their use in
PD patients maybe preferred over other classes of antihy-
pertensive medication.
Symptomatic treatment for cognitive impairment due
to DLB or PDD includes cholinesterase inhibitors. Mod-
est efficacy in randomized, placebo-controlled, double-
blind studies has been demonstrated (Lippa et al., 2007;
Karantzoulis and Galvin, 2013).
Lesion surgery
The first lesion known to improve symptoms of PD was
accidental. Dr. Irving Cooper damaged the anterior cho-
roidal artery while performing aneurysm ligation in a PD
patient, leading to startling improvement in PD symp-
toms (Pearce, 1989).
Thalamotomy has been used to treat tremor with PD
(Jankovic et al., 1995). Pallidotomy has been found to
reduce rigidity (Bravo and Cooper, 1959) and levodopa-
induced dyskinesias, as well as improve motor function
overall in both ON and OFF states (Uitti et al., 1997). Simi-
lar to deep brain stimulation (DBS) surgery, pallidotomy
has been associated with declines in word generation
(Uitti et al., 1997). Due to the ability to make postproce-
dure adjustments with DBS, lesioning procedures have
been phased out in favor of DBS.
Deep brain stimulation
Surgical therapy using DBS is an important therapeutic
option for patients with motor fluctuations. Treatment
with DBS allows for reduced levodopa dosage, resulting
in lower expression of dyskinesias. The stable stimulation
provided by DBS helps with treatment of OFF symptoms,
such as gait freezing.
As DBS is a surgical procedure, anesthesia risk and risk
of hemorrhage, seizure, and infection exists. Potential com-
plications include worsening of cognitive status, including
declines in verbal memory, verbal fluency, timed transcrip-
tion, and word naming (York et al., 2008); worsening of
gait; and dysarthria (Kenney et al., 2007). For these reasons,
patients with lower cognitive scores on screening tests such
as the Montreal Cognitive Assessment (MOCA) test and
patients with significant balance disturbance due to non-PD
Parkinson’s Disease 321
reasons, such as lower extremity neuropathy or clinically
significant microvascular disease (especially in the pons),
are less likely to have an overall functional benefit from
DBS surgery. These effects may be related to the surgical
trajectory and electrode placement (York et al., 2009).
The primary targets for DBS in PD are the subthalamic
nucleus (STN) and pars interna of the globus pallidus (GPi)
(Johnson et al., 2008). Bilateral STN or GPi stimulation has
been shown to reduce “off” periods and reduce dyskinesia
(Obeso et al., 2001). Medication reduction plays a role in
reducing levodopa-induced dyskinesia after subthalamic
nucleus deep brain stimulation (STN DBS) surgery (Russ-
mann et al., 2004). In a case series of 277 implantation pro-
cedures, there were seven cases of intracranial hemorrhage,
two infections necessitating removal of electrodes, and four
cases of persistent neurologic deficit (Obeso et al., 2001). Bilat-
eral STN DBS surgery leads to symptomatic and functional
improvements measured on health-related quality of life
questionnaires, including independence from help, energy
level, controllability/fluidity of movement, and steadiness
when standing or walking (Ferrara et al., 2010). For patients
with levodopa-related motor complications, STN DBS leads
to improvements in the Unified Parkinson’s Disease Rating
Scale, Part III scores above best medical management (Deus-
chl et al., 2006). The pedunculopontine nucleus has also been
considered a possible target (Stefani et al., 2007). Thalamic
DBS has been reported to improve tremor in PD, but it is not
useful in treating other motor aspects of the disease (Ondo et
al., 1998). Hence, it is recommended to reserve thalamic DBS
for PD patients whose disability stems from high-amplitude
tremor (Ondo et al., 1998).
Future directions
James Parkinson had a poignant statement regarding the
disorder: “The unhappy sufferer has considered it as an
evil, from the domination of which he had no prospect
of escape” (Parkinson, 2002). In no less uncertain terms,
better disease-modifying therapies for PD are needed.
Research into these therapeutic modalities is hampered
by the lack of biomarkers both for presymptomatic diag-
nosis and for the following response to therapy. To this
end, the Michael J. Fox Foundation is currently enroll-
ing patients in the Parkinson’s Progression Markers Ini-
tiative (PPMI). Patients in this study and controls will
receive a functional dopamine transporter imaging scan
and will be monitored via serum and spinal fluid stud-
ies (Wu, et al., 2011). If successful, the study will allow
researchers to monitor biomarker response to emerging
therapies. The Longitudinal and Biomarker Study in PD
(LABS-PD) is another study designed to prospectively
measure the evolution of motor and nonmotor features of
PD and sample potential biomarkers (Ravina et al., 2009).
Elevated levels of alpha-synuclein oligomers, as well as
322 Neurologic Conditions in the Elderly
elevation in the oligomer to total alpha-synuclein ratio,
have recently been reported in a study with 32 cases and
28 controls (Tokuda et al., 2010). These findings may serve
as the basis of a future cerebrospinal fluid (CSF) test if
they can be reliably reproduced in larger series (Ballard
and Jones, 2010).
For a closer target timeframe, a new time-release for-
mulation of carbidopa/levodopa, IPX-066, is being
investigated for newly diagnosed PD patients, as well as
patients with motor fluctuations. Other agents, including
the MAO-B and glutamate inhibitor safinamide, are being
tested for these indications. (Schapira et al., 2013b). Ade-
nosine A2A receptor antagonists can control PD symptoms
via GABA and glutamate regulation (Pinna et al., 2013).
The question of how to best focus research resources
remains. Multiple subtypes of PD exist, each with a
potentially different response to a particular medication.
Most research efforts are dedicated to traditional patients
who are “levodopa responders,” but important informa-
tion might be gleaned from following patients who are
poorly levodopa responsive.
Patients who are identified as having scans without evi-
dence of dopaminergic deficit (SWEDDs) are an impor-
tant subgroup (Bajaj, et al., 2010). Although they may be
excluded from some trials, it is important to track them on
a larger scale, to learn more about the progression of their
symptoms as well as pathogenesis.
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 Chapter 12.2
Essential Tremor and Other
Tremor Disorders
Holly Shill
Introduction
Tremor is an involuntary, rhythmic, oscillatory movement
of a part or parts of the body. It is produced by alternating or
synchronous contractions of antagonist muscles (Figure 12.6).
Tremor can be recorded in virtually all normal individuals
through use of electromyography (EMG) and accelerometry.
The vast majority falls into the category of physiologic tremor
and is thought to be necessary for the production of volun-
tary movement (Elble and Randall, 1976; 1978). Only when
the tremor becomes enhanced, either through exaggeration
of this physiologic tremor or through a specific disease (such
as Parkinson’s disease [PD]) may it become bothersome and
warrant treatment. This chapter reviews characterization of
tremor and pathologic tremor conditions.
Clinical characterization of tremor
The patient should be examined in a variety of postures
and movements. Tremor is assessed in the head, neck,
limbs, and trunk. The circumstances in which the tremor
is more prominently seen and its frequency when com-
bined with the body part affected typically point to the
diagnosis. The following classification is useful in dis-
cussing tremors typically encountered in clinical practice.
• Resting tremor occurs in the absence of voluntary
movement and with the body part fully supported.
50.0
25.0
mV
0.0
–25.0
–50.0
Figure 12.6 Acclerometry of tremor showing sinusoidal
oscillations.
Resting tremor is most commonly seen in the upper ex-
tremity, but its presence or absence should also be not-
ed in the legs and the lip and/or jaw. Essential tremor
(ET) in the head/neck may cause a side-to-side (“no-
no”) head tremor, whereas PD in the head causes a lip
quiver or side-to-side jaw tremor. Resting tremor may
be brought out by concentration maneuvers such as
closing the eyes and counting backward from 100 by 7s.
Sometimes Parkinsonian rest tremor may be seen only
when the patient is asked to walk down the hallway
and the now-relaxed arm is noted to develop tremor at
the patient’s side.
• Postural tremor is tremor while voluntarily maintain-
ing posture against gravity. Usually this is assessed by
asking the patient to hold the arms extended in front. It
may also be assessed in the legs in the same manner while
sitting. Maintaining posture with the arms flexed and the
flattened hands approximating the chin, but not touching,
often brings out ET. Rubral tremor, or cerebellar outflow
tremor, may also be seen markedly in this position.
• Kinetic/action tremor is tremor that is seen during vol-
untary movement. Classically, it is examined by having
the patient do finger-to-nose testing or having the patient
run the heel of the foot up and down the opposite shin.
More functional assessment can also be done, such as
having the patient drink from a cup or use the hand to
write. Drawing an Archimedes spiral can bring out the
action tremor of ET (Figure 12.7).
Electrode: EMG4
0.0 250.0 500.0 750.0 1000.0 1250.0 1500.0 1750.0 2000.0
ms
325
326 Neurologic Conditions in the Elderly

Spirals Essential tremor

baseline
Figure 12.7 Archimedes spiral in a patient with ET.
• Task-specific tremor is kinetic tremor during specific,
skilled movement. This term is usually reserved for trem-
or that is brought out only in specific circumstances and is
not seen more generally. Primary writing tremor therefore
is a condition in which tremor is seen only with handwrit-
ing, but not with posture and finger-to-nose maneuvers.
• Orthostatic tremor is tremor of lower extremities or
trunk while standing in place. It is brought out by having
the patient stand without moving for a reasonable length
of time (usually about 1 minute). After a varying latency, a
buckling type movement of the legs is seen in place of trem-
or (Figure 12.8a). If one does an EMG of the muscle during
this leg buckling, high-frequency (13–16 Hz) tremor activ-
ity underlies this outward movement (Figure 12.8b). Ad-
ditionally, because this higher frequency may get into the
auditory range, the tremor may be appreciated through
the use of a stethoscope over the leg muscles.
(a) Electrode: El
15.0
12.5
10.0
V2
Classically, essential tremor (ET) refers to a monosymp-
tomatic tremor condition, most commonly a bilateral,
relatively symmetrical postural and kinetic tremor of the
hands. The term action tremor is often used, referring to
the presence of voluntary muscle activity required to see
the tremor. Guidelines for the diagnosis of ET have been
proposed (Deuschl et al., 1998) and include primary cri-
teria of bilateral action tremor of the hands and forearms,
absence of other neurologic signs (except cogwheel rigid-
ity), and/or head tremor without signs of abnormal pos-
ture (dystonia). Secondary criteria include long duration
(greater than 3 years), positive family history, and benefi-
cial response to alcohol. Red flags that prompt alternate
diagnoses include strictly or strongly unilateral tremor
(suggests Parkinsonism), sudden or rapid onset, and/or
current use of known tremorogenic drugs.
Epidemiologic studies support that ET is a relatively
common condition, and the prevalence goes up with
aging. Meta-analysis of population studies estimates that
it affects about 6.3% of people over 65 and as much as 21%
of those over 90 (Louis and Ferreira, 2010). In a movement
disorder clinic, 60% reported a positive family history of
tremor (Lou and Jankovic, 1991); that percentage is likely
quite a bit lower in a population-based study, particularly
if older age at onset. There is no gender predominance
and no apparent ethnic predisposition.
With time, it is accepted that many patients with long-
standing ET may have mild cerebellar features, such as
gait ataxia (Singer et al., 1994; Hubble et al., 1997). Hear-
ing loss might also be seen with ET, although conclusive
data is lacking (Ondo et al., 2003; Benito-Leon et al., 2007).

More recently, epidemiologic studies have suggested that

7.5
late-onset ET (older than 65 years old) may put a patient at
5.0
increased risk for dementia or cognitive decline (Benito-
2.5 Leon et al., 2006; Bermejo-Pareja et al., 2007). Whether this
0.0 is associated with typical ET, as just defined, or with a
0.0 5.0 10.0 15.0 20.0 25.0 30.0 younger age of onset is unclear. It has been suggested that
Hz ET-like tremor in the elderly may be the first symptom
(b) Electrode: EMG3 of a neurodegenerative disorder such as Alzheimer’s dis-
1000.0 ease (Elble et al., 2007).
The overlap of ET and PD is often discussed. Some
750.0 patients have both conditions in the family, suggesting
V2

some underlying genetic predisposition to both in rare

500.0
cases (Yahr et al., 2003; Spanaki and Plaitakis, 2009). Addi-
tionally, tremor-dominant PD may start as ET (Geraghty
250.0
et al., 1985; Minen and Louis, 2008). In a large Spanish
0.0 epidemiology study, the elderly with action tremor have a
0.0 5.0 10.0 15.0 20.0 25.0 30.0 relative risk of 3.47 of developing PD when followed over
Hz time (Benito-Leon et al., 2005). Although this risk seems
Figure 12.8 (a) The variable, mostly low-frequency spectral peaks high, it must be tempered by the fact that PD is relatively
seen on accelerometry of the leg during orthostatic tremor. (b) The uncommon, and many of the subjects in the study may
narrow 17 Hz spectral peak seen on EMG of the anterior tibialis not have had typical ET as defined in diagnostic crite-
during orthostatic tremor. ria. Specifically, the duration of tremor may have been as

short as 1 year. This suggests that the elderly with rela-
tively short-duration tremor should be followed closely
and not reassured too emphatically as to the benignity of
their tremor.
This link of ET with PD and dementia has led to a
proposal to redefine diagnostic criteria of ET into three
categories (Deuschl and Elble, 2009). First, the term
hereditary ET would be used for those who fulfill the
previous criteria for ET, have at least one affected fam-
ily member, and have onset before age 65. Sporadic ET
would be used for similar patients without a family his-
tory. Finally, senile ET would refer to those older than age
65 who may or may not have a family history. This latter
group may have more degenerative pathology, such as
parkinsonism. At this time, pending widespread accep-
tance of these categories, it seems prudent to be more cau-
tious with elderly-onset patients monitoring for cognitive
decline and parkinsonism.
Pathophysiology of essential tremor
The pathophysiology of ET has been extensively stud-
ied. Routine brain imaging is generally normal, although
magnetic resonance spectroscopy and blood flow imag-
ing have supported abnormalities in cerebellar circuitry
with overactivity in the cerebellar-thalamo-cortical
loop (Hallett and Dubinsky, 1993; Jenkins et al., 1993;
Pagan et al., 2003). Genetic studies have linked ET to
certain chromosomal loci in this often hereditary condi-
tion (Gulcher et al., 1997; Higgins et al., 1997), but pin-
ning down the genetic abnormality has proved elusive.
Polymophphisms in LINGO1 have been linked to ET in
genome-wide association studies (Stefansson et al., 2009),
although causative mutations have not yet been defined
in large ET families. Until recently, there were few neuro-
pathologic studies of patients with ET. Most early studies
have emphasized the lack of consistent brain pathology
in ET. The largest study done was in 20 patients with ET
followed in a movement disorder clinic in Saskatchewan,
Canada (Rajput et al., 2004). No consistent pathologic
abnormalities were found, unless the patient had addi-
tional features of PD (6/20). Another study was done in
11 patients as part of the Honolulu–Asia Aging Study
(Ross et al., 2004). Again, researchers found no consistent
pathology. Recently, two larger series of autopsied ET
patients demonstrated greater cerebellar pathology com-
pared with controls (Louis et al., 2007; Shill et al., 2008).
One of these studies also suggested a greater frequency
of Lewy body pathology restricted to the locus ceruleus
(Louis et al., 2007), but the second study failed to confirm
this finding (Shill et al., 2008), leaving the link between
PD and ET unclear pathologically. Given the imaging
and pathologic studies implicating the cerebellum, it is
likely involved in ET. However, whether it is primarily
Essential Tremor and Other Tremor Disorders 327
involved, indicating a slow neurodegenerative process,
or secondarily affected, as a consequence of longstand-
ing oscillation, is debated. Studies suggesting that the
cerebellar features such as gait ataxia and reduced eye-
blink condition can be improved by alcohol (Klebe et al.,
2005) and DBS (Kronenbuerger et al., 2008), respectively,
support that the cerebellar abnormalities may be partly a
functional consequence of longstanding tremor instead of
degenerative.
Treatment of tremor
Treatment of tremor disorders is a combination of medi-
cal, behavioral, and surgical interventions, guided by per-
sisting symptoms and underlying etiology in many, if not
most, patients.
Essential tremor
ET is one of the most common neurologic conditions and
is disabling for most patients who suffer from it (Busen-
bark et al., 1991; Koller et al., 1994; Brin and Koller, 1998).
Despite the high prevalence and associated impact on
quality of life, with the exception of thalamic deep brain
stimulation (DBS), no therapy has been developed and
approved specifically for this condition. The American
Academy of Neurology has developed practice param-
eters for the treatment of ET (Zesiewicz et al., 2005). The
most commonly used medications and the best studied
are primidone and propranolol.
• Primidone has been studied extensively, and many
studies support its efficacy (Koller and Royse, 1986; Sasso
et al., 1988). Dosing should start at 25–50 mg at bedtime
and increase every several weeks until the desired effect
has been reached or the dose reaches 250–350 mg. Patients
should be warned of the 25% potential for acute reactions
but reassured that this generally improves with time.
Long-term tolerability of primidone seems quite good,
and in the doses typically used for ET (<500 mg) (Sasso
et al., 1991), the incidence of side effects such as sedation,
imbalance, and cognitive changes makes it acceptable for
use in the elderly.
• Propranolol and other beta-blockers have also been well
studied, making them appropriate as first-line therapy for
ET (Cleeves and Findley, 1984; Cleeves and Findley, 1988).
Slow titration is key to achieving the typical effective dose
of propranolol in ET, which ranges from 240 mg to 320 mg
per day. Patients prefer long-acting preparations (Cleeves
and Findley, 1988). Reduction in tremor amplitude is sim-
ilar to primidone, around 40– 50%. Use of a beta-blocker
over primidone should be considered when there is con-
comitant need to treat both cardiovascular conditions and
ET. Relative contraindications for the use of beta-blockers
include congestive heart failure, bronchospastic condi-
tion, diabetes, and second- and third-degree AV heart
328 Neurologic Conditions in the Elderly
block. Side effects of beta-blockers include depression,
fatigue, and impotence.
• Gabapentin has established efficacy in the treat-
ment of epilepsy, as an add-on therapy, and neuropathic
pain, particularly postherpetic neuralgia. A total of 61
patients with ET have been studied in double-blind,
placebo-controlled studies (Pahwa et al., 1998; Gironell
et al., 1999; Ondo et al., 2000). The first study of 20 sub-
jects demonstrated little efficacy but good tolerability of
1800 mg over placebo using a crossover design assess-
ing clinical rating scale (Pahwa et al., 1998). A second 3
month crossover study of 25 subjects compared doses
of 1800 mg and 3600 mg with placebo and showed sig-
nificant improvement (absolute improvement of 3–40%
over baseline, p < 0.05) in the subjects’ global impres-
sions and activities of daily living scales (Ondo et al.,
2000). No additional benefit was gained in 3600 mg/
day over 1800 mg/day. Again, tolerability was fairly
good. A comparator study suggests that gabapentin 400
mg three times daily (TID) may have similar efficacy to
propranolol, given 40 mg TID (Gironell et al., 1999). The
drug also has some evidence to support its use in neu-
ropathic (Saverino et al., 2001) and orthostatic tremor
(Onofrj et al., 1998b; Rodrigues et al., 2005; Rodrigues
et al., 2006). Fifty percent of subjects in a much larger
postherpetic neuralgia studies were over age 75, and the
incidence of these side effects in these studies was only
modestly higher than in studies done in the younger ep-
ilepsy subjects. This fact, as well as the lack of significant
drug interaction or major organ toxicity, has made this
drug a particularly appealing consideration in the elder-
ly. The TID dosing regimen may present some problems
with patient compliance.
• Topiramate is approved for use in epilepsy and mi-
graine. Two of three double-blind, placebo-controlled tri-
als of topiramate in ET in a total of 245 subjects were posi-
tive (Onofrj et al., 1998b; Connor, 2002; Rodrigues et al.,
2005; Frima and Grunewald, 2006; Ondo et al., 2006; Ro-
drigues et al., 2006). The largest study, of 208 subjects,
showed significant improvement in subjective and ob-
jective measurements of tremor at a mean final dose of
292 mg/day (Ondo et al., 2006). Topiramate appears to
be efficacious at doses lower than those used to treat ap-
proved conditions, with studies suggesting benefit below
100 mg/day (Gatto et al., 2003; Ondo et al., 2006). In the
large double-blind study in ET (Ondo et al., 2006), titra-
tion was over 12 weeks, and the average age of subjects
was 61. Dose-limiting side effects were seen in 31.9% of
subjects, with the frequency of cognitive side effects be-
ing 13%. Therefore, those ET patients with advanced age
and/or baseline cognitive impairment may not be appro-
priate for topiramate. The 10–22% frequency of appetite
suppression and weight loss seen in most topiramate
studies and the risk of renal calculi suggest that it should
be used cautiously in frail ET patients.
• Pregabalin is indicated for use in painful diabetic neu-
ropathy, fibromyalgia, and postherpetic neuralgia, and as
adjunctive therapy for adults with partial complex sei-
zures. Two open-label case reports involve patients with
tremor responding to pregabalin (Zesiewicz et al., 2007b;
Alonso-Navarro et al., 2008). A double-blind, placebo-
controlled study of 22 subjects showed significant benefit
in reduction of tremor amplitude at a mean daily dose of
286.8 mg/day (Zesiewicz et al., 2007a). Side effects lead-
ing to dropout occurred in a third of ET subjects. Typical
side effects with pregabalin across studies include dizzi-
ness, sleepiness, dry mouth, and peripheral edema. Less
common side effects include weight gain, blurred vision,
and decreased visual acuity. Rare reports tell of angioede-
ma occurring. It is reasonable to consider using pregaba-
lin in those refractory patients, although additional data
regarding efficacy in ET is needed.
• Botulinum toxin, which works by temporarily denne-
rvating the neuromuscular junction, has been studied in
ET and, is among the movement disorders that may be
amenable to toxin injection (Simpson et al., 2008). An ini-
tial small open-label study of 14 subjects with ET demon-
strated that five had moderate to marked improvement,
supporting the need for additional clinical study (Trosch
and Pullman, 1994). An open-label study of 20 refractory
limb tremor patients showed improvement over baseline
in activities of daily living, tremor rating scores, and ac-
celeometry (Pacchetti et al., 2000). Therapy was tailored to
each subject, based on the pattern of muscle activity, with
a mean total dose of 95.5 units of botulinum toxin type A
(Dysport). Subjects had persistent significant tremor ben-
efit at 3 months, which had worn off by 5 months. A pla-
cebo-controlled study of 25 hand tremor subjects reported
at least mild to moderate improvement in tremor in 75%
with active treatment versus 27% with placebo (Jankovic
and Schwartz, 1991). A second study of 133 subjects us-
ing fixed doses of 50 or 100 units botulinum toxin (Botox)
compared with placebo into forearm wrist flexors and
extensors showed significant improvement in postural
tremor from 4 to 16 weeks after treatment, as measured
by clinical rating scale, but only modestly improved ki-
netic tremor and ADLs (Brin et al., 2001). This decreased
relevant efficacy (kinetic tremor), along with problematic
hand weakness as a side effect, makes consideration of
botulinum toxin in the limb a consideration only for more
refractory and disabled subjects.
Botulinum toxin may be particularly useful for subjects
with intractable head and/or voice tremor, as these symp-
toms typically result from fewer overactive muscles and
may be appropriate for the very focal therapy that the neu-
rotoxin provides. Forty-three subjects with head tremor
underwent open-label injection with botulinum toxin
type A (Dysport) into the bilateral splenius capitus mus-
cles (Wissel et al., 1997). All subjects with isolated head
tremor without dystonia (N = 14) improved over baseline

in terms of clinical rating scales and accelerometry. Toler-
ability is generally good, making this a reasonable option
for disabling head tremor. Studies botulinum toxin injec-
tion in vocal tremor have shown efficacy (Warrick et al.,
2000; Adler et al., 2004). Main adverse effects reported
were breathiness (11/13) and dysphagia (3/13).
DBS of the Vim nucleus of the thalamus should be con-
sidered in drug-refractory ET patients who are appropri-
ate surgical candidates. Significant benefit to tremor is
seen in 70–100% of patients (Blond et al., 1992; Benabid
et al., 1996; Koller et al., 1997) and is clearly more effica-
cious than best medical therapy in these more advanced
patients. Acute side effects related to surgery primarily
include the potential for symptomatic intracranial hem-
orrhage. Long-term hardware complications are possi-
ble, including fracturing of lead, cutaneous erosion, and
infection. Side effects related to stimulation itself include
imbalance and dysarthria, at times compromising near-
perfect tremor control. Battery replacement is necessary
for the device and needs to be performed at least every 2
years for those with high stimulation parameters and up
to every 9 years for those with rechargeable devices.
Unilateral thalamotomy was often done prior to DBS
but is rarely done anymore. It may still be considered for
patients who might live remotely or who might be at high
risk for hardware complications.
Parkinsonian tremor
Although this chapter is not meant to provide extensive
review of the treatment of PD, the treatment of prominent
tremor in the setting of PD is worthy of mention. Tremor-
dominant PD may respond incompletely or not at all to
levodopa therapy, leading the clinician to believe that the
patient does not have typical PD. Dopamine agonist seem
better at suppressing tremor, particularly postural tremor,
than levodopa (Koller et al., 1989). However, patients may
require higher doses than one might typically use in early
PD (Pogarell et al., 2002; Schrag et al., 2002). Anticholin-
ergics can be useful, as it seems that some patients can
respond to them rather than typical dopaminergic therapy
in early disease (Koller, 1986). Amantadine might be tried,
although significant data behind its use in PD tremor is
lacking. Clozapine has been studied in PD tremor and can
be effective, even in those who have failed other thera-
pies (Jansen, 1994), but its use is limited by the potential
side effect of agranulocytosis and the consequent need
for periodic blood monitoring. DBS of the subthalamic
nucleus is quite effective in treating drug-resistant PD
tremor (Krack et al., 1998).
Primary writing tremor
This is a relatively rare condition, and the term is reserved
for tremor that occurs only with writing (type A) or with
the posture of writing (type B). Debate surrounds whether
it is a variant of ET, dystonia, or its own condition.
Essential Tremor and Other Tremor Disorders 329
Phyisologic assessment indicates that it is mostly ET like,
although some cases have agonist/antagonist muscle
contraction typical of dystonia. Treatment can be ET med-
ication, potentially trihexyphenidyl or botulinum toxin
(Papapetropoulos and Singer, 2006). Other task-specific
tremors such as those seen in skilled professionals (golf-
ers, musicians) would be considered similarly (McDaniel
et al., 1989).
Orthostatic tremor
Patients with orthostatic tremor disorder often present
with a chief complaint of unsteadiness with standing
that typically improves with walking (Heilman, 1984).
The legs can be noted to give way, with frequent buck-
ling seen despite absence of true weakness on confronta-
tional testing. The unusual appearance can sometimes be
misdiagnosed as psychogenic. EMG administered while
standing is crucial for the diagnosis, documenting the
typical 13–18 Hz frequency not seen in any other tremor
condition. The tremor is considered central in origin, as it
is highly coherent through the limbs and trunk (Thomp-
son et al., 1986). Primary pathophysiology has not been
elucidated. Treatment of orthostatic tremor is clonazepam
(Heilman, 1984) or gabapentin (Evidente et al., 1998; Ono-
frj et al., 1998b).
Drug-induced tremor
A variety of drugs can cause tremor (Table 12.1). Mostly,
these tremors are enhanced physiologic tremor and clini-
cally may look indistinguishable from early ET. This is
particularly true with tremor due to adrenergic stimula-
tion, such as bronchodiators and caffeine. Some drug-
induced tremors are centrally mediated. This includes
tremors due to dopamine receptor blocking agents such
as neuroleptics or antiemetics. Lithium, cocaine, metham-
phetamines, and withdrawal state (alcohol, benzodiaz-
epines) are also likely centrally mediated.
Valproate is particularly interesting, as it can cause an
action tremor that occurs shortly after starting the drug in
about 10% of patients (Karas et al., 1982), but it also may
rarely cause reversible parkinsonism after some time on
the drug (Onofrj et al., 1998a; Shill and Fife, 2000). Amio-
darone seems to have a similar clinical spectrum, causing
Table 12.1 Drugs that may cause tremor
Caffeine Tamoxifen Tricyclic antidepressants
Bronchodilators Antiemetics Tacrolimus
Valproic acid Neuroleptics Cyclosporine
Amiodarone Reserpine Mexilitine
Lithium Tertrabenazine Cocaine
Methylxanthines Tocainide Methamphetamine
Bronchodilators Levetiracetam
Corticosteroids Thyroid hormone
330 Neurologic Conditions in the Elderly
both tremor and parkinsonism, and can also cause neu-
ropathy (Werner and Olanow, 1989; Orr and Ahlskog,
2009).
Treatment of disabling drug-induced tremor is mostly
aimed at reducing or stopping the offending agent. Some-
times, however, that is not possible when the drug is being
used for potentially life-threatening or very disabling
conditions like schizophrenia (for example, neuroleptics)
or immune suppression after transplant (for example,
tacrolimus). The parkinsonian effect of neuroleptics is
often partially blocked by anticholinergic agents such as
trihexyphenidyl or benztropine but does not respond to
beta-blockers (Metzer et al., 1993). Valproate tremors may
respond to beta-blockers but not to amantadine or benz-
tropine (Karas et al., 1983). Lithium tremor may respond
to beta-blockers (Gelenberg and Jefferson, 1995).
Cerebellar tremor
Cerebellar tremor is typically seen in the setting of a struc-
tural process involving the cerebellar outflow tracks in the
upper brain stem. Vascular, traumatic, and demyelinating
processes are the most common. The tremor is generally a
slow frequency of 2–3 Hz and is exacerbated with action
(intention tremor) and the hand approximating the mouth
in the wing-beating position. Tremor in multiple sclerosis
is often treated similar to ET (Koch et al., 2007). Studies
using serotonergic agents have failed to yield results in
double-blind studies (Bier et al., 2003). Thalamic DBS for
refractory cerebellar outflow tremor can be considered,
but the responses may be less robust than with ET (Koch
et al., 2007; Schuurman et al., 2008; Torres et al., 2010).
Neuropathic tremor
Tremor is not uncommon in both acquired and heredi-
tary neuropathy, particularly demyelinating (Yeung et al.,
1991; Cardoso and Jankovic, 1993; Dalakas et al., 1984).
They can be clinically indistinguishable from ET. Specific
treatments have not been recommended; typically ET
treatments are used.
Psychogenic tremor
Psychogenic tremor is rarely seen in the elderly but is pre-
sented here for completeness (Koller et al., 1989; Shill and
Gerber, 2006; Kenney et al., 2007). This diagnosis should
be considered in a patient, often female, presenting with
an abrupt and often dramatic onset of symptoms. Sev-
eral features allow one to distinguish psychogenic from
organic tremor. The tremor often reduces in amplitude
or disappears with distraction. The fingers are generally
not involved, as they commonly are with ET and PD. The
patients may have a “coactivation sign,” which is a tens-
ing of the muscle felt with passive range of motion of the
limb. Multiple somatizations and other false neurologic
signs often are present (give-way weakness, hemisensory
loss, pseudobradykinesia).
Treatment of psychogenic illness is difficult, evi-
denced by persisting symptoms in many, if not most,
patients (Feinstein et al., 2001; Thomas et al., 2006).
Informing the patient promptly of the diagnosis is par-
amount, as a short duration of symptoms seems to be
the best prognostic indicator. Treatment is a combina-
tion of rehabilitation strategies combined with ongoing
psychiatric and psychological therapy (Thomas and
Jankovic, 2004).
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 Chapter 12.3
Progressive Supranuclear Palsy
Virgilio Gerald H. Evidente
History
In 1955, J. Clifford Richardson, a neurologist at Toronto
General Hospital, was consulted by a 52-year-old friend
for clumsiness, difficulties with vision, and mild forget-
fulness, which progressed to a constellation of signs,
including vertical supranuclear ophthalmoplegia, pseu-
dobulbar palsy, dysarthria, dystonic neck extension, and
mild dementia (Williams et al., 2008). He later observed
similar evolution of ocular, motor, and mental symptoms
in six more individuals. By early 1960s, seven of them had
died and were initially given a neuropathologic diagnosis
of postencephalitic parkinsonism (PEP). However, Rich-
ardson disagreed with their impression, as none of them
had preceding encephalitis. In 1962, Richardson asked
neurology resident John Steele and neuropathologist Jerzy
Olszewski to assist him in reevaluating the pathology of
the seven intriguing cases. Over the next year, Steele and
Olzewski described the anatomy and histopathology of
the disease in seven cases and the detailed localization
of lesions in four of them. Richardson presented the first
clinical report of progressive supranuclear palsy (PSP)
at the June 1963 meeting of the American Neurological
Association in Atlantic City. In the same year, Olszewski
presented the neuropathology at the American Associa-
tion of Neuropathology. In their 1963 reports, Richardson,
Olszewski, and Steele initially called the condition hetero-
geneous system degeneration. Later that year, Richardson
proposed calling it PSP. In Europe, however, it was
referred to as Steele–Richardson–Olszewski syndrome. In
April 1964, the initial publication of PSP reporting nine
patients, seven of whom had died, was published in the
Archives of Neurology (Steele et al., 1964).
Epidemiology
Few studies have looked specifically at establishing the
prevalence of PSP. Earlier reports showed a relatively low
prevalence, though more recent studies yielded higher
estimates. Golbe, et al., conducted a study in New Jer-
sey and reported a crude prevalence of 1.39 per 100,000 in
1988 (Golbe et al., 1988). Schrag et al. conducted a similar
study in London and reported an age-adjusted preva-
lence of 6.4 per 100,000 in 1999 (Schrag et al., 1999). Nath
et al. conducted a study in Newcastle-upon-Tyne and
reported a crude and age-adjusted prevalence of 6.5 per
100,000 in 2001 (Nath et al., 2001). Bower and colleagues
performed an incidence study of PSP and other parkin-
sonian syndromes in Olmsted County, Minnesota, from
1976 to 1990 and found a crude incidence rate of PSP of
1.1 per 100,000 per year (Bower et al., 1997). This increased
exponentially from 1.7 cases per 100,000 per year at ages
50–59, to 14.7 per 100,000 per year at ages 80–99. PSP is esti-
mated to be around 10% of the incidence of Parkinson’s dis-
ease (PD) (Bower et al., 1999). Its peak onset is at age 63, and
no cases have been reported before the age of 40. In a large
autopsy series of the Society for Progressive Supranuclear
Palsy brain bank, the average age at death was 75 ± 8 years,
and the average duration of disease was around 7 years
(usually less than 10 years) (Dickson et al., 2007). There were
slightly more men than women with PSP (M:F = 227:195).
Clinical presentation
The clinical hallmarks of PSP are supranuclear vertical
gaze palsy, pseudobulbar palsy, axial rigidity, and cogni-
tive impairment. In 1996, the National Institute of Neu-
rological Disorders and Stroke (NINDS) and the Society
for PSP (SPSP) sponsored an international workshop to
improve the specificity and sensitivity of the clinical diag-
nosis of PSP (Litvan et al., 1996a). The National Institute
of Neurological Disorders and Stroke-Society of Progres-
sive Supranuclear Palsy (NINDS-SPSP) clinical criteria
classified cases into three categories: possible, probable,
and definite PSP (Table 12.2).
The NINDS-SPSP criteria for probable PSP are highly
specific (100%) but are only 50% sensitive, whereas the crite-
ria for possible PSP are 83% sensitive but only 93% specific.
Nath and colleagues described the clinical features
and prognostic predictors of PSP in 187 cases (Nath et al.,
2003). The most common clinical features were verti-
cal supranuclear gaze palsy (94%), bradykinesia (91%),
falls (87%), postural instability (80%), speech problems
(74%), dysphagia (60%), increased axial tone/retrocollis
(53%), apathy (50%), diplopia/blurred vision (39%), fron-
tal release signs (31%), tremor (21%), photophobia (20%),
eyelid apraxia (17%), need for gastrostomy tube (9%), limb
dystonia (7%), word-finding difficulty (7%), and slow or
hypometric saccades (6%). On examining the symptoms
at onset, it was noted that 69% had mobility problems
(unsteadiness or slowness/weakness of legs), 15% had
cognitive problems (memory impairment, personality
333
334 Neurologic Conditions in the Elderly

Table 12.2 NINDS-SPSP clinical criteria for possible, probable, and definite PSP

Category of PSP Mandatory inclusion criteria Mandatory exclusion criteria Supportive criteria

Possible Gradually progressive Recent encephalitis Symmetric rigidity or bradykinesia,

Onset at 40 years or older Alien limb syndrome, cortical sensory proximal more than distal

Either vertical (upward or downward) deficits, focal frontal or temporoparietal Retrocollis or other cervical dystonias
supranuclear gaze palsy or both slowing atrophy Poor or absent response of
of vertical saccades and prominent postural Hallucinations or delusions parkinsonism to levodopa
instability within 1 year of onset (nonmedication-related) Early onset of dysarthria and dysphagia
No exclusion criteria Alzheimer’s type of cortical dementia Early onset of cognitive impairment in
Probable Gradually progressive (severe amnesia, aphasia, or agnosia) at least two of the following domains:
Onset at 40 years or older Prominent early cerebellar or autonomic apathy, impaired abstract thinking,
Vertical (upward or downward) supranuclear dysfunction (such as severe urinary decreased verbal fluency, utilization or
gaze palsy and prominent postural instability disturbance or orthostastic hypotension) imitation behavior, or frontal release
within one year of onset Severe, asymmetric parkinsonian signs signs

No exclusion criteria (such as bradykinesia)

Definite Clinically possible or probable PSP with Neuroradiologic structural abnormality
histopathology typical of PSP Whipple’s disease

change, depression, anxiety, apathy, or word-finding dif- the righting reflexes, thus making them fall en bloc like a
ficulties), 14% had bulbar/language problems (speech or toppling tree. When they sit from a standing position, they
swallowing abnormities, reduced speech output, palila- often “plop” into their chair en bloc, with a tendency for
lia/echolalia, or dysphonia), 12% had visual problems their feet to be above the floor at the moment their but-
(blurred vision or diplopia), and 13% had a tremor. The tocks hit the chair. Some patients may develop some ataxia
median latency to development of falls in PSP was less due to pathologic involvement of the cerebellum. Corti-
than 1 year from onset, while speech problems developed cospinal tract signs may also be present, including limb
within a median latency of nearly 2 years and swallowing weakness, spasticity, hyperreflexia, and Babinski sign.
difficulties developed within a median latency of 4 years. Cranial nerve examination reveals facial hypomimia,
The vertical gaze palsy is one of the most important reduced blinking (often with a fixed stare), blepharospasm,
symptoms of PSP and usually develops early in the course. or apraxia of eyelid opening. Patients may have a “wor-
A preserved vestibulo-ocular reflex supports the “supra- ried look” or the “procerus sign,” with vertical wrinkles
nuclear” nature of the vertical gaze palsy. Down gaze is in the glabellar region and bridge of the nose, resulting
usually affected before up gaze, whereas horizontal eye from hypertrophy or dystonia of the procerus, corruga-
movements are usually preserved except maybe late in tor muscles, and orbicularis oculi (Romano and Colosimo,
the course (Litvan et al., 1996, Verny et al., 1996). Because 2001) (Figure 12.10). Some may have a “startled look” due
of the difficulty looking down at their plate while eating,
patients often are “messy” eaters. Saccadic velocity is pro-
gressively reduced, such that, in the later stages, the eyes
tend to follow the head as it turns. PSP patients also exhibit
frequent small, paired, horizontal saccadic intrusions dur-
ing fixation (macro-square wave jerks) (Rivaud-Péchoux
et al., 2000). Bilateral internuclear ophthalmoplegia has
also been described in PSP (Flint and Williams, 2005).
The motor symptoms in PSP include shuffling gait, bra-
dykinesia (usually symmetric), hypertonia (axial more
than limb), dystonia (usually retrocollis or truncal exten-
sion; see Figure 12.9), and loss of fine and later gross motor
skills. Tremor, if present, is fine, bilateral, and postural in
the majority. The classic PD medium frequency resting
tremor is atypical for PSP (Quinn, 1997). Both limb apraxia
(difficulty performing simple motor tasks or fine finger
movements) and ideomotor apraxia (difficulty executing
familiar tasks, requiring a sequence of steps) are seen in
PSP patients. Some exhibit gait apraxia, which can lead to
falls. Once they start falling, they are not able to engage Figure 12.9 Patient with PSP with axial hypertonia and retrocollis.

to retraction of the upper eyelids and hypertrophy of the
frontalis muscles; rarely, patients may have dystonia of
the mimetic muscles, resulting in risus sardonicus. Hypo-
phonia is often observed early, with a pseudobulbar speech
developing later. Sialorrhea and swallowing difficulties
may develop early, and the gag reflex is often increased.
Schmidt and colleagues observed that PSP patients exhibit
pathologically decreased pupil diameters in darkness and
that a cutoff of 3.99 mm could differentiate PSP patients
from other parkinsonian syndromes (Schmidt et al., 2007).
Their findings, however, remain to be duplicated.
In 103 consecutive pathologically confirmed PSP cases,
Williams and colleagues observed two clinical phenotypes
of PSP: Richardson’s syndrome (RS) and PSP-parkinsonism
(PSP-P) (Williams et al., 2005). RS made up 54% of all cases
and was characterized by early onset of postural instability
and falls, supranuclear gaze palsy, and cognitive impair-
ment. The PSP-P phenotype comprised 32% of cases and
was characterized by asymmetric onset, tremor, and a mod-
erate initial therapeutic response to levodopa. Patients with
PSP-P were frequently confused with PD. The rest (14%)
could not be separated into the two general phenotypes.
One variant, labeled PSP-pure akinesia with gait freezing
(PAGF), presents with early gait disturbance, micrographia,
hypophonia, and gait freezing (Williams et al., 2007b).
Another set of patients presents with progressive asymmet-
ric dystonia, apraxia, and cortical sensory loss very similar
to corticobasal degeneration (CBD) and has been termed
PSP-corticobasal syndrome (PSP-CBS) (Tsuboi et al., 2005).
Figure 12.10 Patient with PSP with the procerus sign, or “worried
look.”
Progressive Supranuclear Palsy 335
Finally, another rare variant of PSP presents primarily with
speech apraxia, the so-called PSP-progressive nonfluent
aphasia (PSP-PNFA) (Josephs et al., 2005).
Patients with PSP are usually more cognitively impaired
than PD patients in numerous cognitive domains, includ-
ing information processing speed and executive function
(Soliveri et al., 2000). Cognitive and behavioral distur-
bances are more frequent and severe in PSP, often pre-
senting with a frontal type of dementia (Cordato et al.,
2006). In the Folstein Mini–Mental Status Examination
(MMSE), errors are generally mild and restricted to recall
and attention in PD patients, whereas errors are noted in
all MMSE items in PSP patients. In addition, PSP patients
often present with reduced category fluency, naming,
learning, and visuospatial function (Cordato et al., 2006;
VanVoorst et al., 2008). Frontal behavioral deficits in PSP
become more common as the motor deficits worsen.
The “applause sign” (a tendency to initiate an auto-
matic program of applause when one is asked to clap
three times) is abnormal in PSP and helps differentiate
PSP from frontal or striatofrontal degenerative disease,
including frontotemporal dementia (FTD) or PD (Dubois
et al., 2005). In the three clap test, the patient is asked to
clap three times as quickly as possible after demonstra-
tion by the examiner. The performance is normal if he or
she claps only three times (score = 3), or abnormal when
he or she claps four times (score = 2), claps five to ten
times (score = 1), or is unable to stop clapping (score = 0).
Polysomnography on PSP patients reveals sleep dis-
turbance with a sleep efficiency of less than 50% in most
cases, increased rapid eye movement (REM) without ato-
nia, and REM behavior disorder (RBD) (Sixel-Döring et
al., 2009). Clinically significant RBD, however, is about
twice more common in synucleinopathies such as PD than
in PSP. Despite polysomnographic evidence of sleep dis-
turbance, PSP patients often do not verbalize subjective
sleep complaints, possibly due to altered self-perception
as part of their neuropsychological disease.
Differential diagnoses and atypical PSP
Clinically, PSP can be misdiagnosed as or present like PD,
multiple system atrophy (MSA), Alzheimer’s disease (AD),
dementia with Lewy bodies (DLB), CBD (Josephs and
Dickson, 2003), multi-infarct or vascular disease (Josephs
et al., 2002), Whipple’s disease (Averbuch-Heller et al.,
1999), neurosyphilis (Murialdo et al., 2000), familial FTD
(Miyamoto et al., 2001), progressive subcortical gliosis
(Will et al., 1988), progressive multifocal leukoencepha-
lopathy (Alafuzoff et al., 1999), or postencephalitic par-
kinsonism (Pramstaller et al., 1996). Individuals from the
island of Guam may present with clinical manifestations
of amyotrophic lateral sclerosis (ALS) or parkinsonism–
dementia complex (PDC) (Steele, 2005). The phenotypes of
336 Neurologic Conditions in the Elderly
Guamanian ALS–PDC include classic ALS (“lytico”), par-
kinsonism with dementia (“bodig”), parkinsonism without
dementia, PSP, CBD, and Marianas dementia. Those that
present like PSP have clinical features including parkin-
sonism, dementia, supranuclear gaze palsy and other ocu-
lomotor abnormalities, blepharospasm/apraxia of eyelid
opening, and extensor posturing. Guamanian ALS–PDC
was initially thought to be due to intake of flour products
made from seeds of the false sago palm Cycas micronesica,
which contains a neurotoxin rich in beta-N-methylamino-
L-alanine (BMAA). Several genetic studies have been
negative, including those that examined the tau gene.
The steady decline of its annual incidence since 1955 and
increasing age at onset implicates an environmental factor
that ceased many decades ago, perhaps in relation to events
of World War II. In the Caribbean island of Guadeloupe
in the French West Indies, cases of atypical parkinsonism
similar to PSP were described, presenting with symmetric
rigidity and bradykinesia, severe gait and balance prob-
lems, frontal lobe syndrome, and supranuclear gaze palsy
(Caparros-Lefebvre and Elbaz, 1999). The Guadeloupean
parkinsonism was noted to be potentially reversible when
the affected individuals stopped eating anonnaceous fruits
and drinking herbal teas. In the Kii peninsula of Japan, a
clinical syndrome similar to PSP is seen presenting with
atypical parkinsonism, dementia, motor neuron disease,
or a combination of the three phenotypes (Kuzuhara and
Kokubo, 2005). The initial symptom is usually a parkin-
sonian gait or hypobulia/amnesia, followed by akine-
sia, rigidity, occasional tremor, bradyphrenia, abulia and
amnesia, and, finally akinetic mutism. Familial clustering
and continuing morbidity suggest that genetic factors are
likely. On neuropathology, Guamanian ALS–PDC, ALS–
PDC of the Kii Peninsula, and Guadeloupean parkinson-
ism are tauopathies with features similar to PSP.
Of 180 cases of clinical PSP whose brains were exam-
ined in the Society of PSP Brain Bank, only 137 had PSP
on neuropathology, with the other 43 having other patho-
logic diagnoses (Josephs and Dickson, 2003). Of the mis-
diagnosed cases, 70% had CBD, MSA, and DLB. Tremor,
psychosis, early dementia, asymmetric findings, presence
of APOE ∈4, and absence of H1 tau haplotype were fea-
tures that predicted an alternative diagnosis.
We retrospectively reviewed the clinical records of all
pathologically confirmed cases of PSP in the Sun Health
Research Institute Brain and Body Donation Program from
1996 to 2007 (Evidente et al., 2007). Of 990 brain donor sub-
jects, 250 had autopsy by 2007, of which 19 cases fulfilled
the NINDS–SPSP criteria for PSP. Of those 19, only 4 (21%)
had a premortem diagnosis of PSP, while the other 68% had
other clinical diagnoses, including PD (4), PD with demen-
tia (4), parkinsonism with dementia (3), ET (1), ET + PD (1),
parkinsonism (1), and normal control (1). Thus, even among
specialists, the rate of misdiagnosis is quite high, given the
atypical presentations that PSP patients can present with.
A report in 2004 from the Queen Square Brain Bank for
Neurological Disorders noted that of 60 cases that were
clinically diagnosed as PSP on last assessment in life, only
47 (78%) had a diagnosis of PSP on pathology (Osaki et al.,
2004).
PD is by far the most commonly confused disorder with
PSP. Although PSP-P can be hard to differentiate from PD,
one study showed that certain features, such as visual hal-
lucinations, drug-induced dyskinesias, and autonomic
dysfunction, had a high positive predictive value and
specificity for Lewy body pathology/PD compared to
PSP-P (Williams and Lees, 2010). Another synucleinopa-
thy or Lewy body disorder, DLB, can be differentiated
clinically from PSP-P by the occurrence of early cognitive
decline and visual hallucinations (McKeith et al., 1996).
Although autonomic dysfunction is not a prominent
feature in PSP (Brefel-Courbon et al., 2000), there are a
significant number of patients with pathologic PSP that
can be misdiagnosed as MSA premortem. In particular,
on autonomic testing and administering semiquantitative
anamnesis questionnaires, parasympathetic cardiovascu-
lar abnormalities can be prominent in PSP, even to a simi-
lar extent as in PD (Schmidt et al., 2008). In contrast, sym-
pathetic dysfunction is more frequent and more severe in
PD than in PSP patients.
Table 12.3 outlines some of the key clinical features that
help differentiate PSP from other parkinsonian syndromes.
Table 12.3 Clinical features of PSP that distinguish it from other
causes of parkinsonism
Differential diagnosis Distinguishing features
Parkinson’s disease (PD) Unlike PD, PSP usually presents with
early onset of falls within the first year
of onset, vertical supranuclear gaze
palsy, axial rigidity and dystonia, and poor
response to levodopa. Resting tremor is
rare in PSP and common in PD.
Multiple system atrophy Dysautonomia (especially orthostatic
(MSA) hypotension) usually is absent in PSP
and is prominent in MSA.
Dementia with Lewy Hallucinations, early onset of dementia,
bodies (DLB) REM behavior disorder (RBD), and
dysautonomia are key features of DLB
and are uncommon in PSP.
Corticobasal degeneration Limb apraxia, alien limb phenomenon,
(CBD) and cortical sensory signs are common
in CBD and rare in PSP. CBD usually
presents with limb dystonia, while PSP
often presents with axial dystonia.
Vascular parkinsonism Vascular parkinsonism usually
(VP) presents with a stepwise worsening,
whereas PSP is slowly progressive.
Parkinsonism is usually lower body in
distribution in VP and generalized in PSP.
Neuroimaging shows strokes/prominent
ischemic vascular changes in the brain
in VP but not in PSP.
 Progressive Supranuclear Palsy 337

Neuropathology

Macroscopic pathology
Although the overall brain weight of PSP patients is
within normal limits, gross examination of the PSP
brains often shows distinct features (Dickson, 2008).
Atrophy may involve the precentral gyrus, midbrain
tectum, substantia nigra, pons, superior cerebel-
lar peduncle (SCP), and cerebellar dentate nucleus
(Figure 12.11 a–c). There may be dilatation of the third
ventricle and aqueduct of Sylvius. The substantia nigra
shows loss of pigment, while the subthalamic nucleus
and cerebellar dentate nucleus may appear gray due to
myelinated fiber loss.

Microscopic pathology
Neuronal loss, gliosis, and neurofibrillary tangles (NFTs)
affecting the basal ganglia, diencephalon, and brain-
stem are the typical microscopic findings in PSP (Dick-
son, 2008) (Figure 12.12). The brainstem regions most
affected are the globus pallidus, subthalamic nucleus,
substantia nigra, superior colliculi, periaqueductal
gray matter, oculomotor nuclei, locus ceruleus, pontine
nuclei, pontine tegmentum, vestibular nuclei, medul-
lary tegmentum, and inferior olives. The striatum and
thalamus also have some neuronal loss and gliosis, as
well as the basal nucleus of Meynert. The cerebellar den-
tate nucleus may show grumose degeneration, and the
dentatorubrothalamic pathway consistently shows fiber
loss. The spinal cord often shows neuronal inclusions in
the anterior horns, posterior horns, and intermediolat-
eral cell column.
Silver stains (such as Gallyas staining) or tau immu-
nostaining reveal NFTs in the affected areas. “Tufted
(a) (c)
(b)
Figure 12.11 Gross neuropathologic findings in a PSP patient
showing moderate gyral atrophy of the posterior frontal lobes,
paracentral gyrus, and mild to moderate atrophy of the mesial
temporal lobes. (a) Left convexity; (b) right convexity; (c) superior
view. Courtesy of Dr. Thomas Beach.
Figure 12.12 Gallyas staining of the substantia nigra in a patient
with PSP showing neurofibrillary tangles (NFTs). Courtesy of
Dr. Thomas Beach.
astrocytes” are a characteristic feature of PSP, most com-
monly in the motor cortex and striatum (Figure 12.13).
Oligodendroglial lesions called “coiled bodies” appear as
argyrophilic and tau-positive perinuclear fibers (Figure
12.14). Special stains demonstrate argyrophilic, tau-pos-
itive inclusions in both astrocytes and oligodendrocytes.
Electron microscopy reveals that the NFTs in PSP are com-
posed of 15-nm tau straight filaments.
Williams and colleagues aimed to quantify the patho-
logic burden and distribution in the various phenotypes
of PSP [0] (Williams et al., 2007a). They observed that
patients with RS had higher overall mean tau burden than
patients with PSP-P or PAFG. The higher the tau burden
scores, the more widespread the distribution. In fact,
PSP-P patients have been noted to have more restricted,
milder tau pathology, usually involving the subthalamic
nucleus, substantia nigra, and globus pallidus (Williams
et al., 2007a, Jellinger, 2008).
Josephs and colleagues examined the relationship of
disease duration to lesion burden severity in 97 cases with
pure PSP in the Society of PSP Brain Bank (2006). They
observed that as duration of illness increases, there is a
decrease in density of oligodendroglial tau pathology that
is independent of age, gender, APOE ∈4 genotype, Braak
stage, or MAPT H1 haplotype.
338 Neurologic Conditions in the Elderly
Figure 12.13 Gallyas staining of the putamen in a patient with PSP
showing a “tufted astrocyte” on microscopy. Courtesy of
Dr. Thomas Beach.
Biochemistry
Both AD and PSP have accumulation of abnormal tau,
though biochemical studies show differences (Dickson,
2008). In AD, the insoluble tau migrates as three major
bands (68, 64, and 60 kDa) on Western blots. In contrast,
in PSP, the abnormal tau migrates as two bands (68 and
64 kDa), corresponding to the accumulation of 4R tau
based on antibodies. Striatal dopamine levels are reduced
in PSP, though not in the same degree as in PD.
Figure 12.14 Gallyas staining of the frontal cortex in a patient with
PSP showing “coiled body” on microscopy. Courtesy of
Dr. Thomas Beach.
Mixed pathology
We retrospectively reviewed the clinical records of all
pathologically confirmed cases of PSP in the Sun Health
Research Institute Brain and Body Donation Program
from 1996 to 2006 and found 19 PSP cases. Of those, only
11 had pure PSP pathology, while there were 2 cases each
of PSP + PD, PSP + AD, and PSP + AD + DLB, and 1 case
each of PSP + DLB and PSP + PD + AD (Evidente et al.,
2007). Given that PSP primarily involves the elderly, it is
not surprising that some patients may have some degree
of Alzheimer-type pathology (ATP). In most cases, the AD
type of pathology is minor, but in some, it may be suffi-
cient to warrant a diagnosis of concurrent AD. One study
found ATP in 69% of 32 PSP cases reviewed over a 17 year
period, with only 18.75% fulfilling the CERAD criteria for
definite or probable Alzheimer’s disease (Keith-Rokosh
and Ang, 2008). The risk factors for AD in the setting of
PSP are APOE ∈4 genotype, advanced age, and female
sex (Tsuboi et al., 2003). Lewy bodies can be detected in
about 10% of PSP cases, though the frequency is similar to
normal elderly controls (Tsuboi et al., 2001).
Incidental PSP
From the Sun Health Research Institute Brain and Body
Bank Donation program, we observed 5 cases with his-
tologic findings suggestive of PSP with no parkinsonism,
dementia, or movement disorder during life, and who did
not fulfill the clinical criteria of possible or probable PSP
(Evidente et al., 2011). These cases with “incidental PSP”
had a mean age at death of 88.9 years (range 80–94). We
compared the mean Gallyas-positive PSP features grad-
ing for tau for subjects with incidental PSP to those with
clinically manifest PSP. The mean Gallyas-positive PSP
features grading was significantly lower in incidental PSP
compared to clinical PSP cases. Thus, incidental PSP may
represent the early or presymptomatic stage of PSP and
presumably has very early disease.
Genetics
There are rare reports of familial PSP with an autosomal
dominant inheritance and reduced penetrance (Uitti et
al., 1999; Pastor and Tolosa, 2002). Mutations in the micro-
tubule associated protein tau (MAPT) gene have been
identified in patients with a clinical presentation of PSP
(Williams et al., 2007c, Morris et al., 2002). A family with
autosomal-dominant PSP was described to have linkage
to chromosome 1q31.1 (Ros et al., 2005). Only the MAPT
locus has been consistently associated with increased risk
for sporadic PSP (Baker et al., 1999). The MAPT locus
exists as two major haplotypes in European populations:
H1 and H2. Inheritance of two copies of the H1 haplotype
(H1/H1) is a major risk factor for PSP. A novel H2E’A
haplotype in chromosome 17q21 has been observed in

16% of PSP patients, but not in normal controls (Pastor
et al., 2004). Using a pooled genome-wide scan of 500,288
single-nucleotide polymorphisms, a major risk locus was
identified in chromosome 11p12-p11 (Melquiest et al.,
2007). Although there are some kindreds with LRRK2
mutations that present primarily with tau pathology simi-
lar to PSP, mutations in the LRRK2 gene have not been
found in a large series of pathologically confirmed PSP
(Ross et al., 2006). Progranulin (PRGN) gene mutations,
which are associated with FTD linked to chromosome 17
(Baker et al., 2006), have so far not been observed in PSP.
Diagnostic and functional imaging
Oba and colleagues compared cranial magnetic reso-
nance imaging (MRI) of 21 patients with PSP, 23 with PD,
25 with MSA, and 31 normal controls, and noted that the
average midbrain area in PSP (56 mm2) was significantly
smaller than PD (103 mm2) and MSA (97.2 mm2), com-
pared to normal controls (Oba et al., 2005). The authors
also proposed the “penguin silhouette” sign, which they
observed was present in all PSP patients on the midsagit-
tal MRI (Figure 12.15 a–c).
Paviour and colleagues examined the volume of the
SCP in 19 patients with clinical PSP, 10 with MSA, 12 with
PD, and 12 healthy controls, and observed that SCP atro-
phy differentiated PSP from other neurodegenerative dis-
orders and controls with a sensitivity of 74% and specific-
ity of 94% (Paviour et al., 2005).
(a) (b)
(c)
Figure 12.15 Cranial magnetic resonance imaging (MRI) showing
midbrain atrophy in a patient with PSP. (a) Axial MRI showing
atrophy of the midbrain. (b) Sagittal MRI showing atrophy of the
midbrain with the penguin silhouette sign. (c) Magnified view of
the penguin silhouette sign on sagittal MRI.
Progressive Supranuclear Palsy 339
Fluorodeoxyglucose positron emission tomography
(PET) scans of the brain have shown glucose hypometab-
olism in the midline frontal regions, brainstem, and cau-
date nucleus, and hypermetabolism in the cortical motor
areas, parietal cortex, and thalamus (Eckert et al., 2005).
Hypometabolism in the midbrain has been proposed to
be an early diagnostic sign in PSP (Mishina et al., 2004).
Brooks and colleagues examined cranial fluorodopa PET
scans in patients with PD, MSA, and PSP (Brooks et al.,
1990). Patients with PD showed significant reduced mean
uptake of 18F-dopa in the caudate and putamen compared
to controls, with the posterior putamen being severely
impaired (45% of normal) and the anterior Patients with
PSP and MSA had similar depression of mean 18F-dopa
uptake in the posterior putamen as in PD, though patients
with PSP showed equally severe impairment of mean
18F-dopa uptake in the anterior and posterior putamen.
Caudate 18F-dopa uptake was also significantly lower in
PSP than in PD patients.
Treatment
Symptomatic pharmacotherapy
A poor or absent response to levodopa has been pub-
lished as one of the diagnostic criteria for PSP, with
marked or prolonged levodopa benefit being a manda-
tory exclusion criterion (Litvan et al., 2003). Nevertheless,
patients with PSP may have some response to levodopa,
though usually not as robust or sustained as PD patients.
Lang noted an overall response rate to levodopa of 26%
in PSP (Lang 2005). Neiforth and Golbe reported that
38% of 87 PSP patients they retrospectively reviewed
benefited from levodopa (mean daily dose of 1015 mg),
with the improvement being minimal in 31% and mod-
erate in 6% (Nieforth and Golbe, 1993). Litvan, et al.,
documented good response (50–70%) in 2 of 15 patients
with PSP at the first visit after starting levodopa, though
the response was less than 1 year in one patient (Litvan
et al., 1996b). Collins, et al. reported a transient response
to levodopa in 2 of 10 patients with PSP at an average
daily dose of 807 mg (range 500–1500 mg/day) (Col-
lins et al., 1995). Williams, et al. noted that patients with
PSP-P had a moderate initial response to levodopa, while
those with Richardson syndrome were poorly responsive
to levodopa (Williams et al., 2005). Levodopa-induced
dyskinesias were noted in 4% of the 103 cases of PSP that
they described. Kompoliti, et al., reviewed the clinical
profile of 12 autopsy-confirmed PSP patients, 11 of whom
received levodopa at a mean dose of 500 mg/day (range
150–1200 mg/day) (Kompoliti et al., 1998). Improvement
was marked in one patient (60% improvement) and mod-
est in three others. Duration of effectivity was transient in
three and sustained for two years in the patient with an
initial marked response. The latter developed some facial
340 Neurologic Conditions in the Elderly
levodopa-induced dyskinesias toward the end of 2 years of
levodopa therapy. Seven patients were treated with dopa-
mine agonists (six with bromocriptine, one with piribedil);
only one patient had modest improvement. Five patients
received amantadine, with two demonstrating question-
able improvement of parkinsonism and neck dystonia.
Zolpidem, a GABA agonist of the benzodiazepine sub-
type receptor BZ1, which is highest in density in the inter-
nal pallidum, was found to improve motor function and
voluntary saccadic eye movements in ten PSP patients,
compared to placebo or levodopa (Daniele, 1999). Zolpi-
dem has also been reported to benefit dystonia in patients
suffering from X-linked dystonia-parkinsonism (“lubag”)
(Evidente, 2002), although its antidystonia effect in PSP
patients has not been studied.
Neuroprotective pharmacotherapy
Patients with PSP or MSA were randomized to either rilu-
zole or placebo in a double-blind, randomized trial last-
ing 36 months, with the primary endpoint of survival and
secondary efficacy outcome of rate of disease progression
as assessed by functional measures (Bensimon et al., 2009).
Riluzole in that study did not have a significant effect on
survival or rate of functional deterioration in PSP or MSA.
Coenzyme Q10 in combination with vitamin E at
1200 mg/day and 1200 units/day, respectively, has been
shown in a small study to possibly slow functional decline
in early PD (Shults et al., 2002). Coenzyme Q10 has been
observed to increase the ratio of high-energy phosphates
to low-energy phosphates on cranial magnetic resonance
spectroscopy in 21 PSP patients in a short 6 week trial,
with some slight but significant improvement in the PSP
rating scale (Stamelou et al., 2008). Its long-term effect,
especially as related to disease modification or neuropro-
tection, remains to be determined.
Surgery
One patient with possible PSP-P was reported to have
had bilateral STN-DBS, though she was initially diag-
nosed as having advanced PD with dyskinesias and off
periods (Bergmann and Salak, 2008). One year after DBS,
she developed symptoms often seen in PSP, including
emotional lability, marked worsening of balance, dystonic
facies, and oculomotor abnormalities (abnormal vergence,
pursuits, and saccades, and optokinetic nystagmus in the
downward vertical direction). Cranial MRI revealed mid-
brain atrophy suggestive of PSP. The patient continues to
be responsive to DBS 4 years post DBS.
Pedunculopontine nucleus (PPN) DBS has been
reported to potentially improve freezing of gait and cog-
nition in patients with PD (Stefani et al., 2007). Another
case report describes a 70-year-old man with PSP-P who
underwent unilateral PPN-DBS, though he did not mani-
fest any improvement of freezing of gait or cognition
(Brusa et al., 2009).
Three patients with PSP underwent DBS at Emory Uni-
versity in the 1990s, with no benefit noted (Lubarsky and
Juncos, 2008). One patient with PSP misdiagnosed as PD
at the time of DBS was reported to be unresponsive to
stimulation (Okun et al., 2005).
Prognosis
Nath et al. noted that worse survival is associated with older
age at disease onset, probable (as against possible) PSP,
early falls, speech and swallowing problems, percutaneous
gastrostomy tube insertion, and diplopia (Nath et al., 2003).
Longer survival is associated with the presence of a tremor
and a positive response to levodopa. An initial response to
levodopa was reported in 18% of cases. Pathologically con-
firmed PSP cases without a supranuclear gaze palsy during
life have a more prolonged clinical course. O’Sullivan et al.,
reported that male gender, older age at onset, short interval
from disease onset to reaching first clinical milestone, and
the Richardson phenotype were associated with shorter
disease duration to death (O’Sullivan et al., 2008).
Conclusions
Progressive supranuclear palsy is the second most com-
mon cause of parkinsonism, next to idiopathic PD, and is
the most common cause of atypical parkinsonism. Its clini-
cal hallmarks include parkinsonism, early onset of postural
instability and falls, supranuclear vertical gaze palsy and
other oculomotor abnormalities, axial rigidity or dystonia,
and pseudobulbar palsy (with dysarthria, dysphagia, and
emotional lability). Neuroimaging often shows midbrain
atrophy, especially in more advanced cases. Microscopic
pathology findings include neuronal loss, gliosis, and
NFTs affecting predominantly the basal ganglia, dienceph-
alon, and brainstem, with the nuclei most affected being
the globus pallidus, subthalamic nucleus, and substantia
nigra. Tau-positive astrocytes or processes help confirm
the diagnosis on silver staining or immunostaining for tau.
Other neuropathologic hallmarks include tufted astrocytes
and oligodendroglial coiled bodies. Treatment is largely
symptomatic, though often not very helpful. A subset of
PSP patients with predominant parkinsonism (PSP-P) may
exhibit some levodopa responsiveness, albeit temporary
and mild to moderate, at best. Neuroprotective drug trials
and DBS for PSP have so far yielded unsuccessful results.
Acknowledgment
The author wishes to thank Dr. Thomas Beach of the Cleo
Roberts Center for Clinical Research, Banner Sun Health
Research Institute, Sun City, Arizona, for furnishing the
neuropathology slides and pictures.

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 Chapter 12.4
Corticobasal Degeneration
Katrina Gwinn
Overview
Corticobasal degeneration (CBD) is a rare, progressive
neurodegenerative disease. It is characterized clinically
by dopamine-replacement refractory movement abnor-
malities and cortical dysfunction. Clinical diagnosis is dif-
ficult, as symptoms of CBD are similar to those of other,
much more common diseases, particularly Parkinson’s
disease (PD) and progressive supranuclear palsy (PSP).
Neuropathology is the “gold standard” of diagnosis, and
a definitive diagnosis of CBD is possible only after death.
The hallmark of CBD pathologically is neuronal loss and
atrophy of multiple areas of the brain, including the cere-
bral cortex and the basal ganglia, and tau pathology in
both gray and white matter.
CBD was first identified in 1968 by Rebeiz et al., who
evaluated three patients and described them as exhibiting
a disorder characterized by “severe impairment in control
of muscular movements, by abnormalities in posture and
by involuntary motor activity [el] [and with] mental facul-
ties [el] relatively spared until the end.” The original paper
named the disease corticodentatonigral degeneration with
neuronal achromasia; subsequent terms for this disorder
have included corticonigral degeneration with nuclear
achromasia and cortical basal ganglionic degeneration.
Epidemiology
Very little epidemiologic data exists regarding the inci-
dence or prevalence of CBD. Most of the literature is based
on case report series. It is estimated that CBD accounts for
4–6% of parkinsonism. A family history of the disorder is
rare in CBD, and it is believed sporadic. Age of onset is
typically in the seventh decade, with a mean age of onset
around age 63 years. Both men and women may present
with the disease. Although some believe there may be a
slight predominance in women, the data are too sparse to
definitively determine this currently. CBD leads to death
within approximately 8 years after presentation. Risk fac-
tors such as environmental exposures are not known.
Clinical features
Because CBD is rare and has many clinical similarities
to other neurodegenerative disorders, particularly PD
344
and PSP, it is often misdiagnosed, even by neurologists.
Cortical features can also cause CBD to be misdiagnosed
as Alzheimer’s disease (AD) or frontotemporal dementia
(FTD) (Wadia and Lang, 2007). A 1997 study by Litvan et al.,
showed extremely low sensitivity of the clinical diagnosis
of CBD by neurologists (48.3%, at best), with false negatives
being primarily diagnoses of PSP (Litvan et al., 1997). False
positives were uncommon. In that study, the best clinical
predictors of CBD were found to be limb dystonia, ideomo-
tor apraxia, myoclonus, and akinetic-rigid syndrome (par-
kinsonism), with late onset of gait or balance disturbances.
The initial symptoms of CBD are typically asymmetric
rigidity, bradykinesis, and dysmetria (Mahapatra et al.,
2004). It can present in either the arm or the leg. It is
almost invariably asymmetric at onset, though over the
course of the disease, CBD typically becomes bilateral
and affects both upper and lower extremities. Other
initial symptoms may include dysphasia or dysarthria.
Some patients may have memory or behavioral prob-
lems as the earliest or presenting symptoms, despite the
original description of the disorder, which stated that
cognitive dysfunction is rare until late in the disease
(Belfor et al., 2006).
Asymmetrical limb dystonia is seen in almost all
patients with CBD at some point in the course of the illness
and is often the presenting symptom (FitzGerald et al.,
2007). A clenched fist with the thumb adducted to the
palm is common. Dystonia in CBD can be painful. Sinu-
soidal tremor as seen in PD is not common, but tremor
due to dystonia or focal myoclonus is seen and mistaken
for the tremor of PD in some cases. However, dystonic
tremor is not regular and sinusoidal; unlike that of PD,
it is jerky and irregular. Myoclonus itself is often elicited
with a stimulus.
While the name CBD refers to the neuropathologic
features of the disease, there may be striking clinical
cortical features seen in this disorder that can be useful
in distinguishing it from PD and PSP (Scaravilli, Tolosa
and Ferrer, 2005). One of the most talked-about features
of CBD among phenomenologists, though not neces-
sarily always seen, is alien limb phenomenon (alien
hand syndrome). Alien limb phenomenon is believed
to be prevalent in roughly 60% of those people diag-
nosed with CBD. Alien limb phenomenon involves
difficulty controlling the movements of a limb, which
can seem to undertake movements on its own, or a feel-
ing that the limb is not one’s own or is not obeying the
 Corticobasal Degeneration 345

commands of the patient. The movements of the alien cations of a chronic neurodegenerative disorder, such as
limb are believed to be a reaction to external stimuli sepsis or pulmonary embolism.
and not to occur sporadically or without stimulation
(although they may be seen as an avoidance to stimuli).
Diagnostic testing
Like most of the movement disorders, alien limb phe-
nomenon presents asymmetrically in those diagnosed
The gold standard of diagnosis is neuropathologic. How-
with CBD. Mitgehen (continuous tactile pursuit), a sign
ever, ancillary studies can be helpful in ruling out other
of frontal dysfunction, can be observed on physical
disorders in the differential diagnosis and also help
examination (mitgehen means “to go with” in German).
enforce a clinical impression or presumptive diagnosis.
Semipurposeful or purposeful activities can occur in
Electrophysiologic studies, including an EEG (electro-
the alien limb (such as handling clothing or picking
encephalogram), may show changes in brain function
up items). While anecdotally this phenomenon can be
over time that are consistent with the neurodegeneration.
quite dramatic (the hand tries to “strangle” the patient,
However, EEG is not a common test in the evaluation of
for example), usually this is much less directed and is
CBD. No blood test is available for CBD. Urine, CSF, and
described as, “The hand won’t do what I want it to do.”
other laboratory tests are not diagnostic and typically
The hand may interfere with activities of the normal
normal.
hand. Additionally, sensory impairment as a result of
Magnetic resonance imaging (MRI) and single photon
cortical involvement may also be seen and may have
emission computed tomography (SPECT) in CBD can be
odd characteristics (itching, tingling, formication) char-
normal or nonspecific, particularly early in the disease.
acteristic of cortical sensory abnormalities.
Classically, because CBD is associated with cortical atro-
Ideomotor apraxia is an abnormality seen in CBD,
phy, one may see cortical atrophy on MRI and/or SPECT
as well as other disorders in which the patient has the
imaging. In those cases, MRI or SPECT of CBD typically
motor strength to perform a task but cannot do so;
shows asymmetric posterior parietal and frontal corti-
the patient is unable to translate an idea into motion
cal atrophy. Corpus callosum atrophy may also be seen
due to fronto-parietal abnormalities. There is no loss
(Koyama et al., 2007).
of the ability to perform an action automatically, but
Dopamine transporter imaging (DAT, Isoflurane
the action cannot be performed on request. Typi-
I123) scanning was recently approved by the FDA for
cally, the patient cannot imitate a meaningless task
the diagnosis of dopamine deficiency disorders; as the
or symbolic hand gesture. For example, when asked,
use of this imaging technique becomes widespread, it
the patient cannot show the doctor how to comb the
will be interesting to see its utility in evaluation of CBD
hair or brush the teeth. The patient may use the hand
versus other causes of parkinsonism. Other clinical
as a tool (instead of pretending to use a comb, using
tests or procedures that monitor the presence of dopa-
the hand across the top of the head) or make other
mine within the brain (β-CIT SPECT and IBZM SPECT)
errors in use (pretending to comb the mirror instead
may also be of future utility (Rizzo et al., 2008; Seritan
of the hair). The patient may have to look at the hand
et al., 2004).
to perform a task and, when not looking at the hand,
cannot do so. Ideomotor apraxia can also cause dif-
ficulty walking, including trouble initiating walking. Treatment
This can cause stumbling and difficulties in maintain-
ing balance. Some individuals with CBD exhibit limb- No treatment is available to slow the course of CBD,
kinetic apraxia, which involves dysfunction of more and the symptoms of the disease are generally resistant
fine motor movements often performed by the hands to therapy, including dopamine replacement therapy,
and fingers. as well as other anti-parkinsonian agents. Symptomatic
Aphasia in CBD is nonfluent, resulting in disrupted treatment may offer some benefit (Lang, 2005). Tremor
speech patterns and the omission of words. Individu- and myoclonus may be controlled somewhat with ben-
als with this symptom of CBD often lose the ability to zodiazepines. Benzodiazepines or baclofen may help
speak as the disease progresses (Gorno Tempini et al., reduce rigidity. Botulinum toxin injections may be help-
2004). ful to the dystonia. Physical therapy exercises may be
Cortical signs (formerly known as frontal release signs) useful to maintain range of motion of stiff joints. This
can be seen, including a grasp, suck, palmomental, and may prevent pain and contracture and help maintain
snout reflex. Psychiatric features may include depression, mobility. Occupational therapy may be used to design
agitation, irritability, or apathy. adaptive equipment that supports the activities of daily
While the disorder begins asymmetrically, it typically living, thus helping to maintain more functional inde-
“spreads” to involve both sides and all four extremities. pendence. Speech therapy is used to improve articulation
Death is generally caused by pneumonia or other compli- and volume (Hattori et al., 2003).
346 Neurologic Conditions in the Elderly
Neuropathology
Several brain regions are abnormal on postmortem patho-
logic examination in CBD. The cortex is severely affected,
especially frontal and parietal regions. The basal ganglia
are also affected, as the name suggests. Histologically,
astroglial inclusions are seen, as are astrocytic plaques,
especially in the frontal and premotor regions.
Like FTD and PSP, CBD has been found to be a tauopa-
thy; that is, CBD, like these other disorders, results from
the pathologic aggregation of tau protein (Forman et al.,
2002). The pathologic filamentous inclusions in CBD are
composed primarily of abnormally phosphorylated tau,
similar to many other sporadic and familial neurodegen-
erative diseases, such as AD, PSP, Pick’s disease, and FTD
with parkinsonism linked to chromosome 17 (FTDP-17),
collectively referred to as tauopathies (Komori, 1999). In
the central nervous system, six tau isoforms are produced
by alternative splicing. In AD, the filamentous tau aggre-
gates are composed of all six tau isoforms, but in CBD
and PSP, the aggregates are composed predominantly of
4-repeat (4R)-tau. The protein tau is an important micro-
tubule-associated protein (MAP) and is typically found in
neuronal axons. However, malfunctioning of the devel-
opment of the protein can result in unnatural, high-level
expression in astrocytes and glial cells. Astrocytic plaques
prominently noted in histologic CBD examinations.
Neuropathologic diagnostic criteria have been devel-
oped by Dickson and colleagues (2002). These include
core features of focal cortical neuronal loss, substantia
nigra neuronal loss, and cortical and striatal Gallyas/
tau-positive neuronal and glial lesions, especially astro-
cytic plaques and threads, in both white and gray matter.
Supportive features include cortical atrophy, ballooned
neurons, and tau-positive oligodendroglial coiled bod-
ies. It is hoped that these criteria will inform the evalu-
ation premortem as well, as they will allow reevaluation
of patients who meet these standards postmortem and
probably will widen our views regarding what the clini-
cal features of CBD can entail.
Summary
CBD is a rare yet underdiagnosed neurodegenerative
disease. It manifests with asymmetrical parkinsonism, as
well as other movement abnormalities, including myoc-
lonus and dystonia. It also has features of frontoparietal
cortical dysfunction. There are no currently meaningful
interventions for this disorder, and it is inexorably pro-
gressive, with death typically occurring within 8 years of
presentation. It has been found to be a tauopathy, along
with PSP and FTD, and it is hoped that research efforts in
this area will translate into meaningful therapies for the
tauopathies, including CBD.
References
Belfor, N., Amici, S., Boxer, A.L., et al. (2006) Clinical and neuro-
psychological features of corticobasal degeneration. Mech Ageing
Dev, 127: 203–207.
Dickson, D.W., Bergeron, C., Chin, S.S., et al. (2002) Office of Rare
Diseases neuropathologic criteria for corticobasal degeneration.
J Neuropathol Exp Neurol, 61: 935–946.
FitzGerald, D.B., Drago, V., Jeong, Y., et al. (2007) Asymmetri-
cal alien hands in corticobasal degeneration. Mov Disord, 22:
581–584.
Forman, M.S., Zhukareva, V., Bergaeron, C., et al. (2002) Signature
tau neuropathology in gray and white matter of corticobasal
degeneration. Am J Pathology, 160 (6): 2045–2053.
Gorno-Tempini, M.L., Murray, R.C., Rankin, K.P., et al. (2004) Clini-
cal, cognitive, and anatomical evolution from nonfluent progres-
sive aphasia to corticobasal syndrome: a case report. Neurocase,
10 (6): 426–436.
Hattori, M., Hashizume, Y., Yoshida, M., et al. (2003) Distribu-
tion of astrocytic plaques in the corticobasal degeneration brain
and comparison with tuft-shaped astrocytes in the progressive
supranuclear palsy brain. Acta Neuropathologica, 106: 143–149.
Komori, T. (1999) Tau-positive glial inclusions in progressive
supranuclear palsy, corticobasal degeneration, and Pick’s dis-
ease. Brain Pathol, 9: 663–679.
Koyama, M., Yagishita, A., Nakata, Y., et al. (2007) Imaging of cor-
ticobasal degeneration syndrome. Neuroradiology, 49: 905–912.
Lang, A.E. (2005) Treatment of progressive supranuclear palsy and
corticobasal degeneration. Movement Disord, 20: S83–S91.
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cal diagnosis of corticobasal degeneration: a clinicopathologic
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(2004) Corticobasal degeneration. Lancet Neurol, 3: 736–743.
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tatonigral Degeneration with Neuronal Achromasia. Arch Neu-
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 Chapter 13
Sleep Disorders
Sanford Auerbach
Departments of Neurology, Psychiatry and Behavioral Neurosciences, Boston University School of Medicine, Boston,
MA, USA

Summary
• The patterns of sleep in the elderly are determined by the complex effects normal aging has on the physiology of sleep,
as well as by their interaction with concurrent medical problems and the drugs used to treat them
• Sleep deprivation can cause anxiety, irritability, chronic fatigue, and difficulty performing tasks
• Aging is associated with a reduced tolerance of sleep loss but the subjects may either underestimate or overestimate
the amount of quality sleep they get

Introduction Overview of sleep

As in other fields of medicine, the study of sleep in the
aging population can be rather complex. First, one must
have a background in normal sleep and the disorders of
sleep. Then there is the question of understanding the
impact of normal aging. An additional challenge is ana-
lyzing the impact of the many medical problems that
affect the elderly and examining the interaction with
sleep.
Although an interest in sleep can be traced through-
out history, our current knowledge and approach is
quite dependent upon the description of the underly-
ing neurophysiology. In 1875, Caton first recorded the
brain electrical activity of animals (Caton, 1875), but it
was not until 1929 that Berger reported the electroen-
cephalogram (EEG) of man (Berger, 1929). Subsequently,
in 1937, Loomis described the EEG features of what is
now known as nonrapid eye movement (NREM) sleep
(Loomis et al., 1937). He described multiple levels of
NREM, with vertex waves, sleep spindles, K complexes,
and delta slowing. The next major breakthrough came in
1953 when Kleitman and Aserinsky described rapid eye
movement (REM) sleep and the proposed correlation
with dreaming (Aserinsky and Kleitman, 1953). Finally,
in 1957, Dement and Kleitman provided a description of
sleep cycles and a classification system of sleep stages
with four stages of NREM and REM (Dement and Kleit-
man, 1957). This system of description stood the test
of time until some recent modifications offered in 2007
by the American Academy of Sleep Medicine (AASM)
(Iber et al., 2007a).
Sleep is essential for normal human function. Wakeful-
ness (lack of sleepiness), vigilance, and performance on
monotonous tasks deteriorate after a single sleepless
night. Further sleep deprivation leads to more inattentive-
ness and performance failure. Lack of REM sleep is asso-
ciated with anxiety and excitability, as well as difficulty
with concentration and memory. Those deprived of slow-
wave sleep (SWS) generally report chronic fatigue, aches,
stiffness, uneasiness, and withdrawal. “Sleep need” is dif-
ficult to define but usually is accepted as the amount of
sleep required for optimal function during wakeful peri-
ods. Sleep need may vary from one individual to the next
ranging from 3 to 10 hours of sleep over a 24-hour period
(Williams et al., 1970). These principles apply to sleep
that is not interrupted by specific sleep pathology, such
as sleep apnea or periodic limb movements. The relation-
ship of subjective to objective measures of sleep deserves
further comment. In the general population, self-reports
of sleep time often are subject to both overestimates and
underestimates. Overestimates can be attributed, in part,
to the fact that an arousal must be at least 5–6 minutes
in duration if it is to be recalled subsequently as a sus-
tained arousal or period of wakefulness. As a result, sleep
punctuated by recurrent yet brief periods of arousal may
be described as “sound sleep.” Similarly, overestimates of
sleep duration are not uncommon. This overestimation
can be further compounded because healthy older adults
may simply accept a decrease in sleep efficiency as a part
of normal aging. However, aging also is associated with
reduced ability to tolerate sleep deprivation. Given these

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

347
348 Neurologic Conditions in the Elderly
influences, it is clear that objective measures of sleep and
sleepiness are critical to the study of sleep and the effects
of alcohol on sleep.
The nocturnal polysomnogram (PSG) is the standard
method of determining the presence and stage of sleep by
measuring EEG, electromyographic (EMG), and electro-
oculographic (EOG) activity (Rechtschaffen and Kales,
1968). Similarly, the Multiple Sleep Latency Test (MSLT) is
a standard and accepted measure of daytime sleepiness;
it employs polysomnography while a patient is allowed
to take naps on five separate occasions throughout a day
(American Sleep Disorders Association (ASDA), 1992).
Alternative methods may include the mean wakefulness
test (MWT) or the subjective Epworth sleepiness scale
(ESS). The assessment of average sleep latency with a
standardized tool such as the MSLT allows a quantifica-
tion of “sleepiness.” Sleep need often is translated into the
concept of “sleep drive.” Thus, relative sleep deprivation
leads to increased sleep drive, whereas napping lends
itself to a relative decrease in sleep drive. The change in
sleep need with increasing age has been the subject of
considerable study, but such studies often are confounded
by changes in lifestyle, diet, medication use, napping pat-
terns, and the like.
Sleep architecture
Understanding normal sleep is an essential prerequisite
to understanding sleep disorders. Sleep is a dynamic pro-
cess, featuring fluctuations in brainwave activity, muscle
tone, eye movement, and autonomic activity. It consists
of two discrete states: REM and NREM sleep. Each can
be defined in physiologic terms by using the elements
of the PSG: EEG, EOG, and ECG. Formal criteria have
been elaborated in a manual developed by the AASM
(Rechtschaffen and Kales, 1968).
Nonrapid eye movement sleep
Current nomenclature now considers NREM in three
stages (N1–N3). Formerly, NREM was divided into four
stages, but N3 now approximates the combined stages 3
and 4. Stage N3 is often referred to as SWS or delta sleep. In
brief, each stage is characterized by progressively slower
EEG background, lower muscle tone, and decreasing eye
movements. Stage N1 marks the transition from wake-
fulness to drowsiness. Rhythmic activity is replaced by
mixed voltage, 3.0–7.0 Hz theta activity, and a decrease
in muscle tone. Roving eye movements may be present.
Stage N2 features a similar but slower background EEG,
with superimposed “spindles” (low-amplitude, high-
frequency, centrally predominant bursts) and K-com-
plexes (high amplitude, negative or upgoing potential,
immediately followed by lower amplitude, positive or
downgoing potential, with some faster, low-amplitude
activity). Muscle tone may decrease further, whereas eye
movements may disappear entirely. Stages N1 and N2
often are referred to as the “light” stages of NREM sleep
because of the relatively low arousal threshold. Stage N3
(SWS) is characterized by high-amplitude (75 μV), slow-
wave (0.5–2.0 Hz) activity. In N3, K-complexes and spin-
dles are absent and eye movements are not seen. Muscle
tone may be further diminished.
Rapid eye movement sleep
REM sleep, or stage R, does not fit into the same stag-
ing system as NREM sleep and thus sometimes has been
referred to as paradoxical sleep. Although EEG activity
is relatively active, the muscle tone achieves its lowest
state over a 24-hour period (relative muscle atonia). REM
sleep is characterized by rapid eye movements scattered
through the duration of each REM cycle. REM sleep can
be further subdivided into tonic (background EEG, rela-
tive muscle atonia, hippocampal theta activity) and pha-
sic (rapid eye movements, brief muscle twitches, “saw
tooth” waves on the EEG, and pontogeniculo-occipital
spikes, as recorded in animals) components. REM sleep
is associated with the well-formed dream. Individuals
aroused from REM sleep will recall dreams about 80% of
the time. NREM arousals may be associated with recall of
isolated images or thought fragments, but not the well-
formed images of REM sleep. Nightmares are a reflection
of the elements of REM sleep. As the individual initially
awakens from a frightening dream and begins to scream,
no sound emerges because he or she is still paralyzed
with the muscle atonia of REM. It is noteworthy that these
components of REM sleep are not rigidly synchronized.
Another example of this loose synchronization can be
seen in some normal individuals with sleep paralysis as
a benign condition, in which the individual is transiently
“paralyzed” as he or she awakens from sleep.
Sleep rhythms
The components of sleep do not occur randomly through-
out the course of the night. In fact, a clear pattern emerges
from the ultradian or short rhythms of sleep. The “light”
stages of NREM are seen first. They are followed by a
transition to SWS, followed by lighter stages of NREM
again and then REM sleep. Typically, there are three to
four NREM–REM cycles, each lasting 90–120 minutes. As
the night progresses, the relative amount of time spent in
REM increases and the amount of time in SWS decreases.
Thus, REM usually is skewed toward the end of the sleep
period and SWS toward the beginning. More importantly,
sleep–wake rhythms follow a circadian or approximately
24-hour biologic pattern. Sleep–wake is considered a cir-
cadian rhythm that is tightly synchronized with circadian
variations in the core body temperature. The suprachi-
asmatic nucleus of the hypothalamus in animals, and
an analogous structure in humans, with inputs from the
retinohypothalamic pathways, has been identified as the
endogenous pacemaker. Although individuals may have

different periodicities in their clocks (“larks” and “owls”),
many factors maintain or influence these rhythms.
Although activity levels, social cues, mealtimes, and other
external scheduling factors play some role, the most pow-
erful zeitgeber (lightgiver) has proved to be exogenous
light. Presumably, light exerts its influence through reti-
nohypothalamic input to the suprachiasmatic nucleus
(Czeisler et al., 1991). From a clinical perspective, it is help-
ful to view the usual pattern of sleep–wake in terms of the
shifting pattern of the core body temperature. The usual
evening sleep onset occurs as the core body temperature
falls during the “primary sleep permissive” zone. Sleep
continues as the core body temperature continues to fall
and enters the “sleep maintenance zone.” The duration
of sleep and REM sleep follows this circadian cycle, with
most of REM sleep occurring close to the nadir of the tem-
perature cycle. The temperature then begins to rise, reach-
ing its peak at midday. A secondary dip usually occurs in
midafternoon, correlating with a secondary sleep permis-
sive zone, or the so-called “siesta” zone. This nap zone
usually is followed by a relative plateau that has been
related to the “second wind.” Similarly, a secondary rise
occurs in the early morning hours, usually at about 3 am,
when a secondary arousal time occurs and the individual
is susceptible to wakening from any physical or emotional
factor (such as anxiety, pain, or the need to urinate).
Sleep changes with normal aging
Sleep changes associated with a decrease in sleep effi-
ciency, a decrease in stage N3, and an increase in wake
after sleep onset (WASO) with minimal changes on sleep-
onset latency and REM latency. Elderly also find it hard
to adapt to jet lag, shift work, and phase shifts due to
changes to circadian rhythm systems.
Sleep architecture in normal aging
Normal aging is associated with changes in sleep that
progress gradually across the lifespan. Most of these
changes can be seen between the ages of 19 and 60, with
only minimal changes from age 60 to 102 (Ohayon et al.,
2004). Based upon a recent meta-analysis of PSG studies
in healthy normal people, the major features appear to be
a decrease in total sleep time (TST), a decrease in sleep
efficiency, a decrease in SWS, and an increase in WASO.
Other features include increases in N1/N2 and a decrease
in REM sleep. On the other hand, changes in sleep-onset
latency and REM-onset latency are minimal. The observa-
tions were comparable for both men and women (Oha-
yon et al., 2004). Note that these observations are based
on an analysis of the “normal” aging. Studies that allow
for the co-morbidities that accompany aging show greater
changes and a gender difference, with men showing poor-
quality sleep with aging (Redline et al., 2004).
Sleep Disorders 349
Circadian rhythms in normal aging
As with normal sleep architecture, changes in normal
circadian physiology occur with aging. The two most
striking changes are the gradual advancement in circa-
dian phase with aging and the increasing intolerance of
rapid phase changes. The advancing rhythm is reflected
in a tendency toward an earlier sleep time with an ear-
lier rise time. The increasing intolerance of rapid phase
shifts would be reflected in greater difficulties with shift
work or a greater sensitivity to the effects of jet lag. Other
concerns about changes with aging, such as diminished
circadian amplitudes and shortened circadian taus, are
equivocal (Monk, 2005).
Napping and excessive daytime sleepiness
in normal aging
Although regular napping and EDS appear to increase
with aging (Metz and Bunnell, 1990; Ohayon, 2002;
Young, 2004), these observations are seemingly linked to
the presence of comorbidities such as chronic pain and
depression (Foley et al., 2007). Healthy older adults are
much less likely to report regular napping or EDS. Fur-
thermore, napping appears to have only a modest impact
on nighttime sleep and may even contribute to improved
daytime performance (Monk et al., 2001; Campbell et al.,
2005).
Disorders of sleep in the elderly
Sleep disorders are not uncommon, and the prevalence
of most sleep disorders increases with advancing age.
Among adults over the age of 65, more than 50% com-
plain of difficulty sleeping (Foley et al., 1995). Many
factors may contribute to these disturbances, including
medical/psychiatric disturbances and medication use. In
addition, older adults are susceptible to many of the spe-
cific disorders encountered by the general population. We
discuss the disorders most commonly encountered in this
population.
Restless legs syndrome
Restless legs syndrome (RLS) was first described by
Ekbom in the 1940s. For many years, it was thought to
be a rare curiosity, but current epidemiologic studies sug-
gest that it may be one of the most common sleep-related
disorders, with a prevalence as high as 10% (Phillips
et  al., 2000). Pharmacologic studies have indicated that
levodopa and dopamine-receptor agonists are effective
therapies for RLS, pointing out that the disorder is asso-
ciated with a decrease in dopaminergic function in the
brain. However, contradictory results have been obtained
with 18-fluorodopa positron emission tomography (PET)
scans (Trenkwalder et al., 1999). Functional magnetic
resonance imaging (MRI) of patients with RLS suggests
350 Neurologic Conditions in the Elderly
involvement of the cerebellum and the thalamus, with
additional activation of the red nucleus, pons, and mid-
brain when periodic limb movements of sleep (PLMS)
are also present (Bucher et al., 1997). Physiologic studies
have suggested that a disturbance of inhibitory subcorti-
cal pathways, such as the reticulospinal tract, may allow
expression of a normally suppressed neural generator
at the level of the spinal cord (Bara-Jimenez et al., 2000).
About 50% of patients with RLS have a family history
of the condition (Winkelmann et al., 2000), and a recent
report has described a family with linkage to chromo-
some 12q (Desautels et al., 2001). Another advancement
has been the observation of a relationship with low iron
stores in the brain that may be critical in the pathogenesis
of RLS (O’Keeffe et al., 1994; Sun et al., 1998; Earley et al.,
2000; Allen et al., 2001).
The diagnosis of RLS requires the presence of four
essential diagnostic criteria (Allen et al., 2003):
1 An urge to move the legs, which may be accompanied
by unpleasant sensations.
2 Worsening of symptoms during periods of rest.
3 Partial or total relief of symptoms with movement, such
as walking, for at least as long as the activity continues.
4 Worsening of symptoms in the evening or night.
RLS is often accompanied by PLMS, which is a poly-
somnographic finding of recurrent movements of the legs
in a triple flexion pattern during sleep.
RLS is encountered in both men and women and in all
age groups. Parasthesias or a sensation of discomfort is
often a part of the urge to move. The severity of the dis-
order may vary considerably. In some, there may be a sig-
nificant disruption in sleep onset or the ability to sit still
for a long car ride or movie. These paresthesias are usu-
ally bilateral, often more prominent in the legs than in the
arms. The sensations typically are described as burning,
tingling, stabbing, aching, or simple pain. Some patients
complain of sensations of ants crawling or worms bur-
rowing. Symptoms usually are subjective and vary over
the course of the day. They tend to be worse when the
individual is relaxing, especially when preparing for
sleep. Patients may have particular difficulties in enclosed
areas such as airplanes, cars, or trains. Symptoms are vari-
able and may fluctuate over time, with exacerbations and
remissions (Allen et al., 2003). Some patients develop
myoclonus or sudden jerking movements. It is not
uncommon to find an overlap with PLMS. PLMS, how-
ever, occurs during sleep and most commonly in stage
N2 sleep. RLS, on the other hand, occurs during wakeful-
ness and interferes with sleep at the transition between
wakefulness and sleep. Although PLMS may occur in up
to 80% of cases with RLS, PLMS can occur independently.
In addition to the impact on sleep, RLS may be associated
with reduced health-related quality of life, elevated rates
of mood disorders and anxiety disorders, and potentially
increased risk of cardiovascular disease (Yang et al., 2005).
The pathophysiology of RLS is unknown. Disorders
of iron metabolism within the central nervous system
and dopaminergic function have been considered. Many
medical problems have been found to aggravate the
symptoms. Uremia, anemia, and neuropathies have been
implicated in many so-called secondary cases. RLS may
be aggravated or triggered by the use of several medica-
tions, including antidepressants, lithium carbonate, neu-
roleptics, and caffeine (Winkelman et al., 2006).
Treatment of restless legs syndrome in the elderly
The first step in treatment is identifying the disorder.
Older patients, in particular, may not always think to
bring these symptoms to the attention of their clini-
cian. Patients who may suffer from a dementing illness
or other cognitive impairment may not be capable of
describing symptoms, and one needs to suspect the diag-
nosis based upon careful observation. After the clinical
diagnosis is made, careful attention must be directed to
treatable causes or other aggravating factors, such as iron
deficiency, uremia, or aggravating medications. In some
cases, exercise may be helpful. Often it is necessary to
consider medications. In a recent evidence-based review,
the medications considered to be effective were dopami-
nergic agents (levodopa, ropinirole, pramipexole) and
gabapentin. Ropinirole, pramipexole, and a long-acting
formulation of gabapentin are the only agents with formal
FDA approval for this indication. Other medications with
some potential benefit include opioids, benzodiazepines,
and a few other anticonvulsants. Medications considered
to be likely effective include carbamazepine, valproate,
oxycodone, bromocriptine, and clonidine. Finally, sev-
eral were considered to be in the “experimental” group,
including methadone, tramadol, clonazepam, zolpidem,
topiramate, amantadine, magnesium, folate, and dihy-
droergocriptine (Trenkwalder et al., 2008). Care must be
taken in the elderly to consider the potential side effects of
these agents. The benzodiazepines, for instance, may pose
particular problems.
Periodic limb movements of sleep
PLMS is a polysomnographic finding of stereotyped
repetitive movements of the legs during sleep. PLMS are
characterized by episodes of repetitive, stereotyped limb
movements during sleep. Other terms for the condition
include periodic leg movement, nocturnal myoclonus, peri-
odic movements of sleep, and leg jerks. The movements usu-
ally involve the legs (unilateral, alternating, or bilateral),
although the arms also may be involved. Movements
consist of extension of the big toe, in combination with
partial flexing of the ankle, knee, and (sometimes) hip.
The movements often are associated with partial arousal
or overturning, usually too briefly for potential aware-
ness. There can be marked night-to-night variability in
the number of movements (Billiwise and Clarkson, 1988;

Mosso et al., 1988; Edinger et al., 1992). In some cases,
periodic arousals may predominate, with minimal, if any,
evidence of limb movements.
PLMS have a prevalence of 7.6% in the general pop-
ulation (Scofield et al., 2008) and greater than 40% in
community-dwelling individuals aged 65 years or older
(Ancoli-Israel et al., 1991). PLMS is present in more than
80% of patients with RLS. However, the clinical relevance
of PLMS in the absence of RLS or subjective sleep com-
plaints continues to be debated. PLMS associated with
arousal may be of greater importance than the actual
number of movements seen during a study. Periodic limb
movement disorder (PLMD) is defined as the presence of
PLMS in patients with otherwise unexplained hypersom-
nia or insomnia (Hornyak et al., 2006). Nevertheless, the
importance of PLMD remains controversial. As a conse-
quence, few treatment trials are available and most clini-
cians will use medications otherwise indicated for RLS.
Obstructive sleep apnea
Obstructive sleep apnea (OSA) is a common syndrome.
It is a treatable disorder that accounts for many of the
cases of excessive somnolence and insomnia encountered
in most sleep centers. It is one of the few diagnoses that
make PSGs reimbursable by third-party payers.
OSA is characterized by repetitive episodes of sleep-
related upper airway obstructions, which usually are
associated with oxygen desaturation. OSA can be con-
ceptualized as a disorder emerging from an interaction
between anatomy and muscle relaxation as it occurs in
sleep. As muscles relax, airflow can generate vibrations in
the soft tissues of the upper airway, including the soft pal-
ate. Such vibration produces the noise or the snoring. The
role of upper airway muscle relaxation in the pathophysi-
ology also means that certain medications, such as ben-
zodiazepines or alcohol, may aggravate the severity of
the OSA, presumably by the enhanced degree of muscle
relaxation. In some patients, the snoring appears in isola-
tion; in such cases, the term primary snoring is applied.
Further upper airway restriction can result in diffi-
culties along two other dimensions. Muscle relaxation,
especially in the upper airway dilator muscles of the oro-
pharynx (often combined with mild anatomic abnormali-
ties), causes increased airway restriction, which is further
enhanced by the negative pressures generated by normal
respiration (Guilleminault and Stohs, 1991). The sleep
disruption may or may not be apparent to the patient
because, as noted earlier, brief physiologic arousals may
not be recalled. Daytime somnolence often is the prime
complaint, although–-as in other chronic, progressive
disorders–-the patient may adapt to and minimize these
symptoms. The same patient who denies daytime sleepi-
ness or napping may acknowledge an irresistible urge to
doze if allowed to sit in a comfortable chair or when con-
fronted with the monotony of highway driving. Others
Sleep Disorders 351
with concurrent anxiety disorders may not experience
the ease of falling asleep and will simply not be aware
of the sleep deprivation. Similarly, presenting complaints
may be related to difficulties in memory or concentration
that reflect suppression of REM sleep (REM sleep is espe-
cially vulnerable because of the relative muscle atonia).
SWS also can be suppressed and may be associated with
complaints similar to those associated with fibrositis or
fibromyalgia.
In addition to sleep disruption, there are several car-
diopulmonary consequences. Feedback reflexes may be
insufficient to cause arousal (arousal produces return
of muscle tone on cessation of the respiratory events).
Indeed, one might see significant oxygen desaturation
with arrhythmia, systemic and pulmonary arterial hyper-
tension, and polycythemia. These changes can become
chronic, and recent epidemiologic studies have suggested
that OSA plays a role in the development of often-unrec-
ognized hypertension in the general public (Nieto et al.,
2000; Peppard et al., 2000).
The severity of OSA thus can be measured in three
dimensions: snoring, sleep disruption, and cardiopulmo-
nary consequences. It is not unusual to see some linkage,
but the factors may exist independently as well. Manipu-
lation of anatomy or the degree of muscle relaxation can
aggravate OSA. Weight gain or supine sleep heightens the
anatomic risk factors, whereas use of alcohol, benzodiaz-
epines, and other sedatives enhances muscle relaxation
and, thus, the severity of OSA.
Determining the severity of OSA is complicated by the
arbitrary scoring criteria used in most laboratories, as well
as the recent recognition of the upper airway resistance
syndrome, where symptoms may be attributed to events
that do not meet the formal criteria for the definition of
apneas or hypopneas. Fortunately, the establishment
of a new scoring system for these events may minimize
problems in the future (Iber et al., 2007b). Traditionally,
apneas are defined as episodes of 10 seconds in duration
during which airflow falls to less than 10% of baseline.
Obstructive events imply that there is continued respira-
tory effort (Gislason et al., 1987), although there is some
controversy as to how sensitive the effort markers need to
be to determine the absence of effort of the type seen in
central apneas. Hypopneas usually are defined as events
of 10 seconds during which airflow drops to 50% of base-
line or less, with an associated drop in oxygen saturation
or a brief arousal. OSA is considered mild if the number of
events per hour ≥5, moderate if ≥15, and severe if ≥30. In
upper airway resistance syndrome, “unscorable” events
may be associated with sleep disruption or frequent EEG
alpha arousals.
Epidemiologic studies have suggested that snor-
ing occurs in 9–24% of middle-age men and in 4–14%
of middle-age women (Koskenvu et al., 1985; Lugaresi
and Partinen, 1994), although there is a tendency to
352 Neurologic Conditions in the Elderly
under-report snoring (Telakivi et al., 1987). The preva-
lence of OSA in the general male population has been
estimated to be 0.4–5.9% (Lavie et al., 1984; Gislason
et al., 1987; Gislasen et al., 1988; Cingnotta et al., 1989),
with the incidence in men clearly outnumbering that in
women.
Common risk factors include obesity (Telakivi et al.,
1987; Kripke et al., 1997; Phillips and Ancoli-Israel, 2001),
smoking (Lavie et al., 1984; Norton and Dunn, 1985;
Gislasen et al., 1988), alcohol consumption (Issa and
Sullivan, 1982; Kripke et al., 1997), stroke (Shahar et al.,
2001), and age (Young et al., 2002).
Treatment of obstructive sleep apnea
in the elderly
In some respects, the management of OSA in the elderly
follows the usual approaches applied to the general
population. Interestingly, however, there has never been
a demonstration that treatment will have a clear impact
on long-term morbidity or mortality in the elderly (Barbe
et al., 2001; Marin et al., 2005). Nevertheless, it is clear that
patients may benefit from improvements in sleep quality
and efficiency. Therefore, an emphasis should be placed
upon symptom improvement.
Perhaps the first step, after establishing the diagnosis,
is to address factors that may be easily addressed. Body
position, for instance, may play a role in the severity of
the disorder. In some patients, the severity is dependent
on the time spent sleeping in the supine position. Often
patients spend more time sleeping supine when in the
sleep lab because of the imposition of the equipment,
thus distorting the final impression of severity. Simply
by encouraging nonsupine sleep, the severity may be
significantly reduced. Care to reduce nocturnal alcohol
consumption or agents that may enhance muscle relax-
ation may also reduce the severity of the disorder. Weight
reduction is another strategy that may be helpful in the
obese.
The next step is to consider a trial of positive airway
pressure (PAP). Care should be taken to monitor for
common causes of failure to comply with PAP therapy.
Improper education, improper mask fitting, and improper
titration are common problems in compliance failure.
Untreated anxiety or claustrophobia is yet another cause.
Finally, there may also be a failure to recognize the con-
tribution of other factors that may contribute to daytime
sleepiness, such as depression or medication effects that
may mask the benefit achieved by the PAP therapy. Other
options may include dental appliances, usually consid-
ered for milder, nonobese cases, or surgical modifica-
tion. Although tracheostomy is quite effective, it is rarely
considered, for obvious reasons. Among the other sur-
gical approaches, the maxillomandibular advancement
(MMA) procedure is likely the most promising (Aurora
et al., 2010a).
Sleep in degenerative diseases
A special situation of abnormal sleep disorders in the
elderly is degenerative diseases. Alzheimer’s disease
(AD), Parkinson’s disease with dementia (PDD), demen-
tia with Lewy bodies (DLB), multiple systems atrophy
(MSA), and prion diseases all pose different challenges
and disruptions to sleep.
Sleep and Alzheimer’s disease
AD is the most common form of dementia in the United
States. Current estimates indicate that 5.1 million Ameri-
cans are living with AD. The prevalence increases with
age, with 60% of those over the age of 85 years affected.
By the year 2050, an estimated 11 million to 16 million
individuals will have AD (Plassman et al., 2007). Cross-
sectional studies suggest that approximately 25–35% of
individuals with AD have problems sleeping (Dauvil-
liers, 2007). Sleep disturbances in AD are complex. These
patients are susceptible to all of the sleep problems
related to aging, as well as to a progressive deterioration
and decrease in the number of neurons in the suprachias-
matic nucleus (SCN), which is critical in the homeostatic
maintenance of the circadian rhythm (Wu and Swaab,
2007). Common symptoms include nighttime sleep frag-
mentation, increased sleep latency, decreased SWS, and
increased daytime napping.
The interface of Alzheimer’s disease
pathology and sleep
The relationship between sleep pathology and the patho-
genesis of AD may be even more complex. Amyloid-β
(Aβ) accumulation in the brain extracellular space is con-
sidered to be a hallmark of AD, although the precise role in
pathogenesis may be controversial. In a transgenic mouse
model, it has been shown that chronic sleep restriction sig-
nificantly increased and a dual orexin receptor antagonist
decreased Aβ plaque formation. Thus, the sleep–wake
cycle and orexin may play a role in the pathogenesis of
AD (Kang et al., 2009). This relationship between sleep
and the pathophysiology of AD may also be reflected in
the observation that sleep disturbances should be consid-
ered as one of the core noncognitive symptoms of mild
cognitive impairment (MCI), a condition often thought
to be a precursor to AD (Beaulieu-Bonneau and Hudon,
2009).
Certain sleep changes in AD seem to represent an exag-
geration of changes that appear with normal aging. AD
patients spend an increased amount of time in stage 1
sleep, with increased number and duration of awaken-
ings, compared to age-matched non-AD controls (Prinz
et al., 1982b; Reynolds et al., 1985). With disease progres-
sion, it is also difficult to separate EEG features of stage 2
sleep from stage N1 sleep. Sleep spindles and K complexes
are poorly formed. They are also of lower amplitude and

shorter duration and are much less numerous (Prinz et al.,
1982a; Montplaisir et al., 1995). The proportion of NREM
sleep increases with further disappearance of the true
delta wave of SWS (Prinz et al., 1982a, 1982b; Reynolds
et al., 1984; Reynolds et al., 1985; Montplaisir et al., 1995).
The percentage of time spent in REM sleep, which remains
stable with normal aging, is reduced in patients with AD.
A decrease in the mean REM sleep episode duration and
REM sleep percentage can be due to degeneration of the
nucleus basalis of Meynert. The nucleus normally exerts
an inhibitory influence on the nucleus reticularis of the
thalamus, the rhythm generator responsible for NREM
sleep (Buzsaki et al., 1988). REM sleep also depends on
the abundance and integrity of the cholinergic system.
The cholinergic disturbance in AD is accompanied by
worsening of REM sleep. In addition, many subcortical
structures, such as the basal forebrain, distal and superior
raphe nucleus, and reticular formation of the pons and
medulla, seem to be involved in the initiation of sleep and
oscillation between REM and non-REM states. All these
structures may potentially be damaged by the degen-
erative changes that are part of AD. Their deterioration
may explain many of the sleep architecture and rhythm
changes in AD (Weldemichael and Grossberg, 2010). The
impact of REM may also be reflected in the observation
that REM sleep without atonia may be more common in
AD, even though the behavioral correlate of REM sleep
behavior disorder is relatively uncommon (Gagnon et al.,
2006).
A progressive deterioration of circadian rhythms also
occurs with aging. This includes changes in the sleep–
wake cycle manifested by reductions in sleep quality and
impairment in cognitive performance (Oosterman et al.,
2009; Yu et al., 2009). The main reason for the alteration in
sleep–wake cycle is related to alterations in the SCN and
melatonin secretion (Swaab et al., 1984; Reynolds et al.,
1984). Though not clear, genetic risk factors such as in AD
patients who are negative for the APOE-4 allele have also
been implicated in the development of sleep problems
(Yesavage et al., 2004; Craig et al., 2006).
Studies of the circadian core body temperature rhythms
in human subjects have shown a reduction in endogenous
circadian amplitude and a delay in the endogenous cir-
cadian phase of core body temperature in patients with
probable AD (Aschoff, 1960; Mills et al., 1978; Satlin et
al., 1995; Ancoli-Israel et al., 1997). AD patients, however,
have shown only a slight decrease in endogenous circa-
dian amplitude when compared to normal aging, so it is
unclear whether this is simply an exaggeration of normal
aging (Czeisler et al., 1992).
Impact of commonly used medications
in Alzheimer’s disease
Acetylcholinesterase inhibitors (ACHEIs) represent a
group of agents that have been FDA approved for the
Sleep Disorders 353
treatment of AD. The commonly used ACHEIs include
donepezil, rivastigmine, and galantamine. These are of
particular interest because of the concern that the cen-
tral cholinergic effect will have an impact on sleep, par-
ticularly REM sleep. Donepezil treatment enhanced REM
sleep and reduced slow frequencies of REM sleep EEG,
suggesting a possible action upon REM-sleep-related
cholinergic neurons in patients with AD. Furthermore,
REM sleep alpha power may predict the cognitive
response to donepezil (Mizun et al., 2004; Moraes et al.,
2006). Although some reviews suggest no particular
impact of galantamine on REM (Stahl et al., 2004), there
are case reports of galantamine causing unusual night-
mares (Iraqi and Hughes, 2009) and rivastigmine caus-
ing REM sleep behavior disorder (Yeh et al., 2010). The
impact of donepezil on REM is not always clear (Cooke
et al., 2006), but studies suggest an increase in REM with
treatment by donepezil in healthy volunteers after a sin-
gle dose (Kanbayashi et al., 2002). Donepezil may also
reduce decline in recognition performance in individu-
als vulnerable to the effects of sleep deprivation (Chuah
et al., 2009). Of additional note is that cholinergic activity
follows a circadian pattern. As a consequence, improved
function may be seen during the day, but at night, there
is an increased risk of sleep disruption (Davis and Sadik,
2006).
Tauopathies and sleep
Tauopathies include the frontotemporal dementias
(FTDs) including Pick’s disease, primary progressive
aphasia, semantic dementia, FTD with parkinsonism
linked to chromosome 17 associated with mutations in
the gene encoding tau; corticobasal ganglionic degen-
eration (CBGD); progressive supranuclear palsy (PSP);
and argyrophilic grain disease. Sleep disturbances are
prominent in all FTDs, but studies are limited. Nocturnal
agitation and wandering may occur in FTDs and should
be treated the same as in AD (Anderson et al., 2009). The
neuropathology of FTD may explain some of the sleep
disturbances. Diffuse severe degeneration of the orbital,
frontal, basal forebrain, hippocampus, and temporal
areas of the brain may be the direct or indirect cause of
sleep–wake disturbances.
The frequency of PLMS and associated arousals in
patients with FTD is unknown and has not been studied.
RLS, on the other hand, has anecdotally been seen with
frequency in FTD (Boeve, 2008). Hypersomnia has been
anecdotally described in patients with FTD. This was
seen as decreased mean sleep latencies and sleep-onset
REM periods on multiple sleep latency testing. Medica-
tions that are commonly used to treat negative behavior
in FTDs may also affect sleep and wakefulness in patients
with FTDs. As in AD, they may contribute to daytime
somnolence, worsening of cognitive dysfunction, or
insomnia.
354 Neurologic Conditions in the Elderly
Synucleinopathies and sleep
Synucleinopathies include PDD, DLB, and MSA. The
synucleinopathies have early brainstem dysfunction and
cerebral dysfunction, which may account for some of the
sleep disturbances seen in this group.
PDD and DLB patients have circadian rhythm disor-
ders. Experience has shown more commonly advanced
phase disorders, but this has not been systematically
studied. Hypersomnia may occur in all the synucleinop-
athies with more frequency in PDD than in PD without
dementia (Boeve, 2008; Compta et al., 2009). Insomnia
may also occur in patients with synucleinopathies and is
commonly related to medication effect.
Medications may contribute to sleep–wake distur-
bances in PDD and DLB. Dopamine agonists used for
treatment of parkinsonism in patients with PDD may
cause daytime sleepiness, nighttime stimulation, and hal-
lucinations. Anticholinergics may also have nighttime
stimulatory effects and can increase confusion. Acetylcho-
linesterase inhibitors used for dementia in PDD and DLB
may cause insomnia. Antidepressants may contribute to
or exacerbate PLMS and REM sleep behavior disorder
(RBD).
PLMS and RLS occur in this population with unknown
frequency, but increased rates have been reported. They
are treated with increased doses of dopamine agonist
medications during symptomatic times of the day.
RBD is a not uncommon feature of the synucleinopa-
thies. It may precede the onset of PDD or DLB by many
years. Treatment of RBD is necessary when it leads to self-
injurious behavior or injury to the bed partner, or if it oth-
erwise causes sleep fragmentation. Creating a safe sleep
environment is paramount. Melatonin and clonazepam
are used for pharmacologic treatment. Melatonin may be
more desirable due to fewer effects on gait and cognition
than clonazepam (Aurora et al., 2010b).
Patients with parkinsonism as seen in PDD, DLB,
and MSA also have sleep disturbances related to motor
control. Bradykinesia/akinesia, rigidity, tremors, dys-
tonia, and muscle stiffness all contribute to sleep onset
and maintenance difficulty. On the other hand, some
authors have recognized a sleep benefit on the motor
symptoms of PD. Presumably, the gradual increase in
dopaminergic stores through the course of the sleep
period may contribute to some apparent benefit after a
night of sleep.
Patients with MSA typically have similar sleep dis-
turbances to patients with PDD and DLB. In addition,
however, sleep-disordered breathing may be seen more
commonly in patients with MSA. Upper airway obstruc-
tion at the glottis level may lead to obstructive sleep
apnea, and degeneration of the pontomedullary respira-
tory centers may lead to central sleep apnea. Vocal cord
abductor paralysis may lead to clinical stridor and, more
importantly, life-threatening breathing problems.
Prion disorders and sleep
Prion disorders such as fatal familial insomnia (FFI),
Creutzfeldt–Jakob disease (CJD), and Gerstmann–
Straussler–Scheinker disease are rare, and information
on sleep disturbances is sparse. Studies of sleep in CJD
have shown disturbances ranging from profound hyper-
somnia to insomnia. Insomnia was more common than
hypersomnia. Sleep aids such as benzodiazepines and
hypnotic medications were helpful in treating insomnia
in these patients (Wall et al., 2005).
FFI is a rare prion disease characterized by insomnia,
dysautonomia, and motor dysfunction. A case report by
Gistau of a patient with FFI showed hormonal dysregula-
tion of the circadian rhythm, and PSG findings were con-
sistent with a global abnormality of the sleep–wake cycle
(Gistau et al., 2006). In a study by Krasnianski et al., PSG
findings of patients with FFI showed a reduction in rapid
eye movements, decreased sleep efficiency, decreased
SWS, PLMS, and central apnea (Krasnianski et al., 2008).
Clinically, these patients manifested with a wide range
of psychiatric symptoms, vegetative symptoms, and
autonomic dysfunction. FFI may be confused with CJD
because of the rapid cognitive decline and psychiatric
symptoms. However, FFI disease progression is usually
more prolonged, and signs typical of CJD generally occur
late in the disease.
Clinical approaches to sleep disorders
The clinical approach to elderly patients with sleep dis-
orders poses certain problems in addition to dealing with
specific sleep disorders. Therefore, a systematic approach
is critical.
1 The first step is to obtain a careful history of the amount
of sleep actually obtained in a 24-hour period. A diary can
be used, but a careful history often elicits the necessary
information.
2 The next step is to address the issue of timing and to
determine the patient’s probable circadian rhythm. This
can be complicated by shifting work schedules and other
activities. Again, the history is the most powerful tool. A
sleep diary may be helpful.
3 Consider the potential for medical or psychiatric issues
that can interfere with sleep. These are detected through a
careful medical and psychiatric review, including an inven-
tory of medications, exercise, nicotine, alcohol, and other
drug use. Give careful attention to symptoms of anxiety,
depression, nightmares, and post-traumatic stress.
4 Inquire about possible features of intrinsic sleep disor-
ders. Is there evidence of OSA—snoring, sleep disruption,
obesity, hypertension, and morning headache? Is there
a reason to suspect PLMS or RLS? Is there a history of
sleep-disturbing paresthesias or a history of sleep-related
movement disorder?

5 Inquire about the sleep environment. Is the sleep area
conducive to the relaxation required to allow the wake-
to-sleep transition? This is a relative concept; for example,
a television can be hypnotic for some but stimulating for
others.
Occasionally, additional diagnostic studies are required.
Some of these studies are part of the medical evaluation.
Expanded use of a diary can be of value. A PSG should
be considered if OSA or narcolepsy is suspected. A PSG
also is helpful in evaluating parasomnia (abnormal sleep-
related behavior). Finally, an MSLT can be helpful in
documenting hypersomnia or the presence of early-onset
REM.
When the evaluation is complete, the clinician can initi-
ate a strategy to address the sleep problem. This approach
needs to consider the addictive disorder because prob-
lems underlying the addiction must be addressed and
treated.
Care must be taken in selecting medications. When-
ever possible, associated medical or psychiatric condi-
tions should be treated. Only then can “intrinsic” sleep
disorders be treated. For example, RLS and PLMS can be
treated with medications that are not subject to abuse.
OSA usually is treated with continuous PAP devices.
Special attention then can be directed to issues of sleep
hygiene, including the following:
• The sleep environment should be modified to allow for
the relaxation required for the wake-to-sleep transition.
It should be separated from work and play areas. Noise
and lighting should be modified to allow for optimal re-
laxation.
• The times at which caffeine, nicotine, alcohol, and other
medications are used should be assessed and adjusted as
necessary.
• Regular exercise has been found to improve sleep and
should be recommended.
• Adoption of a regular sleep–wake schedule should be
encouraged. Napping is permissible but will reduce the
need to sleep at night.
• Finally, the patient needs to be able to separate sleep
time from other stressors, allowing for a period of relax-
ation. The patient should be instructed to leave the bed-
room whenever he or she is unable to sleep, to avoid the
development of further anxiety.
If the patient still has difficulties with sleep, an under-
lying cause should be sought. Often the cause is some
form of anxiety disorder that requires direct attention.
Relaxation techniques are helpful to some patients, as
are medications. The usual sedating or hypnotic agents
can be used for transient problems. However, in work-
ing with a patient for whom addiction is an issue, it
is wise to consider the sedating antidepressants or
the more active agents used to treat other anxiety-
related disorders, such as selective serotonin reuptake
inhibitors.
Sleep Disorders 355
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 Chapter 14
Autonomic Dysfunction and Syncope
Rohit R. Das
Indiana University School of Medicine, Indianapolis, IN, USA

Summary
• Three main types of syncope include neurally mediated syncope, cardiac syncope, and situational syncope associated
with orthostatic hypotension.
• The clinical features of syncopal events are classified as prodromal symptoms, event symptoms, and post-event
symptoms. The most prominent early symptoms are dizziness and lightheadedness. Other symptoms include a brief
and transient loss of consciousness (TLOC) followed by a short period of confusion, loss of control over volitional
movements, and an upward deviation of both eyes at syncopal onset.
• ECGs are the first step to assessing syncopes. Tilt table testing is important for assessing neurocardiogenic syncopes.
Electroencephalograms (EEGs) help distinguish syncopes from seizures.
• Ongoing research is still looking into the best form of treatment.

Definition and classification of syncope
Definitions of syncope abound. Syncope is most often
defined as a manifestation of transient loss of con-
sciousness (TLOC), the result of decreased cerebral
perfusion caused by a sudden decrease in systolic
blood pressure with loss of postural tone and recovery
without medical intervention–-more specifically, elec-
trical or chemical cardioversion (Kapoor, 2002; Sorajja
et al., 2009).
Historically, syncope has been both well recognized
and well described. Galen believed that syncope repre-
sented an abrupt prostration of the vital facilities without
respiratory changes; he supposed that this was a sign of a
febrile state. He described cardiac syncope as an affliction
of the esophagus or mouth of the stomach, acting in sym-
pathy with the heart. Authors ranging from Hippocrates
in the fourth century BC to Caelius Aurelianus in the fifth
century AD all categorized syncope of cardiac origin as
a separate disorder (Papavramidou and Tziakas, 2010).
Interestingly, in his Aphorisms, Hippocrates states, “Those
who are subject to frequent and severe fainting attacks
without obvious cause die suddenly” (Mirchandani and
Phoon, 2003). Heaton reviewed Shakespeare’s oeuvre and
found at least 18 occasions when a character had a TLOC
while in the grip of extremely heightened emotion; in 12
instances, near fainting is described. The Bard uses the
term swoon in six instances, fainting in five, and trance in
two (Heaton, 2006).
Syncope may be classified into three types based pri-
marily on causative mechanisms: neurally mediated syn-
cope, cardiac syncope, and situational syncope associ-
ated with orthostatic hypotension (Kapoor, 2000; Hirsch
et al., 2005; Parry and Tan, 2010). Table 14.1 gives a more
detailed list of syncopal conditions.
Epidemiology
Using the US National Inpatient Sample Database
between 2000 and 2005, and adjusting accordingly for
the US population as determined by census data, Ashek-
hlee et al. (2009) determined an incidence of 0.83 to
0.91 per 1000 person-years. The sample included more
than 300,000 patients. Syncope has not been well stud-
ied in large community-based cohort studies. Data from
the Dutch CRANS study, which randomly recruited
35- to 60-year-old subjects in Amsterdam, reported a
lifetime incidence of 35%; importantly, the peak age of
incidence was 15 years. The most common self-reported
syncopal triggers were pain, decreased food intake, a
warm external environment, strong emotion, and the
sight of blood (Ganzeboom et al., 2006). The Framing-
ham Heart Study examined the incidence and preva-
lence of syncope in a multigeneration, midlife, commu-
nity-dwelling cohort. A total of 822 subjects developed
at least one syncopal event over an average follow-up
period of 17 years. The incidence of a first syncope was

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

358

Table 14.1 Types of syncope
Neurally mediated syncope Vasovagal
Valsalva syncope
Carotid sinus hypersensitivity
Situational syncope
Needle- or blood-induced syncope
Respiratory
Micturition
Defecation
Laughter
Postprandial
Postexercise
Cardiac syncope Arrhythmias
Organic heart disease
Syncope with orthostatic Primary autonomic failure
hypotension Secondary autonomic failure
Dehydration
Data from Kapoor (2000) and Parry and Tan (2010).
6.2 per 1000 person-years of follow-up and 7.2 per 1000
person-years when adjusted appropriately for age.
Syncope was recurrent in 21.6% of those with an ini-
tial event (Soteriades et al., 2002). When compared to
participants who did not have a syncopal event, those
with a history of syncope had a higher prevalence of
a history of coronary artery or cerebrovascular disease
and were more likely to be taking cardiac and antihy-
pertensive medications.
Using the data from Framingham Study participants,
Chen et al. (2000) created a nested case-control study
to elucidate the risk factors for syncope. Syncope was
predicted by a history of cerebrovascular disease, use
of cardiac medications, and a history of hypertension.
It was unclear whether low body mass index, increased
alcohol intake, or diabetes mellitus predicted a syncopal
episode.
Syncope has also been studied in a variety of circum-
stances. In a study of medical incidents causing diversions
of civilian aircraft, Sand et al. found that syncope was by
far the leading in flight medical emergency, accounting for
more than half of all aircraft diversion (Sand et al., 2009).
Syncope while driving is an important clinical issue. In an
analysis of more than 3800 syncopal patients, Moya et al.
(2009) found that about 10% had had syncope while driv-
ing. Patients who syncopized while driving were more
likely to have a history of stroke and/or heart disease and
had an average age of 56.
In the Framingham Study, syncope was recurrent in
21.6% of those with an initial event; those who had had
a cardiac syncope were at the highest risk of recurrence
(Soteriades et al., 2002). In the Dutch CRANS study, the
median number of syncopal events was 2; the range
extended to five lifetime syncopal events (Ganzeboom
et al., 2006). Sheldon et al. (2006) found that patients
attending a cardiology clinic for vasovagal syncope had
Autonomic Dysfunction and Syncope 359
a median of eight syncopes; the upper limit of the range
extended to 20.
Only a subset of patients with syncope is actually seen
by a physician. A Dutch study estimated that the chief
complaint of a fainting spell accounts for between 2 and 9
visits per 1000 made to a primary care physician. To place
this figure in perspective, only a tenth as many patient
visits were for seizures or epilepsy (Olde Nordkamp
et al., 2009). Syncope is a major issue in emergency depart-
ments and urgent care settings. Fainting spells account
for approximately 1–4% of all emergency room patient
encounters and between 4% and 6% of hospital admis-
sions from the ED; this remains consistent in studies
conducted in different countries. Nordkamp et al. exam-
ined syncope prevalence in an acute care setting in the
Netherlands and found that syncope accounted for nearly
1% of all patient visits. In two-thirds of these patients, a
definitive etiology was established (Olde Nordkamp et
al., 2009). In Ireland, syncope leads to more than 1% of
ER visits but nearly 6% of hospital admissions (McCarthy
et al., 2010). In Italy, this figure stood at 2.3%, with admis-
sions at 4.2% (Numeroso et al., 2010).
Clinical features
The clinical features of syncopal and near-syncopal events
may be conveniently classified as prodromal symptoms,
event symptoms, and post-event symptoms (Wieling
et al., 2009).
Prodromal features
These features may be secondary to cerebral hypoper-
fusion and activation of the autonomic nervous system
(ANS). The most prominent early symptom is a nonspe-
cific sensation of dizziness and lightheadedness (Hirsch
et al., 2005). Retinal hypoperfusion leads to a darkening of
vision with a loss of color vision (van Dijk et al., 2009). The
skin may turn pale in color as a result of peripheral vaso-
constriction, owing to activation of the ANS. Often there
may be a poorly defined sensation of warmth and malaise
immediately preceding syncope (Hirsch et al., 2005). Less
common features include a fixed stare, mydriasis, drool-
ing, and, rarely, loss of memory for the event (Duvoisin,
1961; Duvoisin, 1962; Wieling et al., 2009). In cases when
cerebral hypoperfusion develops less rapidly, patients
may recall more features of their fainting spell and,
accordingly, preserve memories of the event (van Dijk
et al., 2009; Wieling et al., 2009). In a retrospective review,
569 patients with syncope or presyncope were likely to
experience symptoms such as diaphoresis, chest pain
and palpitations, nausea, vertigo, a feeling of warmth,
and dyspnea immediately before syncope (Sheldon et al.,
360 Neurologic Conditions in the Elderly
2002). The occurrence of prodromal features without pro-
gression to loss of consciousness is termed as presyncope
(Sheldon et al., 2009).
Symptoms of syncope
Syncope is associated with a brief and TLOC followed by
a short period of confusion. This phase lasts between 5
and 22 seconds, with a mean of 12 seconds (Wieling et al.,
2009). The actual period of unconsciousness exclusive of
confusion is probably shorter. Studies have found that
during this phase, four-fifth of patients may have invol-
untary automatisms that include fumbles, lip smacking,
and chewing (Wieling et al., 2009).
Syncope is associated with a loss of control over voli-
tional movements. Typically brief flaccid paralysis has
been noted, though rarely, opisthotonus marked by con-
siderable stiffness has been reported (Cotton and Lewis,
1918; Gastaut and Fischer-Williams, 1957; van Dijk et al.,
2009; Wieling et al., 2009). Ninety percent of subjects with
syncope studied using video by Lampert et al. developed
myoclonic activity, which was characterized by multifo-
cality and the lack of a definite rhythm. Often general-
ized myoclonus superimposed on this activity (Lempert
et al., 1994). The pathophysiology of syncopal myoclonus
is unclear; some think that this may be release phenom-
enon whereby the release of cerebral control over lower
(brainstem) centers brings out the myoclonus. (Gastaut,
1974; Wieling et al., 2009). The occurrence of myoclonus
may mimic a convulsion, giving rise to the term convulsive
syncope.
Eye movements during syncope have diagnostic sig-
nificance and have been well studied. The most important
feature is an upward deviation of both eyes at syncopal
onset, which may be preceded by downbeating nystag-
mus (Lempert and von Brevern, 1996). However, this fea-
ture appears to be associated with a more rapidly devel-
oping syncope; a more gradual cerebral hypoperfusion
as demonstrated in ocular globe compression in asymp-
tomatic volunteers led to upward eye deviation in only
20% (Stephenson, 1990). Breathing is typically unaffected,
though this may become labored with prolonged syncope.
Rarely, deep sighs or snores may be noted (Newman and
Graves, 2001). It is important to realize, however, that
transient changes in cerebral perfusion do not appear to
affect brainstem centers that control respiration (Wieling et
al., 2009). Involuntary micturition may occur during syn-
cope. Urinary incontinence can occur in less than a quarter
of patients but is typically associated with a rapid onset
of syncope (Stephenson, 1990; Hoefnagels et  al., 1991;
Newman and Graves, 2001; Wieling et al., 2009).
Certain features are clearly not associated with syn-
cope, including tongue biting and fecal incontinence
(Wieling et al., 2009).
Postsyncopal symptoms
Unlike in a seizure, recovery of consciousness with syn-
cope is rapid. Total duration of syncope from onset to
recovery of consciousness ranges from 20 to 30 seconds
(Wieling et al., 2009). Although post-event confusion
may occur, this more typical of cardiac syncope (Calkins
et al., 1995). Less commonly, flushing (more common with
Stokes–Adams phenomenon), apnea, retrograde amne-
sia, and other mental status changes, such as visual and
auditory hallucinations, may be noted (Formijne, 1938;
Sharpey-Schafer, 1956; Karp et al., 1961; Duvoisin, 1962;
Forster and Whinnery, 1988; Stephenson, 1990; Lempert
et al., 1994; Wieling et al., 2009).
Differential diagnosis
Syncope may be confused with several other related con-
ditions, principally those involving a TLOC. Many, if not
all, can be differentiated from fainting by a careful and
detailed history.
Epilepsy and/or seizures
The most important problem the neurologist faces in this
regard is to differentiate a syncopal episode from a sei-
zure. This is important, given that epilepsy carries signifi-
cant stigma. Additionally, making a diagnosis of epilepsy
(two or more unprovoked seizures or one seizure and an
underlying condition that may provoke seizures; Berg
et al., 2010) leads to the initiation of anti-epileptic medica-
tions that may cause significant side effects. A careful and
thorough history is without substitute in making the cor-
rect diagnosis in cases of TLOC. Partial complex seizures
are the most common form of epilepsy in the elderly, and
several historical features may facilitate making a diag-
nosis. Temporal lobe epilepsy often presents with auras
of jamais vu or déjà vu and an epigastric sensation that
may rise, with the patient losing consciousness before this
reaches the throat. Patients with temporal lobe epilepsy
may encounter many such auras in the past. Visual hal-
lucinations and illusions may suggest an occipital lobe
epilepsy, which is considerably rarer (McKeon et al., 2006;
Panayiotopoulos, 2007).
Unfortunately, physicians rarely correctly arrive at
the appropriate diagnosis of an initial transient event
of loss of consciousness. Reviewing written physician
notes on 118 subjects with loss of consciousness, physi-
cians came to the appropriate diagnosis in less than a
third of all patients. In 16% of patients, the diagnosis
was inappropriate (Hoefnagels et al., 1992). Sheldon et
al. examined whether a simple rating score could help
clinicians differentiate between seizures and syncope

Table 14.2 A point score to differentiate seizures from syncope
Criteria
Awakening with a cut tongue after a typical episode
History of déjà vu or jamais vu prior to episode
Emotional stress associated with episode
Head turning during episode
Unresponsiveness/unusual posturing/jerking of limbs
(all during episode)/no memory post-episode
(Any one of these)
History of confusion after an episode
History of lightheaded spells
History of sweating before episodes
Association between episodes and prolonged sitting and
standing
An overall score of 1 demarcates seizure from syncope, with scores
equal to or >1 suggestive of seizures.
Source: Sheldon et al. (2002). Modified with permission of Elsevier.
(Sheldon et al., 2002). The authors studied patients
in whom the diagnoses of syncope and seizure had
definitely been made and abstracted several histori-
cal features from the medical records of these patients.
Gold-standard diagnostic studies included confirma-
tory electroencephalogram (EEG) for seizures, tilt table
testing for vasovagal syncope, and appropriate ECG
findings for cardiac syncope. Table 14.2 lists the scores
used in that study. After tallying the total score, the
authors found that a score of 1 sharply discriminated
between seizures and syncope, with a number >1 sug-
gesting seizure (Sheldon et al., 2002).
The most common and misleading feature that may
lead to the diagnosis of epilepsy in a patient with
syncope are the myoclonic jerks that may accom-
pany syncope. As discussed earlier in this chapter,
these jerks are most likely a brainstem phenomenon,
whereas myoclonic jerking in seizures are a cortical
phenomenon (Berkovic and Crompton, 2010; Forster
and Whinnery, 1988). On a molecular level, genetic
syndromes that affect the heart in the familial condi-
tions that predispose to syncope have similar pathoge-
netic mechanisms to the familial epilepsies, given that
both conditions are channelopathies (Berkovic and
Crompton, 2010).
If seizures are suspected based on history, it is impor-
tant to obtain neurophysiologic studies, particularly
EEG. The EEG has limited sensitivity in detecting epilep-
tiform activity; evidence suggests that an EEG obtained
closer temporally to the event may have higher degrees
of sensitivity (King et al., 1998; Neufeld et al., 2000). A
head MRI is also important in determining whether the
patient has a cerebral lesion compatible with seizures,
especially mesial temporal lobe sclerosis (McKeon et al.,
2006).
Autonomic Dysfunction and Syncope 361
Nonepileptic seizures
Point
score These events have a variety of appellations and may be
2
referred to as pseudoseizures, psychogenic nonepileptic
1 seizures, psychogenic events, and hysteria. This condition
1 may be associated with up to 30% of referrals to epilepsy
1 clinics and may present as intractable epilepsy (Benbadis,
1 2006). There is an association with a variety of psychiat-
ric comorbidities. McKeon suggests these events may be
differentiated from seizures and from syncope by a care-
1
ful history; the physician should pay attention to clinical
−2
characteristics of the attacks, the patient’s past psychiat-
−2
ric history, and, importantly, a history of prior abuse or
−2
trauma (McKeon et al., 2006). Patients with this condition
may develop syncope-like symptoms during tilt table
testing without any changes in hemodynamic parameters,
suggesting a nonphysiologic event (McKeon et al., 2006).
Psychogenic pseudosyncope
Benbedis and Chichkova examined a phenomenon
described by the authors as “psychogenic pseudosyn-
cope” (Benbadis and Chichkova, 2006), which likely rep-
resents a significant fraction of those patients in whom
the cause of syncope is not clearly established. Using a
single-center prospective study, the authors identified a
total of ten patients over a period of 18 months. Patients
had previously undergone an electrocardiogram (ECG),
echocardiography, Holter monitoring, and tilt table test-
ing. Typically, the duration of symptoms was about 4
years. Nine of these individuals had a habitual syncope
that could be easily triggered by the examining physician.
Concomitant electroencephalographic evaluation dur-
ing the putative syncopal events showed a normal and
appropriate alpha background, suggesting the preserva-
tion of consciousness during the apparent syncopal event
(Benbadis and Chichkova, 2006).
Other conditions
Other conditions that rarely may be misdiagnosed as
syncope include transient ischemic attacks, migraines,
subclavian steal syndrome, and hypoglycemia (Hirsch et
al., 2005). The diagnosis of hypoglycemia may be read-
ily made with a blood glucose measurement and a corre-
sponding past medical history, although occasionally this
may be a more difficult diagnosis to make. Transient isch-
emic attacks (with symptoms lasting less than 24 hours
but more typically lasting only a few minutes), particu-
larly those of the vertebrobasilar circulation, may present
with TLOC but will be accompanied by other neuro-
logic signs that may include nystagmus and/or dyscon-
jugate gaze, cerebellar involvement, and cranial nerve
362 Neurologic Conditions in the Elderly
involvement (Brust, 2005). Basilar migraine is a migrain-
ous headache with vertigo, dysarthria, and diplopia. In a
small fraction of these patients, a confusional state may
occur, but unlike with syncope, there is no clear loss of
consciousness (Raskin and Green, 2005). Subclavian steal
syndrome is characterized by decreased vertebral blood
flow, owing to subclavian stenosis and leading to presyn-
copal symptoms (Hirsch et al., 2005).
Types of syncope
Syncope may be classified into three types based primar-
ily on causative mechanisms: neurally mediated syncope,
cardiac syncope, and situational syncope associated with
orthostatic hypotension.
Neurally mediated syncope
Neurally mediated syncope may be best defined as a
condition during which the ANS is acutely unable to
maintain adequate cerebral perfusion pressures and,
occasionally, a heart rate sufficient to maintain cerebral
perfusion (Grubb and Karas, 1999; Grubb, 2005). Patho-
physiologically, this type of syncope may be defined as
arterial vasodilation in the setting of a relative of abso-
lute bradycardia (Mosqueda-Garcia et al., 2000). The chief
clinical manifestation of this type of syncope is marked
activation of the ANS, characterized by nausea, perspira-
tion, and pallor; these features may be less prominent in
older individuals (van Dijk et al., 2009).
An important historical feature that differentiates this
form of syncope is the presence of a distinct trigger (van Dijk
et al., 2009). Several provocative factors are known, includ-
ing a warm atmosphere, intense exercise, pain, emotional
upsets, and long periods of standing (Grubb, 2005). The
most common causes are fear and pain, followed by stand-
ing (Ganzeboom et al., 2003). Triggered or reflex syncope are
episodes of TLOC definitely associated with specific trig-
gers; they are discussed in more detail in this section.
The upright human posture provides circulatory chal-
lenges to maintaining adequate cerebral perfusion. There-
fore, the ANS plays a crucial role. Standing facilitates the
trapping of a significant volume of blood in the veins
of the lower extremities, which may then lead to a low
volume state and hypotension (Kapoor, 2000). Cardio-
pulmonary baroreceptors and baroreceptors in the arte-
rial system monitor acute changes in blood pressure; this
information is transmitted to the central nervous system
and is used to regulate ANS responses. Several theories
have been developed to explain syncope in the neurally
mediated syncopal model. Sharpey-Schafer has theorized
that reduced left ventricular volume in the setting of
sympathetic activation results in the generation of inhibi-
tory responses that may lead to bradycardia and hypo-
tension (Sharpey-Schafer, 1956; Mosqueda-Garcia et al.,
2000). This is termed the ventricular theory of syncope.
Neurohumeral mechanisms that have been considered
include the role of increased serum epinephrine and sero-
tonin (Mosqueda-Garcia et al., 2000). Reduced blood vol-
ume may have a pathophysiologic role in this condition,
given the fact that an increase in salt intake and the use
of fludrocortisones both have benefits in treating recur-
rent syncope. Baroreceptor dysfunction, thereby result-
ing in “misfiring” of the ANS, has also been implicated
(Mosqueda-Garcia et al., 2000).
Carotid sinus hypersensitivity is a subtype of neurally
mediated syncope. This condition is characterized by brief
and transient LOC with drops and falls, most common
in elder populations associated with 3 seconds of cardiac
asystole, accompanied by a 50 mmHg drop in systolic
blood pressure in response to carotid sinus massage. This
condition is suspected in up to 50% of patients with falls
and syncope (Huang et al., 1988). A clinician diagnoses this
condition by performing a carotid sinus massage, which
involves 5–10 seconds of sinus palpation, initially on the
right and then on the left, first in the supine position and
then in the standing position (Tan et al., 2009). The typical
indications for performing a carotid sinus massage include
fainting after wearing a tight shirt collar, while shaving,
or after an abrupt head turn. It should also be considered
in elderly adults with repeated falls or syncopal episodes
when other investigation are nonrevealing. Contraindica-
tions to performing a carotid massage include recent myo-
cardial infarction, stroke, or transient ischemic attack (TIA),
as well as a carotid bruit, ventricular fibrillation, and ven-
tricular tachycardia (Miller and Kruse, 2005). The Valsalva
maneuver may result in decreased venous return to the
heart and may thereby trigger syncope (Hirsch et al., 2005).
Carotid sinus massage and Valsalva maneuvers can also be
used to evaluate syncope.
A variety of situational syncope syndromes have been
described and may involve a neurally triggered brady-
cardia and hypotension leading to syncope (Hirsch et al.,
2005). The most common are those associated with mic-
turition, cough, and defecation (Kapoor, 2000). Rarer
types of reflex syncope include laughter, post-prandial,
and post-exercise syncope (Nishida et al., 2008). Needle-
and blood-related syncope are fainting spells triggered
by the strong emotional stimuli associated with the sight
of blood or needles. Twelve percent of British medical
students reported at least one syncopal episode while
observing surgical procedures (Jamjoom et al., 2009).
Overall, 8% of teenaged blood donors developed a synco-
pal episode (Reiss et al., 2009). Older blood donors have
a significantly lower risk of syncope with blood donation
(Tondon et al., 2008).
Cardiac syncope
Cardiac syncope, more common in geriatric populations,
is an important form of syncope with a grave prognosis.

This form of syncope is characterized by a sudden dec-
rement in cardiac output, resulting in decreased cerebral
perfusion. Some evidence implicates the responsiveness
of the ANS (van Dijk et al., 2009). In the Framingham
Heart Study, cardiac syncope was highly recurrent and
doubled the risk of mortality as compared to all par-
ticipants with syncope (Soteriades et al., 2002). Cardiac
syncope can be dichotomized into syncope secondary to
cardiac arrhythmias and cardiac syncope secondary to
structural heart disease. Cardiac arrhythmias typically
cause syncope by abruptly reducing cardiac output, and
structural cardiac disease limits the ability of the heart to
increase cardiac output in response to increased circula-
tory need (Brignole, 2007).
Clinical features that suggest the involvement of a car-
diac arrhythmia include loss of consciousness with no
definite prodrome, as well as a history of cardiac prob-
lems and a family history of sudden death (Kapoor, 2000).
The arrhythmias that lead to syncope may be bradyar-
rhythmias (sinus node disease, second- or third-degree
heart block, malfunctioning cardiac pacemaker, or drug
inducement) or tachyarrhythmias (ventricular tachycar-
dia, supraventricular tachycardia, or torsades de pointes).
An important historical feature is that arrhythmias typi-
cally occur in apparently normal individuals (Kapoor,
2002; van Dijk et al., 2009).
Arrhythmias superimpose on structural cardiac disease
and contribute to the development of syncope. Syncope
may be seen secondary to congestive heart failure (CHF).
In a study of 491 patients with CHF (New York Heart
Association Grade III and IV), 12% developed at least
one syncopal episode (Middlekauff et al., 1993; Gopi-
nathannair et al., 2008). Syncope in CHF is significantly
related to ventricular ectopy and ventricular tachycardia
(Olshansky et al., 1999). Other etiologies for structural
heart disease associated with syncope include valvular
heart disease, ischemic cardiac disease, hypertrophic car-
diomyopathy, pericardial disease, and pulmonary hyper-
tension (van Dijk et al., 2009).
Syncope secondary to autonomic dysfunction
The cardinal features of orthostatic hypotension include
dizziness, presyncope, and syncope (Freeman, 2008).
Other features of orthostatic hypotension include weak-
ness, fatigue, nausea, and headache. Freeman described
an unusual headache phenomenon in these patients that
is associated with pain over the back of the neck and
shoulders, which bears the appellation of “coat hanger
headache” (Freeman, 2008). Although these patients may
have hypotension while standing, supine hypertension is
a common feature. In this condition, syncope or presyn-
cope typically occurs during a rapid transition from sit-
ting or lying to a standing position, causing acute arterial
hypotension. Failure of compensatory mechanisms from
a compromised ANS leads to cerebral hypoperfusion
Autonomic Dysfunction and Syncope 363
and subsequent fainting. An additional pathophysiologic
mechanism includes a reduced functional circulatory
blood volume from peripheral pooling of blood, again
due to an impaired ANS (Brignole, 2007).
Freeman classifies autonomic hypotension into that
caused by central nervous system disorders and that
caused by peripheral dysfunction. Central nervous sys-
tem causes include the synucleinopathies multiple sys-
tem atrophy (MSA), Parkinson’s disease (PD), and pure
autonomic failure. Peripheral nervous system causes are
the small fiber neuropathies that are typically caused by
diabetes mellitus and amyloidosis, hereditary sensory
and autonomic neuropathy type III, and, rarely, B12 defi-
ciency, HIV neuropathy, and porphyria (Freeman, 2008).
Mussi et al. examined the frequency of orthostatic hypo-
tension in a review of 259 patients aged 65 or more who
were admitted to an emergency department and found a
prevalence of 12%, with PD being the dominant etiology
(Mussi et al., 2009).
Patients with PD develop autonomic dysfunction later
in the course of the disease, with motor symptoms begin-
ning first; medications used to treat PD may worsen
these symptoms (Freeman, 2008). In a prospective study,
nearly a third of subjects with PD had orthostatic hypo-
tension (Lipp et al., 2009). Neihaus et al. found that even
PD patients without a history of autonomic dysfunc-
tion demonstrated impaired ANS activity in response
to tilt testing, as compared to healthy, age-matched con-
trols (Niehaus et al., 2002). In comparison, in Lewy body
dementia, where clinically dementia symptoms precede
parkinsonism, autonomic dysfunction occurs early in the
disease course (Freeman, 2008). Syncope is a core feature
of this disease (Geldmacher, 2004).
MSA, rarer than either PD or dementia with Lewy bod-
ies, is defined as an adult-onset, progressive, sporadic,
neurodegenerative disease characterized by varying
severity of Parkinsonian features, cerebellar ataxia, auto-
nomic failure, urogenital dysfunction, and corticospinal
disorders (Gilman et al., 2008). Four syndrome complexes
are linked to this diagnosis and comprise striatonigral
degeneration, Shy–Drager syndrome, olivopontocerebel-
lar atrophy, and amyotrophy-parkinsonism. Shy–Drager
syndrome is dominated by autonomic dysfunction and is
associated with depletion of sympathetic preganglionic
neurons in the spinal cord intermediolateral horns. The
post-ganglionic sympathetic neurons are retained; when
the patient is in a supine position, plasma norepinephrine
levels are normal and do not rise when the patient stands
(Louis, 2005). Patients with MSA may have symptomatic
or asymptomatic autonomic failure; autonomic dysfunc-
tion as a criteria for MSA is defined as a decrease in sys-
tolic blood pressure by 30 mmHg or of diastolic blood
pressure by 15 mmHg after a three-minute stand, arising
from 3 minutes in the recumbent position (Gilman et al.,
2008). Lipp and colleagues prospectively examined the
364 Neurologic Conditions in the Elderly
clinical differences between MSA and PD with autonomic
failure. Accuracy of diagnosis is important in this regard,
given that MSA has much graver prognosis than PD. The
authors found that orthostatic hypotension was almost
always present in MSA. The study found that the sever-
ity and pattern of autonomic dysfunction, including anhi-
drosis, in MSA distinguish this condition from PD (Lipp
et al., 2009). Patients with Shy–Drager syndrome treated
with levodopa often have worsening of orthostatic hypo-
tension (Louis, 2005).
Pure autonomic failure is an extremely rare condition
that was first described in 1925. It is characterized by
severe autonomic hypotension, starting typically after the
age of 50 in persons with no other neurologic issues. Lewy
bodies are found in autonomic ganglia (Weimer, 2005).
Klein et al. studied 18 subjects (average age 63), all with
autoimmune antibodies directed against autonomic gan-
glia. Two different clinical patterns were noted. Patients
with high antibody titers had significantly more cholin-
ergic symptoms than those with a low antibody titer. The
latter group was identical clinically to pure autonomic
failure (Klein et al., 2003).
Peripheral nervous system involvement leading to
autonomic dysfunction and syncope has been best stud-
ied in diabetes mellitus. Overt autonomic neuropathy
is delayed for several years after diagnosis of diabetes,
although there is evidence that subclinical autonomic
dysfunction exists early in the clinical course of type II
diabetes mellitus. Factors related to the incidence of dia-
betic autonomic neuropathy include poor glycemic con-
trol, an increased duration of diabetes, higher body mass
index, and female sex (Vinik and Erbas, 2001). A large
clinical trial, the Diabetes Complications and Control
Trial, demonstrated that low long-term blood sugar levels
can ameliorate this condition (1995).
Other neurologic conditions may be associated with
syncope. The population-based CAMERA study dem-
onstrated an increased prevalence of both syncope and
orthostatic hypotension in individuals with migraine.
The authors were unable to explain the pathophysiologic
basis of this finding (Thijs et al., 2006). Case series and
case reports have documented syncope and orthostatic
hypotension in multiple sclerosis, which, in at least some
isolated cases, improved with pulse steroid treatment
(Sakakibara et al., 1997; Funakawa and Terao, 1998; Kan-
jwal et al., 2010).
Investigations
Several evidence-based guidelines have addressed the
issue of diagnosis and management of syncope. The first
step in assessing syncope is to obtain an ECG (Strickber-
ger et al., 2006). The ECG will provide information regard-
ing both cardiac rhythm and junctional abnormalities. In
patients whose history and examination may lead the cli-
nician to suspect a cardiac cause for syncope, the ECG will
serve as a confirmatory test. In patients in whom cardiac
disease is not suspected, the ECG will provide important
information on possible etiology for the fainting spell.
The American Heart Association (AHA) consensus state-
ment on syncope notes that the ECG will be able to clearly
identify two high-risk groups for which an adverse out-
come is likely: hypertrophic cardiomyopathy (a cause of
sudden death in young athletes) and pulmonary embo-
lism (Strickberger et al., 2006). A prolonged ECG may be
recommended when syncopal events are frequent. The
gold standard is the documentation of a cardiac arrhyth-
mia during syncope, thereby establishing causation. The
AHA consensus statement suggests placing an ambula-
tory Holter ECG monitor for 24 to 48 hours. Event-record-
ing devices can be used for up 60 days, and recording is
triggered by a patient-initiated button press. However,
these devices are complex and are associated with higher
rates of patient error. Implantable loop recorders are
placed subcutaneously and may record ECG rhythms for
approximately 14 months (Strickberger et al., 2006).
In patients with syncope and suspected or known
ischemic coronary disease, exercise stress testing is rec-
ommended. Electrophysiologic cardiac studies involve
the placement of cardiac transvenous catheters to assess
sinus and AV node function, but they have a low sensi-
tivity in unselected patients (Strickberger et al., 2006).
The evidence-based guideline from the European Society
of Cardiology also proposed echocardiography to bet-
ter assess structural cardiac disease, as well as carotid
sinus massage when carotid sinus hypersensitivity is sus-
pected. Finally, the European guidelines also suggest a
role of psychiatric consultation when functional episodes
are suspected (Moya et al., 2009).
Tilt table testing is important in the assessment of neu-
rocardiogenic syncope. Specific protocols have evolved
with regard to tilt table testing: the Newcastle Protocols
(Parry et al., 2009). This procedure should be restricted
to cases of syncope in which diagnosis of a neurocardio-
genic etiology is unclear from history or examination or
when the patient is cognitively impaired, has had syncope
while driving, or has had repeated falls with injury. Con-
traindications to this procedure are few and are limited
to critical left ventricular outflow obstruction and mitral
stenosis, and severe coronary or cerebrovascular disease
(Parry et al., 2009).
Patients must be instructed that they are not required
to fast or discontinue medications on the day of the pro-
cedure. The typical equipment used in this test is a tilt
table with foot plate support that can tilt to an upright
position from a supine one, through an angle of 70°.
ECG and blood pressure monitoring accompany the test
(Parry et al., 2009). The patient is typically in the supine
position in a resting state for 20 minutes, followed by a

rapid upright tilt (through 70°) for 40 minutes (Kenny
et al., 2000). Pharmacologically enhanced testing using
either nitrate or isoproterenol may be used (Bartoletti
et al., 2000; Graham et al., 2001; Moya et al., 2009); these
drugs enhance resting heart rate. The tilt table provides a
confirmatory diagnosis only if the patient’s original syn-
copal (or presyncopal) symptoms are reproduced along
with hypotension and/or bradycardia. A combination of
both subjective symptoms and objective signs is required
(Kenny et al., 2000). The sensitivity of the tilt table test
is not well established, and questions remain about both
the validity and reliability of the test (Sagrista-Sauleda et
al., 2001). A negative tilt table testing does not exclude a
vasovagal etiology to syncope (Moya et al., 2009).
EEGs are commonly ordered to differentiate between
syncope and seizures. Typically, interictal EEGs are nor-
mal in most patients with syncope, as well as a signifi-
cant number of patients with seizures. European syncope
guidelines recommend an EEG when there is consider-
able suspicion that an episode was a seizure rather than
syncope. An EEG is also indicated in psychogenic pseu-
dosyncope when the diagnosis may be made with ease
if a typical event is captured during the EEG (Moya et
al., 2009). Cranial computed tomograms, head magnetic
resonance images, carotid duplex imaging, or transcranial
Doppler studies may be ordered only if a clinical indica-
tion exists (Moya et al., 2009).
Prognosis and economic impact
of syncope
Using actuarial analysis techniques and data from the
Framingham Study, Soteriaredes et al. found that syncope
was associated with increased mortality in a mid- and
late-life population. Mortality among all those who had
had a syncopal episode was increased by 31%. In partici-
pants who had had cardiac syncope, the risk of death was
increased twofold. Vasovagal syncope (including ortho-
static hypotension) was associated with the least increase
in mortality. Participants who had a syncopal episode of
unclear etiology had an increased risk of a subsequent
myocardial infarction and/or death (Soteriades et al.,
2002). Alshekhlee et al. used the US National Inpatient
Sample Database to evaluate the prognosis of syncope
and found that the overall mortality rate was 0.28%; the
odds of mortality from syncope increased sharply after
the age of 40 and in those who reported a larger number
of comorbidities (Alshekhlee et al., 2009). Hospital admis-
sion for syncopal evaluation and management appears to
benefit short-term (30-day) outcomes but did not affect
outcomes at one year post-event (Costantino et al., 2008).
Data from the National Inpatient Sample demonstrates
that the median cost of inpatient treatment for syncope in
the United States is about $8500. This amount increases
Autonomic Dysfunction and Syncope 365
dramatically, sometimes up to 11-fold, if cardiac pace-
makers need to be placed (Alshekhlee et al., 2009). The
cost to the Medicare system is approximately $2.4 billion
per annum (Sun et al., 2006).
Management
The management of syncope is best tailored to the under-
lying cause of the TLOC. Neurocardiogenic syncope has
the best prognosis of all syncopal types. There is very
little evidence underlying treatment options for this con-
dition. A beta blocker, atenolol, was effective in a random-
ized controlled trial at improving syncopal symptoms, as
compared to placebo (Mahanonda et al., 1995). In refrac-
tory syncope, a trial of paroxetine appeared to improve
symptoms (Di Girolamo et al., 1999; Kapoor, 2000). Clini-
cal trials have also been performed on transvenous pac-
ing; the majority of these studies have demonstrated effi-
cacy (Brignole, 2003). The pacemakers were designed to
provide cardiac pacing in cases of a concomitant drop in
heart rate in patients who had severe syncopal symptoms
(Kapoor, 2000). A number of other medications are used
in the treatment of syncope without a significant evidence
base. These include disopyramide, clonidine, theophyl-
line, ephedrine, dihydroergotamine, and midodrine (Bri-
gnole, 2003).
An important component of any management strategy
of neurocardiogenic syncope is to provide reassurance to
the patient that this type of syncope is benign. Patients
must be counseled about avoiding triggers of their syn-
cope (Moya et al., 2009).
The treatment of orthostatic hypotension can be
dichotomized into pharmacologic management and
nonpharmacologic mechanisms of treatment. In patients
in whom plasma volume expansion cannot be achieved
with increased fluid and salt intake, fludrocortisone, a
mineralocorticoid, can be used (Freeman, 2008). Because
the primary pathophysiologic mechanism in orthostatic
hypotension is the lack of norepinephrine release, mido-
drine, a peripheral and selective alpha adrenergic recep-
tor agonist can be used. This medication, which is the
only one approved in the United States by the Food and
Drug Administration for orthostatic hypotension, has
been noted in clinical trials to improve standing blood
pressures (Low et al., 1997; Wright et al., 1998; Freeman,
2008). Pyridostigmine, an acetylcholinesterase inhibitor,
has successfully undergone a clinical trial for this condi-
tion (Wright et al., 1998; Singer et al., 2006). Other agents
that have been used to treat orthostatic hypotension
include erythropoietin (Hoeldtke and Streeten, 1993),
ephedrine and pseudoephedrine (Jordan et al., 1998),
clonidine, and dopamine agonists (Freeman, 2008).
Nonpharmacologic interventions must typically be tried
first before considering drug therapy. Most important is
366 Neurologic Conditions in the Elderly
patient education. Patients must be told that they can
minimize symptoms from orthostatic hypotension by
moving slowly from the supine to the standing posi-
tion. Through the day, physical maneuvers may be
attempted to reduce peripheral pooling of blood: these
include tensing the muscles of the lower extremities and
crossing and uncrossing legs. Elastic compression stock-
ings for the lower extremities facilitate lower extrem-
ity venous return. During rest and sleep, a head raise
of 10°–20° reduces supine hypertension that may lead
to diuresis and volume depletion. Medications such as
diuretics and some antihypertensives must be avoided.
Finally, increased salt intake (up to 10 g sodium per day)
and increased liquid intake (water) can improve ortho-
static hypotension (Freeman, 2008).
The treatment of cardiac syncope is complex and is
beyond the scope of this chapter. The consensus state-
ment of the European Society of Cardiology provides
guidelines on the treatment of cardiac syncope (Moya
et al., 2009). Sinus node dysfunction and AV node disease
are both treated with cardiac pacemakers. Supraventricu-
lar tachycardia and atrial flutter are managed with cath-
eter ablation. A malfunctioning cardiac device causing
syncope may need reprogramming or, less commonly,
replacement. Where structural heart disease is implicated
in the causation of syncope, treatment of the underlying
cardiac condition is essential.
Risk prognostication scores in syncope
Several prognostication scores can help the clinician make
decisions about which patients with syncope need further
(often inpatient) workup and which patients can be eval-
uated as outpatients. This is an important issue because
inpatient hospital admission is expensive (Alshekhlee
et al., 2009).
Three risk prognostication scores have been devel-
oped: the San Francisco Syncope Rule (SFSR), Osservato-
rio Epidemiologico sulla Sincope nel Lazio (OESIL), and
the European Guidelines in Syncope Score (EGSYS). The
SFSR is the simplest (Parry and Tan, 2010). Predictor vari-
ables that comprise the SFSR include an abnormal ECG,
history of shortness of breath, CHF, hematocrit less than
30%, and a systolic blood pressure less than 90 mmHg on
initial examination in the emergency department (Quinn
et al., 2004). The authors suggest that considering these
variables in clinical decision making allows for the predic-
tion of future adverse events with a sensitivity of 92% and
a specificity of 62%, though this data has been challenged
(Quinn et al., 2004; Birnbaum et al., 2008). The OESIL
score incorporates other predictors, including age greater
than 65 years and lack of a prodromal history (Colivicchi
et al., 2003). The EGSYS score is the newest prognostica-
tion index and incorporates features including a history
of palpitations prior to syncope, syncope during rest or
exertion, and the absence of precipitating factors for syn-
cope (Del Rosso et al., 2008).
Syncope in the elderly
Syncope accounts for a third of falls in the elderly, a
population that is already at high risk of falling from a
variety of circumstances (Tinetti et al., 2000). Syncope is
incident in about 6% of the elderly; this number rises to
23% of those in assisted living and nursing home facilities
(Ungar et al., 2006). Hospitalization for syncope increases
with increasing age (Moya et al., 2009). Ungar et al. evalu-
ated syncope in people aged 70 or older. Clinically, syn-
cope more typically occurred from the standing position
in older than younger patients. More than 70% of patients
had a prodromal symptom immediately prior to the syn-
copal episode. Neurally mediated (neurocardiogenic and
orthostatic) syncope accounted for two-thirds of all cases
(Ungar et al., 2006). A precise history regarding syncopal
episodes may be difficult to obtain in some older patients,
owing to cognitive impairment (Moya et al., 2009). Sev-
eral factors increase susceptibility to syncope in the
elderly, including reduced oral intake and resultant mild
dehydration, a predisposition to orthostatic hypotension,
and impaired cardiac heart rate variability (Kenny et al.,
2002; Strickberger et al., 2006). Many syncopal episodes in
the elderly are the result of polypharmacy, most often due
to cardiovascular medications (Strickberger et al., 2006).
Syncope while driving, an issue with major public safety
ramifications, occurs most often in patients in their late
50s or older (Sorajja et al., 2009).
In elderly patients, it is important for clinicians to pre-
vent falls and to rapidly identify possible life-threaten-
ing conditions. In the elderly, syncope is typically a mul-
tifactorial process (Strickberger et al., 2006). Though the
assessment of syncope is similar to that with younger
patients, special attention should be paid to gait exami-
nation, as well as cognitive testing (Moya et al., 2009).
Conclusion
Syncope is an important cause of TLOC, with particular
importance in older populations. Future directions of
research include the development of clinical biomarkers
to assist in identifying patients who may be at risk of com-
plications after syncope. Further research is also needed
to refine prognostic risk score systems to enable rapid
risk stratification of patients with syncope. Finally, there
is ongoing research into the best treatment for syncope,
especially cardiac syncope (Parry and Tan, 2010). Ulti-
mately, the key to diagnosing and managing syncope is
careful history and timely reassurance.

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 Chapter 15
Geriatric Epilepsy
David V. Lardizabal
Epilepsy Program and Intraoperative Monitoring, University of Missouri, Columbia, MO, USA

Summary
• Epidemiology: Studies have shown that the incidence of epilepsy increases with age and is much more prevalent in
nursing home residents compared to the elderly in the community.
• Etiology: Symptomatic causes are often due to cerebrovascular diseases which cause stroke or neurodegenerative
diseases such as Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Closed head injuries may also account
for epilepsy.
• Mechanism: Hypothesized as an imbalance of excitatory and inhibitory neurotransmissions, favoring excitation. Stroke-
related seizures are due to biochemical abnormality shortly after the stroke. Chronic processes such as gliosis, removal
of inhibitory influences, and synaptic formation, may also induce seizures 2 weeks after stroke.
• Clinical Diagnosis: An abnormal and excessive neural discharge that clinically manifests as altered consciousness and
motor, sensory, or psychiatric events in a recurrent or stereotyped fashion.
• Differential diagnosis: Syncope, migraine, toxic–metabolic derangement, transient ischemic attacks (TIAs), transient
global amnesia (TGA), dizziness/vertigo, delirium, and intermittent movement disorders are physiologic nonepileptic
events that may be interpreted as epileptic seizures. Additionally, seizures can be caused by psychiatric illness.
• Magnetic resonance imaging (MRI) and electroencephalograms (EEGs) are the diagnostic study tools of choice.
• Approximately 10% of nursing home residents are treated with antiepileptic drugs (AEDs) or anticonvulsants. Nineteen
or more anticonvulsants are available and several more are currently being studied in clinical trials.

Introduction in persons aged 75 years and older. It is estimated that

After stroke and dementia, geriatric epilepsy is the third
most common neurologic condition (Diamond and Blum,
2008; Hommet et al., 2008; Jetter and Cavazos, 2008;
Werhahn, 2009). Epilepsy is a syndromic diagnosis with
different clinical seizure features and etiologies. Clinical
and epidemiologic studies cite 60 or 65 years of age as the
minimum age for geriatric epilepsy. This chapter focuses
on the epidemiology, etiology, clinical features or semiol-
ogy, differential diagnosis, seizure mechanisms, and drug
therapy.
Epidemiology of geriatric epilepsy
The landmark study by Hauser et al. (1993) provided
a good epidemiologic estimate of geriatric epilepsy in
North America. The incidence of epilepsy and of all
unprovoked seizures was determined among the resi-
dents of Rochester, Minnesota, from 1935 to 1984. The age-
adjusted incidence of epilepsy was 44 per 100,000 person-
years. Incidence in males was significantly higher than in
females and was high in the first year of life but highest
half of new-onset epilepsy by 2020 will be from the geri-
atric population (Pugh et al., 2009). The incidence of any
type of first seizure is 50/100,000 for people aged 40–59;
this increases to 127,000 in people older than 60 years. The
incidence of epilepsy in the elderly seems to rise steadily
at the 55- to 64-year age group and increases dramatically
after the age of 65. The highest incidence is approximately
160 per 100,000 person-years and occurs among the 75- to
84-year age group (Hauser et al., 1993).
Hussain et al. (2006) examined the age-specific incidence
and cumulative incidence of epilepsy in a well-defined
cohort of elderly people (n = 1919). The rates of epilepsy
were also analyzed by sex, race, stroke, dementia, head
injury, and depression. Age-specific incidence was 10.6
(per 100,000 person-years) between ages 45 and 59, 25.8
between ages 60 and 74, and 101.1 between ages 75 and
89. Cumulative incidence was 0.15% from age 45 to age
60, 0.38% to age 70, 1.01% to age 80, and 1.47% to age 90.
In addition, the difference in cumulative incidence among
African-American subjects approached statistical signifi-
cance (57.6/100,000 person-years vs. 26.1 in Caucasian,
p = 0 .10), and the difference in incidence among subjects
reporting a history of stroke was significantly elevated

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

370

(p = 0.029). Incidence of epilepsy was not statistically ele-
vated among males, those with dementia, or individuals
reporting a history of head injury or treatment for depres-
sion. Among “healthy” subjects without a history of
stroke, head injury, or dementia, it was observed that the
cumulative risk of epilepsy with onset after age 60 was
1.1%. Little information exists on the incidence of geriatric
epilepsy in other ethnic groups.
The prevalence in epilepsy increases with age and is
estimated to be 5/1000 between 20 and 50 years, 7/1000
between 55 and 64 years, and 12/1000 between 85 and
94 years (Hauser et al., 1996). The prevalence of epilepsy
in nursing home residents is much higher than in the
community-dwelling elderly (Garrard et al., 2000).
Etiology of geriatric epilepsy
Epilepsy in old age is generally an expression of an
underlying disease of the brain. The etiology is impor-
tant because this is usually a determinant of prognosis.
Symptomatic causes of epilepsy in the elderly are usu-
ally due to a cerebrovascular disease or neurodegenera-
tive disease. Stroke and atherosclerosis account for 34.9%
and 14.9% of epilepsy in the elderly, respectively (Ramsay
et al., 2004). Hemorrhagic stroke, cardioembolic ischemic
strokes, and cortical locations favor the development of
epileptic seizures. Population-based studies have shown
that stroke multiplies the risk of epileptic seizures by a
factor of 23 and multiplies the risk of epilepsy in the first
year after the stroke by a factor of 17, compared to the risk
in the comparable general population (Werhahn, 2009).
Early seizures (less than 2 weeks after a stroke) are due
to an acute biochemical abnormality, such as exposure to
the excitatory neurotransmitter glutamate. This can occur
in 2–8% of patients, usually in the first 24–48 hours after
the stroke. About 3–6% may have isolated epileptic sei-
zures. In contrast, late seizures (longer than 2 weeks after
a stroke) are due to chronic processes such as the removal
of inhibitory influences, gliosis, and formation of new
synaptic connections (Werhahn, 2009). Approximately
half of these patients develop focal epilepsy in the first
3 years after the stroke. The frequency of epilepsy after
stroke is 2–4% and is two to four times higher than the
incidence in the same age group without seizures.
Neurodegenerative disease accounts for 12% of geri-
atric epilepsy (Hauser et al., 1993). The prevalence of
dementia is estimated to be 6–8% after 65 years of age
and may rise to 20–30% in subjects older than 85 years. In
patients with dementia, the incidence of seizures is five to
ten times greater than expected in a reference population
(Hesdorffer et al., 1996). In subjects older than 65 years,
dementia and other neurodegenerative diseases account
for 9–17% of the epilepsies seen in the elderly (Hommet
et al., 2008). An estimated 10–22% of Alzheimer’s patients
Geriatric Epilepsy 371
will have at least one unprovoked seizure (Romanelli
et al., 1990; Mendez and Lim, 2003).
Amatniek et al. (2006) studied the cumulative incidence
and predictors of new-onset seizures in mild Alzheimer’s
disease (AD), with a cohort followed prospectively. The
cumulative incidence of unprovoked seizures at 7 years
was nearly 8%. In all age groups, risk was increased com-
pared with a standard population, with an 87-fold increase
in the youngest group (age 50–59 years) and more than
a threefold increase in the oldest group (age 85+ years).
In multivariate modeling, independent predictors of
unprovoked seizures were younger age (relative risk (RR)
0.89 per year increase in age; 95% confidence interval (CI),
0.82–0.97), African-American ethnic background (RR 7.35;
95% CI, 1.42–37.98), more severe dementia (RR 4.15; 95%
CI, 1.06–16.27), and focal epileptiform findings on electro-
encephalogram (EEG) (RR 73.36; 95% CI, 1.75–3075.25).
It was concluded that seizure incidence was increased in
people starting with mild-to-moderate AD. Younger indi-
viduals, African-Americans, and those with more severe
disease or focal epileptiform findings on EEG were more
likely to have unprovoked seizures. In contrast, Scarmeas
et al. (2009) showed in a prospective cohort study a low
incidence (1.5%) of developing epilepsy among patients
with dementia.
Closed head injury accounts for about 6.9% of geri-
atric epilepsy. Head injuries may be secondary to prior
falls or car accidents. In a retrospective study by Lees
(Lees, 2010) head injuries accounted for 10% of the inju-
ries associated with falls. Even though brain tumors
have a minor role (2.7% of cases) as a cause of geriatric
epilepsy (Hauser et al., 1993), they have a major impact
on the prognosis and quality of life of geriatric patients.
Overall, 60% of the primary brain tumors present with
epilepsy and another 10–20% develop epilepsy later in
the course of the disease (Moots et al., 1995; Hildebrand
et al., 2005). The risk for the development of seizures in
brain tumor patients is related to the tumor type. Low-
grade gliomas, such as grade II astrocytomas and gan-
gliogliomas, present more frequently with seizures than
high-grade tumors. Low-grade tumors present with sei-
zures in 60–85% of patients; seizures are seen in high-
grade brain tumors or brain metastases in 15–40% of
patients, respectively (Moots et al., 1995). In the middle-
aged persons and the elderly, malignant gliomas are rel-
atively more common and, if they present with epilepsy
other neurologic deficits, are more obvious. Moreover,
the location of the tumor is related to seizure develop-
ment, which is much more common with cortical than
white matter lesions. The highest risk of development
of epilepsy occurs when the tumor is located in the tem-
poral cortex, the primary sensorimotor cortex, or the
supplementary cortex.
About one-fourth to one-third of new-onset geriat-
ric epilepsy has no known cause (Scarmeas et al., 2009).
372 Neurologic Conditions in the Elderly
Among healthy elderly people without a known cause
(stroke, trauma, or dementia), the cumulative risk of epi-
lepsy after age 60 is about 1.1% (Hussain et al., 2006).
Postulated mechanisms of geriatric
epileptic seizures
The exact mechanism of seizure generation in symptom-
atic epilepsies is not yet fully elucidated. It is believed that
the generation of seizures is due to an imbalance of excit-
atory and inhibitory neurotransmission in which relative
excitation is favored over inhibition. The process leading
to this imbalance for seizure genesis (or epileptogenesis)
is still under intense research. Postulated mechanisms of
seizure generation are discussed in this section.
In stroke-related seizures, early seizures (less than
2 weeks after a stroke) are due to an acute biochemi-
cal abnormality, such as exposure to the excitatory
neurotransmitter glutamate. This can occur in 2–8% of
patients usually in the first 24–48 hours after the stroke.
About 3–6% may have isolated epileptic seizures. In con-
trast, seizures more than 2 weeks after a stroke (late sei-
zures) are due to chronic processes such as the removal
of inhibitory influences, gliosis, and formation of new
synaptic connections (Werhahn, 2009). In neurodegen-
erative diseases, it is postulated that neuronal cell loss
in the hippocampus (CA1), presenelin-1 mutations, and
amyloid beta and neurofibrillary tangle accumulation
may be responsible (Romanelli et al., 1990; Foürstl et al.,
1992; Ezquerra et al., 1999; Takao et al., 2001; Mendez
and Lim, 2003; Mikolaenko et al., 2006; Shrimpton et al.,
2007).
Gliosis (astrogliosis) is a common neuropathologic
finding among patients with head trauma, neurodegen-
erative disease, prior stroke, and central nervous system
(CNS) infections (Tian et al., 2005; Boison, 2006). Current
evidence suggests that astrocyte dysfunction contributes
to epileptogenesis and seizure expression in epilepsy.
The failure of glia to buffer extracellular glutamate or
dysfunctional release of glutamate by glia was shown to
contribute to the maintenance of the paroxysmal depo-
larizing shift that characterizes neuronal dysfunction in
epilepsy. Furthermore, it is postulated that gliosis may
cause a relative deficiency of adenosine, an endogenous
anticonvulsant of the CNS. Experimental evidence also
suggests that adenosine receptors and adenosine kinase
may be part of the pathologic mechanism in the develop-
ment of epilepsy and seizure generation (Boison, 2008).
Adenosine kinase is responsible for the clearance of ade-
nosine, and overexpression of this enzyme may lower
the adenosine levels around gliotic brain tissue. Experi-
ments have shown that decreased adenosine levels by
elevated adenosine kinase activity generates seizures
(Boison, 2008).
The possible mechanisms for epileptogenicity in primary
gliomas include immune-mediated neuronal damage,
GABA receptor dysfunction, serotonin transporter gene
polymorphism, glutamate excitotoxicity in tumors, brain-
derived neurotrophic factors in tumor growth, and altered
cell cycle and DNA repair. The pathogenesis of seizure
development is likely to occur by different mechanisms for
high- and low-grade gliomas (Beaumont and Whittle, 2000;
Brogna et al., 2008; Berntsson et al., 2009). In fast-growing
high-grade gliomas, the focal peritumoral ischemia and
deafferentation of cortical areas due to mass effect may be
causative factors, where gliosis and chronic inflammatory
changes in peritumoral regions of slow-growing gliomas
may predispose for epileptic seizures. Increased levels of
Fe3+ ions due to small bleedings from blood vessels may
contribute to the genesis of seizures and is more likely to
occur in high-grade gliomas. Often epileptic seizures from
high-grade gliomas are difficult to control.
Clinical diagnosis of geriatric epilepsy
Epileptic seizures result from an abnormal and excessive
discharge of neurons, and this is clinically manifested by
sudden, diverse, transitory symptoms, including altered
consciousness and motor, sensory, or psychiatric events
(Hommet et al., 2008). Unfortunately, the diagnosis of epi-
lepsy in the elderly is delayed by 1.7 years. Moreover, the
clinical features in geriatric epilepsy are not similar in the
younger age group and may be the reason for the delay.
The seizures are often difficult to diagnose because they
present with atypical symptoms, particularly prolonged
postictal symptoms (hours to days), memory lapses, con-
fusion, altered mental status, and inattention. Caretakers
unfamiliar with seizure symptoms may take “senior
moments” for granted. Furthermore, aura and automa-
tisms are not consistent features in geriatric seizures
(Pugh et al., 2009). In the diagnosis of epilepsy, the care-
taker plays a vital role in the history and description of
seizure features. Two important elements about epileptic
seizures are relevant in the history. Epileptic seizures are
recurrent and stereotyped. Therefore, careful questioning
to the caretaker may reveal stereotyped episodes of unex-
plained confusion or altered awareness. Some elderly
patients may not be a reliable source of information. As
mentioned earlier, the symptomatic causes of epilepsy
are usually stroke and dementia. The diagnosis of sei-
zures and epilepsy may be particularly difficult in elderly
patients with dementia. These patients may not remem-
ber or complain of seizure symptoms. Some authors have
indicated that seizures may occur early (3 months) or, in
the later stages, 6 or more years after the onset of demen-
tia (Hommet et al., 2008). Among stroke patients, speech
or language impairment may make communication of
seizure symptoms difficult.

Conditions confused as epileptic
seizures (differential diagnosis)
An accurate and detailed history remains a central tenet
for the diagnosis and treatment of epilepsy. It is impor-
tant to remember that not all convulsions are caused by
epileptic seizures. Epileptic seizures can be mimicked
by nonepileptic events that are common in the elderly
age group (Ramsay et al., 2004; Sirven and Ozuna, 2005;
Hommet et al., 2007; Marasco and Ramsay, 2009). These
nonepileptic events may be physiologic or nonphysi-
ologic. Physiologic nonepileptic events usually signify a
systemic single- or multiorgan dysfunction. These physi-
ologic events are syncope, migraine, toxic–metabolic
derangement, transient ischemic attacks (TIAs), transient
global amnesia (TGA), dizziness/vertigo, delirium, and
intermittent movement disorders.
Syncope is the most common physiologic event con-
fused with epilepsy (incidence of 3000 per 100,000). It
also accounts for approximately 3% of all emergency
department visits. Common conditions causing syncope
include cardiac arrhythmia, hypovolemia, orthostatic,
and sudden drop in blood pressure. Convulsive syncope
represents the most confusing feature of this condition.
During convulsive syncope, brief abnormal movements,
including tonic posturing myoclonus or clonic motor,
occur in response to sudden and transient cerebral anoxia
and ischemia. However, abnormal movements are also
reported to occur in 40– 90% of all syncope cases. The
EEG usually shows diffuse theta–delta slowing during
the syncopal event. No epileptiform discharges are asso-
ciated with syncope (Lin et al., 1982; Kapoor et al., 1983a,
1983b; DeMaria et al., 1984; Aminoff et al., 1988; Lempert,
1996).
Migraine in the elderly may have focal, generalized,
transitory, or stereotyped features. This includes visual
hallucinations, marching sensory symptoms, speech
disturbance, confusion, and weakness. In contrast to sei-
zures, migraine symptoms develop over minutes. A his-
tory of migraine should be sought during interview. The
EEG is normal but may sometimes have nonspecific EEG
changes during an attack.
TIAs can be confused as seizures, but the history can
typically differentiate the two. TIAs are associated with
a sudden loss of a neurologic function lasting minutes to
hours. Seizures are usually shorter, lasting seconds to a
few minutes. TIAs are not usually episodic and stereo-
typed. In rare instances, sudden focal ischemia can cause
positive neurologic symptoms, such as focal limb shaking.
Strokes involving the nondominant or dominant parietal
lobe (transcortical sensory aphasia and Wernicke’s apha-
sia) can also be confused as seizures.
Toxic–metabolic conditions should always be consid-
ered in the differential diagnosis of seizures. Occult infec-
tions or early systemic infections (sepsis) can present
Geriatric Epilepsy 373
with acute or episodic confusion/delirium. Metabolic
derangements such as hypoglycemia, hyperglycemia,
thyroid storm, and hypercapnia can occur in the elderly.
CNS infections should also be investigated in patients
with new-onset confusional symptoms (especially with
HIV, Creutzfeldt–Jakob disease, syphilis, and encephali-
tis). Adverse drug reactions can also cause transient neu-
rologic symptoms. The common medications are benzo-
diazepines, barbiturates, antihistamines, and anticholin-
ergic medications.
TGA usually presents with sudden disorientation and
confusion. The patient experiences anterograde amnesia
and tends to repeat the same questions. This usually lasts
8–24 hours, and patients gradually return to their base-
line function. Recent magnetic resonance imaging (MRI)
data suggest that a transient perturbation of hippocampal
function is the functional correlate of TGA because focal
diffusion lesions can be selectively detected in the CA1
field of the hippocampal cornu ammonis. Recent data
suggest that the vulnerability of CA1 neurons to meta-
bolic stress plays a pivotal part in the pathophysiologic
cascade, leading to an impairment of hippocampal func-
tion during TGA (Bartsch and Deuschl, 2010). The inci-
dence is 5–10 per 100,000. About 10–25% have recurrent
events.
Some movement disorders can be transitory and brief.
This can include motor tics, limb or segmental myoclo-
nus, tremor, chorea, and hemifacial spasms. The EEG is
typically normal in movement disorders, and some move-
ment specialists employ EEG back-averaging techniques
in distinguishing epileptic and nonepileptic movements.
The common sleep disorders than can occur in the
elderly are confusional arousals, sleepwalking, noctur-
nal enuresis, and rapid eye movement (REM) behavior
disorder. These disorders can be confused for nocturnal
seizures. Confusional arousals are characterized by the
person awakening from a deep sleep, reacting slowly to
commands, and appearing confused. Non-seizure-related
enuresis occurs during non-rapid eye movement (NREM)
sleep. Sleepwalking involves the patient getting out of
bed and wandering about. REM sleep behavior disorder
(RBD) typically occurs among men over 50 years of age.
RBD has been associated with Lewy body dementia and
Parkinson’s disease. Normally during REM sleep, there
is body atonia. In RBD, the loss of atonia results in loss
of skeletal muscle inhibition, and the patient may act out
dreams. The patient may have flailing arm movements
and may kick, punch, or yell (Frenette, 2010).
Nonphysiologic seizures signify a nonorganic cause of the
seizure. This usually indicates a psychiatric illness. These
include panic/anxiety attacks, conversion or psychogenic
nonepileptic seizures (NES), dissociative states, hyper-
ventilation syndrome, acute psychosis, and malinger-
ing. Psychogenic seizures in the elderly can present with
simple motor movements, complex motor movements,
374 Neurologic Conditions in the Elderly
sensory symptoms, loss of responsiveness, or decreased
responsiveness (Lancman et al., 1996; Drury et al., 1999;
Keraünen et al., 2002; McBride et al., 2002; Kellinghaus
et al., 2004a, 2004b; Abubakr and Wambacq, 2005; Kawai
et al., 2007; Kipervasser and Neufeld, 2007; ).
Diagnostic studies in geriatric epilepsy
After the initial history and physical examination, the
physician who suspects epileptic seizures must formu-
late the etiologic risk factors for the patient’s epilep-
tic seizures. The two most important studies are brain
imaging and EEG. The brain imaging of choice is MRI.
This usually helps identify the anatomic substrate or
symptomatic lesions (stroke, tumors, gliosis, vascular
malformations, parasites). High-resolution MRI with
and without contrast (if no contraindications) is the
modality of choice. The interictal EEG may not always be
diagnostic or supportive for epilepsy diagnosis. A study
performed by Widdess-Walsh et al. (2005) examined 300
EEG records of elderly patients referred for syncope,
encephalopathy, transient unresponsive states, and clin-
ical seizures. Focal and generalized abnormalities were
noted in 9% and 30.7% of the EEG records, respectively.
Only 13 records demonstrated focal sharp waves, and
one record showed generalized epileptiform discharges.
Temporal slow of the elderly is a benign variant and
should be part of the EEG differentials when temporal
slowing is encountered. The EEG should always be cor-
related with the MRI lesion suspected to generate the
seizures. Some MRI lesions may be merely incidental
findings.
Video EEG studies are an important diagnostic tool
in the study of geriatric paroxysmal events or seizures
(Lancman et al., 1996; Abubakr and Wambacq, 2005;
Kawai et al., 2007; Keraünen et al., 2002; McBride et al.,
2002; Kellinghaus et al., 2004a, 2004b; Kipervasser and
Neufeld, 2007). Unfortunately, this is an underutilized
diagnostic procedure. Video EEG studies have a higher
chance of detecting focal or generalized epileptiform dis-
charges. The detection of electrographic seizures confirms
the diagnosis of epilepsy. Importantly, the diagnosis of
paroxysmal nonepileptic events (physiologic or psycho-
genic) adds closure to the diagnosis. Epileptic seizures
have been diagnosed in about 17–46% of elderly patients
admitted for inpatient video EEG monitoring. The diag-
nosis of nonepileptic events ranged from 25% to 55%
(Lancman et al., 1996; Drury et al., 1999; Keraünen et al.,
2002; McBride et al., 2002; Kellinghaus et al., 2004a, 2004b;
Abubakr and Wambacq, 2005; Kawai et al., 2007; Kiper-
vasser and Neufeld, 2007). NES are a frequent problem
in elderly patients. Physiologic and psychogenic NES are
equally frequent in the elderly. Loss of responsiveness
was seen in only 20% of patients with psychogenic NES.
Although most of the patients did not have any evidence
for epilepsy, more than two-thirds of these patients had
been placed on anticonvulsive drugs (Kellinghaus et al.,
2004a).
The ancillary tests are used to identify other causes of
paroxysmal nonepileptic events. These include the com-
plete blood counts, complete metabolic panels, toxicologic
drug screens, blood gases, X-rays, blood or urine cultures,
electrocardiogram, Holter monitors, tilt table testing, and
sleep studies. These ancillary tests are tailored to the indi-
vidual’s differential diagnosis.
Epilepsy syndromes and seizure
classification
The Commission on Classification and Terminology of
the International League against Epilepsy has proposed
four categories of epileptic syndromes in elderly patients
(Van Cott, 2002):
1 Symptomatic localization-related epilepsy: Signs or
symptoms indicate a specific anatomic localization (par-
tial seizures, EEG or brain CT signs of localization).
2 Undetermined epilepsy: The patients are without un-
equivocal generalized or focal seizures and without any
etiologic factors.
3 Isolated, apparently unprovoked epileptic events:
Patients have isolated partial or generalized seizures
without EEG or CT scan abnormalities. No etiologic fac-
tors are identified.
4 Situation-related seizures (acute symptomatic sei-
zures): These can be associated with metabolic disorders
or acute injury to the CNS.
Complex partial seizures (38.3%) are the most com-
mon seizure presentation in geriatric epilepsy (Ram-
say et al., 2004). This is followed by generalized tonic–
clonic seizures (27.1%), simple partial seizures (14.3%),
generalized tonic–clonic seizures and partial seizures
(12.8%), and mixed partial seizures (7.5%). In terms of
seizure semiology, Kellinghaus et al. (2004b) studied the
seizure characteristics of 54 elderly patients 60 years or
older at the time of admission. For 21 of them, at least
one epileptic seizure was recorded. Nineteen patients
had focal epilepsy (nine temporal lobe, two frontal lobe,
two parietal lobe, eight nonlocalized), and two patients
had generalized epilepsy. Seventy-three seizures of the
elderly patients and 85 seizures of the 21 control patients
were analyzed. In 9 elderly patients and 14 control
patients, at least one of their seizures started with an
aura. Eleven elderly patients and 19 control patients lost
responsiveness during their seizures. Approximately
two-thirds of the patients in both groups had automa-
tisms during the seizures. Both focal and generalized
motor seizures (such as clonic or tonic seizures) were
seen less frequently in the elderly.

Drug therapy in geriatric epilepsy
Numerous review articles focus on the pharmacotherapy
of epilepsy in the elderly, but there are few random-
ized clinical trials in geriatric epilepsy (Brodie et al.,
1995; Willmore, 1995, 1998; Brodie et al., 1999; Belmin
et al., 2000; Brodie et al., 2002; Lackner, 2002; Alsaadi
et al., 2004; Leppik et al., 2004; Leppik, 2005; Rowan et al.,
2005; Sendrowski and Sobaniec, 2005; van Breemen and
Vecht, 2005; Leppik, 2006; Mayes, 2006; Pugh et al., 2006;
Gidal, 2007; Saetre et al., 2007; Sajatovic et al., 2007; Dogan
et al., 2008; Ensrud et al., 2008; Pugh et al., 2008; Ramsay
et al., 2008; Stefan et al., 2008; Pugh et al., 2010; Saetre et al.,
2010). Currently, recommendations are based on expert
opinions, and there is a lack of general guidelines/con-
sensus. Recent studies indicate that approximately 10% of
nursing home residents are being treated with antiepilep-
tic drugs (AEDs) (Leppik et al., 2004). The choice of AED
therapy is complicated by the physiologic changes and
comorbid medical conditions.
Pharmacokinetics involves the absorption, distribution,
biotransformation, and renal excretion of the drug. This
includes the genetic background, actual chronologic age,
frailty, dietary habits, exposure to voluptuary substances
(alcohol, cigarette smoke), serum albumin concentrations,
glomerular filtration rate, creatinine clearance, comor-
bidities, and interaction caused by concomitant medica-
tions (Perucca, 2007). The absorption of an AED may be
decreased due to the changes in gastrointestinal motility,
blood flow, and mucosal absorptive surface. The distri-
bution of the drug may be decreased due to decrease of
serum albumin and total body water. Biotransformation
is also decreased because of the decrease in liver mass,
blood flow, activity of cytochrome P450 enzymes, and
phase II conjugation enzymes. Renal elimination is also
decreased because of the decrease in renal weight, glo-
merular filtration rate, renal blood flow, filtration fraction,
and tubular function.
The clearance of most anticonvulsants is reduced by
20–40% in the elderly, as compared to younger adults.
Consequently, this also prolongs the elimination half-life
of AEDs (Diamond and Blum, 2008; Hommet et al., 2008;
Jetter and Cavazos, 2008; Werhahn, 2009). The pharma-
cokinetic changes in the elderly indicate that the initial
drug dosage should be lower and should be titrated in a
slower pace. The target dose may be 50% lower than the
recommended dosages for younger patients. It is appro-
priate to start with one anticonvulsant drug (monother-
apy) (St Louis et al., 2009). The therapeutic end point dur-
ing the titration is no seizures and minimal side effects.
AED polytherapy should be avoided as much as possible
because of the higher risk of side effects. Age-related
pharmacodynamic changes can alter the relationship
between serum AED concentration and drug effects. It
would not be surprising for the laboratory normal range
Geriatric Epilepsy 375
to be “toxic” for the elderly person. When the elderly
patient has no seizures with the medication, the serum
level taken will be the approximate “therapeutic” level.”
This may be lower or within the laboratory normal range.
In some instances, it may even be slightly higher than the
normal range. It may be tempting to lower the AED dose
when the reported serum level is above the normal range.
It is important to emphasize that the patient is being
treated (not the drug level); .as long as no significant
side effects are impairing cognitive or physical abilities,
the AED dose should remain the same. Conversely, if the
drug dosage is lower than the recommended dose and the
patient has no seizures, it is not appropriate to push the
medication higher.
Clinical studies of antiepileptic drugs in
geriatric epilepsy
Nineteen or more anticonvulsants are available in the
market. It is beyond the scope of this chapter to discuss
each anticonvulsant. About 11 studies address the drug
treatment of elderly people with epilepsy (Brodie et al.,
1995, 1999, 2002; Alsaadi et al., 2004; Rowan et al., 2005;
Mayes, 2006; Saetre et al., 2007; Dogan et al., 2008; Ram-
say et al., 2008; Stefan et al., 2008; Saetre et al., 2010).
Of these, five were randomized double-blind, controlled
trials (Brodie et al., 1995, 1999, 2002; Rowan et al., 2005;
Saetre et al., 2007). Brodie et al. (1995) published in 1995
a double-blind study comparing Lamotrigine (LTG) and
Carbamazepine (CBZ) in newly diagnosed epilepsy in
the elderly. Only 151 of the 260 newly diagnosed geri-
atric epilepsy patients completed the 48-week study. In
terms of efficacy, the proportion of patients who were
seizure-free was similar in the LTG group (39%) and the
CBZ group (38%). Generalized epilepsies responded
more favorably than the focal epilepsies. In terms of
tolerability, LTG had fewer drug withdrawals than
CBZ (15% vs. 27%), and the most common cause was
drug rash (9% vs. 13%). This finding was validated in
a multicenter double-blind, controlled study in which
LTG (100 mg/day) showed a more favorable efficacy
and tolerability profile than CBZ (400 mg/day) (Brodie
et al., 1999). In another study published in 2007, Saetre
et al. (2007) compared LTG (100 mg/day maintenance
dose; 500 mg/day maximum dose) with sustained-
release CBZ (400 mg/day maintenance dose; 2000 mg/
day maximum dose). The number of subjects who com-
pleted the 40-week period and were seizure-free in the
last 20 weeks was 48 (52%) in the LTG group and 52
(57%) in the CBZ group. Even though they have no sig-
nificant difference in effectiveness, the LTG group was
better tolerated. Adverse events leading to withdrawal
occurred in 13 (14%) subjects in the LTG group and 23
(25%) subjects in the CBZ group.
376 Neurologic Conditions in the Elderly
Brodie et al. (2002) performed a randomized double-
blind, controlled study comparing Gabapentin (GBP)
and LTG in newly diagnosed epilepsy. The dosage range
of GBP was 1200 and 3600 mg/day. The LTG dose was
100 and 300 mg/day. A total of 309 patients was ran-
domized, and 291 (148 GBP, 143 LTG) were included
in the evaluable population. Overall, 106 (71.6% of
the evaluable population) GBP-treated and 96 (67.1%)
LTG-treated patients completed the study. Eighty
(75.5%) patients taking GBP and 73 (76.0%) taking LTG
remained seizure-free during the final 12 weeks of treat-
ment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%)
LTG-treated patients withdrew because of study drug-
related adverse events. This study showed equal efficacy
and adverse events of GBP and LTG. In a similar study,
Rowan et al. (2005) studied the relative tolerability and
efficacy of LTG and GBP with a traditional AED, CBZ.
This involved 593 elderly patients with epilepsy, and
they were randomly allocated to different treatment
groups: GBP (1500 mg/day), LTG (150 mg/day), and
CBZ (600 mg/day). The average age of the patients was
72 years, and the most common cause for the epilepsy
was stroke. The seizure remission rate after 12 months
of treatment was similar among the three AEDs. Overall,
LTG and GBP were better tolerated than CBZ (Rowan
et al., 2005).
Smaller studies or case series have studied new AEDs
among elderly patients with epilepsy. Ramsay et al. (2008)
performed a pilot trial among elderly patients with partial
seizures treated with Topiramate. Thirty-eight patients
were randomized to 50 or 200 mg/day of Topiramate. Sei-
zure control was similar with the two dosages when used
as monotherapy. With adjunctive therapy, the 200 mg dos-
age was more effective. The most common adverse events
were similar with the two dosages; the symptoms were
somnolence, dizziness, and headache. Cognitive side
effects (13%) were noted in both groups, and six of the
ten patients who experienced it were in the 50 mg group.
A total of 14 patients (18%) discontinued Topiramate due
to adverse events. In Germany, Stefan et al. (2008) did an
open-label, flexible dosing study of Topiramate among
107 elderly patients with epilepsy. The average dose for
monotherapy and adjunctive therapy was 98 mg/day
and 153 mg/day, respectively. About 44% of the elderly
patients were seizure-free, and 78% had more than 50%
reduction of seizures. Quality of life improved and Topi-
ramate was well tolerated.
Alsaadi et al. (2004) showed good response in the use
of Levetiracetam with 14 elderly patients. Eight of the
patients were seizure-free after 6 months of monother-
apy. Four out of five patients were seizure-free when it
was used as their first-line medication. Four of the nine
patients who converted to Levetiracetam monotherapy
after failing a previous AED were also seizure-free after
6 months. Four of the 14 patients had more than 50%
seizure reduction, and only one patient had no seizure
reduction with Levetiracetam.
Dogan et al. (2008) studied 147 elderly patients with
newly diagnosed partial epilepsy and were treated
with Oxcarbazepine monotherapy. About 62.6% of
these patients were in seizure remission for 1 year, with
Oxcarbazepine monotherapy at doses of 900 mg per
day. About 37.4% of the patients were unresponsive at
maximum tolerable doses of Oxcarbazepine. Elderly
patients with cryptogenic partial epilepsy had a favor-
able response (75% remission), while the symptomatic
group of elderly patients had a lower remission (51.9%
remission). Elderly patients with tumor-related epilepsy
had the lowest remission rate in the symptomatic group
(36.7% remission). Oxcarbazepine was well tolerated, and
one patient had symptomatic hyponatremia.
Summary
Geriatric epilepsy is a common neurologic disorder that is
usually caused by stroke and neurodegenerative disease
(AD). Physiologic and nonphysiologic paroxysmal events
may be confused with epileptic seizures. Elderly patients
with epilepsy have a favorable response and tolerance to
new-generation AEDs. Moreover, the AED dosages are
lower due to pharmacokinetic changes that occur in the
older age group.
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 Chapter 16
Vertigo and Dizziness in the Elderly
Terry D. Fife1 and Salih Demirhan2
1
Barrow Neurological Institute, and Department of Neurology, University of Arizona College of Medicine, Phoenix, AZ, USA
2
Marmara University School of Medicine, Istanbul, Turkey

Summary
• Benign paroxysmal positional vertigo (BPPV) is the most common cause of recurrent vertigo and is characterized by
recurrent episodes of vertigo lasting 10–30 seconds.
• Other common types of dizziness include vestibular neuritis, an acute peripheral vestibular disorder that usually results
in unilateral peripheral vestibular loss but spears hearing, Meniere’s disease, an inner ear disorder that is characterized
by recurrent, spontaneous attacks of vertigo and hearing loss, ear fullness, and tinnitus, usually affecting one side, and
bilateral vestibular loss (BVL), results from damage of the balance portion of both inner ears.
• Lesions in the central nervous system (CNS) vestibular pathways can lead to vertigo and imbalance.
• Multiple sclerosis (MS) symptoms include vertigo, dizziness aggravated by head movement, persistent nausea, ataxia,
and imbalance, sometimes with nystagmus or diplopia. Sensory ataxia syndromes, cerebellar ataxia syndromes,
episodic ataxia syndromes, migraine-associated vertigo (MAV), normal pressure hydrocephalus (NPH), and postural
hypertension are further described.

Introduction affect balance to varying degrees in many older people

Disequilibrium and dizziness are common symptoms in
older people and account for significant morbidity. In
the United States, most individuals over 70 years of age
report problems of dizziness and imbalance (National
Institute on Deafness and Other Communication Disor-
ders (NIDCD), 1989). Dizziness and imbalance is a lead-
ing contributor to reduced mobility and falls. Among
Americans 65 years and older, one-third will experience
balance-related falls that are the leading cause of deaths
related to injury.
The effects of aging on balance
(Sudarsky, 1994). The peripheral vestibular end organs
also exhibit the effects of age, though to a lesser degree.
Loss of mid- and high-frequency hearing and speech dis-
crimination is nevertheless very common.
The peripheral vestibular structures show some reduc-
tion in hair cells in the cristae and in the maculae, but the
loss is usually not pronounced or obvious under obser-
vation by light microscopy. The loss of hair cells in these
structures, though modest, leads to measurable reduc-
tions in vestibular nerve fibers. Overall, however, ves-
tibular end organ decline is less important as a cause of
imbalance and falling in older people than is age-related
CNS decline and the cumulative effects of combined sen-
sory and CNS disturbances.

Aging leads to functional and morphologic changes in

most of the neural structures that mediate balance. With
age, the central nervous system (CNS) shows decreases
in astrocytes and neurons in the frontal, parietal, and
hippocampal cortex, and reduced cerebellar Purkinje
cells (Kemper, 1994). Partly as a result, there is loss of
CNS plasticity and alterations in neurotransmitter con-
centrations, with less efficient integration of peripheral
signals (visual, somatosensory, and vestibular). In addi-
tion, age-dependent declines in judgment, conditioning,
muscle strength, joint flexibility, and motor control may
Types of dizziness
Dizziness is a commonly used term that refers to a dis-
turbance in the perception of spatial orientation. Hence,
dizziness is a nonspecific term that can mean vertigo (the
illusion of movement, especially rotation), disequilib-
rium or imbalance, lightheadedness, or near-faintness
(Table  16.1). Imbalance and disequilibrium used here indi-
cate reduction in balance when standing or walking, but
without vertigo or any feeling of motion.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

379
380 Neurologic Conditions in the Elderly
Table 16.1 Classification of dizziness
Type Symptom description
Vertigo Spinning, rotation, tilting
Presyncope Lightheadedness, near-faintness, feeling
of fading out
Disequilibrium without Imbalance when standing or walking,
vertigo unsteadiness
Psychiatric dizziness Chronic floating or rocking, fatigue
Physiologic dizziness Motion sickness, visual vertigo, nausea or
queasiness, fatigue
a
Visual vertigo is dizziness induced by seeing objects in motion (such as ceiling fans, moving traffic, cinematic scenery motion, grocery store
aisles, and movement of crowds of people).
This chapter reviews some of the common causes of
vertigo, dizziness, and imbalance that affect older adults.
Otologic causes are those related to inner ear balance (ves-
tibular) disorders and are discussed first. Following that,
the so-called “central” causes that have some connection
to CNS disease are discussed, along with other important
causes of dizziness or imbalance.
Otogenic dizziness
Benign paroxysmal positional vertigo
Benign paroxysmal positional vertigo (BPPV) is the most
common cause of recurrent vertigo. The prevalence of
BPPV is 11–64 per 100,000. BPPV is also an important health
problem in the elderly population because the prevalence
of BPPV increases with age (Bloom and Katsarkas, 1989).
BPPV is characterized by recurrent episodes of vertigo
lasting usually from 10–30 seconds. The spells of vertigo
are evoked by moving the head in certain directions, as
with looking up or turning over in bed. The Dix–Hallpike
maneuver is a simple bedside examination technique that
induces the vertigo and nystagmus of the most common
form of BPPV (Figure 16.1). Most cases of BPPV relate to
Figure 16.1 Dix–Hallpike test for localization of vertigo detects
most cases of benign paroxysmal positional vertigo related to
the posterior semicircular canal.
Example
Vestibular neuritis, Meniere’s disease, benign paroxysmal positional
vertigo (BPPV), brainstem/cerebellar lesions, migrainous vertigo
Postural hypotension (volume depletion, neurally mediated, other
types), cardiogenic
Sensory ataxia, cerebellar ataxia, bilateral vestibular loss (BVL), many
other causes
Panic disorder, dizziness from anxiety, phobic vertigo
Seasickness, carsickness, airsickness, visual vertigoa
the posterior semicircular canal, but occasionally, the lat-
eral or anterior semicircular canals can be affected. The
directional features of the nystagmus help to identify the
side and semicircular canal affected.
Mechanism
The semicircular canals located in the membranous
labyrinth of the inner ear on each side detect angular
or turning movements of the head. Each labyrinth has
three semicircular canals: anterior, posterior, and horizon-
tal canals. Each has a different orientation so that together
they sense all angular movements. The cupula, located in
the ampulla of each canal, is a motion sensor that bends
with angular movement and sets off neural activity of the
ampullary nerve that is carried via the vestibular nerves
to the brain.
Each labyrinth also has two otolith structures, the sac-
cule and utricle, that detect linear or translational accel-
eration. They are referred to as otolith organs because
they contain maculae, calcium carbonate crystals (oto-
liths) embedded in a gelatinous-protein matrix oriented
to move in response to horizontal and vertical (gravity)
accelerations. The deflection of hair cells in the maculae
of these otolith organs causes neural activity that is also
carried to the brain by way of the vestibular nerve.
BPPV is caused when these calcium carbonate crys-
tals that originate from the macula of utricle become
dislodged and inappropriately end up within the lumen
of one of the semicircular canals. Because the calcium
carbonate crystals are more than twice as dense (spe-
cific gravity 2.7 g/cm3) as endolymph (specific gravity
1.0 g/cm3), they move in response to gravity.
When calcium carbonate crystals dislodge from the
macula of utricle and move within semicircular canals
(canalolithiasis), they evoke endolymph flow and activate
the cupula in that canal. This results in BPPV. The calcium
carbonate crystals may dislodge or fall off the macula of
utricle as a result of trauma or viral infections, but most
cases are spontaneous. When there is canalolithiasis,

certain head movements that cause the otoliths to move
stimulate the ampulla of the affected canal, causing a
burst of vertigo.
Each canal results in its own pattern of paroxysmal
positional nystagmus: the posterior canal type is upbeat-
ing and torsional, with the top pole beating toward the
downward ear; the anterior canal type is downbeating,
sometimes with a minor torsional component; the lat-
eral (horizontal) canal type is horizontal and changes its
direction as the head is positioned in the supine right and
moved to the supine left positions (direction changing
paroxysmal positional nystagmus) (Fife, 2009).
Classification of benign paroxysmal
positional vertigo
BPPV is classified according to the affected semicircular
canal and by whether it is thought to be due to canalolithi-
asis (otoliths freely moving within the canal in response
to gravity) or cupulolithiasis (otoliths adherent to the
cupula and hence less responsive to canalolith reposition-
ing procedures).
In some instances, more than one canal may be simulta-
neously affected. Posterior canal type of BPPV is the most
common type (85–90%) of BPPV because the opening of
the posterior canal is at the bottom of the labyrinth when
lying flat (as when sleeping), so the dense otoliths settle
preferentially into the posterior canal because of gravity.
Diagnosis
The history is generally sufficient to make a presump-
tive diagnosis of BPPV, but observing characteristic nys-
tagmus upon examination is confirmatory. Patients with
BPPV describe episodes of spinning triggered by lying
back in bed, by turning in bed, by bending and straight-
ening, and with certain tilting movements of the head.
Nausea may accompany the spells, but BPPV is not asso-
ciated with diplopia, slurred speech, sensory changes, or
confusion. Occasionally, patients with strong symptoms
or who have a propensity for motion sickness report mild
nausea and floating dizziness for several hours after the
positional vertigo, but most patients feel well between
episodes. Spontaneous episodes of vertigo, vertigo lasting
more than 1 or 2 minutes, and episodes that never occur
in bed or with head position changes should lead one to
consider alternative causes.
Diagnostic tests
The Dix–Hallpike maneuver is used to diagnose the
posterior canal type of BPPV (refer to Figure 16.1). The
maneuver is performed by rapidly moving the head from
an upright position to a head-hanging position, with one
ear 45° to the side. Performing the Dix–Hallpike maneu-
ver to the side affected by posterior canal BPPV results
in a burst torsional and upbeating nystagmus. Hence,
with left BPPV, the nystagmus seen with Dix–Hallpike
Vertigo and Dizziness in the Elderly 381
positioning to the left is clockwise torsional admixed with
upbeating nystagmus; with right BPPV, the nystagmus
is counterclockwise torsional and upbeating. By conven-
tion, the direction of the nystagmus is defined by its fast
phase.
Dix–Hallpike maneuver may sometimes elicit the
horizontal (lateral) canal type of BPPV. However, a more
reliable technique for evoking horizontal canal BPPV is
a supine head turn maneuver, also called the Pagnini–
McClure maneuver (Figure 16.2). The nystagmus of hori-
zontal canal type BPPV is horizontal and changes direc-
tion depending on the head position. That is, with a quick
supine turn of the head to the right, usually the nystag-
mus is paroxysmal horizontal right beating; when the
head is turned to the other side, the nystagmus changes
direction (hence the term direction changing), to become
left beating. This type of direction-changing horizontal
nystagmus is referred to as geotropic, meaning the direc-
tion of the fast phase is toward the ground. Geotropic-
type nystagmus is the most common type of horizontal
canal BPPV nystagmus, but there is a less common and
more difficult-to-treat form that is apogeotropic, mean-
ing that the nystagmus beats away from the ground in
each head position. A variety of specialized maneuvers
address this less common type of BPPV, but no maneuver
has been established as superior to the others, based on
current evidence (Fife, 2009).
An even less common anterior canal form of BPPV is
characterized by paroxysmal downbeating nystagmus
and sometimes torsional component following Dix–
Hallpike positioning. Such downbeat positional nystag-
mus is also seen with CNS lesions of the posterior fossa,
so, when it is encountered, appropriate evaluation to
exclude structural CNS lesions should be considered.
Differential diagnosis
Distinguishing central causes of vertigo from typi-
cal BPPV is important because some forms of central
Figure 16.2 Pagnini–McClure maneuver for evoking horizontal
canal benign paroxysmal positional vertigo is a supine head-turn
maneuver.
382 Neurologic Conditions in the Elderly
positional vertigo may be life-threatening. Because some
brainstem and cerebellar lesions can produce downbeat-
ing positional nystagmus, anterior canal BPPV should be
diagnosed with caution. The general rule is that if the nys-
tagmus fails to respond readily (same day) to positioning
treatments or the direction of nystagmus is atypical, cen-
tral causes should be considered.
Treatment
The main goal of the treatment maneuvers for BPPV is to
clear the misplaced calcium crystals (canaloliths) from the
posterior canal by moving them back into the vestibule. A
number of canalolith-repositioning procedures have been
helpful in moving the calcium crystals and treating BPPV.
The most commonly used and well-established method
of treating posterior canal BPPV is the canalolith reposi-
tioning maneuver, which is a modification of the Epley
maneuver (Figure 16.3). A second technique, the Semont
liberatory maneuver, is equally effective (Figure 16.4) for
posterior canal BPPV. If properly done, these treatment
methods have nearly the same success rate (85–93%).
Generally, antivertiginous medications such as meclizine
are unnecessary because the treatment often eliminates all
symptoms in a matter of minutes. Rarely, BPPV can be
refractory to repositioning maneuvers and requires surgi-
cal occlusion of the affected semicircular canal.
Figure 16.3 Canalolith repositioning maneuver; a modification
of the Epley maneuver is used for treatment of posterior canal
benign paroxysmal positional vertigo.
Figure 16.4 Semont liberatory maneuver is equally effective as
Epley for posterior canal benign paroxysmal positional vertigo.
Prognosis
The generally accepted recurrence rate of BPPV after suc-
cessful treatment is approaching 50% at 5 years of average
follow-up. Because the otolithic membrane of the utricle
always contains calcium carbonate crystals, recurrences
may develop if more calcium breaks loose and becomes
lodged within one of the semicircular canals.
Vestibular neuritis (idiopathic
vestibulopathy)
Vestibular neuritis, also called vestibular neuronitis,
labyrinthitis, and neurolabyrinthitis, is an acute periph-
eral vestibular disorder that usually results in unilateral
peripheral vestibular loss. The relatively sudden loss of
vestibular function results in acute vertigo that lasts days
and slowly recovers over weeks or a few months.
The term vestibular neuritis refers to the acute unilateral
loss of vestibular function that spares hearing. Labyrinthi-
tis refers to acute unilateral loss of both hearing and ves-
tibular dysfunction due to viral infection. Localization of
the effects on the vestibular nerve and labyrinth may vary,
leading some to prefer the term neurolabyrinthitis.
Mechanism
Although vestibular neuritis is generally attributed to
viruses, including herpes simplex virus 1 (HSV-1), com-
pelling confirmatory support for this supposition is lack-
ing in humans. Degeneration of peripheral vestibular
nerve fibers and the neuroepithelium of peripheral recep-
tors have been observed on histopathologic examination
(Goebel et al., 2001).
Many cases of vestibular neuritis selectively involve
only the superior division of the vestibular nerve that
innervates the horizontal and anterior semicircular
canals and the utricle. The inferior vestibular division
that innervates the posterior canal and saccule is more
often spared (Fetter and Dichgans, 1996). The selective
 Vertigo and Dizziness in the Elderly 383

vulnerability may result from a longer course in a more
narrowed pathway in the temporal bone for the superior
division, making it susceptible to the effects of swelling
and entrapment.
Symptoms
The time course of vestibular neuritis and labyrinthitis is
similar, usually evolving over a period of 30 minutes to
several hours. Vertigo is present in all head positions but
is aggravated by head motion; it gradually abates in the
days and weeks that follow.
Diagnosis
Vestibular neuritis should be suspected when there is
acute onset of vertigo that persists and is not specifically
provoked by position changes (although patients may feel
worse with head movement, it is present even at rest ini-
tially). A history of recurrent similar episodes should raise
suspicion for other causes, such as Meniere’s disease.
Examination reveals fast phases of the nystagmus beat-
ing away from the affected ear. Importantly, the direction
of nystagmus does not alter with changes in head position
or gaze. The nystagmus fast phase increases during gaze
in the direction of the fast phase and diminishes or abates
with gaze away from the fast phase. This is referred to as
Alexander’s law and is characteristic of acute peripheral
vestibular loss. The nystagmus of acute unilateral vestibu-
lar loss decreases within the first 12–36 hours in most cases,
so spontaneous nystagmus subsides fairly soon after the
onset. A head impulse test remains abnormal indefinitely
after significant unilateral vestibular loss (Wuyts, 2008).
Differential diagnosis
It is important to be certain that there is no central cause
of the acute vertigo. Small cerebellar strokes or hemor-
rhage can also produce acute vertigo that may mimic
vestibular neuritis (Lee and Cho, 2004). Cerebellar or
brainstem strokes, however, usually exhibit other signs,
such as unilateral dysmetria, slurred speech, hemibody
numbness, diplopia, or nystagmus that changes direction
when changing the direction of gaze (gaze-evoked nys-
tagmus). The head impulse test is typically abnormal in
peripheral causes and not in most central causes. Nystag-
mus of peripheral origin adheres to Alexander’s law, as
mentioned, and remains unidirectional. Meanwhile cen-
tral nystagmus may change direction, depending on the
direction of gaze, or may be purely downbeat or torsional.
The first attack of Meniere’s might easily be mistaken for
vestibular neuritis. Meniere’s attacks, however, usually
subside within 8 hours, whereas residual symptoms con-
tinue for days to weeks in vestibular neuritis. Recurrences
of vertigo in Meniere’s disease are common, whereas a
second attack of vestibular neuritis is uncommon (recur-
rence incidence is 2% over a lifetime).
Diagnostic tests
Videonystagmography (VNG) with caloric vestibular
testing can help confirm the presence of unilateral periph-
eral vestibular loss. A greater than 24% asymmetry in
caloric vestibular nystagmus suggests a pathologic loss
of vestibular function. VNG need not be done in the first
days of the vertigo, as unilateral vestibular loss remains
detectable for the rest of the patient’s life.
Brain MRI or head CT should be obtained in patients
with vertigo accompanied by focal neurologic symptoms
or severe headache because vestibular neuritis is usually
painless.
Treatment
In the early days following acute unilateral vestibular
loss, vestibular suppressants (Table 16.2) may be helpful
in ameliorating vertigo and nausea. Within a few days
of nausea subsiding, vestibular suppressants should be
stopped because these medications may delay or limit
CNS adaptation to the acute vestibular loss (Hain and
Yacovino, 2005).

Table 16.2 Motion sickness and vestibular suppressant medications

Medication Brand name Dosage and form Adverse effects

Dimenhydrinate Dramanine 50 mg p.o. bid Urinary retention, dry mouth

Meclizine Antivert, bonine 12.5–50 mg p.o. tid or qid Urinary retention, dry mouth
Promethazine Phenergan 12.5–50 mg p.o. or IM q 4–6 h; 50 mg suppos pr qid Slightly lowered seizure threshold
Diazepam Valium 2–7.5 mg p.o. tid or qid Dose-dependent sedation
Lorazepam Ativan 0.5–2 mg bid or tid Dose-dependent sedation
Clonazepam Klonopin 0.25–1 mg p.o. bid or tid Dose-dependent sedation
Scopolamine Transderm scop Patch 1 q 3 days Urinary retention, dry mouth
Metoclopramide Reglan 10–20 mg p.o. q4–6 h; 10–20 mg IV q 6 h Extrapyramidal effects
Prochlorperazine Compazine 10–20 mg p.o. q4–6 h; Extrapyramidal effects
10 mg IV q 6 h;
25 mg suppos p.r. q 6 h
Ondansetron Zofran 4–8 mg p.o., sl, or IV q 4–6 h Fatigue, diarrhea
384 Neurologic Conditions in the Elderly

Table 16.3 Home habituation exercises for recovery from vestibular loss

Exercise Description

1. Fixation during head Turn the head quickly from side to side and then up and down while focusing on your thumb held out directly in front of
turning you. As you move your head, move your thumb so that it is right in front of you and you can keep your focus on it. As
you move your head, your focus should be fixed on your thumb. Repeat these exercises for 30–60 s at least five times
daily. This exercise helps to improve your ability to focus on things while your head is moving from side to side.
2. Head movement Practice slowly turning the head from side to side while seated and then later while standing with your feet shoulder
habituation width apart. Gradually increase the speed of head movements. The head turning can include side-to-side and up-and-
down movements rapidly and repetitively, with eyes open and in good lighting. When you can do this standing still, try
to walk (eyes open) forward while turning the head side to side, gradually increasing the speed of head turns. This helps
you to become more used to rapid movements of the head, which are often a source of momentary imbalance.
3. Rapid head movement Practice getting up from the lying-down position to standing as quickly (but carefully) as possible. This may be done on
habituation a sofa or bed. Practice getting up toward the left side and toward the right side. Be careful not to fall. Get up quickly five
times to each side, gradually trying to increase the quickness but without falling. This helps improve the coordination of
quick movements of the head and body. Rapidly bend over and then straighten five consecutive times. Do this exercise
twice. Time yourself and try to gradually increase your speed; eventually, try adding an about-face (180° turn) after each
bend.
4. Tightrope exercise Walk heel to toe, as though walking a tightrope. This can be done in a hallway or corridor where there is something to
hold on to, if needed. Gradually try to achieve 10 steps (heel touching toe) without holding on or taking a side step. This
improves the inner ear balance and cerebellar balance function.
5. Standing balance test Stand with the feet together (touching) and try to maintain the position for 15 s. After you accomplish that, try closing
your eyes, with someone nearby to keep you from falling. Work to eventually be able to stand with feet together and
eyes closed for 8 s. This trains you to keep your balance using ankle sensation and inner ear signals. If you are able to do
this for 8 s, practice standing on one leg (eyes open) or while standing on a foam pillow. Eventually, try to stand for 10 s
on foam with eyes closed and to stand on one leg for 12 s.
6. Walk and quick turns Walk 10 steps down in a corridor or hallway and then turn right and walk back to the starting point. Do this five times
turning to the right, then five times turning toward the left. Time how long it takes you and try to improve your speed,
being careful to avoid falling. This helps walking balance and balance with turns.

At that point, the patient should begin moving his
head from side to side, extending the activity each day
until capable of undergoing more extensive vestibular
exercises (Table 16.3). Vestibular exercises accelerate
recovery using intrinsic neuroplasticity and cerebellar
adaptation (Gittis and du Lac, 2006), allowing the brain
to accommodate the unilateral vestibular loss with com-
plete or nearly complete recovery over several months.
Studies in primates and humans indicate that vestibular
exercises accelerate the recovery from a unilateral ves-
tibular loss and improve the overall balance function
(Sadeghi et al., 2007).
Acute use of prednisone 60 mg daily for a week, much
as one might treat Bell’s palsy, may help reduce the sever-
ity of vestibular neuritis if given in the first few days,
though more randomized controlled trials are needed to
confirm a clinically relevant benefit.
One exception is in herpes zoster oticus and Ramsay
Hunt syndrome. Both represent a recrudescence of vari-
cella zoster virus that can lead to hearing loss or residual
facial paresis. If varicella zoster (shingles) is suspected,
the patient should be treated with corticosteroids and
either acyclovir, famciclovir, or valacyclovir. Herpes zos-
ter oticus may cause painful vesicles in the sensory distri-
bution of the seventh cranial nerve, usually a small patch
deep in the external ear canal or occasionally behind the
ear. When accompanied by ipsilateral Bell’s palsy, the
syndrome is referred to as Ramsay Hunt syndrome.
Meniere’s disease
Meniere’s disease is an inner ear disorder that is char-
acterized by recurrent, spontaneous attacks of vertigo
and hearing loss, ear fullness, and tinnitus, usually
affecting one side. The prevalence of Meniere’s disease
is about 1:150,000 people, affecting males and females
about equally and with a peak incidence between 40 and
60 years of age.
Symptoms
Unilateral ear fullness, hearing fluctuation, and change
in the pitch of tinnitus may precede typical attacks of
Meniere’s disease. Vertigo attacks in Meniere’s disease are
random, often severe, and last 1–6 hours. In most cases,
patients are unable to walk or move comfortably during
attacks, due to prominent nausea and vomiting. In early
Meniere’s, fluctuating unilateral low frequencies hearing
loss is evident. However, over time (usually years), the
hearing loss progresses and becomes permanent.

Occasionally, patients may experience sudden unex-
pected falls without loss of consciousness. These drop
attacks are referred to as “otolithic crises of Tumarkin”
and may lead to serious injury. They may occur from
abrupt neural surges of the utricle or saccular, which sud-
denly distort the patient’s sense of vertical, resulting in
the fall.
Mechanism
Meniere’s disease is idiopathic but seems to result from
endolymphatic hydrops. Endolymphatic hydrops refers
to the sudden movement of the perilymph into the endo-
lymph compartment, leading to swelling in the labyrinth.
The bony labyrinth contains these structures, so actual
swelling is limited but stretching of the endolymphatic
space causes the acute disturbance of vestibular and hear-
ing function associated with the attacks. The tendency for
such endolymph accumulation may be partly mechanical
obstruction of endolymph and dysregulation of the elec-
trochemical membrane potential between the endolymph
and the perilymph.
If the underlying causes of endolymphatic hydrops
are known such as syphilis or autoimmune inner ear dis-
ease, the terms Meniere’s syndrome and delayed or secondary
endolymphatic hydrops may be used to distinguish them
from idiopathic Meniere’s disease. Nevertheless, pri-
mary (Meniere’s disease) and secondary endolymphatic
hydrops often follow a similar clinical course, although
bilateral involvement is more common in secondary
hydrops.
Diagnosis
Meniere’s and endolymphatic hydrops are clinical diag-
noses based on the history and confirmed by low-fre-
quency hearing loss and vestibular loss on the affected
side. Patients with a history of multiple attacks of vertigo
but with no hearing loss should receive more careful eval-
uation for other possible causes, such as migraine-asso-
ciated vertigo (MAV) or idiopathic recurrent vestibular
neuritis.
Differential diagnosis
Conditions that can produce symptoms that resemble
those of Meniere’s disease include perilymph fistula,
recurrent labyrinthitis, MAV, luetic otitis, and autoim-
mune inner ear diseases.
Diagnostic testing
VNG and audiometry are the most helpful adjunctive
tests in those with a suggestive history. The brain MRI is
normal in Meniere’s disease.
Treatment
Acute treatment of Meniere’s disease hinges on miti-
gation of the vertigo and vomiting using medications
Vertigo and Dizziness in the Elderly 385
(Table  16.2). No treatments are known that effectively
restore and arrest hearing loss or tinnitus. However, if
attacks of vertigo, ear fullness, fluctuating hearing, and
tinnitus all cease, further hearing loss may be prevented.
Prevention of further attacks is generally attempted by
a sodium-restricted diet of <1500 mg daily often along
with a thiazide diuretic such as hydrochlorothiazide
25 mg with triamterene 37.5 mg daily. Betahistine is not
approved for interstate transport in the United States
but may have a role in some cases of Meniere’s disease
and is dosed at 8–16 mg three times daily. Betahistine can
be legally compounded in the United States or can be
obtained from outside the United States for personal use.
If sodium restriction and pharmacologic therapies fail
to prevent vertigo attacks, invasive methods include
transtympanic gentamicin or corticosteroid injections,
endolymphatic mastoid shunting, vestibular neurectomy,
or, in those with no serviceable hearing, labyrinthec-
tomy. Bilateral Meniere’s occurs in about 10% of patients.
In patients with bilateral Meniere’s, surgical treatment
options must be considered carefully because it may not
always be possible to determine which labyrinth is the
dominant cause of symptoms; treatment of both sides
risks creating bilateral vestibular and hearing loss.
Bilateral vestibular loss
Bilateral vestibular loss (BVL), referred to as Dandy’s
syndrome, results from damage of the balance portion of
both inner ears.
BVL may have a number of causes, including ototoxic
medication exposure, bilateral Meniere’s disease, sarcoid-
osis, bilateral ear surgery, some congenital disorders, and
autoimmune inner ear disease. Among these, the most
commonly encountered cause of acquired BLV is vestibu-
lotoxic medication, usually from gentamicin. Neverthe-
less, in one study, 25% of older patients with an imbalance
of unknown origin had previously undetected BVL sig-
nificantly contributing to their imbalance (Fife and Baloh,
1993).
Mechanism
Ototoxins such as aminoglycoside, cisplatin, and some
organic solvents may cause BVL. The aminoglyco-
sides selectively damage vestibular or cochlear cells.
Streptomycin and gentamicin are the more vestibulo-
toxic drugs, thus damaging vestibular function more
than hearing. On the other hand, neomycin and kanamy-
cin are more cochleotoxic and so can cause hearing loss
more than vestibular loss. Tobramycin is intermediary.
Aminoglycosides block membrane channels of hair cells
and accumulate in hair cells, leading to cellular apopto-
sis. Cisplatin ototoxicity may be mediated in part by the
formation of superoxide anions. A mutation in human
386 Neurologic Conditions in the Elderly
mitochondrial 12S RNA gene at nucleotide A1555G has
been shown to be associated with susceptibility to irre-
versible hearing loss, but not vestibular loss, caused by
aminoglycosides.
Symptoms
As vestibular function declines, some vertigo may occur.
When BVL is fully present, it causes unsteadiness that is
worse when walking, especially in darkness or on uneven
ground. However, if the patient makes hand contact with
a wall while walking, balance significantly improves.
Oscillopsia, the perception of bouncing, jumbled, or blur-
ring vision, is another salient symptom of severe BVL.
Oscillopsia, due to vestibular hypofunction, is evident
during head motion because the vestibulo-ocular reflex
(VOR) is insufficient to stabilize vision during head
movements.
In a patient reporting new unsteadiness or dizziness
who has recently received aminoglycoside antibiotics,
BVL should be suspected. The onset of symptoms may
begin from 5 to 20 days after exposure. Elevated peak
and trough levels of gentamicin, for example, increase the
likelihood of toxicity, but some patients develop vestibu-
lar loss even when dosage has been properly monitored
and administered. Toxicity may occur whether gentami-
cin is administered intravenously, transtympanically (by
injection), or by peritoneal dialysis, but does not occur
from gentamicin eye or ear drops.
Diagnosis
Patients with BLV may exhibit an abnormal Rom-
berg test, bilaterally abnormal head impulse tests, and
dynamic visual acuity test. The latter is considered
abnormal when visual acuity drops three lines on a Snel-
len chart or Rosenbaum card during rapid head shaking.
There may be some mild nystagmus, but this is gener-
ally not prominent if the vestibular loss is symmetric or
chronic.
Diagnostic testing
VNG with caloric testing shows bilaterally reduced nys-
tagmus, and rotational chair testing is confirmatory for
BLV when it shows reduced VOR gain responses during
chair rotations at all frequencies.
Differential diagnosis
In addition to ototoxin exposures, other causes of BVL
include bilateral sequential vestibular neuritis, idiopathic
or heritable BLV, bilateral Meniere’s disease, autoimmune
inner ear diseases, meningitis, luetic otitis, trauma, and
bilateral acoustic neuromas.
Treatment
When possible, the underlying cause of BLV should be
treated. When the source of the vestibular loss has been
maximally addressed, the next step in treatment is to
promote adaptation and substitution, with the goal of
improving balance. Vestibular physiotherapy can be
helpful in achieving this, in part through exercises such
as those outlined in Table 16.3. With severe BLV, the brain
must rely on vision and somatosensation to help the
patient adjust and improve balance. Studies indicate that
vestibular rehabilitation improves dynamic visual acuity,
reduces complaints of oscillopsia, and reduces VOR gain
asymmetry (Brown et al., 2001).
CNS causes of dizziness and imbalance
Lesions in the CNS vestibular pathways can lead to ver-
tigo and imbalance. In general, the brain can adapt and
adjust to acute vestibular asymmetry, so acute vertigo
usually implies an event leading to sudden vestibular
asymmetry. For example, a stroke may lead to sudden
onset of vertigo, whereas an acoustic neuroma (vestibular
Schwannoma) is very slow growing and does not usu-
ally lead to vertigo, even though it causes vestibular loss.
Vertigo is not prominent with acoustic neuromas because
the loss of vestibular function occurs so slowly that adap-
tation occurs incrementally.
Ascribing a CNS lesion as the explanation of vertigo is a
matter of determining whether the lesion is anatomically
related to pathways important for vestibular function or
balance, as outlined in Table 16.4.
Epileptic vertigo
A seizure involving the vestibular cortex is a rare cause
of dizziness or vertigo. Rarely, vertigo may occur as an
isolated symptom of epilepsy (Bladin, 1998).
Mechanism
The cause is a focal seizure in the cerebral cortex near the
temporal lobe that processes vestibular signals. Curiously,
there is some suggestion that the vestibular cortex is more
likely on the right side (Fasold, 2002).
Symptoms
In most cases, patients are already known to have epi-
lepsy and may have auras or partial seizures manifesting
with dizziness. In most cases, other clinical features sug-
gest seizures such as automatisms, loss of awareness, and
convulsions that follow the aura of vertigo.
Diagnosis
MRI imaging should be undertaken when this diagnosis
is strongly considered. EEG monitoring may be necessary
to confirm a seizure mechanism when there is no struc-
tural lesion in brain imaging.
 Vertigo and Dizziness in the Elderly 387

Table 16.4 CNS regions that may be associated with vertigo, nystagmus, or ataxia

Anatomic location Structures affected Signs or symptoms Lesion example

Dorsolateral medulla
Floor fourth ventricle
Anterior cerebellar vermis
Dorsal cerebellar vermis
Superior cerebellar
peduncle
Middle cerebellar peduncle
Inferior cerebellar peduncle
Vestibular nuclei, root entry zone CN 8
Vestibular nuclei, especially superior
vestibular nucleus
Cerebellar connections
Flocculus, nodulus, uvula connections;
dorsal vermis; fastigial nucleus
Cerebellar efferents
Pontocerebellar fibers
Vestibulocerebellar afferents
Nausea, nystagmus, vertigo, ataxia
Nausea, nystagmus, vertigo, ataxia
Ataxia
Nystagmus, ataxia, possibly
vertigo, saccadic dysmetria
Positional vertigo
Ataxia, dysarthria, ipsilateral limb
clumsiness
Medulloblastoma, metastasis, MS
Medulloblastoma, cysts
Alcohol-related cerebellar ataxia
Cerebellar degeneration
MS
Pontine infarct, cavernous
malformation
Cavernous malformation, AVM

Anterior cerebellum
Vestibular cortex
Dorsal midbrain
Flocculus, nodulus, uvula Vertigo, ataxia, gaze-evoked Basilar meningitis
nystagmus
Superior temporal gyrus Vertigo Partial epilepsy
riMLF, iCajal Dysconjugate vertical/torsional Cavernous malformation, pinealoma,
nystagmus, vertical gaze disorders AVM

MS, multiple sclerosis; AVM, arteriovenous malformation; riMLF, rostral interstitial nucleus of the medial longitudinal fasciculus; iCajal, interstitial
nucleus of Cajal.

Differential diagnosis Atlantoaxial subluxation is a serious medical condi-

Depending on the duration of spells, transient ischemic
attacks, migrainous vertigo, and episodic ataxia may
cause similar episodes.
Treatment
Antiepileptic treatments aimed at managing partial epi-
lepsy are advised when the underlying cause cannot be
readily eliminated.
Craniocervical junction syndromes
The vestibulocerebellum and posterior medulla are key
vestibular structures located at the craniocervical junc-
tion, and lesions in this area may lead to vertigo. Condi-
tions that occur at this location include Chiari malforma-
tion, atlantoaxial subluxation, and, more rarely, basilar
impression.
A Chiari malformation is a congenital condition in
which the cerebellar tonsils did not fully migrate rostrally
during development, leaving the caudal-most cerebellum
(the cerebellar tonsils) wedged in the foramen magnum.
In severe cases, this may lead to vertigo, occipital head-
aches, nystagmus, and ataxia in early childhood. In other
cases, these features develop much more insidiously
and may not present until adulthood. Midsagittal MR
brain imaging reveals inferiorly located cerebellar tonsils
(>5 mm below the foramen magnum), and treatment in
appropriately selected cases entails suboccipital decom-
pression surgery.
tion that is usually due to erosion or malformation of
the ligaments holding C1 and C2 together. It may occur
from trauma but occurs more commonly in patients with
Down’s syndrome and patients with rheumatoid arthri-
tis. Patients with rheumatoid arthritis and Down’s syn-
drome reporting severe headaches, neck pain, and vertigo
should be evaluated with flexion and extension cervical
spine radiographs. Cervical spine and brain MRI studies
may fail to show the laxity of the ligaments, so they are
not sufficient to exclude this condition.
A final anatomic condition that may lead to central
vertigo related to the cervicomedullary junction is basilar
impression or basilar invagination. In this condition, the
floor of the skull becomes distorted or the tip of the dens
(odontoid process of C2) is pushed up rostrally, narrow-
ing the foramen magnum and compressing the medulla
or vascular structures of the lower brainstem. In older
adults, the conditions most likely to cause this include
Paget’s disease of the bone and osteogenesis imperfecta.
Vascular causes, brainstem and
cerebellar strokes, and hemorrhage
Vascular causes such as strokes, or TIA involving the ves-
tibular cortex, are rare causes of dizziness or vertigo.
Mechanism
Vertebrobasilar insufficiency refers to transient episodes
of inadequate blood flow through the vertebral and
388 Neurologic Conditions in the Elderly
basilar arteries that supply the brainstem and cerebellum.
Focal vascular narrowing by atherosclerosis is the most
common cause.
Rarely, occlusion or stenosis of the subclavian artery just
proximal to the origin of the vertebral artery causes rever-
sal of blood flow in the ipsilateral vertebral artery. Hence,
it is called subclavian steal syndrome because the subcla-
vian “steals” flow from the vertebrobasilar syndrome to
supply the upper limb. Vertigo and other symptoms of
vertebrobasilar insufficiency are precipitated by exercise
of the upper extremities. Angiography can localize the
site of the narrowing and the reversal of blood flow.
Symptoms
Transient ischemic attacks (TIA) in the vertebrobasi-
lar vascular system may cause vertigo, imbalance and
ataxia, slurred speech, nystagmus, diplopia and drop
attacks, headaches, and visual hallucinations or visual
field defects. Vertigo may be an isolated initial symptom
of vertebrobasilar insufficiency (Fife et al., 1994) or may
go along with other brainstem symptoms, as mentioned
earlier (Grad and Baloh, 1989). In most cases, treatment of
vertebrobasilar insufficiency consists of controlling vas-
cular risk factors and using antiplatelet drugs. Table 16.5
details clinical features of several brainstem vascular syn-
dromes that may be associated with vertigo.
Cerebellar strokes due to occlusion of the vertebral
artery, posterior inferior cerebellar artery (PICA), ante-
rior inferior cerebellar artery (AICA), or superior cerebel-
lar artery (SCA) can lead to isolated cerebellar infarction
(Amarenco, 1991). If the infarct affects portions of the cer-
ebellum that carry vestibular inputs, vertigo and ataxia
will likely follow. Small cerebellar infarctions in the cer-
ebellar hemispheres are less apt to cause vertigo or sub-
stantial ataxia than are midline or parasagittal lesions or
those affecting the flocculus or nodulus.
Spontaneous intraparenchymal cerebellar may occur
as a late effect of hypertensive vasculopathy. The ini-
tial symptoms may include vertigo, nausea, vomiting,
Table 16.5 Selected vascular syndromes associated with vertigo and ataxia
Vascular syndrome Blood supply
Vertebrobasilar TIA Vertebral arteries, basilar artery, Atherosclerosis
PICA or AICA, rarely SCA
Lateral medullary stroke PICA
(Wallenberg’s syndrome)
Lateral pontine stroke AICA
AICA, Anterior inferior cerebellar artery; PICA, Posterior inferior cerebellar artery; SCA, Superior cerebellar artery.
headache, and inability to stand or walk. Involvement of
the cerebellum can usually be distinguished from periph-
eral vestibular vertigo because the former results in dys-
metria and limb clumsiness, neither of which occurs with
peripheral vestibular lesions.
Diagnosis
The diagnosis is suspected when a patient has vascular
risk factors with symptoms and signs localizing to the
brainstem or cerebellum.
Diagnostic tests
A CT of the head readily and rapidly detects intracra-
nial hemorrhage. A brain MRI with diffusion weighted
imaging can confirm acute or recent stroke. MR angi-
ography and CT angiography are the most commonly
employed imaging studies to flow in the cerebral
arteries.
Differential diagnosis
Conditions that can produce focal neurologic findings
that are fleeting and in whom no vascular occlusive
disease is seen include disorders leading to cardiogenic
thromboemboli (including paradoxical emboli), hyper-
viscosity syndromes, Bickerstaff’s basilar migraine, and
mitochondrial cytopathies.
Treatment
Treatment should focus on ameliorating the underlying
cause by addressing vascular risk factors, as well as the
use of cholesterol-lowering and antiplatelet aggregation
medications. A variety of endovascular approaches are
finding a role in acute stroke management, including
administration of intra-arterial tPA, angioplasty, stenting,
and mechanical thrombolysis (Nogueira et al., 2009).
For patients with completed infarction, the same issues
apply, but with the addition of physical therapy to accel-
erate and improve overall recovery and return of func-
tion.
Common cause Features
Vertigo, clumsiness, dysarthria, diplopia, drop attacks, ataxia
Atherosclerosis Vertigo, ipsilateral facial numbness, limb dysmetria, Horner’s
or vertebral artery syndrome, diplopia, lateral pulsion of saccades, asymmetric
dissection gaze nystagmus, slurred speech, falling to one side,
contralateral loss of pain and temperature sensations
Atherosclerosis Vertigo, ipsilateral facial numbness, facial weakness, hearing
loss, limb dysmetria, Horner’s syndrome, diplopia, lateral
pulsion of saccades, asymmetric gaze nystagmus, slurred
speech, falling to one side, contralateral loss of pain and
temperature sensations

Large cerebellar infarcts that produce edema can have
life-threatening consequences if the edema compresses
the fourth ventricle or dorsal brainstem. Hence, large cer-
ebellar infarcts and cerebellar hemorrhages are potential
neurosurgical emergencies.
Multiple sclerosis
Multiple sclerosis (MS) is usually considered a disease of
younger people between ages 20 and 40 years, but about
10% of patients have onset after the age of 50. Equilibrium
disorders caused by involvement of spinal cord, brain-
stem, and cerebellar structures are common in patients
with MS. However, peripheral vestibular disorders such
as BPPV are also quite common among patients with a
history of MS (Frohman et al., 2000), so a CNS should
not necessarily be assumed to be the cause of patients
with MS.
Mechanism
MS is an inflammatory, demyelinating disease of the CNS.
Pathologically, it is characterized by inflammatory mono-
cytes and lymphocytes around blood vessels and regions
of loss of oligodendrocyte-derived myelin, referred to as
plaques, that localize predominantly in the CNS white
matter.
Demyelinating lesions in parts of the brain that are
interrelated with the vestibular system can result in
vertigo and nystagmus (Table 16.4). Among the more
notorious locations for a plaque to lead to vertigo or
ataxia is the nodulus, midline or parasagittal cerebel-
lum, middle cerebellar peduncle, and dorsolateral
medulla at the root entry zone of the vestibulocochlear
nerve.
Symptoms
Possible symptoms include vertigo, dizziness aggravated
by head movement, persistent nausea, ataxia, and imbal-
ance, sometimes with nystagmus or diplopia.
Diagnosis
The presence of persisting nystagmus, particularly gaze-
evoked nystagmus or spontaneous vertical nystagmus or
other central types of nystagmus (such as periodic alter-
nating nystagmus or seesaw nystagmus) indicate CNS
localization and MS as the cause. A new plaque may not
always be visible by MR imaging, so further workup may
be needed in some cases to exclude peripheral vestibular
causes.
Diagnostic tests
Brain MRI with contrast is one of the most sensitive stud-
ies for detecting new plaques in a relevant part of the
CNS. Quantitative vestibular testing may reveal local-
izing ocular motor findings and examines the functional
integrity of the peripheral vestibular system.
Vertigo and Dizziness in the Elderly 389
Differential diagnosis
The main differential diagnostic considerations are
peripheral vestibular disorders and migrainous vertigo.
Treatment
Treatment should be directed at the underlying mecha-
nism. If due to MS, clinical judgment should dictate
whether the symptom justifies using intravenous corti-
costeroids or changing immunomodulating medications.
If it is peripheral vestibular in origin, vestibular physi-
cal therapy or temporary use of some of the medications
described in Table 16.2 may be helpful.
Sensory ataxia syndromes
Many patients use the term dizziness to describe poor
equilibrium. A category of disorders that result in poor
balance on the basis of somatosensory dysfunction or spi-
nal cord ataxia may produce this kind of unsteadiness.
Mechanism
This group of disorders is varied, but the cause of imbal-
ance results from disruption of spinal cord or peripheral
nerve afferent sensory inputs to the brain. Hence, joint
position sensation and loss of vibratory sensation in the
lower limbs become impaired. These disorders thus are
sometimes referred to as sensory ataxia syndromes. These
disorders may include dorsal root ganglionopathies, large
fiber demyelinative peripheral neuropathies (ataxic neu-
ropathy), severe polyneuropathies, and lesions affecting
white matter tracts (dorsal columns) of the spinal cord,
as may occur in tabes dorsalis from syphilis or subacute
combined degeneration from vitamin B12 deficiency. The
list of such conditions is long and beyond the scope of
this chapter, but clinicians should be aware of this type of
disorder when patients complain of dizziness but actually
mean unsteadiness and imbalance.
Symptoms
With sensory ataxias, there is impairment of distal joint posi-
tion and vibration sensation that may be described as feel-
ing numb in the feet or feeling like walking in thick socks.
Patients note balance difficulty, particularly in darkness.
Diagnosis
With some spinal cord disorders affecting pyramidal (cor-
ticospinal) tracts, deep tendon reflexes in the lower limbs
may be brisk, possibly with extensor plantar responses.
With diseases of the dorsal root ganglia, dorsal roots or
peripheral nerve reflexes may be absent. Sensory loss may
include joint position sense and vibratory sense, some-
times also with loss of pain and temperature sensations,
depending on the type of sensory fibers affected. The
Romberg test is typically positive.
390 Neurologic Conditions in the Elderly
Diagnostic tests
Motor and sensory nerve conduction velocity mea-
surements, and sometimes somatosensory-evoked
potentials (SSEPs), may help to localize whether large
fiber, small fiber, sensory or motor, or mixed nerves are
affected; gauge conduction block; and assess whether
the process is likely related to abnormal spinal cord
dysfunction. Cerebrospinal fluid (CSF) studies may
show elevated CSF protein in certain demyelinating
neuropathies, and nerve biopsy may also be indicated
to assess for demyelinating neuropathy or vasculitic
neuropathy. MR imaging of the spinal axis excludes
structural lesions within the spinal cord and extramed-
ullary lesions compressing the cord. When there is no
sensory level or other more localizing clues, MR imag-
ing of the cervical, thoracic, and lumbosacral regions is
sometimes necessary.
Treatment
Treatment varies widely, depending on the cause. Demy-
elinating neuropathies may be responsive to plasma
exchange or intravenous immunoglobulin. Vasculitis
neuropathies may respond to corticosteroids, cyclophos-
phamide, or a variety of other immunomodulating medi-
cations. Subacute combined degeneration may improve
with vitamin B12 supplementation. Tabes dorsalis due
to syphilis may be treated with intravenous aqueous
penicillin G. HIV-1 associated vacuolar myelopathy may
improve with highly active antiretroviral therapy.
Cerebellar ataxia syndromes
Various late-life cerebellar syndromes may cause imbal-
ance and dizziness.
Mechanism
The underlying cause of most ataxias is cerebellar degen-
eration with loss of cerebellar Purkinje and granule cells.
The cause for this in some of the dominantly inherited
ataxias relates to CAG trinucleotide repeats. CAG is the
codon for the amino acid glutamate. Hence, excessively
long polyglutamine strands form in certain proteins. The
mechanism by which the glutamine repeats lead to cell
death is the focus of ongoing research.
Other ataxias may be due to recessively inherited
causes, or at least appear sporadic, as there is no family
history. Some of these represent more purely cerebellar
degenerative disorders, and some exhibit prominent cer-
ebellar features but are part of a wider multiple system
atrophy and are termed MSA-C. Their precise mechanism
is unknown.
Friedreich’s ataxia is a recessively inherited disorder
caused by expanded GAA repeats that lead to transcrip-
tion of deficient amounts of frataxin, a protein important
in mitochondrial regulation desulfurase functions. This
condition usually has onset in childhood or young adult-
hood but may continue on to later adulthood. Subacute
cerebellar degeneration is a paraneoplastic disorder asso-
ciated with anti-Purkinje cell (anti-Yo) antibodies asso-
ciated usually with ovarian carcinoma. Gluten ataxia
is a controversial entity due to gluten sensitivity and is
associated with anti-gliadin antibodies that presumably
improves with avoidance of dietary gluten (Hadjivassiliou
et al., 2002; Lock et al., 2005).
Fragile X ataxia tremor syndrome (FXTAS) is a genetic
neurodegenerative disorder affecting mostly men that is
due to an increased number of cytosine-guanine-guanine
(CGG) repeats in the fragile X (FMR1) mental retardation
gene on the X chromosome. If the number of CGG repeats
is extensive (>200 repeats), the patient develops fragile X
syndrome. Carriers are those with a permutation that may
be passed along to their daughters, who, in turn, have a 50%
chance of passing it along to their children; in some cases,
this leads to an expansion to the full fragile X syndrome.
Finally, a variety of neurodegenerative disorders may
initially present with dizziness and a feeling of poor equi-
librium before telltale signs become apparent. Nascent
progressive supranuclear palsy, corticobasilar degenera-
tion, various extrapyramidal disorders, and multiple sys-
tem degenerations can be perplexing in an older person
when the only initial symptom is mild imbalance. The
development of tone changes, ocular motor abnormalities,
or cognitive findings eventually clarifies the diagnosis.
Symptoms
Most ataxias are characterized by slowly progressive limb
and gait ataxia, dizziness, dysarthria, and abnormal eye
movements. Patients report imbalance and poor limb
coordination, declining handwriting, and worse balance
when fatigued. Dysarthric speech is also commonly
aggravated by fatigue. These ataxias may present with
dizziness or simply poor balance and may have onset late
in life. FXTAS usually has onset at about age 60 years and
affects men and only rarely women. Symptoms of FXTAS
include new-onset anxiety; reclusive behavior; cognitive
decline, including impairment of memory and executive
functions, but less commonly overt dementia; ataxia; and
intention tremor (Jacquemont et al., 2003).
Diagnosis
Horizontal gaze-evoked nystagmus and impaired smooth
pursuit are probably the most commonly encountered
clinical signs, along with truncal ataxia and limb clum-
siness. Spontaneous downbeat nystagmus may be seen
with any cerebellar ataxia but is particularly common
in SCA6. Central positional downbeating nystagmus
may also be observed, along with limb dysmetria and
impaired diadochokinesis. The gait base widens in time,
and steppage becomes visibly clumsy.

Diagnostic test
Patients with cerebellar ataxia should have a brain MRI to
exclude structural lesions. Genetic testing is available for
Friedreich’s ataxia, many of the autosomal dominant spi-
nocerebellar ataxias, and FXTAS (DNA test for the FMR1
gene). In addition, a characteristic region of increased sig-
nal on a T2-weighted brain MRI can be seen in the middle
cerebellar peduncles, and cerebellar white matter is pres-
ent in FXTAS (Brunberg et al., 2002).
Treatment
Few treatments exist for the ataxias in general. Vitamin E
deficiency ataxia can be treated with vitamin E. Gluten
ataxia may improve with avoidance of dietary gluten.
Physical therapy may result in some functional improve-
ments in some ataxia patients (Ilg et al., 2009).
Episodic ataxia syndromes
The episodic ataxias (types 1–6) represent a relatively rare
group of sporadic and heritable ataxia disorders charac-
terized by recurrent episodes of vertigo and ataxia. While
onset may begin in childhood or early adulthood, symp-
toms may continue undiagnosed well into late adulthood.
Mechanism
These syndromes are due to abnormal ion channels due to
various mutations in the P/Q-type voltage-sensitive cal-
cium channel (CACNA1A), in the case of episodic ataxia
type 2 (EA2). Episodic ataxia type 1 (EA1) is due to muta-
tions in the voltage-gated potassium channel (KCNA1).
Symptoms
Episodic ataxia type II manifests with recurrent vertigo
and ataxia often associated with other signs and symp-
toms, such as diplopia, vertical nystagmus, and dysar-
thria. The episodes may begin in childhood and continue
into adulthood. Spells often last minutes to several days
and are often periodic. They represent an important treat-
able cause of vertigo because ataxia and vertigo attacks
may subside with the use of acetazolamide (Diamox).
EA1 differs from EA2 because the attacks of vertigo and
ataxia are shorter in duration, myokymia is present even
between attacks, and attacks do not respond as well to
acetazolamide.
Diagnosis
The diagnosis should be suspected in a patient with a
long history of recurrent bouts of unexplained vertigo
associated with slurred speech and ataxic gait. Down-
beat spontaneous or positional nystagmus even between
spells lends further support for the diagnosis but is not
present in all cases. Responsiveness to acetazolamide is
further confirmation of the diagnosis of EA2.
Vertigo and Dizziness in the Elderly 391
Diagnostic tests
No specific diagnostic tests for this diagnosis exist. Brain
MRI may show midline cerebellar vermis atrophy, but
this is not always present. There are no commercially
available genetic studies for the episodic ataxias at pres-
ent, so diagnosis is made by history and response to acet-
azolamide.
Differential diagnosis
Considerations include transient ischemic attacks from
vertebrobasilar insufficiency, MAV, and, in some cases,
incipient Meniere’s disease without hearing loss. The
presence of dysarthric speech during spells or interic-
tal myokymia in the case of EA1 should help exclude
Meniere’s and other otogenic causes of vertigo. SCA6
may be characterized by episodic vertigo and ataxia in
some cases.
Treatment
Treatment with acetazolamide is often effective for EA2,
but treatment for the other episodic ataxia subtypes is not
well established.
Migraine-associated vertigo
Migraine is a common syndrome characterized by severe
headaches, nausea, and altered bodily perceptions.
Though migraine is more common among younger peo-
ple, it is also fairly common in older people (Wijman et
al., 1998; Haan et al., 2007). Migraine may also be associ-
ated with vestibular symptoms such as episodic vertigo
and chronic motion sensitivity. Vertigo and motion sick-
ness unaccompanied by headache may also occur with
migraine and together are referred to as migrainous ver-
tigo, MAV, or vestibular migraine.
Mechanism
The cause of MAV is not completely understood. How-
ever, evidence suggests a likely CNS origin, possibly
leading to hypersensitization of brainstem nuclei to
sensory information, including nociception (headache,
allodynia), auditory stimuli (phonophobia), vestibular
stimuli (vertigo, motion sickness, visual vertigo), vision
(photophobia), and olfaction (osmogenic headaches and
nausea) (Cuomo-Granston and Drummond, 2010). Both
environmental and genetic factors participate in MAV
mechanisms.
Symptoms
The vertigo comprises recurrent vertigo episodes, general
motion sensitivity and motion sickness, and visual ver-
tigo. Visual vertigo, also called optokinetic motion sick-
ness, is a syndrome in which observing objects in motion
causes dizziness, nausea, and many of the symptoms of
392 Neurologic Conditions in the Elderly
motion sickness, even though the individual is not in
motion (Guerraz et al., 2001). Migraine headaches are also
fairly common in MAV, even if they are not temporally
associated with the vertigo attacks.
Diagnosis
Patients’ descriptions of vertigo in MAV are often dif-
ferent from those of other diseases that lead to vertigo
attacks. In MAV, the duration of vertigo varies widely
(Neuhauser et al., 2001), whereas most otogenic ves-
tibular disorders have stereotypic duration: Meniere’s
attacks last hours, benign positional vertigo lasts 10–30
seconds, and vestibular neuritis goes on for days to
weeks. Vertigo and headache do not always occur at the
same time as vertigo in MAV; in fact, vertigo is often
present in the absence of migraine headache (Cutrer
and Baloh, 1992; Neuhauser et al., 2001). Hence, the
diagnosis is clinical and partly based on exclusion of
other causes, along with a family or personal history
of migraine.
Diagnostic tests
Vestibular studies may show minor degrees of positional
nystagmus, but often these studies are normal. Hearing is
unaffected in MAV. Brain MRI is also normal.
Differential diagnosis
Fluctuating unilateral hearing loss should point to
Meniere’s. In patients with vascular risk factors, tran-
sient ischemic attacks should be considered. If the vertigo
is evoked by turning in bed or changing head position,
benign positional vertigo should be considered.
Treatment
MAV is not life-threatening, so mild cases require no spe-
cific treatment and can be managed with antivertiginous
medications (Table 16.2). Avoiding triggers such as stress,
certain foods, irregular sleep, and skipped meals may be
helpful. When the symptoms are frequent or severe and
interfere with the quality of life, migraine prophylac-
tic medication may be necessary. These may include the
daily use of verapamil, propranolol or similar beta-adren-
ergic blockers, tricyclic amines, topiramate, or sodium
divalproex. MAV has been found to have an associa-
tion with Meniere’s disease. In such patients, Meniere’s
should be concurrently managed with sodium restriction
and diuretics.
Normal pressure hydrocephalus
Normal pressure hydrocephalus (NPH) is characterized
by a triad of progressive gait disturbance, cognitive defi-
cits, and urinary incontinence. It is most commonly seen
in older adults.
Mechanism
NPH develops gradually when the rate of CSF absorp-
tion slows and is gradually outpaced by its production.
Prior subarachnoid hemorrhage, meningitis, and trauma
may predispose to this process. Most commonly, the
hydrocephalus is communicating, though mild cases of
aqueductal stenosis and slowly decompensating long-
standing overt ventriculomegaly of adulthood (LOVA)
can present similarly later in life. In NPH, the ventricles
gradually enlarge until the point that the elastic capac-
ity of the brain tissue is exceeded and CNS function
becomes impaired.
Symptoms
The most common and first symptom of NPH is gait dis-
turbance. Gait disturbance in patients with NPH ranges
in severity from mild imbalance to inability to walk.
Patients may have difficulty turning and can therefore be
mistakenly diagnosed with Parkinson’s disease. Patients
typically report poor balance, unsteadiness, and difficulty
walking but do not report spinning vertigo.
Cognitive deficit is presented as mild dementia with a
loss of interest in daily activities, forgetfulness, difficulty
dealing with routine tasks, and slowed mental process-
ing. Impairment in bladder control ranges from urinary
frequency to complete loss of bladder control.
All three symptoms of the triad (gait disturbance, cog-
nitive deficits, and urinary incontinence) are common in
older people, which can create a challenge to clinicians. It
is nevertheless important to try to exclude NPH because
patients may respond remarkably well to CSF shunting
when the diagnosis is correct.
Diagnosis
Making a diagnosis of NPH depends on history, exami-
nation, response to CSF removal, and brain imaging.
The presence of the entire triad (gait imbalance, urinary
incontinence, and dementia) is not necessary to make a
diagnosis. As mentioned, the earliest feature is a decline
in gait, with short, slow steps; apraxia of gait; and general
slowing. Because distinguishing clinically among early
extrapyramidal syndromes may be difficult, a trial of car-
bidopa/levodopa is sometimes advisable.
Diagnostic testing
Brain MRI or CT shows enlarged cerebral ventricle that
is disproportionate to any cortical atrophy. Thus, ven-
triculomegaly, along with a history of slowly progres-
sive gait disturbance, should raise suspicion for NPH.
Common steps for clarifying the diagnosis include CSF
studies, measurement of opening pressure, and removal
of 30–40 mL CSF on a trial basis to see if the patient
improves. A 3-day lumbar CSF drain is also helpful but
controversial, due to the expense and invasive nature of
this assessment.

Differential diagnosis
Other causes of gait impairment should be excluded
before making a diagnosis of NPH. Patients with demen-
tia but a fairly normal gait are unlikely to have NPH.
Patients with gaze-evoked nystagmus are more likely to
have a late cerebellar degeneration and will not benefit
from shunting. The condition most commonly confused
with NPH is probably striatonigral degeneration (MSA-P)
or dopa nonresponsive parkinsonism.
Treatment
The most common treatment for NPH and the only
widely accepted treatment is CSF shunting. Shunting is
surgically implanting a CSF catheter, usually in the right
lateral ventricle, that is attached to a valve regulator,
sometimes with an anti-siphon valve apparatus, which
is then attached to another longer catheter placed under
the skin that drains into the peritoneum. The shunt chan-
nels CSF away from the brain to the peritoneum, where it
can be absorbed. Improvement can be dramatic in some
patients immediately following shunt placement.
Psychological causes of dizziness
Psychological factors contribute to symptoms in many
patients with dizziness (Furman et al., 2001; Savastino et
al., 2007). Dizziness and vertigo often lead to a sense of
loss of control, which seems to foster anxiety more than
do other recurrent or chronic medical symptoms. Vertigo
from a vestibular disorder may evoke anxiety or may
exacerbate previously well-controlled psychiatric condi-
tions (Staab and Ruckenstein, 2003). Psychiatric disor-
ders therefore both cause and result from dizziness. In
addition, fear of falling is a common problem among the
elderly, and dizziness reinforces this fear (Arfken et al.,
1994).
Patients with chronic dizziness have a variety of com-
mon symptoms that, in some cases, may be part of the
underlying cause of vertigo and dizziness or may be a
secondary consequence of anxiety due to their symptoms.
The so-called “brain fog” and difficulty concentrating is
common. Depression, frustration, irritability, and loss of
confidence in doing previously easy tasks (such as driv-
ing, speaking in public, and traveling) are all reasonably
common but must be viewed not only as the possible
result of the dizziness symptoms, but also as a response
to the process of seeking and obtaining medical care in the
health-care system and functioning with their symptoms
in society.
In many cases, establishing rapport with the patient,
explaining the interplay between anxiety and dizziness,
and treating any remediable otogenic vestibular disorders
goes a long way to unwinding the patient’s anxiety. In
some cases, working with a vestibular physical therapist
Vertigo and Dizziness in the Elderly 393
can help restore confidence and improve patients’ anxiety
and function (Meli et al., 2007).
A number of psychiatric disorders appear to predispose
to dizziness as well. These may include panic disorder,
generalized anxiety, and some of the phobias. In these
disorders, the dizziness is more commonly described as
floating, rocking, or simply impending loss of control;
when severe, agoraphobia may develop.
Any underlying otogenic or other cause of dizziness
should be treated first, or the ongoing symptoms will con-
found treatment of the secondary anxiety issues. When
medication becomes necessary to manage the anxiety
symptoms, intermittent use of a benzodiazepine such as
diazepam, lorazepam, alprazolam, or clonazepam can be
helpful. When symptoms occur daily, serotonin reuptake
inhibitors (Staab and Ruckenstein, 2005) or serotonin nor-
epinephrine reuptake inhibitors may be helpful and allow
benzodiazepines to be used more sparingly.
Postural hypotension
Postural or orthostatic hypotension is common in older
people (Hiitola et al., 2009). What constitutes a clinically
significant decline in blood pressure varies, but in gen-
eral, a drop in systolic blood pressure of 20 mm Hg or
more upon assumption of the upright position compared
to lying or sitting is considered abnormal. How low the
blood pressure drops and patients’ reported symptoms
are also relevant to determining whether orthostatic
intolerance should be treated. Syncope will occur if blood
pressure declines enough, but some patients have enough
forewarning and instinctively avoid syncope by sitting as
soon as they feel the onset of the dizziness. Consequently,
not all patients with problematic orthostatic hypotension
report syncope.
Mechanism
Any condition that transiently reduces global cerebral
blood flow can cause postural hypotension. Cardiac
causes include heart failure, valvular heart disease, bra-
dycardia, and other dysrhythmias. Neurally mediated
hypotension, also known by other names such as vasova-
gal near-syncope and neurocardiogenic near-syncope, are
due not to cardiac dysfunction, but to transient and inap-
propriate autonomic function. This may occur at random
times or be delayed (Gibbons and Freeman, 2006) so that
initial orthostatic vital signs are normal, but as the patient
remains standing, the blood pressure later drops.
Symptoms
Low blood pressure causes symptoms such as dizzi-
ness, faintness, or lightheadedness, often described as on
394 Neurologic Conditions in the Elderly
the verge of passing out; only infrequently is spinning
reported. Patients may report feeling warm, sweaty, or
cold and clammy and feeling nauseated when the blood
pressure declines. In older patients, these autonomic
responses to hypotension may be muted, and patients
simply feel weak or feel like they may fall.
Diagnosis
The diagnosis of orthostatic hypotension should be
suspected when lightheadedness occurs initially upon
standing or there is a history of syncope or near-syncope.
Measurement of orthostatic vital signs can be confirma-
tory but may miss some causes, such as delayed ortho-
static hypotension (Gibbons and Freeman, 2006) and
many cases of vasovagal hypotension (Ward and Kenny,
1996).
Diagnostic tests
Tilt table testing is currently the test of choice for patients
with unexplained syncope or those in whom hypotension
is suspected but not easily documented (Tan et al., 2009).
Treatment
Correcting the underlying cause is the most direct treat-
ment, when that is possible. Reducing the dosage or
altering antihypertensive medications may help in some
cases. Fludrocortisone or midodrine may help increase
blood pressure, but one must be careful to avoid supine
hypertension. Pyridostigmine, indomethacin, and, in
some instances, pindolol may be indicated for some
forms of postural hypotension. Lifestyle activities to
avoid prolonged standing or to pause upon initially get-
ting up may be enough for some patients to avert serious
symptoms.
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 Chapter 17
Disorders of the Special Senses
in the Elderly
Douglas J. Lanska
Neurology Service, Veterans Affairs Medical Center, Great Lakes Health Care System, Tomah, WI, USA

Summary
• Age-related changes in the visual, auditory, olfactory, and gustatory systems are often believed to represent “normal”
aging, but they generally represent a combination of normal aging changes in the sensory systems, combined with
cumulative toxic insults, medication effects, and the effects of comorbid disease.
• The risks of drug toxicity are increased by age-related changes in drug metabolism or drug clearance from the body, by
frequent polypharmacy in this patient population, by a greater likelihood of comorbid disease often involving multiple
organ systems, and by a lower general capacity to maintain homeostasis in the setting of any toxic or metabolic
disruption.
• Modality-specific perceptions can be impaired in several different ways: decreased sensitivity to sensory stimuli
(decreased acuity), abnormal or distorted quality of sensory stimuli (illusions), and perceptions without stimulation
(hallucinations).
• Regardless of sensory modality, disorders of the special senses in the elderly can be conveniently divided into
conductive, sensorineural, and central disorders, where (1) conductive disorders involve transmission of the sensory
stimuli to the sensory receptors (usually but not always by impeding transmission), (2) sensorineural disorders involve
dysfunction of the sensory receptors or conduction of signals from the sensory receptors to the brain, and (3) central
disorders involve dysfunction of processing of sensory information within the central nervous system, particularly
within the brainstem and cerebrum. In general, treatment of conditions causing a conductive loss of one of the
special senses is more likely to result in significantly improved function than is treatment of a condition causing a
sensorineural loss.
• Illusory misperceptions are particularly common with impairments in function of the corresponding sensory modality.
Clinically disabling presentations of illusions and hallucinations in the elderly most commonly involve the special sense
of vision, less so that of hearing, and least so the chemosensory domains of smell and taste.
• Release hallucinations are spontaneous sensory phenomena that occur in the setting of sensory loss, and when
possible should be distinguished from hallucinations with an “irritative” mechanism.
• Many of the common disabling visual disorders of the elderly are primarily ocular and, therefore, fall within the primary
domain of the ophthalmologist or optometrist. These include presbyopia, cataracts, vitreal separations, macular
degeneration, and glaucoma.
• Functionally significant hearing loss is common in the elderly (affecting about a third of those age 70 or older). Hearing
loss in the elderly can adversely affect quality of life and compromise an older individual’s ability to carry out routine
activities and interact socially, thereby contributing to isolation, frustration, disappointment, and depression.
• Disorders of the chemosensory senses, smell and taste, are usually less disabling than disorders of the other special
senses (vision and hearing). Nevertheless, olfactory impairment is a significant contributor to perceived disability and
lower quality of life among elderly patients and is a significant predictor of subsequent cognitive decline. Gustatory
disorders in the elderly that are not secondary to olfactory disorders should prompt consideration of systemic factors,
including medication use, toxin exposures, autoimmune disorders, nutritional disorders, depression, psychosis, cancer,
and endocrine and metabolic disorders.

Elderly individuals have a different profile of dysfunction of multiple comorbid disease states, and a greater likeli-
of the special senses than younger individuals, due in part hood of toxic effects of medications. Certainly, age-related
to a constellation of physiologic aging-related changes in changes in the visual, auditory, olfactory, and gustatory
the individual sensory systems, the frequent occurrence systems (such as presbyopia, presbycusis, presbyosmia,

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

396

and presbygeusia) often are believed to represent “nor-
mal” aging. However, they generally represent a combi-
nation of normal aging changes in the sensory systems,
combined with cumulative toxic insults, medication
effects, and the effects of comorbid disease. In addition,
many clearly pathologic conditions are strongly age-
related and are much more common among the elderly
than among younger individuals. For example, among
the most common conditions causing a marked loss of
visual acuity are cataracts, open-angle glaucoma, and
macular degeneration. All these conditions are strongly
age-associated and are much more common in the elderly.
The elderly are also more likely to be receiving medica-
tions to treat diseases and are generally much more suscep-
tible to the toxic side effects of such medications. The risks of
drug toxicity are increased by age-related changes in drug
metabolism or drug clearance from the body (for example,
resulting from changes in liver and kidney function), by
frequent polypharmacy in this patient population (with
associated, often pronounced increases in adverse effects
from drug interactions), by a greater likelihood of comor-
bid disease (often involving multiple organ systems), and
by a lower general capacity to maintain homeostasis in the
setting of any toxic or metabolic disruption. Furthermore,
any new symptoms, impairments, or disabilities resulting
from a new insult to homeostasis in the elderly are likely
to act synergistically with existing impairments and dis-
abilities to produce disproportionate declines in functional
performance. Unfortunately, although many (but not all)
toxic effects of medications are potentially reversible if
caught early, side effects of medications in the elderly are
often overlooked, being erroneously attributed to aging
itself or to comorbid disease states, and cause unnecessary
disability and even mortality.
General considerations
Clinically, modality-specific perceptions can be impaired
in several different ways: decreased sensitivity to sensory
stimuli (decreased acuity), abnormal or distorted quality
of sensory stimuli (illusions), and perceptions without
stimulation (hallucinations). Not generally considered
among misperceptions in clinical contexts are ambigu-
ous stimuli that can be variously interpreted or misinter-
preted by normal individuals (optical illusions).
Sensory deficits
Decreased (or absent) vision, hearing, smell, and taste
are referred to, respectively, as visual loss or impairment
(blindness), hearing loss or impairment (deafness or anacu-
sis), hyposmia, microsmia, or olfactory hypesthesia (anos-
mia), and hypogeusia or gustatory hypoesthesia (ageusia).
Each of these sensory deficits may have a “conductive”
or sensorineural basis (depending on the author or
Disorders of the Special Senses in the Elderly 397
circumstance, conductive is sometimes stated conversely
as obstructive). Thus, for example, decreases in visual acu-
ity may be conductive (obstructive) if impediments are
preventing the conveyance of light to the photorecep-
tors of the retina (as with corneal opacities, cataracts, or
intraocular hemorrhage). Similarly, conductive hearing
loss occurs if there are impediments to the conveyance of
sound through the external and middle ears to the cochlea
(for example, impacted cerumen or middle ear effusion),
conductive hyposmia occurs if there are impediments to
the conveyance of odorants to the olfactory neuroepithe-
lium (as with chronic rhinosinusitis or nasal polyps), and
conductive hypogeusia occurs if there are impediments
to the conveyance of gustatory (sapid) stimuli to the taste
buds (as with thrush, glossitis, radiation-induced xerosto-
mia, Sjögren’s syndrome, or anticholinergic medications).
Because saliva plays such an important role as a transport
medium for tastants, conductive hypogeusia often results
from conditions that interfere with saliva production.
Sensorineural disorders involve the receptors them-
selves (“sensory”) or the afferent neural pathways
involving the respective cranial nerves, tracts, or central
processing centers of the brain (collectively, “neural”).
Sensorineural disorders can be further subdivided by
types of receptors involved, extent and location of recep-
tor involvement within the sensory organ, and location
and extent of involvement within the neural pathways.
Sensorineural visual impairment, hearing impairment,
and hyposmia are all fairly common as isolated entities in
the elderly, whereas sensorineural hypogeusia or ageusia
as an isolated problem is extremely rare, even in highly
selected referral populations (Pribitkin et al., 2003).
In general, treatment of conditions causing a conduc-
tive loss of one of the special senses is more likely to result
in significantly improved function than is treatment of
a condition causing a sensorineural loss (Seiden et al.,
1992). For example, cataract surgery, removal of impacted
cerumen, drug treatment of chronic sinusitis, and discon-
tinuation of anticholinergic drugs may all significantly
benefit conductive losses of different special senses. Still,
in many examples, sensorineural loss may be treated and
functional performance may be improved with appropri-
ate interventions, including optical magnification and
adjustment of contrast for macular degeneration, and uti-
lization of hearing aids for sensorineural hearing loss.
Distortions and other misperceptions
If an abnormal sensory percept has no evident corollary
in the external milieu, the percept is considered to be
internally derived (a hallucination); if there is an external
correlate that has been distorted or misinterpreted, the
percept is considered to be externally derived but aber-
rantly processed (an illusion). However, in elderly patients
with multifactorial sensory impairments and cognitive
dysfunction, clearly distinguishing between illusions and
398 Neurologic Conditions in the Elderly

hallucinations may be difficult. In any case, in many situa- within the corresponding visual association cortex that is
tions, both categories of misperceptions occur as part of the interpreted as a perception, even though there is no cor-
same disease process or as a result of concomitant disease. responding sensory stimulus (a hallucination). A release
Illusory misperceptions are particularly common with mechanism for hallucinations is supported by (1) a sensory
impairments in function of the corresponding sensory deficit in the same modality as unimodal hallucinations,
modality. These can include distortions of form (as with with onset of hallucinations in conjunction with or follow-
dysmorphopsia), size (as with macropsia or micropsia), ing the sensory deficit; (2) variable content; (3) awareness
distance (as with pelopsia or teleopsia), character (as with of the hallucinatory nature of the perception; and (4) no evi-
achromatopsia, aliosmia, or dysgeusia), or location (as dence of seizures or other irritative phenomena (including
with allesthesia) of a stimulus, as well as multiplicity illu- no other positive motor or sensory phenomena, not par-
sions (such as monocular diplopia, polyopia, or diplacu- oxysmal in character, no epileptiform discharges on elec-
sis) and perseverations (such as palinopsia) (Ffytche and troencephalography, and unresponsive to administration
Howard, 1999). Hallucinations can occur with or without of anticonvulsant medications) (Cogan, 1973; Lanska et al.,
impairments in function of the corresponding sensory 1987a; Lanska and Lanska 1993; Braun et al., 2003; Lanska,
modality and can be simple (as with phosphenes, pho- 2005). Release hallucinations can occur in normal individu-
topsias, or subjective tinnitus) or complex (as with formed als with pansensory deprivation (Heron et al., 1956; Heron,
complex visual hallucinations [VHs], or voices, or musi- 1957). Similarly, modality-specific release hallucinations
cal hallucinations). can occur experimentally (Heron, 1957) or pathologically
Clinically disabling presentations of illusions and hal- (Lanska et al., 1987a; Lanska and Lanska, 1993) with uni-
lucinations in the elderly most commonly involve the modal sensory deprivation.
special sense of vision, less so that of hearing, and least In contrast, an “irritative” mechanism for hallucinations is
so the chemosensory domains of smell and taste. Visual supported by any of the following: (1) stereotyped content;
misperceptions generally indicate either dysfunction in (2) lack of awareness of the hallucinatory nature of the per-
the eye and/or neural visual pathways, comorbid medi- ception (termed hallucinosis); and (3) evidence of a poten-
cal or neurologic conditions, alcohol or sedative/hypnotic tially irritative process (such as migraine, tumor, or seizure)
withdrawal, and drug toxicity (as with anticholinergic or (Cogan, 1973; Braun et al., 2003). However, the clinical dis-
dopaminergic medications). The frequency of both cat- tinction between epileptic and release hallucinations is not
egories of visual misperceptions is markedly increased in always clear, and both types can occur in the same patient
the presence of confusional states, delirium, and various (Table 17.1). Spontaneous neuronal discharges, which
neurodegenerative diseases (such as Parkinson’s disease can occur with both seizures and deafferentation, may be
[PD], dementia with Lewy bodies [DLB], Alzheimer’s involved with both mechanisms (Levison et al., 1951; Echlin
disease [AD], and various other dementing disorders). and Battista, 1963; Chattha and Lombroso, 1972; ).
Patients with delirium have specific visual perceptual
deficits that cannot be accounted for by the degree of gen- Table 17.1 Comparison of ictal hallucinations and release
eral cognitive impairment (Brown et al., 2009). hallucinations
Whether misperceptions affect a sensory modality Characteristic Ictal hallucinations Release hallucinations
globally or are in some sense restricted may give valu-
able localizing information. For example, visual misper- Duration Brief (s to min) Often persistent (min
to h)
ceptions that are monocular (such as metamorphopsias
Variability Often stereotyped Usually variable and
and photopsias) indicate prechiasmal pathology, whereas change over time;
binocular misperceptions generally indicate retrochias- rarely stereotyped
mal pathology. Homonymous misperceptions indicate Content Simple or complex Simple or complex
unilateral retrochiasmal pathology that may be further Sensory deficit No (except possibly Yes
localized, depending on both the extent to which the in modality of incidental)
misperceptions are restricted within the visual fields and hallucination
the presence of any associated symptoms and signs. Environmental No Common (low light,
triggers closing or opening
In trying to characterize the VHs observed among non-
eyes, saccadic eye
psychotic patients with visual impairments, Cogan usefully movements)
distinguished what he called “release” hallucinations from Associated ictal Often No
other types of hallucinations, particularly those associated behavior, including
with “irritative” processes (Cogan, 1973). Release hallucina- alterations of
tions are spontaneous sensory phenomena that occur in the consciousness
setting of sensory loss. Sufficient impairment or removal of Epileptiform Often No
discharges or seizures
normal afferent inputs to the primary visual cortex appar-
demonstrated on EEG
ently allows, disinhibits, or “releases” spontaneous activity

The VHs that occur in patients with Lewy body alpha-
synucleinopathies (such as PD and DLB), other demen-
tias, and delirium are dealt with separately in the section
on vision. Such VHs are not adequately accounted for
within Cogan’s simple dichotomy of nonpsychotic hallu-
cinations into release and irritative types.
Examination
Clinical examination of the special senses in an elderly
patient by a geriatrician or neurologist requires careful
general physical and neurologic examinations augmented
by several office examination techniques. In many cases,
further assessment by an ophthalmologist (for ocular dis-
turbances), audiologist and otolaryngologist (for auditory
disorders), or otolaryngologist (for auditory, olfactory, or
gustatory disorders) is appropriate.
Office testing of vision as part of a neurologic examina-
tion in elderly patients should include visual acuity testing
of each eye with and without pinhole (to check for uncor-
rected refractive errors), Amsler grid testing of each eye
to check for disorders of the central visual fields (such as
scotomata and metamorphopsia), monocular and binocu-
lar confrontational assessments of the peripheral visual
fields, pupillary reflex testing, and ophthalmoscopy.
The penlight shadow test is a helpful screening test for
a narrow anterior chamber depth—tangential illumina-
tion of the eye from the lateral side normally illuminates
the entire iris, but with an abnormally narrow anterior
chamber, the iris is bowed forward and the nasal iris is at
least partly in shadow (not illuminated) (Lanska, 2006).
Generally when 50% or less of the nasal iris is illuminated
with the penlight shadow test, there is a moderate or high
risk of angle closure with pharmacologic pupillary dila-
tion (Townsend, 1991). If there is no history of glaucoma
and if screening with a penlight is performed accurately
and the results are negative, the risk of dilating a poten-
tially occludable angle is less than 0.3% (Patel et al., 1995).
Gonioscopy by an ophthalmologist or optometrist is the
definitive test for determining anterior chamber depth.
Elderly individuals who have obvious hearing difficulty
or recognize that they have hearing impairment should
have otoscopy and audiometry (Nondahl et al., 1998;
Bagai et al., 2006). Elderly individuals who are asymp-
tomatic from a hearing perspective should be screened
for hearing loss, preferably with the whispered voice test
(Uhlmann et al., 1980; Pirozzo et al., 2003; Bagai et al.,
2006), the calibrated finger rub auditory screening test
(CALFRAST; Torres-Russotto et al., 2009), or a handheld
audiometer. Application of the whispered voice test pro-
duces the greatest gain in diagnostic certainty of any of the
available bedside screening tests among both demented
and nondemented elderly patients. Asymptomatic elderly
individuals who perceive a whispered voice generally
require no further testing, while those unable to perceive
a whispered voice require audiometry (Bagai et al., 2006).
Disorders of the Special Senses in the Elderly 399
Tuning fork tests (the Rinne, Weber, and Bing tests) are
not useful for general bedside hearing screening and can
be abandoned for this purpose (Bagai et al., 2006); even
in diagnostic situations, the results of these tests can be
misleading (Stankiewicz and Mowry, 1979; Miltenburg,
1994; Pirozzo et al., 2003; Vikram and Naseeruddin, 2004;
Bagai et al., 2006; Boatman et al., 2007).
Hearing loss as measured with audiometry is catego-
rized commonly according to American National Stan-
dards Institute references for signal intensity: normal,
10–26 dB; mild loss, 27–40 dB; moderate loss, 41–55 dB;
moderately severe loss, 56–70 dB; severe loss, 71–90 dB;
and profound loss, 91+ dB (Campbell, 1998). Categoriza-
tion of the degree of hearing loss is generally based on
the pure tone average of three standard frequencies in the
speech range (the average of air-conduction thresholds
at 500, 1000, and 2000 Hz) but may be specified for each
frequency region (low, mid, or high frequencies on the
audiogram) (Campbell, 1998).
Office testing of smell can include well-standardized,
commercially available tests (such as the University of
Pennsylvania Smell Identification Test, or UPSIT) or crude
approaches utilizing identification of a few readily avail-
able odorants (such as oil of wintergreen or oil of cloves)
(Doty et al., 1984a, 1984b; Doty, 2007a); more complicated
odor identification and detection tests are also available
but are rarely practical outside specialized diagnostic
laboratories (Doty, 2007a). The UPSIT is a forced-choice
olfactory discrimination test that uses microencapsulated
odorants in standardized “scratch ‘n’ sniff” booklets.
UPSIT scores are standardized by gender and age, and
can be used to identify degrees of hyposmia and some
malingerers. Irritant substances, such as ammonia, are
sometimes employed when psychogenic or malingered
anosmia is a consideration, because such substances are
perceived via trigeminal afferent pathways instead of
through the olfactory system.
Office testing of gustatory function remains somewhat
crude (Schuster et al., 2009). Testing of taste thresholds
is problematic because salivary function and size of the
tongue area stimulated influence threshold assessment,
taste intensity may be depressed even with normal rec-
ognition thresholds, and changes in threshold detection
do not necessarily correlate with suprathreshold taste
intensity. Nevertheless, complicated and time-consuming
procedures are available for whole-mouth assessment
of thresholds for each of the four primary tastes (sweet,
sour, salty, and bitter) (Yamauchi et al., 2002a, 2002b).
Newer technologies, such as using flavor-impregnated
taste strips (similar to currently available commercial
breath-freshening strips) or tasting tablets are in devel-
opment and can potentially include assessment at mul-
tiple thresholds for all of the primary tastes, including
umami (savory) gustatory sensation (Ahne et al., 2000;
Smutzer et al., 2008; Landis et al., 2009).
400 Neurologic Conditions in the Elderly

Categorization of sensory disorders by (3) central disorders involve dysfunction of processing

modality and level of dysfunction
Regardless of sensory modality, disorders of the special
senses in the elderly can be conveniently divided into con-
ductive, sensorineural, and central disorders, where (1)
conductive disorders involve transmission of the sensory
stimuli to the sensory receptors (usually but not always
by impeding transmission); (2) sensorineural disorders
involve dysfunction of the sensory receptors or conduc-
tion of signals from the sensory receptors to the brain; and
sensory information within the central nervous system,
particularly within the brainstem and cerebrum. This is
essentially the classical categorization for auditory dis-
orders, but it can also be applied to visual and chemo-
sensory disorders (Table 17.2). Especially for the visual
system, central disorders can be further divided by the
involvement of precortical afferent pathways, primary
sensory cortex, and association cortex), but such consid-
erations are beyond the scope of this chapter.

Table 17.2 Selected disorders of the special senses in the elderly

Modality Category

Conductive Sensorineural Central

Vision Presbyopia Age-related macular degeneration Late-life migraine accompaniments

Dermatochalasis Diabetic retinopathy Retrochiasmal visual field defects (MCA- or PCA-territory
Astigmatism Retinal detachment stroke)
Myopia Glaucoma Poststroke unilateral inattention or neglect
Hyperopia Amaurosis fugax Visual agnosia
Cataracts Retinal artery occlusion Anton’s syndrome
Monocular diplopia Retinal vein occlusion Heidenhain variant of CJD
Vitreal detachment AION (nonarteritic and arteritic) Epileptic visual hallucinations
Vitreal hemorrhage Progressive painless optic neuropathy Visual hallucinations with retrochiasmal visual field defects
(paraneoplastic, neoplastic) Visual hallucinations in neurodegenerative diseases and
Bonnet syndrome delirium
Hearing Cerumen impaction Presbycusis Pure word deafness
Serous otitis media Noise-induced hearing loss Auditory agnosia
Objective tinnitus Ototoxic drugs Auditory hallucinations
Sudden SNHL Brainstem auditory hallucinosis
Herpes zoster oticus
Superficial siderosis
Meningitis
Carcinomatous meningitis
Subjective tinnitus
Olfaction Upper-respiratory infection Presbyosmia Epileptic olfactory auras
Chronic rhinosinusitis Drug toxicity Hyposmia in PD and DLB
Nasal polyposis Tobacco smoking Hyposmia in other neurodegenerative diseases
Dentures Head injury
Hypothyroidism
Influenza-like infection
Subfrontal meningioma
Gustation Poor oral hygiene Presbygeusia Depression
Lingual plaque Drug toxicity Stroke
Dental caries or periodontal Nutritional deficiencies (such as niacin, Hypogeusia in PD and DLB
disease cobalamin, or zinc)
GERD Hypothyroidism
Upper-respiratory illness Diabetes
Thrush Bell’s palsy
Oral cancer Influenza-like infection
Xerostomia Burning mouth syndrome

AION, anterior ischemic optic neuropathy; CJD, Creutzfeldt–Jakob disease; DLB, dementia with Lewy bodies; GERD, gastroesophageal reflux;
MCA, middle cerebral artery; PCA, posterior cerebral artery; PD, Parkinson’s disease; SNHL, sensorineural hearing loss.
Note: Disorders in bold font are discussed in greater detail later. These disorders were selected because of their general importance in a geriatric
population (based on frequency, impact on quality of life and disability, and so on), the strength of association of disease prevalence or incidence
with aging, diagnostic concerns (such as frequency with which the diagnosis is missed), conceptual factors (for example, to contrast different
etiologies), treatment implications, and the need for the special expertise of a geriatrician or geriatric neurologist. Other topics are not further
discussed or are mentioned briefly.

Vision
Many of the common disabling visual disorders of the
elderly are primarily ocular and, therefore, fall within
the primary domain of the ophthalmologist or optom-
etrist. These age-related conditions include presbyopia,
cataracts, vitreal separations, macular degeneration, and
glaucoma. Nevertheless, it is essential for geriatric neu-
rologists and geriatricians to recognize these disorders, to
appropriately direct referrals and minimize unnecessary
or inappropriate evaluations. Furthermore, the geriatri-
cian and geriatric neurologist should ensure that risk fac-
tors for the development of disabling visual impairment
are appropriately addressed, that primary and second-
ary prevention is undertaken when appropriate (includ-
ing use of antioxidants and mineral supplements for
secondary prevention of severe macular degeneration),
and that rehabilitation approaches are utilized that maxi-
mize residual visual function (including use of accessible
publishing and adaptive low-vision aids). Maximizing
vision can help patients achieve their functional potential,
improve overall quality of life, and minimize problems
with multisensory disequilibrium, falls, falls with injury,
depression, and cognitive impairment.
The most important disorders contributing to vision
impairment in the elderly include senile cataracts, age-
related macular degeneration, primary open angle glau-
coma, and diabetic retinopathy. In the Framingham Eye
Study, at age 75–85 years, approximately half had cata-
racts, more than a quarter had age-related macular degen-
eration, and about 7% (about 1 in 14) had primary open
angle glaucoma and a similar proportion had diabetic
retinopathy (Kini et al., 1978).
About 20% of individuals age 70 years and older have
functionally significant vision impairment, and about
2% report blindness in both eyes (Campbell et al., 1999).
Severe visual impairment is particularly disabling for
elderly patients and is a risk factor for various complica-
tions, including falls and hip fractures (Lamoreux et al.,
2008; Kulmala et al., 2009). Even normal elderly have lost
the ability to accommodate and generally have difficulty
in conditions of low contrast and low luminance.
Conductive visual disturbances
Visual disturbances can be categorized as conductive if
they interfere with light transmission to the photorecep-
tive retina. Such disturbances can be unilateral or bilat-
eral. Examples commonly seen among geriatric patients
include dermatochalasis (when redundant or dehiscent
skin from the eyelid droops across the path of light to
obscure at least a portion of the cornea); corneal abnor-
malities (a pterygium extending to cornea); abnormalities
of ocular shape that interfere with proper focusing of an
image on the retina (astigmatism, myopia, or hyperopia);
or age-related changes in the crystalline lens that preclude
Disorders of the Special Senses in the Elderly 401
focusing at near (presbyopia), interfere with light trans-
mission (cataracts), or disrupt light transmission between
the lens and the retina (posterior vitreal detachment).
Dermatochalasis and pterygia are obvious by visual
inspection; dermatochalasis characteristically produces
superior temporal visual field defects in affected eyes,
and pterygia can produce astigmatism or visual field
defects. Cataracts are readily recognized by loss of a red
reflex with pupillary reflex testing using a penlight and, if
dense, can interfere with ophthalmoscopy.
A useful clinical test for many conductive visual dis-
turbances is the pinhole test. By looking through a “pin-
hole” (a small-diameter hole measuring 1–2 mm in an
otherwise opaque card or occluder), the patient views
through a narrow visual angle. This minimizes existing
focusing problems, such as problems from inadequately
corrected astigmatism, myopia, hyperopia, or presbyopia,
or from corneal or lenticular irregularities. Demonstrat-
ing an improvement in measured visual acuity using a
pinhole (a “positive” pinhole test) establishes a conduc-
tive (ocular) basis contributing to the impairment in
visual acuity. For similar reasons, a pinhole can also be
used to assess patients with complaints of monocular dip-
lopia. Monocular diplopia typically occurs when light is
multiply directed along different trajectories because of
aberrations in the light-transmitting portions of the eye
(typically the cornea or lens). Ocular causes of monocular
diplopia include refractive problems (such as astigma-
tism), poorly fitting contact lenses, corneal abnormalities
(such as resulting from dry eye or prior ocular surgery),
iris abnormalities (such as iridotomy or iridectomy),
lenticular abnormalities (such as cataracts or position-
ing problems with intraocular lens implants), or retinal
abnormalities (such as epiretinal membrane). Usually
with monocular diplopia, the second image is a less dis-
tinct and partially superimposed “ghost” or “halo” of the
first image. Eliminating this second image when viewing
through a pinhole confirms a conductive (ocular) basis
for the complaint, which may (depending on the cause)
respond to refraction, a trial of artificial tears, or a contact
lens trial.
Several conductive visual disorders that are common in
geriatric patients—including presbyopia, senile cataracts,
and posterior vitreal detachment—are discussed in fur-
ther detail.
Presbyopia
Presbyopia is a normal age-related condition (literally
“elderly vision” or “old age vision”) in which the lens of
the eye gradually loses its ability to accommodate, mak-
ing it difficult to see objects up close and often leading
to squinting, eyestrain, and headaches. Accommodation
is the process by which the eye changes optical power
to maintain a clear image (focus) on an object as the dis-
tance to the object changes. The focusing power of the eye
402 Neurologic Conditions in the Elderly
depends on the elasticity of the crystalline lens, which
gradually declines as people age, partly as a result of
continued growth of the lens throughout life. People usu-
ally notice symptoms of the condition in their late 40s, as
they need to hold reading materials farther away to focus
on them; by this time, accommodation amplitude has
decreased sevenfold, from 7 diopters at age 15 to about
1 diopter at age 40. By age 60, the eyes have usually lost
most of the elasticity needed to focus up close. Symptoms
can include difficulty reading fine print, particularly in
low-light conditions; eyestrain when reading for long
periods; blur at near distances; and transient blur when
transitioning between viewing distances. Some patients
report that their arms have become “too short” to hold
reading material at a comfortable distance. Presbyopia,
like other focusing defects, is much less noticeable in
bright sunlight because then the iris closes to a smaller
diameter (in effect, accomplishing the same thing as a
clinical “pin hole” acuity test).
Presbyopia can be corrected with reading glasses or
half-glasses for those who do not need glasses for dis-
tance vision or with bifocals or contact lenses for those
who do. Inexpensive over-the-counter reading glasses
are readily available with corrective lenses that cover a
wide range of magnification levels. Some people choose
to correct one eye for near vision and one eye for distance
vision using different contact lenses; this approach, called
“monovision,” eliminates the need for bifocals or read-
ing glasses, although it can affect depth perception and
some elderly patients may not tolerate it. Newer bifocal
or multifocal contact lenses also can correct for both near
and far vision with the same lens. In addition, surgical
procedures can provide solutions for those who do not
want to wear glasses or contacts. In some patients, pres-
byopia can be corrected by intraocular lens implants at
the time of cataract surgery. Although eye exercises and
various devices (such as glasses with an array of pinholes)
have been marketed to delay or improve presbyopia, their
effectiveness has not been demonstrated.
Senile cataracts
Senile cataracts are due to age-related opacification of the
crystalline lens of the eye, a result of progressive dena-
turation and aggregation of lens proteins. The condition
usually affects both eyes, but typically with asymmetric
onset. Cataracts produce slowly progressive visual loss
and are potentially blinding if untreated. Cataracts also
cause loss of contrast sensitivity so that contours, shad-
ows, and colors are less vivid. Early in cataract develop-
ment, the power of the lens may be increased (as a result
of lenticular swelling), causing or exacerbating myopia.
The gradual yellowing and opacification of the lens may
reduce perception of blue colors. Glare, and occasionally
monocular diplopia or polyopia, can also occur as light is
scattered by the cataract into the eye. An affected eye has
an absent red reflex, and the opacified lens may compro-
mise adequate ophthalmoscopy.
Over time, the lens cortex liquifies to form a milky
white fluid (Morgagnian cataract), which can cause severe
inflammation if the lens capsule ruptures. Untreated cata-
racts can also cause secondary angle-closure glaucoma
(phacomorphic glaucoma) due to lens swelling (intumes-
cence). In the final stage, lens shrinkage is associated with
complete loss of transparency.
According to estimates by the World Health Organiza-
tion, age-related cataracts are responsible for blindness
in 18 million people, or approximately half of the cases
of blindness around the world. In addition to advanced
age, cataracts may be caused or accelerated by long-term
ultraviolet light exposure, cigarette smoking, radiation,
diseases (such as diabetes, hypertension, and glaucoma),
drugs (such as corticosteroids and quetiapine), and ocu-
lar trauma. Risk factors for moderate nuclear opacities
include female gender, nonwhite race, and smoking (Age-
Related Eye Disease Study Research Group, 2001a).
When a cataract is sufficiently developed to require
surgery, the most common approach is capsulotomy with
extracapsular cataract extraction (ECCE), in which only
the front of the lens is removed, while the back of the lens
capsule remains intact and provides support for the lens
implant. Ultrasound is sometimes used to break up the
cataractous lens, in conjunction with simultaneous irriga-
tion and aspiration (phacoemulsification). The catarac-
tous lens is replaced with a permanent plastic intraocular
lens implant. Although traditional intraocular lenses are
monofocal, newer multifocal lenses can minimize sub-
sequent dependence on glasses. Cataract operations are
usually performed as day surgeries under local anesthe-
sia. Potential complications of cataract surgery include
endophthalmitis, posterior capsular opacification, and
retinal detachment.
Posterior vitreous detachment
Posterior vitreous detachment (PVD) is a common age-
related condition in which the vitreous humor separates
from the retina. As a person ages, the delicate collagen
framework of the vitreous gel deteriorates, causing the
vitreous to shrink and develop pockets of liquefaction,
and potentially to suddenly separate from the retina.
When this happens, symptoms can include monocular
flashes of light (photopsias), a sudden marked increase in
the number of floaters, or a ring of floaters located to the
temporal side of the central vision. PVD by itself does not
normally threaten sight, but it may lead to traction and
distortion of the retina, as well as retinal tears or detach-
ment. Acute symptoms generally subside over a period of
several days to several months.
Approximately two-thirds of individuals over age
70 have evidence of PVD. Risk factors for PVD include
age and myopia (Akiba, 1993; Morita et al., 1995;

Yonemoto et al., 1996; Hayreh and Jonas, 2004). PVD
is rare in emmetropic people under age 40 years, but it
increases progressively with age to a prevalence of greater
than 80% among those in their 90s (Akiba, 1993). People
with myopia greater than 6 diopters are at higher risk of
PVD at all ages. Because the underlying changes develop
symmetrically in both eyes with age, PVD may develop
in the second eye within a few years of developing in the
first eye (Hikichi, 2007).
As a PVD proceeds, areas of adherent vitreous may pull
on the retina. Vitreous traction may stimulate the retina,
with resultant flashes that can look like a circle. If enough
traction occurs, the retina may tear at these points. If
there are only small point tears, these can allow glial
cells to enter the vitreous and proliferate to create a thin
epiretinal membrane that distorts vision. In more severe
cases, vitreous fluid may seep under the tear, separating
the retina from the back of the eye and creating a retinal
detachment. Retinal vessels may tear in association with a
retinal tear, or occasionally without the retina being torn.
If a retinal vessel is torn, leakage of blood into the vitreous
cavity is often perceived as a “shower” of floaters. The
risk of retinal tears and detachment associated with vitre-
ous detachment is higher in elderly individuals, patients
with severe myopia and myopic retinal degeneration, and
those with a familial or personal history of previous reti-
nal tears or detachment.
Retinal detachment is the separation of the neuro-
sensory layer of the retina from the underlying choroid
and retinal pigment epithelium, a situation that rapidly
produces ischemic degeneration of photoreceptors. Pre-
senting symptoms in the affected eye include the sud-
den onset of photopsias (flashing lights), new and more
prominent floaters (often with PVD), decreased visual
acuity, and metamorphopsia (wavy distortion of viewed
objects). Vision loss may be curtain-like, filmy, or cloudy.
Permanent vision loss can be minimized or prevented by
rapid diagnosis and prompt treatment.
Prompt examination of patients experiencing vitreous
floaters combined with expeditious treatment of any reti-
nal tears is the most effective means of preventing associ-
ated retinal detachments (Byer, 1994). The risk of retinal
detachment is greatest in the first 6 weeks following a vitre-
ous detachment, but it can occur more than 3 months after
the event. Patients initially diagnosed as having uncompli-
cated PVD have a greater than 3% chance of developing a
retinal tear within 6 weeks, but the risk is greater if at least
10 new floaters develop or if vision is subjectively reduced
during this period (Hollands et al., 2009).
Patients with the acute onset of monocular floaters
or flashes, and patients with known PVD and a change
in symptoms, should be urgently evaluated by an oph-
thalmologist for high-risk features of retinal tear and
detachment. The prevalence of a retinal tear under these
circumstances is approximately one in seven (Hollands
Disorders of the Special Senses in the Elderly 403
et al., 2009). Subjective visual reduction is the most
important symptom associated with retinal tear, so
visual acuity should always be assessed in this situation
(Hollands et al., 2009).
The success of retinal reattachment surgery is now
greater than 90%. The major cause of failure is develop-
ment of proliferative vitreoretinopathy (PVR), a com-
plex inflammatory reaction involving development of
epiretinal membranes, which are essentially scars formed
chiefly by cells of pigment epithelial and glial origin.
Epiretinal membranes can exert traction and reopen pre-
viously closed retinal tears, create new tears, bulge and
distort the macula (macular pucker), obscure the macula,
or cause macular edema (Machemer, 1988; Asaria and
Gregor, 2002). Often, this results in visual distortions that
are visible as bowing, blurring, or segmental size altera-
tions when looking at lines on an Amsler grid or on chart
paper. Surgeons can remove or peel the epiretinal mem-
brane through the sclera in conjunction with vitrectomy
and improve vision by two or more lines on the Snellen
chart. The chance of visual improvement is reported to
be approximately 80–90%. Surgery is not usually recom-
mended unless the distortions are functionally disabling,
because of potential but rare surgical complications,
including endophthlamitis, retinal detachment, glau-
coma, retinal bleeding, cataract progression, and recur-
rence of the membrane.
Sensorineural visual disturbances
Sensorineural visual disturbances involve the retinal ele-
ments and the transmitting neural pathways to the lateral
geniculate nucleus (optic nerves, optic chiasm, and optic
tracts). Examples of sensorineural visual disturbances
seen among geriatric patients include age-related macu-
lar degeneration, glaucoma, amaurosis fugax, embolic
branch retinal artery occlusions, arteritic anterior isch-
emic optic neuropathy (from giant cell arteritis), and pro-
gressive painless optic neuropathy. VHs associated with
sensorineural vision loss (such as Bonnet hallucinations)
also are considered here—the primary pathology is typi-
cally at a sensorineural level, although the hallucinations
themselves are generated centrally.
Among the sensorineural disorders, those that affect the
sensory elements in the retina are initially identified and
assessed with tonometry (to measure intraocular pressure
[IOP] and assess for glaucoma), visual acuity measure-
ment, visual field testing (including central visual field
testing with the use of an Amsler grid), ophthalmoscopy,
and collateral cerebrovascular studies and cranial imag-
ing if there is evidence by history or examination of ocular
vascular compromise or embolic phenomena (for exam-
ple, a history of amaurosis fugax or ophthalmoscopic
evidence of branch retinal emboli, including Hollenhorst
plaques, which are cholesterol emboli seen at bifurcations
of retinal arterioles). Sensorineural visual disorders that
404 Neurologic Conditions in the Elderly
affect the retro-retinal neural (anterior visual) pathways
are typically identified and assessed in clinical office prac-
tice by visual field testing, visual acuity testing, pupillary
light reflex testing, and the swinging flashlight test for
an afferent pupillary defect. Sudden onset of a unilateral
optic neuropathy in the elderly often indicates a vascular
problem (such as embolic, atherosclerotic vaso-occlusive,
or arteritic), whereas a unilateral painless progressive
optic neuropathy may indicate a malignancy (such as
paraneoplastic process, metastasis, or carcinomatous or
lymphomatous meningitis) (Lanska et al., 1987b).
Several sensorineural visual disorders that are com-
monly encountered in geriatric patients and that prefer-
entially affect the elderly are discussed in further detail.
These include age-related macular degeneration, glau-
coma, the arteritic anterior ischemic optic neuropathy
seen with giant cell arteritis, and nonarteritic anterior
ischemic optic neuropathy (NAION).
Age-related macular degeneration
Age-related macular degeneration (abbreviated vari-
ously as AMD or ARMD) affects older adults (typically
>60 years) and results in a progressive loss of central
vision because of damage to the retinal macula. Visual
loss from AMD is often disabling and greatly impacts
quality of life, to a degree with moderate disease similar
to that of severe cardiac angina or a fractured hip; severe
disease adversely affects quality of life more than that of
dialysis, and very severe disease adversely affects quality
of life to a degree comparable to end-stage prostate cancer
or a catastrophic stroke (Brown et al., 2005). In particular,
the loss of central vision and loss of visual acuity can irre-
versibly result in loss of reading, facial recognition, and
driving (Ehrlich et al., 2008). AMD is the leading cause
of irreversible severe vision loss and of legal blindness in
patients over age 60 years (Klein et al., 1997b).
In the “dry” (nonexudative) form, yellow deposits of
cellular debris called drusen accumulate between the
retinal pigment epithelium and the underlying choroid,
whereas in the later and more severe “wet” (exudative)
form, neovascularization develops from the choroid
behind the retina. Vision loss generally progresses rela-
tively slowly in dry AMD (over years), whereas wet AMD
may progress rapidly (over weeks). Although only about
10–15% of people with AMD have the wet form, it causes
most of the vision loss associated with the condition; 85%
of those with wet AMD lose all central vision and have
acuity measured in the 20/200–20/400 range (that is, can
read the big E or the second line of the eye chart).
Most people with early pathologic changes of dry
AMD have preserved vision. As drusen increase in size
and number, the retinal pigment epithelium under the
macula is increasingly disturbed and becomes atrophic,
causing secondary degeneration of the overlying macular
retinal photoreceptors and the development of a blurred
and dim spot in central vision (a central scotoma). Drusen
can also cause pigment epithelial detachment (patients
are often told that they have a “blister” or “bump” on
the retina). As the entire macula becomes affected in the
late stages of dry AMD, so-called geographic atrophy of
the macula develops. In wet AMD, brittle blood vessels
break down and fragile new blood vessels grow under the
macula (choroidal neovascularization from the chorio-
capillaris through Bruch’s membrane into the subretinal
space). These blood vessels are prone to leak blood and
fluid, often causing extensive macular damage and, ulti-
mately, development of a discaform (disc-shaped) gray
scar. “Advanced” AMD is considered to include the late
stage of dry AMD along with wet AMD.
AMD affects approximately 10% of patients 66–74 years
of age, and 30% of patients 75–85 years of age. Risk fac-
tors for AMD or progression to advanced AMD include
age, female gender, family history, race (higher in Cau-
casians than people of African descent), hypertension,
hypercholesterolemia, high fat intake, obesity, cigarette
smoking, and lower dietary intake of long-chain polyun-
saturated fatty acids and fish (Age-Related Eye Disease
Study Research Group, 2000, 2001a; Clemons et al., 2005;
Age-Related Eye Disease Study Research Group et al.,
2007; SanGiovanni et al., 2007, 2008, 2009). The strongest
and most consistent risk factors are smoking and age
(Hyman and Neborsky, 2002). Several genes have also
been associated with the development of AMD, includ-
ing a major risk variant within the complement factor H
gene (CFH). Evidence regarding the role of sunlight is
conflicting.
The most common symptom of dry AMD is blurred
vision, which is limited to the center of the visual field.
Objects of regard (in the center of vision) often look dis-
torted and dim, and colors look faded due to a loss of con-
trast sensitivity. Reading print and seeing other fine details
becomes increasingly impaired, but affected patients can
generally see well enough to walk and perform most rou-
tine activities. As the disease progresses, patients may
need more light to read or perform everyday tasks. The
central scotomas gradually get larger and darker, and in
the later stages, recognition of faces becomes increasingly
difficult unless the faces are very close to the affected indi-
vidual. In wet AMD, straight lines may appear distorted
and wavy (metamorphopsia) when fluid from the leaking
blood vessels gathers and lifts the macula.
Although loss of central vision in AMD profoundly
affects visual function, markedly impairs performance in
certain activities (such as reading and driving), and can
lead to legal blindness, it never causes complete blind-
ness. The macular area affected by AMD is approximately
only half of a centimeter in diameter and comprises
about 2% of the retinal surface, while the remaining 98%
of the retinal surface (which is responsible for periph-
eral vision) remains unaffected by AMD. Although the

macula corresponds to such a small fraction of the total
visual field, at least half of the visual cortex is devoted to
processing macular information (Horton and Hoyt, 1991;
McFadzean et al., 1994).
Persons older than 55 years should have dilated eye
examinations to determine their risk of developing
advanced AMD. Outside of an ophthalmologic practice,
central vision should be assessed by measuring visual
acuity and by using an Amsler grid. An Amsler grid is
a simple office tool for assessing macular health that is
essentially a pattern of regularly spaced, intersecting,
horizontal and vertical lines resembling graph paper with
a fixation spot marked in the middle as a black dot. With
normal vision, all lines surrounding the black dot look
straight and evenly spaced, with no missing or distorted
areas; with AMD or other macular diseases, the lines can
look bent or otherwise distorted, and sections may be
missing. Further ophthalmologic diagnostic procedures
may include fluorescein angiography and optical coher-
ence tomography (OCT).
Although there is no known way to prevent macular
degeneration, lifestyle modification has been advocated
based on identified risk factors, including the following:
abstinence from tobacco; a healthy diet that is high in
fruits, green leafy vegetables, nuts, and fish, and low in
red meat and animal fat; regular exercise; a normal blood
pressure; and a healthy weight.
Currently, there is insufficient evidence to support the
role of dietary antioxidants, including the use of dietary
antioxidant supplements, for primary prevention of early
AMD (Chong et al., 2007). People with established AMD
may benefit from secondary prevention with dietary sup-
plements, as used in the Age-Related Eye Disease Study
(AREDS; Age-Related Eye Disease Study Research Group,
2001b). The AREDS formula consisted of antioxidants
(vitamin C, 500 mg; vitamin E, 400 IU; and beta-carotene,
15 mg) plus zinc (80 mg, as zinc oxide) and copper (2 mg,
as cupric oxide). However, beta-carotene has been found
to increase the risk of lung cancer in smokers, vitamin E
has been associated with an increased risk of heart fail-
ure in people with vascular disease or diabetes, and zinc
has been associated with an increase in hospitalization for
genitourinary conditions (Lonn et al., 2005; Johnson et al.,
2007; Evans, 2008; Gallicchio et al., 2008; Tanvetyanon and
Bepler, 2008).
Because peripheral vision is not affected in AMD,
affected individuals can learn to use their remaining
vision to continue most activities, although they may need
extra ambient light or magnification to perform optimally.
Accessible Publishing provides a variety of fonts and for-
mats for published books to make reading easier, includ-
ing much larger fonts for printed books, audiobooks, and
books with both text and audio. Adaptive low-vision aids
can also help patients with AMD use remaining vision
more effectively and can improve the quality of life. Adap-
Disorders of the Special Senses in the Elderly 405
tive devices include inexpensive handheld magnifying
glasses, magnifiers mounted on height-adjustable stands,
special eyeglass lenses, and reading telescopes (mounted
on eyeglasses or handheld). More expensive video magni-
fiers project printed material on a closed-circuit television
(CCTV) monitor, television, or computer screen and allow
adjustments of magnification, brightness, and contrast. A
more portable device is also available that rests on read-
ing material and projects a magnified image onto a pair
of eyeglasses. In 2010, the Food and Drug Administration
(FDA) approved an implantable (intraocular) telescope
for treatment of AMD.
Although no established medical or surgical treat-
ment is available for dry AMD, treatments for wet AMD
may include anti-angiogenics (anti-Vascular Endothelial
Growth Factor, or anti-VEGF agents), laser photocoagu-
lation, and photodynamic therapy. Anti-VEGF agents,
including ranibizumab and pegaptanib, can cause regres-
sion of the abnormal blood vessels and improvement of
vision when injected every 4–6 weeks directly into the
vitreous humor of the eye; complications can include
endophthalmitis, increased IOP, traumatic cataract, and
retinal detachment. Laser photocoagulation seals newly
developed choroidal blood vessels to lessen the chance
that the vessels will damage the macula, but in the pro-
cess, it produces small retinal scars and associated scoto-
mas; because of this, laser photocoagulation has increas-
ingly been replaced by newer treatments, including use of
anti-VEGF agents and photodynamic therapy. Photody-
namic therapy uses a low-energy laser to activate a pro-
drug (verteporfin) as it passes through the retinal blood
vessels; the light-activated drug stops and sometimes
reverses neovascularization.
Glaucoma
Glaucoma is a group of eye diseases with progressive
optic neuropathy associated with loss of retinal neu-
rons and the nerve fiber layer, due to impaired drainage
of aqueous humor, typically with abnormally elevated
IOP (above 21 mm Hg or 2.8 kPa, with normal values of
16 ± 5 mm Hg), “cupping” of the optic nerve head (with
enlargement of the optic cup so that the cup-to-disc, or
C/D, ratio is >0.5), and visual field defects related to the
optic nerve damage. Glaucoma is more prevalent in the
elderly, even compensating for the fact that mean IOP
slowly rises with increasing age (Patel et al., 1995).
Aqueous humor is produced by the ciliary bodies,
enters the posterior chamber (bounded posteriorly by the
lens and the zonules of Zinn and anteriorly by the iris),
and flows through the pupil of the iris into the anterior
chamber (bounded posteriorly by the iris and anteriorly
by the cornea). Aqueous humor is drained from the ante-
rior chamber of the eye through a trabecular meshwork
via Schlemm’s canal into scleral vascular plexuses. IOP is
a function of the production of liquid aqueous humor by
406 Neurologic Conditions in the Elderly
the ciliary bodies of the eye and its drainage through the
trabecular meshwork.
Two main categories of glaucoma exist: closed angle
and open angle. Both forms typically present after age 50
(Patel et al., 1995). Closed-angle glaucoma (also known as
“narrow-angle” or “angle-closure” glaucoma) is the less
common category, representing approximately 10% of the
cases in the United States but up to half of the cases in
Asian countries. Closed-angle glaucoma can present as a
medical emergency, with the sudden onset of severe eye
pain and redness, often with associated symptoms and
signs: headache; malaise; nausea and vomiting; halos
seen around bright lights; blurred vision and reduced
visual acuity; a fixed, mid-dilated pupil; corneal clouding
(due to edema); and severely elevated IOP (>30 mm Hg)
(Lanska, 2006). Closed-angle glaucoma can produce irre-
versible vision loss in a matter of hours (Lanska, 2006).
This type is so named because the iridocorneal angle of
the anterior chamber of the eye (the junction of the cornea
and sclera externally with the iris internally) is narrow
or occluded, which blocks sufficient absorption of aque-
ous humor through the canal of Schlemm. In individuals
with primary closed-angle glaucoma, the angle is con-
genitally narrow. This may be exacerbated with age and
the development of synechiae (effectively “scars” due
to prolonged contact between the iris and the trabecular
meshwork seen on slit-lamp examination), ultimately
resulting in symptomatic disease; other individuals with
some forms of secondary glaucoma may acquire a simi-
lar defect (for example, as a result of a mature cataract
or diabetic neovascularization). Closed-angle glaucoma
should be considered in the differential diagnosis of any
patient with new-onset headache developing after age
50, especially with an acute red eye and reduced vision,
but also with short-duration headaches (4 hours or less)
that do not meet criteria for a defined headache syndrome
(Shindler et al., 2005; Lanska, 2006). The more common
major category of glaucoma—primary open-angle glau-
coma (POAG), in which there is reduced flow through the
trabecular meshwork—presents more insidiously with
progressive, painless visual loss without acute attacks.
Unfortunately, in many patients, this is not recognized
until significant visual loss has occurred. Most affected
patients are, in fact, asymptomatic, even at the point at
which significant vision loss has already occurred. Signs
of open-angle glaucoma include elevated IOP, visual field
loss, and glaucomatous disc changes. Both categories of
glaucoma can ultimately result in complete blindness if
untreated.
Physical findings that suggest glaucoma include ele-
vated IOP, large C/D ratios, and asymmetric cupping
between the two eyes. Although elevated IOP may result
in a hard globe clinically, tonometry is required to prop-
erly assess this. Signs of glaucoma progression include
increasing C/D ratio, development of disc pallor, disc
hemorrhage, nasal displacement of disc vessels, and pro-
gression of visual field damage. Although elevated IOP is
the strongest-known risk factor for glaucoma, it is neither
necessary nor sufficient to induce vision loss. Neverthe-
less, there is a exposure–response relationship between
IOP and the risk of damage to the visual field. Because
IOP varies during the day, with the highest readings in
the early morning, a single normal tonometry reading
does not rule out glaucoma. The term ocular hypertension
is used for cases having constantly elevated IOP without
evident associated optic nerve damage; the term normal-
tension (or low-tension) glaucoma is used when typical
glaucomatous visual field defects are associated with a
normal or low IOP. The C/D ratio attempts to quantify
the extent of axonal (nerve fiber) loss by comparing the
diameter of the cup to the diameter of the optic nerve
head (disc). Increases in cupping or nerve fiber loss indi-
cate poorly controlled glaucoma. In end-stage glaucoma,
the nerve may be “completely cupped”—pale and atro-
phic. Visual fields, even using careful perimetric tech-
niques, are often not helpful for diagnosis in the early
stages because a considerable number of neurons must
be lost before visual field changes can be detected. Glau-
comatous field loss mainly involves the central 30° of
vision. The earliest changes are enlargement of the blind
spot, nasal scotomas (nasal step) followed by peripheral
arcuate (Bjerrum) defects extending from the blind spot
to the horizontal raphe. With further progression, further
constriction of the visual field may progress to “tunnel
vision” and total blindness.
Risk factors for developing glaucoma include ele-
vated IOP, older age (older than 50 years), family his-
tory of glaucoma in a first-degree relative (especially in
a sibling), myopia, diabetes, cardiovascular diseases,
black race, Hispanic ethnicity, and the presence of disc
hemorrhages. Glaucoma is a leading cause of blindness
among African Americans and Hispanics. Regardless of
race or ethnic group, individuals older than age 60 are
“at risk” for developing glaucoma and should get eye
examinations at least every 2 years. Although there is no
“cure” for glaucoma, early diagnosis and treatment can
control glaucoma before vision loss or blindness occurs
or prevent further progression if damage has already
occurred.
Treatment of glaucoma usually includes prescription
eye drops and/or surgery to lower IOP. Several different
classes of medications are used to treat glaucoma, each of
which may have local and systemic side effects. Prosta-
glandin analogs (such as latanoprost, bimatoprost, and
travoprost) increase uveoscleral or trabecular outflow of
aqueous humor. Parasympathomimetic agents (such as
pilocarpine) cause contraction of the ciliary muscle, which
opens the intertrabecular spaces and thereby allows
increased outflow of aqueous humor. Beta-adrenergic
receptor antagonists (such as timolol, levobunolol, and

betaxolol) and carbonic anhydrase inhibitors (such as
dorzolamide, brinzolamide, and acetazolamide) decrease
aqueous humor production by the ciliary body. Alpha-
2-adrenergic agonists (such as brimonidine and apracloni-
dine) work in a dual fashion by both decreasing aqueous
humor production and increasing outflow. Unfortunately,
poor compliance with medications and follow-up visits is
a major reason for vision loss in glaucoma patients.
Acute angle-closure glaucoma is a medical emergency
and is initially treated with topical miotics (for example,
pilocarpine 2%, one drop every 15–60 minutes, up to
2–4 doses total), beta blockers (for example, timolol 0.5%,
one drop), and alpha-adrenergic agonists (for example,
apraclonidine 1%, one drop), in conjunction with oral or
intravenous carbonic anhydrase inhibitors (for example,
acetazolamide 500 mg by mouth or IV) (American Opto-
metric Association, 2001; Lanska, 2006).
Surgery is indicated when glaucomatous optic neuropa-
thy worsens (or is expected to worsen) and the patient is
on maximum tolerated medical therapy. Surgical treat-
ments for closed-angle glaucoma include Nd-YAG laser
peripheral iridotomy or surgical iridectomy. Laser iri-
dotomy creates an opening in the iris to allow the aqueous
humor to move more easily to the drainage site; because
the risk of binocular closed-angle glaucoma is high, the
procedure is usually done on both eyes even if only
one eye is initially symptomatic. Laser iridotomy prevents
further attacks of acute glaucoma, but some individuals
with chronic angle closure still have elevated IOPs and
require eye drops indefinitely. Some patients require
peripheral iridectomy (surgical removal of a section of
the peripheral iris); this creates an opening between the
anterior and posterior chambers to relieve the pressure
difference between the two compartments, which helps to
open the angle. Cataract surgery can also prevent attacks
of acute narrow-angle glaucoma because removal of the
swollen cataractous lens allows the iris to move posteri-
orly, opening the angle. Argon laser trabeculoplasty (ALT),
which applies the argon laser to the trabecular meshwork
to facilitate outflow of aqueous, can be used as an adjunct
to medical therapy for open-angle glaucoma. Filtering
procedures bypass the normal drainage mechanisms of
the eye by allowing direct access of aqueous from the
anterior chamber to the subconjunctival tissue, either by
trabeculectomy or by insertion of a silicone drainage tube.
Amaurosis fugax
Amaurosis fugax (literally “fleeting blindness”) is as
transient monocular visual loss that is attributed to isch-
emia or vascular insufficiency (Amaurosis Fugax Study
Group, 1990). Patients usually report diminished or
absent vision in one eye that progresses over a few sec-
onds and lasts for seconds to minutes, followed by com-
plete recovery (Amaurosis Fugax Study Group, 1990).
Amaurosis fugax episodes last 5 minutes or less in about
Disorders of the Special Senses in the Elderly 407
two-thirds of patients, 15 minutes or less in about four-
fifths of patients, and only occasionally for an hour or
more (Goodwin et al., 1987). Although amaurosis fugax
episodes are usually short-duration “negative” visual
phenomena (scotomas), a significant minority of patients
have long attacks or positive visual phenomena such as
scintillations, flashing lights, and shimmering. Therefore,
among patients with transient monocular visual loss,
clinical symptoms alone do not adequately discriminate
episodes due to carotid atherosclerosis from those due
to so-called “retinal migraine” (which is more properly
labeled as presumed retinal vasospasm) (Goodwin et al.,
1987; Hill et al., 2007).
Patients with altitudinal (usually with the “shade com-
ing down” rather than “up” to the horizontal raphe) or
lateralized transient monocular visual loss are more
likely to have carotid artery stenosis, ulcerated carotid
artery plaques, cardiac sources of emboli, or visible reti-
nal emboli than patients with other visual loss patterns,
such as diffuse, constricting, patchy, or sectorial visual
loss (Bruno et al., 1990). Apparently, the altitudinal and
lateralized transient monocular visual loss patterns are
typically caused by embolism to retinal branch vessels,
whereas the other visual loss patterns are typically caused
by nonembolic mechanisms. Recurrent events tend to fol-
low the same pattern. Transient central scotomas are not
part of the clinical spectrum of amaurosis fugax (Good-
win et al., 1987; Bruno et al., 1990).
Episodes most commonly result from embolism into
the ophthalmic circulation from the ipsilateral common
carotid artery and its branches. Examination may dem-
onstrate an ipsilateral anterior cervical bruit and pos-
sibly ophthalmoscopic evidence of retinal emboli, such
as one or more Hollenhorst plaques (bright copper or
yellowish glinting of reflective cholesterol emboli, often
lodged at bifurcations of retinal arterioles), or migrating
white plaques or fixed white plugs associated with plate-
let-fibrin and calcific emboli (Fisher, 1959; Hollenhorst,
1961; David et al., 1963; Marshall and Meadows, 1968;
Hooshmand et al., 1974; Ellenberger and Epstein, 1986).
Such microemboli are most commonly associated with
atheromatous lesions of the ipsilateral carotid artery, but
they can originate from the aortic arch or carotid siphon
or, less commonly, from calcific cardiac valvular dis-
ease. However, atheromatous microemboli responsible
for amaurosis fugax can also elude ophthalmoscopic
confirmation because such emboli usually fragment
quickly and disappear from view (even if evidence of
their presence can be shown with fluorescein angiogra-
phy) (Muci-Mendoza et al., 1980). Hollenhorst plaques
do not occlude the arterioles and are themselves uncom-
monly associated with visual symptoms (and hence are
usually noticed in asymptomatic people), in contrast to
the white plugs associated with platelet-fibrin and cal-
cific emboli, which are usually noticed when examining
408 Neurologic Conditions in the Elderly
symptomatic patients (David et al., 1963; Ellenberger
and Epstein, 1986).
Particularly in the elderly, amaurosis fugax is an
important marker of generalized atherosclerotic dis-
ease. Men overwhelmingly predominate among cases
of amaurosis fugax in older people, approaching 90%
among individuals older than 50 years (Parkin et al.,
1982). In the elderly, about two-thirds of the cases
are attributable to significant stenosis, ulceration, or
occlusion of the ipsilateral carotid artery or occlusion
of the ipsilateral common carotid artery (Parkin et al.,
1982; Adams et al., 1983). Most of the remainder have
no significant ipsilateral internal or common carotid
artery pathology, but a minority have other identifiable
pathology (such as ophthalmic artery stenosis, migraine
accompaniments or equivalents, giant cell arteritis,
NAION, cardiac emboli, polycythemia, thrombocyto-
sis, other hyperviscosity syndromes, congestive heart
failure, or papilledema) (Marshall and Meadows, 1968;
Adams et al., 1983). In Caucasian populations, carotid
artery pathology responsible for amaurosis fugax is pre-
dominantly extracranial, whereas in Asian populations,
amaurosis fugax is typically due to thromboembolism
from intracranial carotid artery atheromatous lesions
(most commonly with internal carotid artery stenosis at
the siphon) (Terao et al., 2000). Other possible etiologies
include micro-thromboemboli from the heart or aorta,
and hemodynamic retinal vascular insufficiency (Terao
et al., 2000). Antiplatelet therapy is least likely to be
effective when amaurosis fugax is due to hemodynamic
mechanisms (Terao et al., 2000).
Although amaurosis is a significant risk factor for ipsi-
lateral cerebral infarction (especially when it occurs in
association with an occluded or severely stenosed ipsi-
lateral internal carotid artery), patients with isolated
amaurosis fugax are at less risk for completed strokes
than are otherwise similar patients with cerebral hemi-
spheric transient ischemic attacks (TIAs) (Marshall and
Meadows, 1968; Hurwitz et al., 1985; Poole and Ross
Russell, 1985). Amaurosis fugax is associated with sig-
nificantly increased risks of myocardial infarction,
death from myocardial infarction, and sudden death,
compared with the general population adjusted for age
(Pfaffenbach and Hollenhorst, 1973; Hurwitz et al., 1985;
Poole and Ross Russell, 1985), and overall life expec-
tancy is significantly reduced (Poole and Ross Russell,
1985). The most frequent cause of death is myocardial
infarction (Pfaffenbach and Hollenhorst, 1973; Poole and
Ross Russell, 1985).
Although amaurosis fugax associated with atheroscle-
rotic occlusive disease may precede central retinal artery
occlusion, branch retinal artery occlusion, or NAION,
visual sequelae from retinal infarction are uncommon,
affecting 6% of cases in one series (Parkin et al., 1982), and
are largely unpredictable (Marshall and Meadows, 1968).
Retinal artery occlusion
The central retinal artery, the first branch of the ophthal-
mic artery, supplies blood to the inner retina. The cen-
tral retinal artery enters the eye at the optic disc, where
it bifurcates into superior and inferior branches, each of
which then bifurcates into nasal and temporal branches.
Retinal artery occlusion most commonly involves
the central retinal artery, less commonly a branch reti-
nal artery, and rarely a cilioretinal artery. Central retinal
artery occlusion (CRAO) deprives the entire inner retina
of its blood supply unless a cilioretinal artery is present
(an anatomic variant present in about 15–30% of eyes in
which a branch of a short posterior ciliary artery exits the
optic disc separately from the central retinal artery and
typically supplies a portion of the macula). Branch reti-
nal artery occlusion (BRAO) affects specific retinal artery
branches, most commonly the temporal vessels. CRAO
rapidly causes retinal infarction (ocular stroke) and is typ-
ically associated with sudden, painless, monocular blind-
ness that is often permanent. Partial loss of the visual field
may occur with BRAO. There may be a history of anteced-
ant amaurosis fugax.
On examination, visual acuity with CRAO is typically
finger counting or worse, unless a cilioretinal artery is
present, in which case central vision may be preserved.
With CRAO, the pupil may be dilated with a minimal,
sluggish reaction to light. Funduscopic examination in
CRAO shows retinal pallor and edema, a “cherry-red
spot” at the fovea (due to visualization at the fovea of the
preserved underlying choroidal vascular bed, which is
supplied by the posterior ciliary arteries), and attenuation
of retinal arterioles with interrupted columns of blood
within the retinal vessels (so-called “boxcarring,” for its
resemblence to train boxcars). In contrast, with BRAO,
fundoscopic examination shows retinal pallor and edema
in the distribution of the affected vessel only. Occlusion
of a cilioretinal artery produces macular edema and typi-
cally affects central vision.
Risk factors for retinal artery occlusion include age
older than 70 years, atherosclerosis, diabetes, hyperten-
sion, giant cell arteritis, hypercoagulable states, migraine,
glaucoma, and optic nerve head drusen. CRAO and
BRAO are most often associated with atheromatous
disease but can be associated with giant cell arteritis in
5–10% of the cases. Occlusion of a cilioretinal artery in an
elderly patient is considered prima facie evidence of giant
cell arteritis, although it can also be seen with retinal vein
occlusion or in isolation due to nonarteritic conditions
(Hayreh et al., 2009).
Animal studies have demonstrated that irreversible
ischemic damage can occur after approximately 100 min-
utes following complete CRAO, whereas recovery is pos-
sible for shorter periods of complete CRAO (Hayreh and
Weingeist, 1980; Hayreh et al., 1980). However, complete
occlusion of the central retinal artery is rare in humans,

so some degree of recovery is occasionally possible even
after 2–3 days of ischemia.
In any case, because irreversible damage may occur
within hours of occlusion, patients should be referred
immediately to an ophthalmologist for emergent man-
agement. Immediate actions that may be beneficial prior
to ophthalmologic consultation include digital massage
of the eyeball and various techniques to increase retinal
perfusion pressure. Ocular massage is performed by the
patient, who is instructed to digitally massage the affected
eyeball through closed eyelids for 15–30 minutes. Ocular
massage produces a fluctuating IOP, which may facilitate
disintegration of the embolus and movement of embolus
fragments into distal branches of retinal vessels, thereby
minimizing the area of retinal infarction and helping to
preserve vision. Techniques intended to improve retinal
perfusion pressure that nonophthalmologists can admin-
ister in the emergency room include supine positioning
of the patient and intravenous administration of acetazol-
amide (500 mg), although the relative utility and mar-
ginal benefit of these approaches is unclear (Beatty and
Au Eong, 2000).
Although aggressive stepwise regimens have been
promoted based on small case series, the role of these
approaches is unclear, as is the role of individual com-
ponents of these regimens, including administration of
systemic osmotic agents (such as intravenous manni-
tol or oral glycerol) and anterior chamber paracentesis
(Rumelt et al., 1999). Techniques that are no longer in
favor because of doubtful clinical benefit or recognized
complications include inhalation of carbogen (95% oxy-
gen and 5% carbon dioxide), retrobulbar injection of
vasodilator drugs, and systemic administration or throm-
bolytic agents (Beatty and Au Eong, 2000). Marginally
higher rates of good visual outcomes (visual acuity of
20/40 or better) have been reported with selective intra-
arterial injection of fibrinolytic therapy with urokinase or
tissue plasminogen activator (TPA) into the ophthalmic
artery, but the technique is not universally available and
may be associated with serious complications (Beatty and
Au Eong, 2000).
Long-term management includes dietary counseling,
promotion of smoking cessation, risk factor modification
(including hypertension, diabetes, and hyperlipidemia),
administration of antiplatelet therapy (generally aspirin),
and appropriate management of comorbid, contributing,
or causal factors (such as coronary artery disease, carotid
stenosis, giant cell arteritis, hypercoagulable states, car-
diac valvular disorders, and complex arrhythmias). As
with amaurosis fugax, the most common cause of death
in patients with retinal artery occlusions is cardiovascular
disease.
Visual prognosis varies depending on the level of
occlusion, the presenting visual acuity, and the duration
of visual impairment (Beatty and Au Eong, 2000; Mason
Disorders of the Special Senses in the Elderly 409
et al., 2008; Hayreh et al., 2009). The visual outcome after
CRAO is typically poor (when the macula is not supplied
by a cilioretinal artery), with final visual acuity of finger
counting or worse in the affected eye in about two-thirds
of the patients, and final visual acuity of 20/40 or bet-
ter in only about one-fifth of the patients (Beatty and Au
Eong, 2000). In contrast, the visual outcome with BRAO is
relatively good, with 60–90% of patients with permanent
BRAO having visual acuity of 20/40 or better at follow-
up (Mason et al., 2008; Hayreh et al., 2009).
Anterior ischemic optic neuropathy
Anterior ischemic optic neuropathy (AION) is a stroke
syndrome of the optic nerve head and anterior optic
nerve, characterized by acute, painless, (generally) uni-
lateral visual loss associated with optic disc edema and
other manifestations of optic nerve dysfunction. Findings
include loss of central vision, achromatopsia (generally in
proportion to the loss of visual acuity), nerve fiber layer
visual field abnormalities (with altitudinal defects most
commonly, but also possibly central or cecocentral sco-
tomas, or arcuate patterns), a relative afferent pupillary
defect, and commonly associated disc and peripapillary
nerve fiber layer hemorrhages (Hayreh, 1974a). Optic disc
edema starts to resolve in 7–10 days and is followed by
optic atrophy after approximately 1–3 months (Hayreh,
1974b; Hayreh and Zimmerman, 2008b). The edema and
atrophy may involve the entire disc or may be restricted
to a sector (Hayreh, 1974b).
AION may be either arteritic (as with AAION, due to giant
cell arteritis) or nonarteritic (as with NAION, due to causes
other than giant cell arteritis). NAION is the most common
type and one of the most prevalent visually crippling dis-
eases in the elderly (Hayreh, 2009). Although less common,
arteritic AION is an ocular emergency that requires early
diagnosis and immediate treatment with systemic high-
dose corticosteroids to reduce the amount of residual vision
loss in the affected eye and to prevent irreversible vision loss
in the contralateral eye (Lueck, 2010).
Nonarteritic anterior ischemic
optic neuropathy
Nonarteritic anterior ischemic optic neuropathy (NAION)
is the most common acute optic neuropathy and one of the
most common causes of sudden vision loss in the elderly
(Hattenhauer et al., 1997). NAION typically presents with
sudden monocular visual loss, often noted upon awaken-
ing. Vision in that eye is described as being obscured by a
dark shadow, often involving just the upper or lower half
of vision. Most cases of NAION involve the loss of either
the upper or the lower half of the visual field (a hemifield),
although a small proportion present with almost total loss
of vision or a scotoma. Normal visual acuity does not rule
out NAION—indeed, about half the eyes with NAION
present with almost normal visual acuity (20/30 or better)
410 Neurologic Conditions in the Elderly
at the initial visit (Hayreh and Zimmerman, 2008b). There
is generally no pain, although a dull orbital ache may be
noted in up to 10% of the cases. Unlike CRAO or arteritic
AION, premonitory symptoms, such as amaurosis fugax,
are absent in NAION. Acutely with NAION, the optic
disc edema is pale pink or even hyperemic with frequent
associated flame-shaped hemorrhages; in arteritic AION,
half show chalky-white edema of the optic disc with rare
hemorrhages (Hayreh, 1974b). Segmental or diffuse pallor
without cupping is the typical end-stage disc appearance
after NAION (Danesh-Meyer et al., 2001).
In contrast with classical NAION, incipient NAION is
characterized by asymptomatic optic disc edema with no
visual loss attributable to NAION. A diagnosis of incipi-
ent NAION should be considered when a patient presents
with unilateral asymptomatic optic disc edema, particu-
larly in those who have had classic NAION in the fellow
eye and in those with other identified risk factors for
NAION, particularly diabetes (Hayreh and Zimmerman,
2007a).
Visual impairment with NAION may progress over
several days but is then generally stable thereafter. About
40% of NAION eyes with moderate or severe impairment
at presentation experience spontaneous improvement in
visual acuity within the first 3–6 months (Hayreh and
Zimmerman, 2008b; Hayreh, 2009). After 3–6 months,
visual acuity and visual fields generally do not change sig-
nificantly (Hayreh and Zimmerman, 2008b). Final visual
acuity is 20/40 or worse in about half of the affected eyes,
20/70 or worse in about a quarter, and finger counting
or worse in about an eighth (Hayreh and Zimmerman,
2008b).
Blood flow velocities of the nasal short posterior cili-
ary arteries and the central retinal artery are consider-
ably reduced in patients with acute NAION, compared
with controls (Kaup et al., 2006). The posterior ciliary
arteries are the predominant blood supply to the pre-
laminar and laminar portions of the optic nerve, as the
pial plexus is the predominant blood supply (with con-
tributions from the posterior ciliary arteries, extraneural
branches of the central retinal artery, and small pene-
trating orbital arteries) for the immediate retrolaminar
optic nerve.
Predisposing factors for NAION include a congenitally
“crowded” small optic disc with a small C/D ratio (<0.2)
and raised IOP (Katz et al., 1990). A “crowded” disc can be
noted on ophthalmoscopy and is referred to as a “disc at
risk.” The laminar and prelaminar vessels have high extra-
mural pressures because of IOP; any sudden decrease in
blood pressure or increase in IOP can decrease perfusion
pressure to the optic nerve head and compromise blood
flow to this area, causing infarction, with resulting edema,
compression, and further ischemia (Eagling et al., 1974).
The determining factor for development of AION is the
perfusion pressure in the anterior portion of the optic
nerve (the difference between blood pressure in the pos-
terior ciliary arteries and IOP). The posterior ciliary arter-
ies do not need to be occluded to produce AION (Hayreh,
1974a).
As would be expected of a stroke syndrome, the non-
arteritic form of AION is often associated with vascu-
lopathic risk factors, including hypertension, diabetes,
smoking, hypercholesterolemia, ischemic heart disease,
and hyperhomocysteinemia, as well as low vitamin B6
(pyridoxine) levels (presumably through the effect of
pyridoxine on homocysteine metabolism) (Salomon et al.,
1999a; Pianka et al., 2000; Weger et al., 2001; Giambene et
al., 2009). In addition, a high proportion (>2/3) of patients
with NAION have sleep apnea, which may partly
explain why approximately three-fourths of patients
with NAION discover visual loss on first awakening or
when they first use vision critically after sleeping (Mojon
et al., 2002). Indeed, obstructive sleep apnea is the most
frequent disorder associated with NAION, and affected
patients should undergo overnight pulse oximetry or
preferably polysomnography (Palombi et al., 2006; Li et
al., 2007). Finally, although the risk of NAION after cata-
ract extraction is low, with approximately 1 occurrence in
every 2000 cases (McCulley et al., 2001), patients with uni-
lateral NAION are at a significantly higher risk of devel-
oping NAION in the fellow eye after cataract extraction
(McCulley et al., 2001, 2003; Lam et al., 2007).
Although NAION has been anecdotally reported with
the use of phosphodiesterase type 5 inhibitors (PDE5i)
in men with erectile dysfunction (ED) (Pomeranz et al.,
2002; Pomeranz and Bhavsar, 2005; Danesh-Meyer and
Levin, 2007), particularly in those with a small C/D ratio
(Pomeranz et al., 2002), a causal relationship has not been
established. Because ED and NAION share common
risk factors, some men with ED are expected to develop
NAION. Although the World Health Organization and
the FDA have labeled the association between use of
PDE5i and risk of NAION as “possibly” causal (Danesh-
Meyer and Levin, 2007), available data do not suggest an
increased incidence of NAION in men who took sildenafil
for ED (Gorkin et al., 2006). Sildenafil is generally well
tolerated at a dose of 50 or 100 mg in elderly men with ED
(Giuliano et al., 2010). The incidence of NAION in men
receiving sildenafil treatment for ED was estimated using
pooled safety data from global clinical trials and Euro-
pean observational studies (Gorkin et al., 2006). Based on
clinical trial data in more than 13,000 men and on more
than 35,000 patient-years of observation in epidemiologic
studies, the estimated incidence of NAION is 2.8 cases per
100,000 patient-years of sildenafil exposure, which is sim-
ilar to estimates reported in general US population sam-
ples (2.52 and 11.8 cases per 100,000 men aged ≥50 years).
Similarly, a meta-analysis of 67 double-blind, placebo-
controlled trials and a postmarketing safety database
did not reveal any new safety risks relating to NAION

(Giuliano et al., 2010). Nevertheless, sudden vision loss in
one or both eyes warrants immediate cessation of PDE5i
use and urgent assessment (Hatzimouratidis, 2007).
NAION rarely affects the same eye more than once,
presumably because infarcted axons in a tight scleral
canal relieve the crowding and reduce the chances of a
subsequent attack (Quigley et al., 1985). However, in a
person with a history of NAION, the unaffected eye has a
15% risk of developing NAION within 5 years; increased
incidence of NAION in the fellow eye is associated with
poor baseline visual acuity in the incident eye and with
diabetes (Newman et al., 2002). Aspirin (325 mg per day)
may be effective in reducing the frequency of second
eye involvement with NAION (Salomon et al., 1999b),
although available evidence for this is conflicting (New-
man et al., 2002). To minimize the risk of further visual
loss in the fellow eye or the same eye, risk factor modifica-
tion is essential.
Because arteritic AION is similar in presentation to
NAION, elderly patients with suspected NAION must be
evaluated to exclude arteritic AION. An erythrocyte sedi-
mentation rate (ESR) and C-reactive protein (CRP) level
should be obtained emergently, and if any clinical fea-
ture suggests giant cell arteritis, a temporal artery biopsy
should be performed (regardless of the ESR) (Lueck, 1996).
In the absence of clinical features of giant cell arteritis, an
elevated ESR, or bilateral simultaneous AION, temporal
artery biopsy is unlikely to be positive and is considered
unnecessarily invasive (Lueck, 1996). In any case, it is gen-
erally prudent to obtain ophthalmology consultation in
such cases. Additional diagnostic studies recommended
in the evaluation of NAION include a complete blood
count, fasting blood glucose, hemoglobin A1c, fibrinogen,
serum protein electrophoresis, fasting lipid profile, and
fluorescein angiography (Lueck, 1996, 2010).
Although high-dose oral corticosteroids have long
been advocated (Hayreh, 1974c), high-quality evidence
has not supported this recommendation. Recent trials
have provided more convincing support for the conten-
tion that systemic steroid therapy during early stages in
NAION (and nonarteritic posterior ischemic optic neu-
ropathy [PION]) has a significant beneficial effect for
visual outcome (Hayreh, 2009). NAION eyes treated dur-
ing the acute phase with systemic corticosteroids resulted
in a significantly higher probability of improvement
in visual acuity and visual fields than in the untreated
group (Hayreh and Zimmerman, 2008a). Both visual acu-
ity and visual fields improved for up to 6 months after
onset of NAION but were static thereafter (Hayreh and
Zimmerman, 2008a). It appears that rapid initiation of
steroid therapy is essential to achieve maximal improve-
ment and to minimize axonal injury and permanent dam-
age (Hayreh and Zimmerman, 2008a). Presumably, the
faster resolution of optic disc edema with corticosteroids
(Hayreh and Zimmerman, 2007b) decreases compression
Disorders of the Special Senses in the Elderly 411
and thereby improves blood flow in the capillaries at the
optic nerve head. This improves function and helps pre-
serve surviving axons (Hayreh and Zimmerman, 2008a).
Several other treatments have been proposed for
NAION, but available evidence is inadequate to support
their use. For example, results of treatment with intra-
vitreal injection of high-dose triamcinolone acetonide
are limited and conflicting. Although this treatment has
been anecdotally reported to improve recovery of visual
acuity and optic disc edema (but not visual fields) in
patients with NAION (Kaderli et al., 2007), particularly in
patients with a relatively short history of visual loss due
to NAION (Yaman et al., 2008), other case series suggest it
is not markedly effective in increasing visual acuity after
acute NAION (Jonas et al., 2007). Furthermore, at least
theoretically, intravitreal injection in NAION eyes could
be harmful because this increases the volume in the eye-
ball, with a resultant rise in IOP, and could potentially fur-
ther compromise the perfusion pressure of the ischemic
optic nerve head (Hayreh and Zimmerman, 2008a). The
use of levodopa has also been proposed for the treatment
of recent-onset NAION (Johnson et al., 1996, 2000) but
is unproven (Simsek et al., 2005), based on the conflict-
ing results of several small trials. Side effects of levodopa
(such as dizziness, orthostatic hypotension, vomiting, and
cardiac arrhythmia) were noted during the most recent
trial (Simsek et al., 2005).
Visual loss with giant cell arteritis
(arteritic AION or AAION)
Giant cell arteritis (GCA) (also known as temporal arteritis,
cranial arteritis, or granulomatous arteritis) is a systemic,
necrotizing, large-vessel vasculitis seen in patients typically
over age 50, with incidence increasing progressively with
age; it is most common in Causasians over age 70 years
(González-Gay and García-Porrúa, 2001; González-Gay,
2005; Watts et al., 2005). GCA is a medical emergency
because there is a high risk of developing permanent blind-
ness in one or both eyes if diagnosis is delayed or if the
disease is improperly managed; fortunately, blindness is
almost entirely preventable if GCA is identified quickly
and treated urgently and aggressively with systemic cor-
ticosteroids. Therefore, it is essential to maintain a high
degree of clinical suspicion for GCA, especially in Cauca-
sians over age 60 years (González-Gay, 2005).
Polymyalgia rheumatica (PMR) is a much more com-
mon but closely related inflammatory disorder of elderly
patients. It consists of pain and stiffness in the shoulder
and pelvic girdles, often with associated fever, weight
loss, nonspecific somatic complaints (such as malaise),
and an elevated ESR; it typically responds rapidly and
completely to small doses of prednisone (typically much
smaller than required for GCA). GCA and PMR may be
manifestations of the same underlying disease and often
coexist—GCA occurs in about 20% of patients with PMR.
412 Neurologic Conditions in the Elderly
GCA should be suspected when an elderly patient
complains of sudden visual loss, new-onset headache,
jaw claudication, or the musculoskeletal manifestations
of PMR. Clinical manifestations of GCA can include acute
visual loss, headache, tenderness and sensitivity on the
scalp, fever, jaw claudication, tongue claudication and
necrosis, diplopia, and tinnitus. Clinical criteria most
strongly suggestive of GCA include jaw claudication,
CRP above 2.45 mg/dl, neck pain, an ESR of 47 mm/h
or more, and age greater than 75 years, in approximately
that order (Hayreh et al., 1997). CRP is more sensitive
(98–100%) than ESR (76–92%) for detection of GCA, but
ESR combined with CRP provides the best sensitivity and
specificity (close to 100% for both test indices) (Hayreh
et al., 1997; Parikh et al., 2006). Physical examination
may demonstrate abnormalities in the temporal arteries
(such as tenderness, induration, or lack of pulsatility) or
other cranial arteries (for example, in the facial artery as it
crosses the mandible). Patients with GCA also frequently
have hematologic abnormalities, including thrombocyto-
sis (an acute phase reactant), leukocytosis, and anemia,
but the platelet count, white cell count, hemoglobin,
and hematocrit do not alone or collectively significantly
improve diagnosis of GCA compared with the combina-
tion of CRP and ESR (Costello et al., 2004).
About half of the patients with biopsy-confirmed GCA
present with ocular involvement due to ischemia (Hayreh
et al., 1998b). Ocular symptoms almost always include
visual loss of varying severity but may also include a his-
tory of amaurosis fugax (in about a third of cases) and,
uncommonly, transient diplopia or eye pain (Hayreh,
1991; Hayreh et al., 1998b). Both eyes are involved in
about half of the patients with ocular symptoms (a rare
situation with NAION).
Blindness with GCA is usually due to AION (∼80%),
but occasionally, patients demonstrate cilioretinal artery
occlusion, posterior ischemic optic neuropathy, and, rarely,
ocular ischemia (Hayreh, 1991; Hayreh et al., 1998b). In
almost all patients with GCA, fluorescein fundus angiog-
raphy demonstrates occlusive disease of one or more of
the posterior ciliary arteries, in occasional patients com-
bined with CRAO (the central retinal and posterior ciliary
arteries often arise by a common trunk from the ophthal-
mic artery, and arteritic involvement of this trunk results
in both distal vessels becoming occluded) (Hayreh et al.,
1998b).
Arteritic AION (AAION) in GCA is distinguished from
NAION by early massive visual loss, chalky-white optic
disc swelling acutely (if present, in about half of cases),
frequently associated cilioretinal artery occlusion, high
ESR and CRP levels, nonfilling of the choroid on fluo-
rescein fundus angiography, and characteristic patho-
logic changes on temporal artery biopsy (Hayreh, 1974b;
Hayreh, 1990). Patients with AAION generally have
more severe visual loss than do patients with NAION—
although only a few cases of NAION result in near total
loss of vision, most cases of AAION involve nearly com-
plete vision loss. Also, eyes affected with AAION show
significant excavation and enlargement of the optic cup
when compared with contralateral uninvolved eyes
(Danesh-Meyer et al., 2005b). In contrast to the global or
sectorial optic disc atrophy without cupping seen as a
late ophthalmoscopic finding with NAION, the end-stage
optic disc appearance in AAION is cupping (Danesh-
Meyer et al., 2001; Hayreh and Jonas, 2001).
About 20% of patients with GCA and visual loss do not
have any systemic symptoms suggestive of GCA (Hayreh
et al., 1998a). Therefore, in the elderly, amaurosis fugax
or acute visual loss with an acute ocular ischemic lesion
(particularly AION), in combination with an elevated
CRP level, should raise a high index of suspicion for
GCA, regardless of the ESR or the presence of systemic
symptoms.
A markedly elevated CRP level or ESR in association
with other clinical features of the disease strongly sug-
gests GCA, whereas a normal ESR makes GCA unlikely
(Smetana and Shmerling, 2002). ESR is low (less than
50 mm/h) in only a small percentage of patients with GCA
(≤5%) (Wise et al., 1991; Salvarani and Hunder, 2001), and
most such patients have a history of PMR or corticoste-
roid therapy (Wise et al., 1991). GCA patients with a low
ESR are less likely to present with visual symptoms or to
develop blindness (Salvarani and Hunder, 2001).
A biopsy should be performed to confirm a suspected
diagnosis of GCA, especially because long-term manage-
ment with corticosteroids may be required, often with
associated toxicity and significant secondary morbidity
(Elliot et al., 1983; Hall et al., 1983; González-Gay et al.,
2001a; González-Gay, 2005). Because of the high cost of
blindness, decision analyses suggest that suspicion of
disease must be very low (less than 1.4%) not to biopsy
(Elliot et al., 1983). Bilateral biopsy is the cheapest initial
diagnostic procedure (although, in practice, this is rarely
done), and if a unilateral biopsy is negative, a second
biopsy is always cost effective (Elliot et al., 1983). Tempo-
ral artery biopsy is performed under local anesthesia and
should be done at the most symptomatic site. There is no
consensus on the optimal specimen length for a temporal
artery biopsy—although temporal artery biopsy speci-
mens of from 2 to 5 cm in length have been advocated
to confirm a suspected diagnosis of GCA (partly because
of purported spotty inflammatory involvement of ves-
sels in GCA, so-called “skip lesions”) (Klein et al., 1976;
Kent and Thomas, 1990), a temporal artery biopsy length
of at least 0.5 cm may be sufficient to make a diagnosis
of GCA (Mahr et al., 2006); others have found a mini-
mum length of 1.5 cm necessary to optimize diagnostic
sensitivity allowing for tissue shrinkage (González-Gay,
2005; Taylor-Gjevre et al., 2005), and still others have
reported that segments of at least 2.5 cm are needed

(González-Gay et al., 2001a, 2001b; González-Gay, 2005).
In general, about 40–65% of patients referred for tempo-
ral artery biopsy have positive results (Allison and Gal-
lagher, 1984; Smetana and Shmerling, 2002). Temporal
artery biopsies in GCA classically show marked intimal
thickening, a mononuclear cell infiltrate predominating
at the media-intima junction, or, in the media, giant cells
and histiocytic inflammation related to disrupted elastic
tissue (Allison and Gallagher, 1984; Mahr et al., 2006).
Giant cells and granulomatous inflammatory changes are
not essential for diagnosis, but their absence is considered
atypical (Allison and Gallagher, 1984; Mahr et al., 2006).
The frequency of a positive temporal artery biopsy
varies as a function of the timing of the biopsy relative
to initiation of corticosteroid therapy—in one study of
cases diagnosed on the basis of clinical findings, ESR, and
plasma viscosity, temporal artery biopsy was positive in
82% of those biopsied prior to corticosteroid therapy, in
60% of those biopsied within 1 week after starting corti-
costeroid therapy, and in only 10% of those biopsied more
than 1 week after starting corticosteroid therapy (Allison
and Gallagher, 1984). Other authors have found higher
rates of positive biopsy results after starting steroids and
have found that temporal artery biopsy may be diagnosti-
cally useful even several weeks after institution of cortico-
steroids (Achkar et al., 1994; Ray-Chaudhuri et al., 2002).
In any case, temporal artery biopsy should generally be
done before patients are committed to long-term cortico-
steroid therapy (Hall et al., 1983; González-Gay, 2005).
Patients with biopsy-proven GCA have more severe
disease with a higher risk of severe ischemic complica-
tions and permanent visual loss compared with biopsy-
negative patients (González-Gay et al., 2001a). A small
number of clinical features are helpful in predicting the
likelihood of a positive temporal artery biopsy among
patients with a clinical suspicion of disease. In a system-
atic review, the only historical features that substantially
increased the likelihood of GCA among patients referred
for biopsy were jaw claudication and diplopia (Smetana
and Shmerling, 2002). The absence of any temporal
artery abnormality (such as beading, prominence, and
tenderness) was the only clinical factor that modestly
reduced the likelihood of disease (Smetana and Shmer-
ling, 2002).
In patients with visual symptoms, chances of clinical
improvement are better with early diagnosis and imme-
diate institution of corticosteroid therapy. All affected
patients must be treated on a long-term basis with ade-
quate amounts of systemic corticosteroids to prevent fur-
ther visual loss in either eye and to manage the systemic
manifestations of GCA. Unfortunately, visual loss due to
GCA is often profound (mean visual acuity of 20/400)
and subsequent visual recovery is uncommon—only
about 4–5% of GCA patients with visual loss show any
visual improvement with high-dose steroid therapy, as
Disorders of the Special Senses in the Elderly 413
judged by improvement in both visual acuity and cen-
tral visual fields, and 4–27% develop further visual loss
despite high-dose steroid therapy (Hayreh et al., 2002;
Hayreh and Zimmerman, 2003a, 2003b; Danesh-Meyer
et al., 2005a; Loddenkemper et al., 2007). If visual dete-
rioration occurs after starting appropriate corticosteroid
therapy, it is usually within the first 5 or 6 days of treat-
ment (Hayreh and Zimmerman, 2003a, 2003b; Danesh-
Meyer et al., 2005a). Risk factors for early visual deterio-
ration include older age, elevated CRP, and disc swelling
(Loddenkemper et al., 2007). Risk factors for an increased
risk of permanent visual loss include a history of tran-
sient visual ischemic symptoms, jaw claudication, and an
elevated platelet count (González-Gay et al., 1998; Liozon
et al., 2001).
Although a number of authorities have advocated
intravenous megadose steroid therapy (1 g of IV meth-
ylprednisolone daily for 3 days) for patients with GCA
who have experienced vision loss (González-Gay, 2005),
no convincing evidence shows that this approach is more
effective than high-dose oral prednisone therapy (60–80
mg per day) in improving vision or preventing visual
deterioration due to GCA (Hayreh and Zimmerman,
2003a, 2003b). Other immunosuppressant medications,
such as methotrexate, have been used with mixed results
in GCA, usually for potential steroid-sparing in patients
with unacceptable side effects from corticosteroid therapy
(Pipitone et al., 2005). Evidence from observational stud-
ies suggests that adding low-dose aspirin to traditional
corticosteroid therapy may decrease the risk of visual loss
and strokes in patients with GCA (Nesher et al., 2004a,
2004b); until randomized, controlled trial data are avail-
able, the expected risks and potential benefits the imple-
mentation of this approach (Hellmann, 2004).
The most reliable and sensitive parameters to regulate
and taper steroid therapy are the ESR and CRP levels, not
the presence or absence of systemic symptoms (Hayreh
and Zimmerman, 2003a). Patients should be maintained
on high-dose prednisone until both the ESR and CRP
stabilize at low levels (usually after several weeks), after
which prednisone can be very slowly tapered, using ESR
and CRP levels as guides. Although somewhat controver-
sial, in general it takes at least 2–3 years (and, not uncom-
monly, 5–7 or more years) to reach the lowest mainte-
nance dose of prednisone (the dose at which the ESR and
CRP remain low and stable) (Kyle and Hazelman, 1990;
Hayreh and Zimmerman, 2003a). Most patients need to
be maintained indefinitely on modest doses of predni-
sone (16 mg per day or less) (Hayreh and Zimmerman,
2003a). Less than 10% of the patients are ultimately able
to stop prednisone entirely and maintain stable ESR and
CRP levels (Hayreh and Zimmerman, 2003a). Monitoring
for corticosteroid-associated side effects (such as osteopo-
rosis and diabetes) and for relapses and flare-ups is essen-
tial for chronic management of GCA.
414 Neurologic Conditions in the Elderly
Positive spontaneous visual phenomena with
blindness (Bonnet syndrome)
In the late eighteenth century, Charles Bonnet reported
VHs in elderly persons who were cognitively normal
(including Bonnet’s 89-year-old grandfather, Charles
Lullin, and, later, Bonnet himself) (Berrios and Brook,
1982; Eperjesi and Akbarali, 2004; Jacob et al., 2004; Lan-
ska, 2005). In 1936, de Morsier eponymously recognized
Bonnet’s report and designated Bonnet syndrome as a
syndrome of VHs in elderly persons with ocular lesions
and intact cognition (de Morsier, 1936; Ffytche and How-
ard, 1999). Three decades later, though, de Morsier tried
to remove ocular disease from the syndromic definition
and, by that time, considered Bonnet hallucinations as
VHs occurring among the elderly with intact cognition,
regardless of etiology (de Morsier, 1967).
The eponym of Bonnet syndrome (sometimes referred
to as Charles Bonnet syndrome) is now most commonly
used to refer to VHs in visually impaired individuals with
full alertness and unimpaired cognition (this is the opera-
tional definition used for this chapter) (Lanska, 2005).
Other definitions are also employed, however, which
leads to confusion—indeed, because of the varying defini-
tions, a number of authors have argued that the eponym
is no longer useful (Cole, 2001; Burke, 2002; Lanska, 2005).
Some authors accept as Bonnet hallucinations cases with
unformed VHs (photopsias), cases without visual impair-
ment, or cases with dementia or other cognitive impair-
ment, while others restrict cases to elderly patients,
to patients with complex formed VHs, or to cases with
prechiasmal visual impairment. However, limiting the
definition of Bonnet hallucinations to complex VHs may
have no localizing value or etiologic specificity (Lepore,
1990; Santhouse et al., 2000; Burke, 2002; Wilkinson, 2004).
Therefore, most now accept that these hallucinations can
include both simple and complex VHs, including geomet-
ric shapes, animals (zoopsias), human figures, buildings,
or landscape scenes.
Bonnet hallucinations are usually well defined and
clear, often elaborate, VHs without associated olfactory,
gustatory, auditory, or tactile hallucinations. They may
appear suddenly, are not under voluntary control, and are
persistent though usually intermittent. The hallucinations
may be stationary or in motion, altered in size (small or
“Lilliputian” figures), sometimes grotesque or distorted,
and frequently chromatic (colored). Patients generally
have full or partial retention of insight, without delu-
sions or psychosis, and without associated intoxication
or withdrawal. The hallucinations are generally neutral
or pleasant and nonthreatening, but they may cause dis-
tress, especially because patients are aware that the visual
images are not “real.”
The frequency of Bonnet hallucinations may range from
daily to weekly, and the duration of individual VHs is
usually a few minutes but may be shorter or longer, from
seconds up to a full day. Triggers for Bonnet hallucina-
tions can include low light levels, fatigue, and emotional
stress. Bonnet hallucinations often occur with eyes open
and disappear with eyes closed. Some patients can ter-
minate their hallucinations with closing or opening their
eyes, attempting to fixate vision on or away from the hal-
lucination, or making saccades to one side.
Although it has been suggested that Bonnet syndrome
may be an early marker for dementia, most studies do
not indicate any cognitive impairment in most patients
with Bonnet syndrome. Nevertheless, some patients are
afraid to report such hallucinations to their physicians
because they are concerned that these indicate mental
illness or the incipient development of dementia and
therefore fear that reporting such experiences will com-
promise their autonomy. Many affected patients express
relief when they are informed that such hallucinations
are relatively benign and are not related to insanity or
dementia.
Many authors have suggested a “release” mechanism
associated with modality-specific sensory deprivation as
the basis of Bonnet hallucinations, and some have referred
to this phenomenon as “phantom vision” akin to phan-
tom limbs in patients with loss of somatosensory input
after an amputation. In support of a release mechanism
for Bonnet hallucinations, sensory deprivation and a low
level of arousal favor development of the hallucinations
but are not required for their development (Teunisse et al.,
1996). Deafferentation produces an increase in excitability
of the deafferentated neurons and an increase in spontane-
ous activity (Levison et al., 1951; Echlin et al., 1952; Lance,
1976; Eysel et al., 1999; Burke, 2002). High-frequency
bursts of synchronized, though nonepileptic, neural activ-
ity in areas of deafferentated cortex may be necessary for
these hallucinations (Burke, 2002).
Single-photon emission computed tomography
(SPECT) studies of patients with Bonnet syndrome have
shown hyperperfusion in the lateral temporal cortex, stri-
atum, and thalamus, presumably representing the results
of central nervous system plasticity and compensation
(Adachi et al., 2000). Functional magnetic resonance
imaging (MRI) studies indicate that Bonnet hallucinations
are associated with increased ventral extrastriate activ-
ity, which persists even between hallucinations (Ffytche
et al., 1998). The location of increased activity correlates
with the type of hallucination, with colored VHs associ-
ated with activity in the posterior fusiform area, faces
associated with activity in the left middle fusiform area,
objects associated with activity in the right middle fusi-
form area, and textures associated with the collateral sul-
cus (Ffytche et al., 1998). The relative frequency of certain
complex forms (such as faces) may reflect the amount of
association cortex devoted to representing these forms or
the magnitude of the distributed network processing such
forms (Lance, 1976; Wilkinson, 2004).

Bonnet hallucinations may terminate spontane-
ously, upon improving or stabilizing of visual loss; with
improved lighting; or on improving grief, loneliness, or
social isolation (Sonnenblick et al., 1995; Razavi et al.,
2004). Diverse treatments have also been reported to alle-
viate Bonnet hallucinations, but almost all of these are
anecdotal reports, being based on small samples (often
single cases) in uncontrolled trials. Bonnet hallucinations
are generally not resolved or improved with anticonvul-
sants, atypical antipsychotic medications, antidepres-
sants, or benzodiazepines, although there are anecdotal
reports of occasional patients who seem to respond to
such medications. In rare cases of Bonnet syndrome asso-
ciated with visual impairments from temporal arteritis,
steroid treatment can result in prompt resolution of VHs,
even with persistent visual loss (Sonnenblick et al., 1995;
Razavi et al., 2004); the implications of this are not fully
clear but may suggest that other mechanisms may be
involved in continuing such hallucinations beyond sim-
ple “release” mechanisms.
Central visual disturbances
Late-life migrainous accompaniments
and equivalents
In the 1980s, Fisher distinguished so-called “late-life
migrainous accompaniments” from TIAs, both of which
can be accompanied by headache (Fisher, 1980, 1986). As
with other migrainous auras, late-life migrainous accom-
paniments (or sans headache, preferably termed “late-life
migrainous equivalents”), by definition, occur in individ-
uals older than 40 years of age, particularly in the elderly.
Painful cephalic vasodilation (perceived as headache)
may not occur in older patients with transient migraine
accompaniments because of vascular rigidity and ath-
erosclerosis (Aring, 1972; Meyer et al., 1998). Late-life
migrainous accompaniments and equivalents occur more
frequently in men than women (Fisher, 1986).
Patients with late-life migraine accompaniments expe-
rience a “build-up” and “progression” of symptoms, often
with a characteristic “march” of symptoms from one area
of the body to another, with symptoms that are not typi-
cal of acute strokes or TIAs (Fisher, 1986): TIAs and sen-
sory stroke are sudden in onset and usually not reversible
(Fisher, 1982; Dennis and Warlow, 1992). The typical dura-
tion of the march of a late-life migraine accompaniment or
equivalent (15–60 minutes and generally 15–25 minutes)
is longer than a seizure march (usually 1–2 minutes) and
most TIAs, although migraine equivalents and accom-
paniments may have a shorter duration (4–15 minutes
in about a third of cases), and the duration of migraine
accompaniments/equivalents overlaps the usual range of
duration for TIAs (Martí-Vilalta et al., 1979; Levy, 1988;
Bots et al., 1997; Wijman et al., 1998; Kidwell et al., 1999;
Weimar et al., 2002). Migrainous accompaniments and
equivalents are occasionally prolonged (over 1 hour), in
Disorders of the Special Senses in the Elderly 415
which case they are classified as prolonged migraine aura.
Visual symptoms are the most common symptom cate-
gory for late-life migraine accompaniments and include
scintillating scotomata, transient blindness, homonymous
hemianopsia, blurring of vision, and difficulties with
visual focusing (Fisher, 1980, 1986). Typical visual aura
consisting of scintillating scotomas are highly characteris-
tic of migraine, especially when they are gradual in onset
and progressive (Aring, 1972). Less common symptoms
include aphasia, tinnitus, deafness, dysarthria, paresthe-
sias, ataxia/incoordination, and syncope.
Clinical features supporting a diagnosis of late-life
migrainous accompaniments or equivalents include the
following:
• Scintillating scotomata that gradually expand and mi-
grate.
• A “march” of paresthesias, scotoma, or other symp-
toms.
• Serial progression of migrainous accompaniments in a
course atypical for or inconsistent with cerebrovascular
disease (such as from visual symptoms to paresthesias to
aphasia).
• Occurrence of at least two identical attacks (because
stereotyped episodes are common with migraine accom-
paniments/equivalents and are unlikely with cerebral
emboli), especially if attacks occur over a prolonged pe-
riod of several years (because persistence of stereotyped
spells over a prolonged course is unlikely with cerebro-
vascular disease of any type).
• Associated headache (in ∼50% of cases).
• Duration of 15–60 minutes, and usually 15–25 minutes
(much longer than a typical seizure and shorter than most
TIAs).
• A benign course without permanent sequelae.
• Normal vascular imaging (if performed).
Although older theories of migraine attributed migraine
auras solely to cerebral vasoconstriction and the subse-
quent headache to cerebral vasodilation, such archaic
theories are now recognized as inadequate to explain fun-
damental features of migraine. Although cerebral blood
flow does change during the course of classic migraine
headaches with relative hypoperfusion during the aura,
headache actually begins during the period of hypoperfu-
sion (Olesen et al., 1990). Newer theories recognize neu-
rogenic and electrochemical processes as critical for trig-
gering and propagating migraine auras and for produc-
ing the associated headache, perhaps by stimulating local
vascular nociceptors (Olesen et al., 1990). Migrainous
auras are now thought to represent the clinical manifesta-
tions of the so-called “spreading depression of Leão,” a
wave of electrocortical hyperactivity followed by a wave
of inhibition, usually beginning in the visual cortex, pro-
gressing across the cortex at approximately 2–5 mm/min,
and potentially involving sequentially sensory cortex,
motor cortex, and language areas (Leao, 1944; Lauritzen,
416 Neurologic Conditions in the Elderly
1994; Porooshani et al., 2004; Tfelt-Hansen, 2010). Ini-
tiation and propagation of cortical spreading depression
depend partly on increased extracellular potassium ion
concentration and excitatory glutamate.
Late-life migraine accompaniments and equivalents
are typically benign events that generally do not require
an elaborate diagnostic evaluation. Persistent neurologic
deficits are rare, even when attacks continue for years.
Standard migraine therapy may be helpful to treat accom-
panying headaches, although vasoconstricting agents
(such as ergotamines and triptans) are best avoided in the
elderly, especially if there are significant cardiovascular
or cerebrovascular comorbidities or vascular risk factors.
Medications for aborting migraine headaches are usu-
ally not necessary to treat late-life migraine equivalents
(sans headache) because the phenomena are transient and
unaccompanied by headache.
Heidenhain variant of Creutzfeldt–Jakob disease
A form of Creutzfeldt–Jakob disease (CJD) with pre-
dominant visual symptoms in the early stages and rapid
progression was described by Heidenhain in 1929 and is
now known as the Heidenhain variant (Heidenhain, 1929;
Meyer et al., 1954; Foundas et al., 2008). The Heidenhain
variant occurs in some 10–20% of cases of CJD (Kropp
et al., 1999; Lueck et al., 2000). Visual manifestations can
include blurred vision, visual field restriction, dyschro-
matopsia, metamorphopsia, VHs, visual agnosias, corti-
cal blindness, and anosognosia for blindness (Anton’s
syndrome) (Kropp et al., 1999). Because of visual difficul-
ties, patients typically stop reading and watching televi-
sion even before marked dementia has developed (Kropp
et al., 1999). Ophthalmologic examination does not reveal
marked abnormalities, and new glasses do not signifi-
cantly improve function in such patients. The vast major-
ity of Heidenhain cases are homozygous for methionine
at codon 129 of the prion protein gene (PRNP) (Kropp
et al., 1999). This is the same PRNP genotype as the myo-
clonic variant, PcPCJD type 1 or CJDM/M1 (Parchi et al.,
1996). EEG findings are more prominent over the occipital
lobes; periodic sharp-wave complexes are evident on EEG
in most cases (Kropp et al., 1999; Foundas et al., 2008).
Cerebrospinal fluid (CSF) studies typically show 14-3-3
protein and may show elevated levels of neuron-specific
enolase (Kropp et al., 1999). When the Heidenhain variant
is suspected, MRI with proton-weighted imaging, fluid-
attenuated inversion recovery (FLAIR), and diffusion-
weighted imaging (DWI) should be obtained to confirm
the diagnosis (Kropp et al., 1999; Shiga et al., 2004). MRI
T2- and proton-weighted sequences frequently show
symmetric hyperintensities in the basal ganglia and may
show a pronounced increase in signal intensity in the cal-
carine and extra-calcarine occipital cortex, as well as focal
atrophy of the visual cortex (Kropp et al., 1999). Pathologi-
cally, Heidenhain variant cases demonstrate degeneration
throughout the visual pathways, with loss of ganglion
cells and bipolar cells in the retina, demyelination in the
optic nerve, neuronal loss in the lateral geniculate gan-
glion, and severe degeneration in the occipital cortex, par-
ticularly the calcarine cortex (Foundas et al., 2008). Patho-
logic changes in the occipital lobe of Heidenhain variant
cases are more prominent than in non-Heidenhain cases
of CJD, whereas damage is less severe in the cingulated
gyrus and basal ganglia in the Heidenhain cases than in
the others (Kropp et al., 1999).
Visual hallucinations due to central pathology
Medication-induced visual hallucinations
Drugs associated with VHs in the elderly include drugs
with anticholinergic properties (atropine, diphenhydr-
amine, and amitriptyline), dopaminergic properties
(L-dopa and dopamine agonists), and various psychotro-
pic agents (bupropion, doxepine, and lithium). In most
cases, these appear to affect central nervous system neu-
rotransmission, involving particularly cholinergic, dopa-
minergic, or serotonergic pathways. As such, they can
affect brainstem centers involved with both arousal and
sleep and, in particular, can affect brainstem reticular cen-
ters involved in generating rapid eye movement (REM)
sleep.
Epileptic visual hallucinations
Epileptic VHs are typically brief, stereotyped, and frag-
mentary simple VHs that may be associated with other
manifestations of seizures; epileptic complex VHs can
occur but are rare (Manford and Andermann, 1998). As
demonstrated by intracranial EEG recordings and direct
cortical stimulation studies, epileptic VHs are due to
pathologic excitation of visual cortical areas. Electrical
stimulation of the occipital cortex produces simple VHs in
the contralateral visual hemifield, while electrical stimu-
lation of the temporo-occipital or parieto-occipital cortex
produces complex VHs (for example, involving people,
animals, or scenes) in both visual hemifields (Penfield and
Perot, 1963). Focal cortical resections can produce com-
plete remission of epileptic complex VHs, demonstrat-
ing that visual association cortex is both necessary and
sufficient for their generation (Manford and Andermann,
1998).
Visual hallucinations (Bonnet syndrome)
with retrochiasmal visual field defects
Bonnet hallucinations are most commonly identified in
elderly patients with bilaterally decreased visual acuity,
but similar VHs also occur in patients with visual field
defects, and even occasionally in patients with visual field
defects and normal central visual acuity (Lance, 1976;
Kolmel, 1985; Wender, 1987; Cole, 1999, 2001). From a
definitional perspective, patients with unstructured lights
(such as flashes, sparkles, and zig-zag lines—referred to

by some as phosphenes), simple structured images (such
as geometric figures occurring in a repetitive pattern—
referred to by some as photopsias), and complex VHs (such
as people, animals, and landscapes) had similar lesions
on brain imaging (Vaphiades et al., 1996), suggesting no
unique anatomic area for each type of positive spontane-
ous visual phenomena. Although some have referred to
these as Bonnet hallucinations, the appropriateness of
that eponym in this circumstance has been reasonably
questioned (Cole, 2001). In patients with VHs related to
visual field defects, the VHs are typically restricted to the
abnormal visual field. Retrochiasmal lesions associated
with hallucinations are typically smaller than those caus-
ing a hemianopsia without associated Bonnet hallucina-
tions and frequently spare the visual association cortex.
Large lesions destroying the anterior visual association
cortex appear to preclude development of such halluci-
nations, suggesting that some intact visual association
cortex is necessary to experience these complex hallucina-
tions (Vaphiades et al., 1996). The complex nature of the
VHs also presumably indicates that they are generated in
the visual association cortex. In some cases of complete
cortical blindness (as in Anton’s syndrome), patients may
be unaware of their deficit.
Central visual disorders in parkinsonism
Visual symptoms are common in PD and include com-
plaints of dry eyes, reading difficulties, difficulty esti-
mating spatial relations, and complex VHs (Biousse et
al., 2004; Archibald et al., 2009). Nevertheless, visual
abnormalities in PD are usually clinically occult and
unlikely to be uncovered during routine neurologic
examination or by ordinary high-contrast visual acu-
ity testing (Rodnitzky, 1998). With the use of special
examination techniques, though, defects have been
identified in visuospatial orientation, visual object and
facial recognition, visual acuity, color vision, contrast
sensitivity and discrimination, the blink reflex, pupil
reactivity, ocular convergence, saccadic and smooth
pursuit movements, and visual evoked potentials
(Rodnitzky, 1998; Biousse et al., 2004; Armstrong, 2008).
The decreased blink rate and use of anticholinergic
medications may contribute to ocular surface irritation,
altered tear film generation or persistence, and xerosis
(Biousse et al., 2004).
In neurodegenerative disorders with parkinsonism as
a prominent feature, VHs occur predominantly in disor-
ders with Lewy body pathology, such as PD and DLB).
In contrast, VHs occur rarely in progressive supranu-
clear palsy (PSP, a tauopathy) and multiple system atro-
phy (MSA, an alpha-synucelinopathy, but without Lewy
bodies) (Williams and Lees, 2005; Williams et al., 2008).
In one study, VHs occurred in 50% of the patients with
PD, 73% of the patients with DLB, and only 7% of the
patients with non-Lewy body parkinsonism (Williams
Disorders of the Special Senses in the Elderly 417
and Lees, 2005). Therefore, among patients with unclas-
sifiable or undetermined forms of parkinsonism, VHs
are a strong indicator of underlying Lewy body pathol-
ogy (PD or DLB) (Williams and Lees, 2005; Williams et
al., 2008). The distribution of Lewy bodies in the tempo-
ral lobe among patients with PD or DLB is more strongly
related to the presence and duration of VHs than to the
presence, severity, or duration of dementia. Cases with
well-formed VHs have high densities of Lewy bodies
in the amygdala and parahippocampus, and cases with
early VHs have higher densities of Lewy bodies in para-
hippocampal and inferior temporal cortices (Harding
et al., 2002).
Visual hallucinations in Parkinson’s disease
VHs have been reported in a large percentage of patients
with PD, from 8% to 60%, with most estimates approxi-
mating 40% at some point in the illness (Fénelon et al.,
2000; Barnes et al., 2003; de Maindreville et al., 2005;
Diederich et al., 2005; Meral et al., 2007; Papapetropou-
los et al., 2008). VHs in patients with PD can be associ-
ated with behavioral problems and are a risk factor both
for nursing home placement and for mortality (Goetz
and Stebbins, 1993, 1995). In patients with PD, illusory
visual misperceptions often precede VHs (Diederich et
al., 2005). Hallucinations in patients with PD are typi-
cally complex visual images, occurring during wakeful-
ness with eyes open and without clear precipitants, but
less frequently, they can involve other sensory modali-
ties (occasionally auditory or, rarely, olfactory or tactile)
(Goetz et al., 1998; Inzelberg et al., 1998; Fénelon et al.,
2000; Barnes and David, 2001; Fénelon et al., 2002; de
Maindreville et al., 2005; Papapetropoulos et al., 2008).
They are commonly mobile and last for periods of sec-
onds to minutes. The content is variable within and
between affected individuals and can include people,
animals, buildings, or scenery.
Since the availability of levodopa in the late 1960s and
1970s, it has become clear that dopaminergic medica-
tions (and also anticholinergic medications) can trigger
the onset of hallucinations. This has led to discussion
and even controversy over the relative contribution of
medications, the underlying disease process, and vari-
ous comorbidities to the development of hallucinations
in patients with PD. VHs occur even in the absence of
delirium, dementia, or major depression, suggesting that
hallucinations can be part of the disease process itself
(Biousse et al., 2004). Nevertheless, VHs are significantly
more frequent in patients with PD and concomitant delir-
ium, dementia, or depression, and also significantly more
frequent in PD patients treated with dopaminergic or
anticholinergic drugs.
Risk factors for VHs in PD include older age, longer
duration of illness, more severe motor impairment, axial
rigidity, olfactory impairment early in the disease course,
418 Neurologic Conditions in the Elderly
ocular disorders (including worse visual acuity), cognitive
decline or dementia, depression, sleep disturbances, auto-
nomic dysfunction, and various medications (Sanchez-
Ramos et al., 1996; Klein et al., 1997a; Kraft et al., 1999;
Fénelon et al., 2000; Barnes and David, 2001; Holroyd et al.,
2001; Onofrj et al., 2002; Barnes et al., 2003; Kulisevsky and
Roldan, 2004; de Maindreville et al., 2005; Pacchetti et al.,
2005; Papapetropoulos et al., 2005; Williams and Lees,
2005; Matsui et al., 2006b; Onofrj et al., 2006; Oka et al.,
2007; Barnes et al., 2010; Stephenson et al., 2010).
Patients with a diagnosis of PD who developed early
dopaminergic drug-induced VHs (within 3 months of
starting dopaminergic therapy) often had hallucinations
during daytime and nighttime, frightening hallucinatory
content with paranoia, and accompanying nonvisual hal-
lucinations; within 5 years, such patients are typically
found to have an underlying psychiatric illness or another
neurodegenerative disorder (Goetz et al., 1998). There-
fore, the early onset of dopaminergic drug–related VHs
should prompt consideration of alternative diagnoses,
either a comorbid psychotic illness or an evolving parkin-
sonism-plus syndrome, DLB, or AD with extrapyramidal
signs (Goetz et al., 1998).
VHs in PD are not adequately accounted for within
Cogan’s simple dichotomy of nonpsychotic hallucina-
tions into release and irritative types; they depend on
attentional and visual perceptual impairments, as well as
the interactions of multiple processes within scene per-
ception, rather than simply the activation or release of
specific visual areas (Collerton et al., 2005). Indeed, vari-
ous authors have suggested that VHs in PD may result
from a combination of faulty perceptual processing of
environmental stimuli, less detailed recollection of expe-
rience, frontal executive dysfunction, involvement of
brainstem sleep centers, impaired attention, and altered
levels of arousal, combined with intact image genera-
tion (Manford and Andermann, 1998; Barnes et al., 2003;
Barnes and David, 2001; Stebbins et al., 2004; Collerton
et al., 2005; Diederich et al., 2005; Ozer et al., 2007; Barnes
and Boubert, 2008; Barnes et al., 2010; Goetz et al., 2010;
Koerts et al., 2010; Bronnick et al., 2011). PD with VHs is
associated with increased activation in the visual asso-
ciation cortex and deficits in the primary visual cortex
(Holroyd and Wooten, 2006). Association of impaired
vision, or impaired visual object processing in occipital
and temporal extrastriate visual cortices, supports a con-
tribution from impaired “bottom-up” visual processing in
the development of VHs in patients with PD (Meppelink
et al., 2009). A wide range of neuropsychological deficits
can contribute to the emergence of VHs in PD, including
poorer performance in language, verbal learning, seman-
tic fluency, and visuoperceptive functions (Ramírez-
Ruiz et al., 2006). Patients with PD and VHs sleep less
than nonhallucinating patients and also have increased
awakenings, reduced sleep efficiency, and increased
daytime sleepiness, suggesting that VHs in some PD
patients may be a symptom of inadequate sleep and pro-
longed daytime sleepiness (Barnes et al., 2010), or that
pathways involved in the generation of VHs are related
directly or indirectly to pathways involved with sleep.
However, although PD patients with VHs often have
concurrent sleep disorders, sleep disorders in the absence
of VHs do not seem to be predictive of the subsequent
development of VHs (Goetz et al., 2010). Cholinergic and
serotonergic pathways are associated with both sleep
disturbances and VHs in PD (Manford and Andermann,
1998; Manganelli et al., 2009). Involvement of cholinergic
and serotonergic brainstem centers (such as cholinergic
pedunculopontine nuclei and serotonergic raphe nuclei)
may account for overlaps between PD and REM behavior
disorder, and between VHs seen with PD and those seen
with LSD, peduncular hallucinosis, and narcolepsy. REM
sleep-related dream imagery intruding into wakefulness
may account for VHs in some PD patients, as part of a
REM sleep disorder that may include sleep-onset REM
periods in the daytime, Stage 1 REM during the night, and
post-REM delusions at night (Arnulf et al., 2000; Nomura
et al., 2003; Kulisevsky and Roldan, 2004). Dysfunction of
frontal areas associated with attention could precipitate
VHs through abnormal processing of relevant and irrel-
evant visual stimuli (Ramírez-Ruiz et al., 2008).
Preliminary attempts have been made to model the
development of VHs in PD (Collerton et al., 2005; Died-
erich et al., 2005; Papapetropoulos, 2006). According to
one such multicomponent model, VHs in patients with
PD may represent a dysregulation of the gating and filter-
ing of external perception and internal image production
(Diederich et al., 2005). Contributing factors to the devel-
opment of VHs in such patients can include impaired
primary vision, aberrant activation of visual association
and frontal cortices, lack of suppression or spontane-
ous emergence of internally generated imagery (ponto-
geniculo-occipital system), intrusion of REM dreaming
imagery into wakefulness, changes of perceptual filtering
capacities through fluctuating vigilance, and medication-
related overactivation of mesolimbic systems (Diederich
et al., 2005).
PD patients with VHs had gray matter volume reduc-
tions in the lingual gyrus and superior parietal lobe
(Ramírez-Ruiz et al., 2006). Hypoperfusion of the visual
pathway was closely related to VHs in Parkinson’s dis-
ease—patients with PD and VHs had significant perfu-
sion reductions in the bilateral inferior parietal lobule,
inferior temporal gyrus, precuneus gyrus, and occipital
cortex, compared with nonhallucinatory patients (Mat-
sui et al., 2006a). The relative regional cerebral glu-
cose metabolic rate was greater in the frontal areas in
PD patients with VHs, particularly in the left superior
frontal gyrus (Nagano-Saito et al., 2004). Cases with
well-formed VHs have high densities of Lewy bodies

in the amygdala and in frontal, temporal, and parietal
cortical areas, with early VHs relating to higher densi-
ties in parahippocampal and inferior temporal cortices
(Harding et al., 2002; Papapetropoulos et al., 2006, 2008).
The alpha-synuclein burden (presumably as an indicator
of Lewy body pathology) in limbic regions, particularly
the amygdala and anterior cingulate gyrus, is strongly
related to dementia in PD, as well as to VHs when there
is an underlying dementia (Papapetropoulos et al., 2006;
Kalaitzakis et al., 2009).
VHs in PD are a considerable cause of morbidity and
are an important predictor of cognitive decline, place-
ment in institutional care, and mortality (Goetz and Steb-
bins, 1993; Klein et al., 1997a; Goetz et al., 1998; Aarsland
et al., 2000; Archibald et al., 2009). In patients with PD and
so-called “benign hallucinations” (with retained insight),
hallucinations seldom stay benign (Goetz et al., 2006).
Most progress to loss of insight or develop delusions
within 2 years, and most require either a reduction in Par-
kinson’s disease medications to treat hallucinations or,
less commonly, treatment with neuroleptic medications.
Thus, the concept of benign hallucinations is prognosti-
cally misleading, as these hallucinations herald serious
consequences in a relatively short time frame of several
years.
VHs in patients with PD and dementia may resolve
with acetylcholinesterase inhibitors (donepezil), dual
inhibitors of acetylcholinesterase and butylcholinesterase
(such as rivastigmine), and atypical antipsychotic medi-
cations (such as clozapine or quetiapine) (Diederich et al.,
2000; Bullock and Cameron, 2002; Fernandez et al., 2009).
These do not appear to act by normalization of sleep
architecture (Kurita et al., 2003; Sobow, 2007; Fernandez
et al., 2009).
Visual hallucinations in dementia with
Lewy bodies
Parkinsonism and VHs are critical elements in the clinical
diagnosis of DLB in conjunction with dementia and fluc-
tuating levels of cognition. Recurrent complex VHs are, in
fact, a core clinical feature of DLB, occurring in about two-
thirds to three-quarters of the affected patients (McKeith
et al., 1996; Del Ser et al., 2000; Olichney et al., 2005; Wil-
liams and Lees, 2005). For diagnosis of probable DLB, the
consensus criteria require progressive cognitive decline of
sufficient severity to significantly interfere with social or
occupational functioning, with at least two of the follow-
ing: recurrent VHs; fluctuating cognition with pronounced
variations in alertness and attention; and spontaneous
motor manifestations of parkinsonism (McKeith et al.,
1996). Other supportive features may include repeated
falls, syncope, neuroleptic sensitivity, systematized delu-
sions, hallucinations in other sensory modalities, urinary
incontinence preceding severe cognitive dysfunction,
and a rapidly progressive course (Hansen et al., 1990;
Disorders of the Special Senses in the Elderly 419
Perry et al., 1990; Del-Ser et al., 1996; McKeith et al., 1996,
2000). Some cases diagnosed as PD in earlier reports
would probably now be diagnosed as having DLB.
VHs typically occur early in the course of DLB,
whereas, in contrast, they generally occur only in the sec-
ond half of the disease course in PD (Williams and Lees,
2005). Because VHs are commonly present in both PD and
DLB, VHs by themselves are not good predictors of DLB
pathology; the absence of VHs early in the disease course,
though, suggests that the patient does not have DLB, but
is instead highly predictive of PD with dementia (Hard-
ing et al., 2002).
VHs in DLB are most common during periods of
diminished consciousness but are nevertheless much
more persistent than the transient perceptual dis-
turbances that occur in other dementias or delirium
(McKeith et al., 1996). VHs in DLB are also exacerbated
by visual impairment or low-light environments and
may be temporarily relieved by increased environmen-
tal stimulation, including increased social interaction
(McKeith et al., 1996). They are usually detailed and
may be of normal size or Lilliputian. Typically, they
consist of faces, people, or animals, but they can be of
three-dimensional inanimate objects (such as buildings,
trees, or flowers). VHs of people are usually of strangers,
although it is not uncommon for affected patients to see
images of living or deceased friends or relatives. Hal-
lucinations in other sensory modalities may also occur
in patients with DLB, but nonvisual hallucinations are
much less common than VHs. Emotional responses to
these hallucinations are variable (typically ranging from
indifference to amusement or, less often, fear), but some
degree of insight into their unreality is often maintained
(McKeith et al., 1996).
In addition to VHs, patients with DLB frequently have
visuospatial and visuoconstructive disabilities, visual
agnosias, and delusional misidentification syndromes
(Mori et al., 2000). Visuospatial and visuoconstructive
abilities are more severely affected in DLB than in AD,
with corresponding relative decreases in occipital blood
flow and glucose metabolism in the primary visual cortex
and in the visual association cortex (Mori et al., 2000).
Structural and functional central nervous system
changes have been linked to VHs in DLB. DLB and PD
patients with VHs had more frontal gray matter atrophy
than nonhallucinators, with the impairment being greater
in the DLB group (Sanchez-Castaneda et al., 2010). VHs in
DLB are related to dysfunction of the parietal and occipi-
tal association cortices, whereas misidentifications are
related to dysfunction of the limbic–paralimbic structures
(Nagahama et al., 2010). Deficits in the cholinergic system
are pronounced in DLB and are more severe in patients
with VHs (Satoh et al., 2010). VHs in DLB are associated
with impaired glucose metabolism in the medial occipi-
tal cortex (Satoh et al., 2010). Donepezil treatment can be
420 Neurologic Conditions in the Elderly
effective in treating VHs in DLB, with concomitant reduc-
tion in glucose metabolism in the medial occipital cortex
(Satoh et al., 2010).
Visual hallucinations in Alzheimer’s disease
VHs are also common in various non-Lewy body neuro-
degenerative diseases, including AD. Cognitive impair-
ment alone (from whatever cause) can be associated with
VHs, even in the absence of visual impairment. VHs and
other neuropsychiatric symptoms (such as agitation,
aggression, delusions, and perseverative verbal or motor
behavior) are very common in patients with dementia,
often refractory to available treatments, and associated
with increased caregiver burden and poor outcomes for
patients, including precipitation of institutionalization
(Sink et al., 2005).
When environmental modification is not effective,
various medications can be considered to treat hallucina-
tions, delusions, paranoia, and aggression that are causing
distress. However, the efficacy of available medications—
including typical and atypical antipsychotics, antidepres-
sants, various “mood stabilizers,” cholinesterase inhibi-
tors, and memantine—is, at best, marginal for treating
VHs and other problematic neuropsychiatric manifesta-
tions in patients with dementia (Sink et al., 2005). These
agents can be associated with many side effects, some of
which are severe. Pharmacologic treatments of dementia-
related behavioral symptoms should therefore be used
cautiously at minimum dosages, monitored closely for
side effects and efficacy, and evaluated for tapering or
discontinuation within 6 months of stabilization of symp-
toms and every 6 months thereafter.
Visual hallucinations in delirium
Abnormal perceptions are common in acutely confused
patients and may include illusions and hallucinations.
Whereas illusions are the distortion or misinterpretation
of an actual physical stimulus, hallucinations are unpro-
voked perceptual experiences that occur in the mind in
the absence of an external physical stimulus. Hallucina-
tions in acute confusional states are typically visual or a
combination of visual and auditory, but polymodal hallu-
cinations can occur with delirium (unlike release halluci-
nations or irritative hallucinations, which are unimodal).
Particularly with delirious states, hallucinations of any
type may be terrifying and associated with paranoid
delusions. Psychotic hallucinatory–delusional behavior
may at times obscure the deficit in attention that is the
fundamental clinical feature of acute confusional states.
Indeed, the prominence of secondary psychotic behavior
in a confused patient may result in the incorrect diagno-
sis of a functional psychosis. Although confused patients
present acutely with impaired attention and often with
an altered level of arousal, memory impairment, and
disorientation, patients with functional psychoses, such
as schizophrenia and manic-depressive psychosis, have
a history of preexisting abnormal behavior and are alert
and generally attentive (unless attention is disrupted by
active hallucinations), with preserved memory and orien-
tation. In general, psychiatric illness does not cause severe
confusion, disorientation, or an altered level of conscious-
ness. In addition, the hallucinations in confusional states
are generally visual or mixed and vary throughout the
day, generally being worse at night. The hallucinations
of functional psychoses, on the other hand, are gener-
ally auditory and less susceptible to diurnal variation.
Furthermore, the delusions of confused patients are com-
monly paranoid but generally relate to the immediate
situation and change rapidly in content; the delusions of
paranoid schizophrenics are stable and systematized, typ-
ically concerning expansive, global ideas such as world-
wide plots or the FBI. The causes of VHs in delirium are
likely varied, depending on the type (agitated, apathetic)
of delirium and the underlying causes.
Hearing
Functionally significant hearing loss is common in the
elderly, affecting about a third of those age 70 or older
(Campbell et al., 1999). This can adversely affect quality of
life and compromise an older individual’s ability to carry
out routine activities and interact socially, thereby con-
tributing to isolation, frustration, disappointment, and
depression (Mulrow et al., 1990). Ability to understand
spoken speech is often interpreted as an indicator of cog-
nitive abilities, especially in the elderly, so impaired hear-
ing often negatively influences how other people perceive
and interact with an elderly person; it also contributes not
infrequently to inappropriate diagnoses of dementia by
clinicians. In addition, hearing impairment is a significant
predictor of postural imbalance and falls in older individ-
uals (Viljanen et al., 2009).
Conductive hearing disturbances
The most common causes of conductive hearing loss in
the elderly is impacted cerumen. Objective tinnitus can
also be considered a “conductive” hearing problem—in
this case, not a “negative” symptom (due to impairment
or impedance of conduction), but rather a “positive”
symptom produced by conduction of vascular and other
persistent or rhythmic cranial noises to the cochlea.
Cerumen impaction
Cerumen is a yellowish, waxy substance secreted in the
outer cartilaginous portion of the external auditory canal.
Cerumen consists of shed layers of skin and a combina-
tion of viscous secretions from sebaceous glands and
modified apocrine sweat glands. Cerumen protects the
skin of the canal, assists in cleaning and lubrication, and

may provide some protection from water and infectious
agents. Excess or impacted cerumen can impair hearing
by blocking sound transmission through the canal or by
interfering with movement of the eardrum, both of which
produce conductive hearing loss.
Physiologic cleaning of the ear canal occurs as a result
of a “conveyor belt” process of epithelial migration, aided
by jaw movement. The cerumen in the canal is also car-
ried outward, taking with it any dirt, dust, and particulate
matter that may have gathered in the canal. Jaw move-
ments assist this process by dislodging debris attached to
the walls of the ear canal.
Several techniques can effectively remove problematic
cerumen from the external auditory canal, including ceru-
menolysis (using softeners, or cerumenolytics), syringing
with warm water (sometimes with so-called “ear wash”
devices), and manual removal with a curette. Although
softeners are more effective than no treatment, it is
unclear which specific softeners are most effective (Bur-
ton and Doree, 2009; Clegg et al., 2010). Commercially
or commonly available cerumenolytics include various
oils (such as olive oil and baby oil); glycerol; carbamide
peroxide (6.5%) with glycerine; urea, hydrogen perox-
ide, and glycerine; sodium bicarbonate in water; and
sodium bicarbonate with glycerine. Generally, a ceru-
menolytic should be used 2–3 times daily for 3–5 days
prior to cerumen extraction. Even if impacted cerumen
is not resolved by using a softener, such agents generally
facilitate removal by subsequent syringing or curettage.
The effectiveness of irrigation methods or mechanical
removal is equivocal based on available data (Clegg et al.,
2010). Proper technique is essential—potential complica-
tions of syringing include perforation of the drum (the
most common injury resulting in significant disability),
iatrogenic otitis externa, and iatrogenic physiologic ver-
tigo (from using an irrigating solution at a temperature
other than body temperature) (Wilson and Roeser, 1997;
Ernst et al., 1999). The liquid used to irrigate the ear canal
is usually water, normal saline, a solution of sodium
bicarbonate, or a solution of water and vinegar. To avoid
injuring the canal and the tympanic membrane, the water
stream should not be instilled at an uncomfortable rate
or force—it is much better to irrigate slowly for a long
period than to irrigate too forcefully and risk a signifi-
cant injury. Curettage is most appropriate when the ear
canal is only partially occluded and the material is not
adhering to the skin of the ear canal. Otoscopy should be
performed after removal of cerumen, to ensure that the
canal is clear and that no irritation of the canal or other
injury has occurred.
Use of cotton swabs should be discouraged because
they tend to push most of the earwax farther into the
canal. If not used carefully, they can also irritate or abrade
the canal, result in external otitis media, or produce a
tympanic membrane perforation.
Disorders of the Special Senses in the Elderly 421
Objective tinnitus
Objective tinnitus is a perceived sensation of sound that
occurs in the absence of external acoustic stimulation but
that the examiner can also hear (for example, by placing
a stethoscope over the patient’s external auditory canal,
orbit, cranium, and neck). Objective tinnitus results from
transmission of sounds generated near the ear from
respiration, vascular noises, or muscular contractions.
Objective tinnitus is much less common than subjective
tinnitus, but it often has an identifiable cause and may
be curable, whereas subjective tinnitus is often idiopathic
and is seldom curable (Lanska, 2013a). Objective tinni-
tus may be associated with a variety of vascular noises
arising from vascular stenoses (particularly of the carotid
arteries), the internal jugular vein or jugular bulb, arte-
riovenous malformations or fistulas, cavernous heman-
giomas, aneurysms, and vascular tumors (Lanska, 2013a).
Audiometry is generally normal with pulsatile tinnitus,
but occasional cases may have associated conductive or
sensorineural hearing loss.
Unilateral pulsatile tinnitus is by far the most common
type of objective tinnitus, but it may also be subjective
(Lanska, 2013a). Usually, it is a benign symptom result-
ing from normal vascular sounds, possibly exacerbated by
anxiety, insomnia, caffeine, or exercise. Pulsatile tinnitus,
however, can be a symptom of a more serious problem.
Pulsatile tinnitus is generated from cardiac or arterial
noises and is usually harsh and synchronous with the
pulse. It may occur because of blood turbulence near areas
of arterial narrowing (such as carotid bruits), near areas
of abnormal blood flow (such as arteriovenous malforma-
tions, carotid-cavernous fistulas, or vascular tumors), by
increased blood flow (such as anemia, thyrotoxicosis, or
hypertension treated with agents that lower peripheral
vascular resistance), by transmission of heart sounds (such
as aortic stenosis or mechanical heart valves), or as a result
of intracranial hypertension (Sismanis, 1998, Jun et al.,
2003; Sismanis, 2003). Pulsatile tinnitus may occur with
Paget’s disease, apparently because of neovasculariza-
tion and the formation of arteriovenous fistulae within the
temporal bone (Sismanis, 1998). Pulsatile tinnitus follow-
ing head trauma may indicate a traumatic arteriovenous
malformation, carotid-cavernous fistula, or carotid dissec-
tion. Although vascular loops in contact with the eighth
cranial nerve are generally considered a normal variant,
individuals with unilateral hearing loss are twice as likely
to have such loops in the symptomatic ear than in the
asymptomatic ear, and individuals with pulsatile tinnitus
are reportedly 80 times more likely to have a contacting
vascular loop on the symptomatic side than individuals
with nonpulsatile tinnitus (Chadha and Weiner, 2008).
Patients with hydrocephalus commonly develop pulsa-
tile tinnitus. Pulsatile tinnitus with increased intracranial
pressure may result from several (not mutually exclu-
sive) mechanisms: (1) turbulence as blood flows from the
422 Neurologic Conditions in the Elderly
hypertensive intracranial vessels to the lower-pressure
jugular bulb; (2) augmentation of venous and cerebrospi-
nal fluid pulsations because the accompanying arterio-
lar dilation allows a greater transmission of the arterial
pulse; and (3) transmission of systolic CSF pulsations to
the walls of the venous sinuses, which, in turn, produces
turbulent flow in the sinuses. The noise may be unilat-
eral because of asymmetries of jugular vein flow, with the
bruit occurring on the side of greatest jugular vein flow.
It is attenuated by maneuvers that decrease jugular vein
flow (such as jugular vein compression ipsilateral to the
tinnitus, a Valsalva maneuver, or turning the head). It also
remits transiently with lumbar puncture or permanently
with definitive treatment of intracranial hypertension
(such as with shunting).
In patients with pulsatile tinnitus, clinical evaluation
should include assessment of vascular risk factors, fun-
duscopy to exclude papilledema, otoscopy to exclude a
retrotympanic mass, assessment of the effect of jugular
bulb pressure on the tinnitus, auscultation for cranial and
carotid bruits, and examination for evidence of occlusive
vascular disease elsewhere in the body. Head MRI with
gadolinium enhancement should be obtained in patients
with unexplained unilateral tinnitus (with or without
hearing loss) and in patients with hearing loss suspicious
for retrocochlear pathology. Suspected carotid stenosis
can be evaluated with duplex ultrasonography, magnetic
resonance angiography, computed tomography (CT)
angiography, or, less commonly now, with conventional
angiography. In patients with evidence of increased intra-
cranial pressure (such as headache and papilledema), CT
or MRI should be performed to exclude a mass lesion; in
addition, lumbar puncture should be performed if there
is communicating hydrocephalus and no mass lesion
on brain imaging. Angiography or magnetic resonance
venography may be helpful if dural sinus thrombosis
is suspected. In patients with a retrotympanic lesion on
otoscopy, it is important to distinguish an aberrant carotid
artery, abnormal jugular bulb, and glomus jugulare
tumor; CT of the temporal bones is recommended (Sis-
manis, 1998), but other structural and vascular imaging
studies may also be helpful.
Forms of pulsatile tinnitus related to vascular pathol-
ogy may be curable with surgery or endovascular proce-
dures (Shah et al., 1999; Zenteno et al., 2004). For example,
pulsatile tinnitus resulting from carotid stenosis may be
cured with carotid endarterectomy (Louwrens et al., 1989;
Carlin et al., 1997; Norman et al., 1999; Kirkby-Bott and
Gibbs, 2004), carotid ligation (Carlin et al., 1997), or angio-
plasty and stenting (Emery et al., 1998). Pulsatile tinnitus
caused by hydrocephalus remits transiently with lumbar
puncture or permanently with definitive surgical treat-
ment of intracranial hypertension.
The cervical venous hum, another common cause of
objective tinnitus, is caused by turbulence in the internal
jugular vein, which causes the vessel walls to vibrate. It
is an innocuous murmur but is often mistaken for more
sinister sounds. Most patients with venous hums are
asymptomatic, but occasionally venous hums are the
source of disturbing objective tinnitus. Objective tinnitus
associated with a venous hum is a continuous murmur
with pulse-synchronous (diastolic) accentuation of vari-
able character (from a hum, to a musical whistle, to a roar)
that can be heard in the anterior neck and sometimes the
upper chest. Clinically, it is best detected with the bell of a
stethoscope, and it is typically loudest beneath the lower
lateral border of the sternal attachment of the sternoclei-
domastoid muscle and just superior to the medial end of
the clavicle. It can be unilateral or bilateral, but when uni-
lateral, it is typically present on the right side. It can be
precipitated or accentuated with turning the head away
from the auscultated side as the internal jugular vein is
stretched and pulled against the transverse process of the
atlas and as the contraction of the ipsilateral sternocleido-
mastoid muscle removes pressure on the vein and, thus,
increases flow on that side. Clinically, it can be confirmed
by eliminating the sound with moderate pressure over the
internal jugular vein a few inches above the clavicle with
a finger pressed lateral to the thyroid cartilage (which is
insufficient to interfere with the carotid artery pulse), and
often accentuated with release of this pressure or by pres-
sure on the contralateral internal jugular vein.
A venous hum is a normal finding in the vast majority
of cases and can be detected by appropriate examina-
tion in 25–50% of the older adults (Jones, 1962; Fowler
and Gause, 1964; Lanska, 2008, 2011a). Less commonly, it
may occur or be accentuated (to the point that it is symp-
tomatic) in various disease states (as with anemia; aortic
insufficiency; thyrotoxicosis; intracranial arteriovenous
malformations that produce increased cerebral blood
flow; high cardiac output states, such as with fever; in
dialysis patients with anemia and arteriovenous fistu-
las; or with pulmonary or other arteriovenous fistulas).
Venous hums may be bilateral with hyperdynamic car-
diac states and may be associated with cranial or orbital
bruits if the underlying cause of a secondary venous
hum is an intracranial arteriovenous malformation.
Symptomatic secondary venous hums may resolve with
treatment of the underlying condition or, in selected
cases, by an external device to compress the internal jug-
ular vein, by mastoidectomy, or by internal jugular vein
ligation. Internal jugular vein ligation typically results
in immediate and permanent relief of the pulsatile tin-
nitus associated with venous hums, although there is
a theoretical risk of precipitating a venous hum on the
opposite side because of the increased contralateral flow
postsurgically. Angiography is recommended prior to
internal jugular vein ligation, to exclude other vascular
pathology and to ensure normal venous drainage on the
opposite side.

Objective tinnitus associated with abnormal clonic mus-
cular contractions of palatal or middle ear muscles may
occur as an intermittent series of sharp, regular clicks, or
with palatal myoclonus as a fairly regular, continuous
clicking sound. Clicks occur over a wide frequency range
(from 10 to 300 Hz). Several distinct entities can produce
this type of objective tinnitus: (1) symptomatic palatal
myoclonus (associated with brainstem and cerebellar dys-
function); (2) essential palatal myoclonus (without associ-
ated neurologic dysfunction or neuropathology); and (3)
stapedial myoclonus (restricted to the stapedius muscle)
(Deuschl et al., 1990). In patients with rhythmic tinnitus
from palatal myoclonus, the key to diagnosis is to recog-
nize the palatal contractions. Pressing a gloved finger on
the affected side of the palate in the direction of the Eusta-
chian tube opening can result in temporary cessation of
tinnitus, even while the muscular contractions continue.
Stapedius myoclonus may be precipitated by loud sounds
and is often associated with facial nerve pathology (such
as hemifacial spasm and sometimes Bell’s palsy).
The clicking sounds associated with palatal myoclonus
have been localized to the opening of the Eustachian tube,
presumably with release of sound energy as the surface
tension holding the tube closed is suddenly broken. As a
result, tympanometry may demonstrate rhythmic changes
in middle-ear compliance (Slack et al., 1986). Symptom-
atic palatal myoclonus is usually caused by a lesion in the
Guillain–Mollaret triangle (between the dentate nucleus,
the inferior olive, and the red nucleus); typically, the cause
is vascular, especially in the elderly but, less commonly,
demyelination, head trauma, syphilis, electric shock, and
other causes may be responsible. These lesions produce
hypertrophic degeneration of the inferior olive, as well as
secondary rhythmic, synchronized discharges that act on
a variety of brainstem motor nuclei, causing nystagmus,
palatal contractions, extrapalatal tremors (of the chin and
platysma), and sometimes ear clicks. Essential palatal
myoclonus is less well understood but is thought to result
from a distinct brainstem oscillator that stimulates the tri-
geminal motor nucleus, causing rhythmic contraction of
the tensor veli palatini muscle, Eustachian tube opening,
and ear clicks (Deuschl et al., 1990).
Injections of Clostridium botulinum toxin into the leva-
tor veli palatini and tensor veli palatini muscles may be
the most useful approach to suppressing the tinnitus
associated with palatal myoclonus (Saeed and Brookes,
1993, 1996; Bryce and Morrison, 1998). The most common
side effects of Clostridium botulinum treatment are paresis-
induced Eustachian tube obstruction and velopharyngeal
weakness, with nasal regurgitation and dysphagia (Saeed
and Brookes, 1993; Bryce and Morrison, 1998); tympanos-
tomy tube placement can relieve discomfort associated
with Eustachian tube dysfunction, and careful titration
can minimize side effects (Bryce and Morrison, 1998).
Patients may also receive some benefit from tinnitus
Disorders of the Special Senses in the Elderly 423
masking (Saeed and Brookes, 1993). Palatal myoclonus
has anecdotally been reported to respond to various oral
medications, but results with oral medications are incon-
sistent, at best (Deuschl et al., 1990). Several surgical pro-
cedures to treat the associated tinnitus have also been
reported with variable results; in some cases, the surgi-
cal procedures have made the patients worse. Psycho-
therapy, application of cocaine to the nasopharynx, otic
ganglion blockade with anesthetic agents, stimulation of
the corneal reflex, acupuncture, hypnosis, relaxation exer-
cises, and other approaches have also been tried without
much success.
Objective tinnitus associated with a patulous Eusta-
chian tube may be described variously as a blowing
sound, an ocean roar, a low-pitched sound, a flapping
sound, or a click. It is synchronous with respiration and
usually more marked in the upright position. It is more
common in women and has been associated with weight
loss and mucosal atrophy (due to atrophic rhinitis or
radiotherapy) (Peifer et al., 1999; Ng and van Hasselt,
2005). Physical examination and audiometry are usually
normal, although occasionally, the tympanic membrane
may be observed to move synchronously with respira-
tion, or tympanometry can demonstrate oscillations syn-
chronous with respiration (Ng and van Hasselt, 2005;
Takasaki et al., 2008). A suspected patulous Eustachian
tube can be confirmed by temporary resolution of tinni-
tus with the head recumbent, or with sniffing, snorting,
or a Valsalva maneuver (McCurdy, 1985; Ciocon et al.,
1995).
Sensorineural hearing disturbances
Healthcare professionals and family members can improve
communication with hearing-impaired patients by facing
the person (so that the impaired person can easily see face
and lip movements); speaking in a lower register with
short, simple sentences; and eliminating extraneous back-
ground sounds when possible. Hearing aids are the prin-
cipal form of rehabilitation for sensorineural hearing loss
(SNHL) and can specifically improve communication and
reduce hearing handicap (Working Group on Communi-
cation Aids, 1991; Gates and Rees, 1997). Hearing aids are
effective for treating mild to moderate hearing loss when
the device is appropriately selected and fit for the patient,
and when the patient is motivated and able to use the
device. Even in demented patients, hearing aids are gen-
erally well tolerated and reduce disability caused by hear-
ing impairment, so dementia is not a reason to preclude
evaluation for a hearing aid; however, hearing aids do not
reduce cognitive dysfunction, behavioral problems, or
psychiatric manifestations in such patients (Allen et al.,
2003). In addition, assistive devices (such as a built-in
telephone amplifier, low-frequency doorbells, amplified
ringers, close-captioned television decoders, flashing
alarm clocks, flashing smoke detectors, and alarm bed
424 Neurologic Conditions in the Elderly
vibrators) and training in “speech reading” (using visual
cues to help determine what is being spoken) are help-
ful for many elderly patients with presbycusis and other
forms of SNHL (Gates and Rees, 1997; Working Group on
Communication Aids for the Hearing-Impaired, 1991).
Instruction in sign language should be considered for
those with severe hearing loss not corrected by a hear-
ing aid. For selected patients with profound hearing loss
that is not improved by a simple hearing aid, a cochlear
implant device may provide functional hearing; there is
no absolute age threshold for this procedure for appropri-
ate patients. Cochlear implantation may improve audio-
logic performance and quality of life in elderly patients,
even into their 80s (Kunimoto et al., 1999; Eshraghi et al.,
2009; Sprinzl and Riechelmann, 2010). Pain and transient
vertigo are the most common complications reported in
elderly patients following cochlear implantation (Esh-
raghi et al., 2009).
Common causes of SNHL in the elderly include
aging (presbycusis), noise exposure, and vascular occlu-
sive disease (Gates et al., 1993). Distinguishing among
these various causes is facilitated by attention to history
(noise or toxin exposure, trauma, and so on), onset and
course of hearing loss, whether the hearing loss is unilat-
eral or bilateral, the distribution of hearing loss as a func-
tion of sound frequency, associated manifestations (such
as vertigo), and family history. Subjective tinnitus is often
associated with SNHL and therefore is considered in this
section, although the perceived abnormal sounds are gen-
erated centrally, probably by a “release” mechanism akin
to that proposed for Bonnet VHs.
Presbycusis
Presbycusis (literally “elderly hearing” or “old age hear-
ing”) is the gradual loss of hearing that occurs in most
people as they grow older. The term presbycusis is gen-
erally used to incorporate all processes that contribute to
hearing loss over time, including both extrinsic insults
(noise, ototoxic agents, and disease) and age-associated
physiologic degeneration. Presbycusis affects about one-
third of the people aged 65 and older, and up to half of
the people aged 75 and older, although some estimates
place the proportion of elderly patients affected much
higher (Sprinzl and Riechelmann, 2010). Hearing loss
associated with presbycusis is usually a fairly symmetric
sloping high-frequency SNHL that results primarily from
accumulated damage to the inner ear, particularly a loss
of sensory hair cells in the cochlea (sensory presbycusis).
Some individuals may have contributions from other
sources, including central (brainstem), neural (ganglion
cell loss), strial or “metabolic” (strial atrophy), and pos-
sibly cochlear conductive or mechanical (stiffness of the
basilar membrane) sources (Working Group on Speech
Understanding and Aging, 1988; Gates and Rees, 1997;
Bao and Ohlemiller, 2010).
Environmental noise exposure is a major contributor to
sensory presbycusis, the most common type of presbycu-
sis. Neural and central types of presbycusis are rare but
are significant because amplification typically does not
benefit patients with purely neural or central lesions (in
contrast with the significant benefit often afforded to those
with sensory presbycusis). Low-frequency hearing loss is
considered typical of strial or “metabolic” presbycusis,
and this type of presbycusis is associated with comorbid
cardiovascular disease, especially in women (Gates et al.,
1993). The term metabolic presbycusis for presbycusis
associated with strial atrophy is so named because the
stria vascularis is the metabolic pump that generates the
endocochlear potential (Gates and Rees, 1997).
Patients affected by presbycusis find that the speech
of others sounds mumbled or muffled, and they have
particular difficulty perceiving or discriminating high-
pitched consonants (ch, f, k, s, t, or th), compared with
lower-pitched vowel sounds. They have more difficulty
hearing the higher-pitched voices of women and children
than they have hearing men’s voices, and they typically
have difficulty understanding conversations when there
is background noise. Some sounds may be distorted or
perceived as overly loud—when talking at a regular pitch
and volume, the patient may have difficulty discrimi-
nating speech sounds, whereas compensatory efforts by
the speaker to talk in a lower register and more loudly
can produce an irritated response from the patient (“You
don’t have to yell!”). Presbycusis is often associated with
subjective tinnitus. In addition, it contributes significantly
to isolation and depression in the elderly.
Risk factors for presbycusis include repeated exposure
to loud noises, smoking, certain medications (such as
cancer chemotherapy, particularly with cisplatin; some
antibiotics, particularly aminoglycosides; loop diuretics;
and aspirin and other anti-inflammatory agents), several
comorbid conditions (such as cardiovascular disease,
hypertension, diabetes, and renal failure), and a family
history of presbycusis.
Folic acid may be helpful in slowing the decline of
hearing in the speech frequencies (0.5–2.0 kHz) due to
presbycusis in populations without folic acid food forti-
fication programs (Durga et al., 2007). The effect of folic
acid supplementation in countries that have folic acid
food fortification programs (such as the United States,
Great Britain, and Hungary) is not clear.
Noise-induced hearing loss
Worldwide, approximately one-sixth (16%) of disabling
hearing loss in adults is attributable to occupational noise
exposure, with significant variation in different subre-
gions (Nelson et al., 2005). The effects of exposure to occu-
pational noise are higher in males than in females because
of differences in both workforce participation and the type
of occupations. With aging, prior noise-induced cochlear

damage and resulting SNHL are compounded by other
factors that compromise hearing (such as ototoxins and
age-related organ damage) (Lanska, 2013b). Most of
this disability is preventable with appropriate engineer-
ing controls to reduce noise generation or propagation
and with appropriate use of hearing protectors (Lanska,
2013b).
Occupational noise exposure is the most important pre-
ventable cause of hearing loss in the United States, but
it accounts for less than 10% of the burden of hearing
loss (most of the rest is age-related) (Dobie, 2008). Noise-
induced hearing loss (NIHL) is generally attributable to
unprotected exposures above 95 dBA. It often becomes
clinically apparent in middle-aged or elderly individu-
als when age-related threshold shifts are added to prior
noise-induced shifts. Other factors that can synergistically
augment the effect of noise in damaging cochlear hair
cells include hereditary predisposition and certain envi-
ronmental exposures, such as smoking and exposure to
toxic solvents in car paints.
Patients with NIHL typically present with the gradual
onset of bilateral, high-frequency SNHL (Fransen et al.,
2008). They usually have a history of recreational or occu-
pational noise exposure, usually without hearing protec-
tion, occurring over many years. With continued noise
exposure, hearing loss is progressive. Although NIHL is
typically bilateral, it may be worse in one ear. In shotgun
or rifle users, NIHL is typically worse on the side oppo-
site the patient’s dominant hand, whereas handgun users
may have worse hearing loss on the same side as the
dominant hand.
NIHL adversely affects quality of life (Muluk and
Oguztürk, 2008). Patients may hear vowels better than
consonants because vowels have predominantly low-fre-
quency content, whereas consonants have predominantly
high-frequency content. High-frequency voices (such as
children’s voices) may be difficult for these patients to
understand, especially with background noise. Shout-
ing does not help understanding because it primarily
increases the intensity level of vowels rather than conso-
nants; in addition, loud sounds are often uncomfortable
for such patients because of recruitment. Sounds are also
frequently distorted, so that a pure tone may be heard as
a buzz, broad-band noise, or a complex mixture of tones.
Some patients experience diplacusis (the perception of a
single auditory stimulus as two separate sounds, which
may differ in pitch or in time).
Subjective tinnitus is a common associated feature of
NIHL and, for some patients, may be the most troubling
symptom. Tinnitus intensity levels established with loud-
ness matching techniques correlate with hearing levels
at the frequency of most severe hearing loss (Man and
Naggan, 1981). In the presence of normal hearing, how-
ever, tinnitus should not necessarily be ascribed to noise
exposure, as the presence of tinnitus in those with normal
Disorders of the Special Senses in the Elderly 425
hearing is not associated with present noise level, dura-
tion of noise exposure, or cumulative noise exposure
(Rubak et al., 2008).
NIHL results from cochlear damage, particularly near
the base of the cochlea. Brief exposure to loud noise
(hours to days) may produce only a temporary threshold
shift (Osguthorpe and Klein, 1991). More prolonged expo-
sure to loud sounds, even at levels that are not uncom-
fortable or painful, results in permanent injury and loss
of cochlear hair cells (Osguthorpe and Klein, 1991). Dam-
age to cochlear hair cells is often initially confined to a
small area 5–10 mm from the base of the cochlea, the area
involved in sensing frequencies around 4000 Hz. Hear-
ing at 4000 Hz is important for speech discrimination in
noisy environments (Osguthorpe and Klein, 1991). Hair
cells undergo apoptosis in response to noise damage, but
the supporting cells are not able to regenerate (Cotanche,
2008). Considerable cochlear hair cell damage can occur
before hearing thresholds are affected. The basis for the
relatively selective damage to the basal cochlea is not clear,
but mechanical, vascular, and toxic-metabolic theories
have been proposed—the mechanical theory postulates
shear forces from a “jet effect” at this location, whereas
the vascular theory maintains that this region is suscep-
tible to ischemia because it is at the juncture of the main
cochlear and cochlear ramus arteries, and the toxic-meta-
bolic theory implicates late development of free radicals
in mitochondria followed by excitotoxic neural swelling
and induction of apoptotic cell death in the organ of Corti
(Lim and Melnick, 1971; Yamane et al., 1995; Henderson
et al., 2006; Le Prell et al., 2007). Noise sensitivity tends to
aggregate in families, and twin studies have implicated
a genetic component to NIHL (Heinonen-Guzejev et al.,
2005).
Nonmodifiable risk factors associated with NIHL
include increasing age, male gender, and genetic pre-
disposition; modifiable risk factors include voluntary
exposure to loud noise, lack of hearing protection, smok-
ing, lack of regular exercise, poor diet, poor dentition,
diabetes, and cardiovascular disease (Wild et al., 2005;
Daniel, 2007; Lanska, 2013b). Some of these risk factors
may simply be noncausal associations (such as lack of
regular exercise, poor diet, and poor dentition).
With acute noise exposure, the threshold shift may be
temporary, with hearing gradually returning to baseline
levels over the period of approximately a day (Osguthorpe
and Klein, 1991). With repeated noise exposure, hearing
only partially returns to baseline levels, and the threshold
shift becomes permanent and progressive. Independent
risk factors for NIHL include older age, male sex, and
greater noise exposure (Bauer et al., 1991; Neuberger et
al., 1992). Common associated symptoms include tinni-
tus, sound distortion, and diplacusis.
Audiograms show bilateral SNHL, often with a char-
acteristic notch at 4000 Hz (Bauer et al., 1991; Osguthorpe
426 Neurologic Conditions in the Elderly
and Klein, 1991; Neuberger et al., 1992; Griest and Bishop,
1998; McBride and Williams, 2001). A 6000 Hz notch is
variable and of limited importance (McBride and Wil-
liams, 2001). With progression of SNHL, this “noise
notch” at 4000 Hz deepens and hearing loss extends into
lower frequencies. Speech discrimination is not affected
until late in the disease process. Otoacoustic emissions
may provide earlier identification of noise-induced dam-
age than pure tone thresholds alone and may identify
cochlear dysfunction extending beyond the frequency
range suggested by the audiogram (Balatsouras, 2004).
Although a variety of definitions have been proposed
in the literature, SNHL can be considered asymmetric
if the interaural difference in pure tone thresholds is
at least 10 dB at two frequencies or at least 15 dB at
one frequency (Urben et al., 1999). Asymmetric SNHL
is fairly common as a result of noise exposure or on an
idiopathic basis (Chung et al., 1983; Pirila, 1991; Pirila
et al., 1992; Urben et al., 1999). However, asymmet-
ric SNHL can rarely be an indication of retrocochlear
pathology (Urben et al., 1999; Baker et al., 2003) or of
tertiary syphilis. Patients with asymmetric SNHL may
be followed with serial audiograms (every 6 months)
if they have known significant asymmetric noise expo-
sure or have no recent changes in hearing or word
recognition, no risk factors for syphilis (or a negative
fluorescent treponemal antibody test), and no associ-
ated symptoms (such as vertigo) (Urben et al., 1999).
Patients without a history of significant asymmetric
noise exposure or other known cause of asymmetric
SNHL, as well as those with progression of asymmet-
ric SNHL, should undergo brainstem auditory-evoked
response (BAER) testing (Urben et al., 1999). MRI is not
a cost-effective screening technique for retrocochlear
lesions among all patients with asymmetric SNHL; it
should be reserved for cases with a high clinical sus-
picion or cases with abnormal or inconclusive results
from BAER testing (Urben et al., 1999). The “rule 3000”
is a clinical decision rule that can help guide a more
cost-effective approach to utilization of MRI in patients
with asymmetric SNHL—if asymmetric SNHL of at
least 15 dB is present at 3000 Hz, MRI should be per-
formed; if there is less than 15 dB of asymmetry at this
frequency, patients can be followed biannually with
audiometry (Saliba et al., 2009).
Although affected patients may be fitted with hearing
aids, this does not generally restore hearing to normal,
and sounds are often distorted. Therefore, prevention
is essential. At-risk subjects should routinely use hear-
ing protection when in loud environments. Education is
critical because many affected individuals are reluctant
to wear hearing protection, and many who wear it do
not wear it consistently or, in some cases, do not use it
correctly. If feasible, environmental controls should be
placed to control noise exposure.
In an occupational setting in the United States, the
Occupational Safety and Health Administration (OSHA)
requires baseline and annual audiometric pure-tone air-
conduction threshold testing of both ears for employees
exposed to at least 50% of the permissible noise expo-
sure level. Hearing protection is recommended for time-
weighted average sound exposure levels of 85 dBA or
more; it is required for levels of 90 dBA or more. Hearing
protection is also required if a worker has experienced a
significant threshold shift, even if occupational exposure
is less than 90 dBA time-weighted average. Hearing pro-
tection must decrease the employee’s noise exposure to
less than 85 dBA time-weighted average. However, even
at somewhat lower noise levels, some employees may
develop permanent NIHL (Osguthorpe and Klein, 1991).
Furthermore, OSHA regulations do not cover many
workers exposed to excessive noise, including farmers,
construction workers, and employees of small businesses.
Recreational noise exposure is usually less frequent and
of shorter duration than occupational noise exposure, but
it may readily compound occupational noise damage.
Many power tools, lawnmowers, firearms, and sound
speakers exceed safe sound exposure levels. For example,
approximate dBA sound levels are 90 for a lawnmower,
100 for a chain saw, and 140 for a shotgun blast.
Hearing protection should be worn if individuals have
to raise their voice to carry on a conversation easily. Hear-
ing aids (most of which are vented) are inadequate for
hearing protection. Hearing protection devices commonly
available include earmuffs or earplugs. Earmuffs usually
have higher noise-reduction ratings than earplugs, but
some individuals find earmuffs to be hot, cumbersome,
or cosmetically unappealing, any of which can adversely
affect usage (Arezes and Miguel, 2002). For difficult-to-fit
external auditory canals, custom earplugs can be made
from an earmold impression. Special ear plugs are also
available for special needs (for cosmetic considerations,
hunting, singing, or specific work environments). Poorly
fit earplugs or ear muffs are much less effective and may
not adequately protect hearing. Earplugs can be worn
in combination with earmuffs in extremely high-noise
environments, but combination use disrupts sound
localization (Simpson et al., 2005) and the maximum noise
reduction is approximately 50 dB because of bone con-
duction through the skull (Osguthorpe and Klein, 1991).
Sudden deafness
“Sudden” deafness is defined as SNHL of 30 dB or more
in at least three contiguous frequencies (on a standard
audiogram), occurring over less than 3 days (Lanska,
2013c). Although generally a monophasic illness, recur-
rences can occur with some etiologies. Depending on the
etiology and on damage to associated structures, associ-
ated manifestations may include aural fullness or pres-
sure, tinnitus, vertigo, nausea and vomiting, and various

brainstem and cerebellar signs. In patients with sudden
SNHL, tinnitus is associated with worse high-frequency
hearing loss, whereas aural fullness and pressure sensa-
tions are typically associated with low-frequency hearing
loss (Sakata et al., 2008). Tinnitus and sensations of aural
fullness improve with improvements in hearing (Ishida
et al., 2008). The condition occurs most commonly in the
fifth and sixth decades, but cases among the elderly are
not unusual, particularly for bilateral involvement and/
or cases of vascular etiology (Oh et al., 2007).
Sudden deafness typically occurs with the interruption
of sensorineural structures involved with hearing, but
it can rarely occur with brainstem or cerebral damage.
Cochlear or eighth nerve infarction may occur in isolation
or with concomitant infarction of the labyrinth, brain-
stem, and cerebellum. Acute bilateral hearing impairment
suggests vertebrobasilar occlusive disease, but hearing
loss associated with vertebrobasilar insufficiency is most
frequently unilateral. Viral infections, inflammatory con-
ditions, or autoimmune disorders that produce sudden
hearing loss generally involve the labyrinth or eighth
nerve. Ménière syndrome involves the labyrinth. Tumors
and meningitis that produce sudden hearing loss gener-
ally involve the eighth nerve. The frequent spontaneous
recovery of hearing loss and improvement with steroid
therapy suggest that, in many cases, there is a potentially
reversible metabolic inner-ear process disrupting the
endocochlear potential rather than immediate hair-cell
degeneration (Sismanis, 2005).
Sudden hearing loss can be caused by a variety of
disorders, including inner ear or eighth-nerve isch-
emia, viral infection of the labyrinth or cochlear nerve,
Ménière disease, intralabyrinthine membrane rupture,
and autoimmune or inflammatory causes (Lanska, 2013c).
Uncommon causes include retrocochlear masses, demye-
linating disease, syphilis, Lyme disease, meningitis, carci-
nomatous meningitis, arteritis, perilymph fistula, toxins,
barotrauma, head injury (especially with temporal bone
fracture, but also with inner ear concussion), and otologic
surgery (Lanska, 2013c).
The putative cause is identified in about 15% of the
cases, and the remainder is almost always unilateral and
considered idiopathic after evaluation (Rauch, 2008).
Only a small minority (∼1%) has an identified retroco-
chlear cause (such as a mass, demyelinating disease, or
stroke) (Rauch, 2008). Rare bilateral cases may be due to
malingering, conversion disorders, and neurologic causes
(such as vertebrobasilar occlusive disease, carcinomatous
meningitis, paraneoplastic syndromes, encephalitis, or
meningitis) (Koda et al., 2008; Rauch, 2008). Mitral valve
prolapse, mitral leaflet thickening, mitral regurgitation,
and left atrial enlargement are risk factors for “idiopathic”
sudden SNHL, and presumably, these associations reflect
an increased risk of cochlear or eighth-nerve ischemia
(Vazquez et al., 2008).
Disorders of the Special Senses in the Elderly 427
Various mechanisms have been proposed, including
those attributing sudden deafness to vascular insults,
infectious (especially viral) agents, autoimmune or
inflammatory mechanisms, or disruption of labyrinthine
membranes. Of the nonidiopathic cases, vascular and
infectious etiologies are the most common, and the patho-
physiology of these is best understood.
The blood supply to the inner ear is via the inter-
nal auditory artery (also called the labyrinthine artery),
which typically originates from the anterior inferior cer-
ebellar artery (AICA). The internal auditory artery and
its branches are end arteries, so even transient ischemia
can cause permanent inner-ear damage (Lanska, 2013c,
2013d). The organ of Corti within the cochlea is particu-
larly sensitive to ischemia. Obstruction of either the inter-
nal auditory artery or inferior cochlear vein produces
rapid loss of function; electrical activity deteriorates
within 60 seconds of interruption of blood flow. Cochlear
function may return to normal if blood flow is restored
within 8 minutes of complete obstruction, but not if blood
flow is interrupted for more than 30 minutes. External hair
cells and the ganglion cells of the cochlea are particularly
vulnerable to arterial obstruction, whereas the vestibular
end organs are relatively resistant. Arterial obstruction
produces histologically evident changes in cochlear hair
cells within 30 minutes, followed in a few hours by exten-
sive necrosis and, ultimately, severe fibrosis and ossifica-
tion by 6 months. Inner ear ischemia occurs most com-
monly in the setting of thromboembolic disease of AICA
or the basilar artery, or uncommonly with migraine, fat
emboli, thromboangiitis obliterans, severe hyperlipid-
emia, macroglobulinemia, leukemia, and other causes of
hypercoagulation or hyperviscosity.
Sudden deafness in AICA infarction is often due to
cochlea dysfunction from ischemia, but mixed central
and peripheral dysfunction also occurs, making recog-
nition of the components difficult. AICA supplies the
inner ear as well as the lateral pons, middle cerebellar
peduncle, flocculus, and anterior part of the cerebellar
lobules. As a result, AICA-territory infarction can cause
ipsilateral hearing loss with or without tinnitus, as well as
a range of labyrinthine, brainstem, and cerebellar symp-
toms and signs. Other manifestations include nystag-
mus, ipsilateral facial numbness, ipsilateral facial paresis,
vertigo, dysarthria, vomiting, unsteadiness, ipsilateral
hemiataxia, and contralateral loss of pain and tempera-
ture sensation on the limbs and body. Occasionally, iso-
lated vertigo or isolated auditory disturbance may occur
as TIAs preceding AICA-territory infarction (Amarenco
et al., 1993; Lee and Cho, 2004). Bilateral sudden deafness
may occur as a prodrome of AICA-territory infarction in
the presence of severe vertebrobasilar occlusive disease.
Although AICA-territory infarction can be confused with
posterior inferior cerebellar artery (PICA) territory infarc-
tion (Wallenberg syndrome), because of shared signs
428 Neurologic Conditions in the Elderly
(such as Horner syndrome, facial sensory impairment,
vestibular signs, dysmetria, and contralateral impairment
of pain and temperature sensation), severe facial paresis,
hearing loss, and tinnitus are atypical for PICA-territory
infarctions, and their presence should alert the clinician to
AICA-territory infarction.
The clinical manifestations of superior cerebellar artery
syndrome include ipsilateral Horner syndrome, ipsilateral
limb ataxia, contralateral SNHL (due to involvement of
the lateral lemniscus carrying decussated ascending audi-
tory information), contralateral superficial sensory loss,
vertigo, nystagmus, nausea, and vomiting (Murakami
et al., 2005).
Hearing loss occurs in about one-fifth of patients with
vertebrobasilar insufficiency and vertigo (Yamasoba et al.,
2001). Deafness associated with vertebrobasilar insuf-
ficiency mainly involves the cochlea rather than central
auditory pathways (Yamasoba et al., 2001; Lee and Baloh,
2005). Tinnitus and vertigo are frequent accompaniments,
as are a wide range of brainstem and cerebellar symptoms
and signs (Lee et al., 2003; Sauvaget et al., 2004).
Ischemia may also occur with vascular obstruction in
the venules and capillaries draining the inner ear. Venous
obstruction produces early epithelial edema, followed by
hemorrhage into the epithelium and perilymphatic and
endolymphatic spaces, hair cell damage with secondary
ganglion cell degeneration, and later fibrosis and ossifi-
cation. The most common cause of venous obstruction
causing sudden deafness is increased blood viscosity. The
“hyperviscosity syndrome” includes a number of diverse
clinical manifestations, including sudden or progres-
sive hearing loss, headache, fatigue, vertigo, nystagmus,
visual disturbances, and mucosal hemorrhages (Nomura
et al., 1982; Andrews et al., 1988). Ophthalmoscopic find-
ings include markedly distended and tortuous (“sausage-
shaped”) retinal veins and retinal hemorrhages, similar to
the pattern seen in retinal vein occlusion.
Viral neurolabyrinthitis may be part of a systemic viral
illness or may be an isolated viral infection of the labyrinth
and eighth nerve. Many patients report an upper respira-
tory illness within 1–2 weeks prior to the onset of symp-
toms. The manifestations are unilateral and may include
clinically evident aural or vestibular symptoms, or both.
When hearing loss is incomplete, it is usually most severe
at high frequencies. Some cases may develop posterior
semicircular canal benign paroxysmal positional vertigo
with preservation of lateral semicircular canal function
(Karlberg et al., 2000). Herpes zoster oticus may be associ-
ated with vesicles in the external auditory canal, burning
pain in the ear, unilateral Bell’s palsy, unilateral hearing
loss, tinnitus, vertigo, and transient spontaneous nys-
tagmus. Pathologic studies in patients with viral neuro-
labyrinthitis and sudden deafness have shown evidence
of viral damage to the cochlea and auditory nerve, simi-
lar to that seen in patients with well-documented viral
disorders (such as mumps). A large number of viruses
have been associated with viral neurolabyrinthitis, but
Herpes simplex virus type 1 and herpes zoster oticus have
been particularly associated with sudden SNHL (Wilson,
1986; Rabinstein et al., 2001). Proof of viral etiology in
individual cases is difficult to establish, with the excep-
tion of herpes zoster oticus, where the clinical features are
often fairly obvious and characteristic.
Sudden SNHL in the elderly may also occur from medi-
cations, including nonsteroidal anti-inflammatory drugs
(McKinnon and Lassen, 1998) or aminoglycosides. Rapid
ototoxic hearing loss is much more common in patients
with poor renal function.
Initial evaluation should include careful history and
examination to identify likely toxic, otologic, or systemic
causes, including evaluation of Lyme titers and syphi-
lis serologies. Audiograms should also be obtained to
demonstrate the pattern and severity of hearing loss,
which are helpful prognostically. Audiograms should be
obtained before and within 24–48 hours after initiation
of treatment and then serially over the course of a year
(for example, at 2, 6, and 12 months after onset) (Rauch,
2008). MRI and possibly BAER testing should be consid-
ered to exclude a retrocochlear lesion in unilateral cases,
whether or not apparent improvement or recovery with
steroid therapy is taking place. Cranial imaging is also
important to exclude brainstem or cerebellar lesions, and
MRI may identify a number of other pathologies (such as
vascular abnormalities and demyelination), but MRI does
not visualize the inner ear well enough to reliably iden-
tify infarction and is insensitive to abnormalities (such as
enhancement) associated with cochleitis or labyrinthitis.
In patients who cannot have an MRI, CT and BAER stud-
ies should be considered, although these are less sensitive
than MRI for detection of retrocochlear pathology.
As a result of a high rate of spontaneous recovery, and
because a large proportion of cases are ultimately con-
sidered to be idiopathic even after extensive evaluation,
some authorities have advocated a staged approach to
diagnostic testing. Patients with likely systemic causes
or clinically evident neurologic abnormalities should
have diagnostic testing without delay. In patients with-
out other clinical findings, further diagnostic evaluation
can possibly be delayed for a month to see if spontaneous
improvement occurs. Note, though, that improvement
with steroids (in the absence of MRI or BAER) can result
in failure to identify important clinical conditions, includ-
ing retrocochlear masses. If improvement does not occur
or if other symptoms or signs develop, more extensive
diagnostic testing is indicated and should include cranial
imaging.
Additional diagnostic studies can include imaging of
cerebral vessels, BAER, electronystagmography with
bithermal caloric irrigation, vestibular-evoked myogenic
potentials, lumbar puncture, and various blood studies.

BAER studies may show absence of wave I or all wave-
forms, but may also show absence of wave I with delay
of wave III and wave V if dysfunction is also occurring
in the retrocochlear eighth nerve and brainstem auditory
nuclei and pathways (Verghese and Morocz, 1999). Elec-
tronystagmography with bithermal caloric testing may
demonstrate ipsilateral horizontal canal paresis. In cases
of clinically suspected sudden hearing loss resulting from
hyperviscosity, the following blood studies can be con-
sidered: serum viscosity determination, complete blood
count, syphilis serologies, ESR, serum protein, serum pro-
tein electrophoresis, and lipid studies.
The overall prognosis depends on the underlying eti-
ology, but a high rate of spontaneous resolution occurs
overall (in about two-thirds of cases) (Eisenman and
Arts, 2000; Yimtae et al., 2001; Penido Nde et al., 2005;
Stahl and Cohen, 2006). Most patients show either initial
rapid recovery or a gradual and slow recovery (Harada,
1996), but the spontaneous recovery that occurs typi-
cally is within the first 2 weeks after onset (Mattox and
Simmons, 1977). Improvement in hearing levels tends to
occur mostly in the low to mid frequencies and is better
in those with preserved otoacoustic emissions (Ishida et
al., 2008). Those with initial rapid recovery have the best
prognosis, with a smaller degree of hearing loss at the first
examination, greater degree of hearing improvement,
and smaller degree of residual hearing loss once stable
(Harada, 1996). Patients with upsloping or with lower-
or middle-frequency hearing loss generally have a better
prognosis (Eisenman and Arts, 2000; Zadeh et al., 2003).
Putative negative prognostic factors include old age, lon-
ger time since onset of symptoms before treatment, more
severe hearing loss, flat or downsloping audiograms,
tinnitus, vertigo, elevated ESR, and associated diabetes.
Audiovestibular residua or late effects can also include
tinnitus, benign paroxysmal positioning vertigo, and
Ménière syndrome.
In isolated inner ear infarction, the vertigo, nystagmus,
and autonomic manifestations resolve over days to weeks,
but deafness and canal paresis typically remain (Millikan
and Futrell, 1990; Watanabe et al., 1994; Kim et al., 1999;
Lanska, 2013d). If no brainstem symptoms develop and
brain imaging is normal, the risk of recurrence or subse-
quent stroke is rare (Millikan and Futrell, 1990; Kim et al.,
1999). Patients with labyrinthine ischemia due to verte-
brobasilar insufficiency can have an overall good progno-
sis with anticoagulation or antiplatelet therapy (Fife et al.,
1994) or, rarely, with surgical or endovascular correction
(Strupp et al., 2000). However, patients with inner ear
infarction combined with brainstem or cerebellar infarcts
have a worse prognosis (Gomez et al., 1996), particularly
if associated with occlusive disease of the basilar artery
(Ferbert et al., 1990; Huang et al., 1993).
Sudden SNHL is associated with an increased risk of
stroke within 5 years of onset; in one cohort study, 13%
Disorders of the Special Senses in the Elderly 429
of the patients with SNHL had a stroke within 5 years,
compared with 8% in the controls. After adjusting for
other risk factors, those with SNHL had a risk of stroke
1.6 times greater than controls (Lin et al., 2008).
Management is complicated in part because the under-
lying etiology is not known in most patients. Oral cortico-
steroids (prednisone or methylprednisolone) are consid-
ered the “current standard treatment” of idiopathic sud-
den deafness (Rauch, 2008) and may be modestly effective
according to several observational studies and small ran-
domized, controlled trials, although systematic reviews
and meta-analyses indicate that the value of steroids
remains unclear because of conflicting evidence from
available trials and because of technical limitations of
available studies. Most of the reported benefit of steroids
is within the first 1–2 weeks after onset (although this is
also the typical timeframe for spontaneous recovery), and
little, if any, benefit can be expected if initiated 4 weeks or
longer after onset (Rauch, 2008). Steroids can also be con-
sidered in patients with sudden hearing loss and known
recent viral infections, autoimmune disease, or meningi-
tis. Intratympanic steroids are not inferior to oral steroids
and can provide a therapeutic option if steroids are con-
traindicated, although administration of intratympanic
steroids is moderately uncomfortable, inconvenient, and
more costly (Rauch et al., 2011). Associated vertigo and
the concomitant nausea and vomiting should be treated
symptomatically with medications. Vestibular rehabilita-
tion should be begun early (Lanska, 2009).
The efficacy of antiviral agents, anticoagulants, vaso-
dilators, rheologic agents, free radical scavengers,
hyperbaric oxygen, ginkgo products, and other drugs is
unproven in patients with idiopathic sudden hearing loss
(Kanzaki et al., 2003; Conlin and Parnes, 2007a, 2007b;
Rauch, 2008). Most studies have been uncontrolled trials,
and results are not clearly different than the natural his-
tory of this condition. Except for cases of herpes zoster
oticus—which should be treated with acyclovir—
available data also do not suggest a benefit of antiviral
agents in clinically diagnosed viral neurolabyrinthitis
(Stokroos et al., 1998).
Superficial siderosis
Superficial siderosis is an uncommon (though increasingly
recognized) potentially devastating syndrome caused by
recurrent subarachnoid hemorrhage with accumulation
of hemosiderin and other iron-containing pigments in the
leptomeninges, superficial cerebral cortex, brainstem, cer-
ebellum, cranial nerves, and spinal cord (Lanska, 2013e).
Common features include progressive SNHL, cerebellar
ataxia, pyramidal signs (such as spastic paraparesis and
quadriparesis), ataxia, and headache (Lanska, 2013e). The
progressive SNHL may be the presenting or predominant
symptom, may be slowly progressive over many years,
and may be caused by a combination of retrocochlear
430 Neurologic Conditions in the Elderly
and cochlear damage (Lanska, 2013e). Superficial sidero-
sis should be considered in all patients presenting with
progressive SNHL and ataxia. In conjunction with hear-
ing loss, some patients develop peripheral vestibular dis-
orders with associated caloric weakness, disequilibrium,
dizziness, and vertigo (Lanska, 2013e). Associated cranial
nerve abnormalities can include anosmia or hyposmia,
anisocoria, optic neuropathy, visual field deficits, fourth
nerve palsy, diplopia, nystagmus, trigeminal neuropa-
thy, hemifacial spasm, SNHL, intermittent vertigo, and
dysarthria (Lanska, 2013e). Other clinical features seen
in a minority of patients include seizures, cranial nerve
abnormalities, spinal myoclonus, polyradiculopathy and
sciatica, neck- or backache, urinary incontinence, somato-
sensory deficits, and acute intracranial pressure crises
superimposed on chronic intracranial hypertension. Neu-
ropsychological testing has demonstrated impairments in
speech production, visual recall memory, and executive
functions (van Harskamp et al., 2005). A significant num-
ber of cases may be asymptomatic, possibly reflecting a
milder form of disease or a presymptomatic state. A wide
variety of conditions may cause superficial siderosis,
including cerebral amyloid angiopathy (Alafuzoff, 2008;
Feldman et al., 2008), cerebral or spinal arteriovenous
malformations, cavernous malformations, intracranial
aneurysms, cerebellar tumors, pontine hematoma, and
spinal surgery complicated by a dural tear and pseudo-
meningocele formation (Cohen-Gadol et al., 2005).
Superficial siderosis is caused by recurrent subarach-
noid hemorrhage with dissemination of heme by circu-
lating cerebrospinal fluid, with subsequent accumulation
of intracellular and extracellular hemosiderin and other
iron-containing pigments in the leptomeninges, brain
surface, brainstem, cerebellum, cranial nerves, and spinal
cord (Koeppen and Dentinger, 1988; Koeppen et al., 2008;
Lanska, 2013e). Large mononuclear phagocytes contain-
ing granules of hemosiderin (siderophages) can be dem-
onstrated pathologically. Histology demonstrates severe
damage to the eighth cranial nerve and cerebellum, pre-
sumably because glial catabolism of ferritin within these
structures preferentially facilitates deposition of heme in
these locations.
When superficial siderosis is suspected, a thorough
evaluation is needed to localize the source of bleed-
ing. MRI is the most important diagnostic study, in
conjunction with lumbar puncture and selective use of
angiography (Lanska, 2013e). MRI studies demonstrate
hemosiderin deposition along the superficial surfaces of
the brain, brainstem, cerebellum, and spinal cord (Pelak
et al., 1999; Kumar, 2007). Hypointense rims around
involved central nervous system structures are com-
monly seen on T2-weighted images, and hyperintense
rims may be demonstrated on T1-weighted images.
CT may show widespread meningeal enhancement
or cerebellar atrophy. Although CT may suggest the
diagnosis of superficial siderosis, MRI is more sensitive
and specific. When superficial siderosis is diagnosed on
brain imaging and no source is identified, spinal imag-
ing is essential. Dural diverticula, pseudomeningoceles,
and other dural defects (including transdural leaks) are
usually best shown on myelography or CT myelogra-
phy. Angiography may reveal various vascular malfor-
mations. In some cases, vascular malformations identi-
fied on angiography were not identified with MRI or
myelography. In many cases, angiography also does not
identify the source of bleeding, probably because of the
small volume of ongoing, intermittent blood leakage.
Lumbar puncture may demonstrate recurrent or persis-
tent xanthochromia, red cells, a slightly elevated white
cell count, increased protein, increased iron and ferritin
levels in the cerebrospinal fluid, and siderophages. CSF
may be normal because bleeding is typically intermittent
and of small volume (Kumar, 2007). Although used in
the past (Willeit et al., 1992), there is little current role
for diagnostic brain biopsy. Nevertheless, even with
thorough diagnostic evaluation, the source of bleeding
remains unidentified in many cases (Miliaras et al., 2006;
Kumar, 2006, 2007).
The prognosis is often poor—the condition may be pro-
gressively disabling or fatal (Lanska, 2013e). Management
is directed primarily at resection of the source of bleeding.
Symptomatic treatment can be helpful in treating second-
ary manifestations, including headaches and seizures.
Even with successful surgical resection of the causative
lesion (when that is identified), significant functional
recovery cannot be anticipated (Lanska, 2013e). However,
generally progression is lessened or averted, at least in
the short periods of follow-up reported (Schievink et al.,
1998). Bilateral profound hearing loss from superficial
siderosis is not an absolute contraindication for cochlear
implants, although results are inconsistent and often dis-
appointing (Lanska, 2013e).
Herpes zoster oticus
Herpes zoster oticus (sometimes referred to as Ramsay
Hunt syndrome when associated with facial paresis) is
caused by reactivation of varicella-zoster virus (VZV)
that had been dormant in the seventh and eighth nerves
following previous infection with chicken pox (Lanska,
2013f). VZV, a member of the alpha-subfamily of Her-
pesviridae, is an enveloped DNA virus, whose genome
consists of a linear double-stranded molecule of DNA.
Primary infection with VZV causes chickenpox, an acute,
generally mild infection of children. Following chicken-
pox, VZV remains latent in sensory ganglia and reacti-
vates in about 15% of infected people over their lifetimes,
resulting in herpes zoster, or “shingles” (Wigdahl et al.,
1986). Approximately two-thirds of patients with herpes
zoster are 65 years of age or older (Lin and Hadler, 2000).
Both the incidence and severity of herpes zoster increase

sharply with age (Hope-Simpson, 1965; Edmunds et al.,
2001). An initial episode of herpes zoster does not appar-
ently protect against or significantly increase the risk of a
subsequent episode (Hope-Simpson, 1965).
Risk factors for herpes zoster in adults include increas-
ing age, bone marrow and organ transplants, lymphoma,
HIV infection, treatment of AIDS with protease inhibitors,
and systemic lupus erythematous (Lanska, 2013f). There
is no significantly increased risk of a subsequent diagno-
sis of malignancy following the onset of herpes zoster;
therefore, there is little evidence to support an aggres-
sive search for malignancy in patients diagnosed with
herpes zoster, although some data suggest that the sites
of primary tumor or local radiotherapy may predispose
to development of herpes zoster in that specific location
(Lanska, 2013f).
Herpes zoster oticus often presents with preeruptive
(pre-herpetic) pain, allodynia, burning, or itching, gener-
ally localized to the ear and mastoid region. An erythem-
atous maculopapular rash progresses to clusters of clear
vesicles on an inflamed base; such skin lesions may vari-
ably affect the tympanic membrane, the external auditory
canal, the auditory meatus, and, less commonly, the exter-
nal ear, adjacent skin of the mastoid process, the mucous
membranes of the soft palate (presumably via the greater
superficial petrosal nerve), and the anterior two-thirds of
the tongue (presumably via the chorda tympani nerve)
(Shapiro et al., 1994). Vesicle fluid quickly changes from
clear to purulent. The vesicles crust over after 3–5 days.
Associated constitutional symptoms can include lymph-
adenopathy, headache, malaise, and fever. Ultimately, the
skin lesions heal over 2–4 weeks, often leaving residual
scarring and pigmentary changes.
Otologic complications include tinnitus, SNHL, hyper-
acusis, vertigo, nystagmus, and skew deviation. Abnor-
mal hearing is associated with otalgia and herpetic rash,
but not with severity of facial paresis (Wayman et al.,
1990). Audiologic findings demonstrate both sensory
(cochlear) and neural (retrocochlear) hearing impair-
ment (Abramovich and Prasher, 1986; Wayman et al.,
1990). Hyperacusis is not simply attributable to seventh
nerve dysfunction as a result of loss of the stapedial reflex
(McCandless and Schumacher, 1979) because hyperacu-
sis is also described with an intact stapedial reflex (Cit-
ron and Adour, 1978; Wayman et al., 1990); in some cases,
hyperacusis may result from damage to inhibitory effer-
ent fibers in the seventh nerve (Citron and Adour, 1978).
Facial palsy may precede, occur simultaneously with,
or follow the rash in Ramsay Hunt syndrome (Aizawa
et al., 2004; Kim and Bhimani, 2008). In most cases, in
adults, the rash occurs slightly before or around the same
time as the facial paresis (DeVriese and Moesker, 1988;
Kim and Bhimani, 2008). Facial palsy can be associated
with decreased lacrimation and hypogeusia or dysgeusia
on the anterior two-thirds of the tongue. Facial paresis is
Disorders of the Special Senses in the Elderly 431
usually maximal within 1 week of onset, and increasing
severity of paresis is associated with increasing age. Ram-
say Hunt syndrome is more likely than Bell’s palsy to be
associated with a complete clinical facial paralysis (Robil-
lard et al., 1986; Adour, 1994).
Herpes zoster may also occur as a cranial polyneu-
ropathy. In unusual cases, other central nervous system
structures may be involved, with manifestations includ-
ing cerebellar abnormalities, multifocal vasculopathy and
posterior circulation strokes, hemiparesis, encephalitis,
and aseptic meningitis. Causes of these symptoms may
include meningeal involvement, demyelinating events,
and vasculitic involvement (Ortiz et al., 2008).
Impaired cell-mediated immunity is an important fac-
tor in the reactivation of VZV and development of clini-
cal herpes zoster, whereas humoral immunity has little or
no role in preventing virus reactivation and development
of clinical herpes zoster (Ikeda et al., 1996; Arvin, 2005).
VZV-specific T cells are thought to be critical for main-
taining the virus-host equilibrium and preventing her-
pes zoster. This is consistent with known risk factors for
herpes zoster, including leukemia and lymphoma, bone
marrow transplant, and HIV infection. Waning of the cell-
mediated immune response to VZV with age may help
explain the marked increase in herpes zoster with age.
Pathologic findings include perivascular, perineural,
and intraneural round-cell infiltration of the seventh
and eighth nerves and, in some cases, the modiolus and
organ of Corti in the cochlea, and the skin of the external
auditory meatus (Guldberg-Moller et al., 1959; Blackley
et al., 1967; Zajtchuk et al., 1972). Although the genicu-
late ganglion may show scattered lymphocytic infiltra-
tion, most of the neurons in the ganglion are well pre-
served (Guldberg-Moller et al., 1959; Blackley et al., 1967;
Zajtchuk et al., 1972).
VZV DNA is present in the geniculate ganglia of
affected patients (Furuta et al., 1992; Wackym et al., 1993;
Furuta et al., 1997; Wackym, 1997; Thiel et al., 2002) in
neurons and in perineuronal satellite cells (Gilden et al.,
2000). VZV DNA may also be present in the auditory
and vestibular primary afferent ganglia, and in the facial
nerve sheath, CSF, middle ear mucosa, and vesicles on
the auricles or oral cavity (Wackym et al., 1993; Wackym,
1997; Murakami et al., 1998; Ohtani et al., 2006). Latent
VZV is not integrated into the human chromosome, but
instead may exist in a circular or end-to-end arrangement
(Clarke et al., 1995).
The live-attenuated varicella vaccine (Varivax) was
licensed by the FDA in 1995. VZV vaccination can prevent
or reduce the occurrence of chickenpox, herpes zoster,
and associated complications among those immunized
(Oxman, 1995; Anonymous, 1996; Seward et al., 2002;
Goldman, 2005; Vázquez and Shapiro, 2005; Yih et al.,
2005). As a result of introducing this vaccine, there has
been a dramatic decline in the incidence of varicella
432 Neurologic Conditions in the Elderly
in surveillance areas with moderate vaccine coverage
(Seward et al., 2002; Goldman, 2005; Yih et al., 2005). How-
ever, while the incidence of varicella decreased dramati-
cally as varicella vaccine coverage in children increased,
the incidence of herpes zoster increased (Yih et al., 2005).
Although several potential explanations are possible, it
seems likely that the observed increase in herpes zoster
is because of a loss of “immunologic boosting” (including
loss of exposure to wild-type VZV) for those previously
infected with varicella-zoster (Goldman, 2005). This loss
of immunologic boosting would allow a waning of cell-
mediated immunity and would lead to a relative increase
in herpes zoster incidence in the population.
Secondary prevention of herpes zoster is now pos-
sible for older adults previously infected with chicken-
pox. In 2005, Oxman et al. reported a large randomized,
double-blind, placebo-controlled trial of a high-potency,
live-attenuated VZV vaccine (Arvin, 2005; Gilden, 2005;
Oxman et al., 2005). More than 38,000 adults over age 60
were enrolled. The VZV vaccine markedly reduced the
morbidity from both herpes zoster and postherpetic neu-
ralgia among older adults. After a median of more than
3 years of surveillance, VZV vaccine reduced the inci-
dence of herpes zoster by 51%, the burden of illness due
to herpes zoster by 61%, and the incidence of postherpetic
neuralgia by 67%. Local reactions at the vaccination site
were generally mild, and the vaccine had low rates of
serious adverse events, hospitalization, and death. The
FDA licensed this vaccine (Zostavax) in 2006 for use in
people age 60 years and older. The live VZV vaccine has a
minimum potency at least 14 times greater than the mini-
mum potency of the vaccine licensed to prevent varicella
because a much higher potency is needed to produce a
significant increase in cell-mediated immunity to VZV in
older adults (Oxman et al., 2005). The vaccine is adminis-
tered as a single subcutaneous injection, preferably in the
upper arm.
Herpes zoster oticus can usually be diagnosed clini-
cally, although the difficulty is increased in the absence
of a rash or in the presence of other neurologic manifesta-
tions (such as hemiparesis or cranial polyneuropathy). In
high-risk settings (such as hospitals and nursing homes),
rapid case identification is important to prevent suscep-
tible people at high risk (such as immunocompromised or
pregnant individuals) from developing serious complica-
tions of VZV infection.
Laboratory testing for VZV is not routinely required,
but it can be helpful in selected cases to confirm the diag-
nosis (Gilden et al., 1998; Gilden et al., 2000; Sweeney
and Gilden, 2001). Laboratory diagnosis or VZV infec-
tion can include (1) varicella-zoster IgM antibody in
blood or CSF, or a significant rise in serum IgG antibody
level; (2) isolation of VZV from vesicles, blood, or CSF in
immunocompromised patients, although VZV is labile
and difficult to recover from swabs of cutaneous lesions;
(3) demonstration of VZV antigen by direct fluorescent
antibody testing in material swabbed from the base of a
freshly unroofed fluid-filled vesicle or in lesion crusts; or
(4) detection of VZV DNA by polymerase chain reaction
(PCR) tests performed on clinical specimens from cuta-
neous lesions, tears, saliva, or blood monocytes. Because
viral proteins persist after the virus is no longer repli-
cating, direct fluorescent antibody tests may be positive
when viral cultures are negative. Virus isolation should
be attempted in cases with severe disease, especially in
immunocompromised cases. Virus can usually be cul-
tured from zoster lesions for 7 days or longer, and results
may be available within 2–3 days.
CSF may be normal or may show lymphocytosis and
occasionally a modest elevation of protein concentration.
Almost two-thirds of patients have a modest CSF pleocy-
tosis (<250 cells/mm3). VZV IgM antibody and VZV DNA
(by PCR techniques) can be demonstrated in CSF (Gilden
et al., 1998; Gilden et al., 2000), which can be diagnosti-
cally helpful in some cases of zoster sine herpete. Varia-
tions in commercial, real-time PCR tests can impact the
sensitivity of diagnostic testing.
The membranous labyrinth normally appears on
T1-weighted MRI images as a nonenhancing interme-
diate-signal-intensity structure surrounded by the low-
signal intensity of the petrous temporal bone (Downie et
al., 1994). In approximately 50–70% of cases with facial
nerve palsy due to the VZV, variable degrees of gado-
linium enhancement occur in the seventh and eighth cra-
nial nerves, the labyrinth, the geniculate ganglion, and
the internal and external auditory canals. In rare cases,
there may also be enhancement of the pontine facial nerve
nucleus. Gadollinium enhancement of inner ear struc-
tures and cranial nerves following VZV infection typi-
cally lasts less than 6 weeks but may persist for at least
6 years in rare patients (Zammit-Maempel and Camp-
bell, 1995). However, such protracted resolution of gad-
ollinium enhancement warrants consideration of other
causes of labyrinthitis or intracanalicular mass lesions.
Some studies have found no clear prognostic indicators
based on MRI images. Others, however, have suggested
that enhancement limited to the geniculate ganglion and
to the labyrinthine segment of the facial nerve indicates a
good prognosis for facial nerve recovery, whereas wide-
spread enhancement of the facial nerve is often associated
with a poor prognosis (Berrettini et al., 1998).
Recovery of hearing loss following herpes zoster oti-
cus is generally excellent, although incomplete in some
patients (Wayman et al., 1990; Adour, 1994). Prognostic
indicators of poor hearing recovery include advanced
age, retrocochlear hearing loss, hearing loss affecting the
speech frequencies (∼250–8000 Hz), vertigo, and male
gender (Wayman et al., 1990). Elderly patients, in particu-
lar, can be disabled by severe and persistent imbalance
(Adour, 1994). Herpes zoster oticus is more likely than

Bell’s palsy to be associated with a complete clinical facial
paralysis and a less complete clinical recovery. Facial
paresis in herpes zoster oticus completely resolves in
about one-half to two-thirds of patients after incomplete
loss of function, usually within about 2 months; complete
recovery is achieved in only about 10% of the patients
after complete loss of facial nerve function. The majority
of the remaining cases are left with mild residual signs,
but about 10% are left with an “unsatisfactory” outcome
(Heathfield and Mee, 1978). Factors associated with less
complete recovery are older age, vertigo, diabetes melli-
tus, and hypertension (Yeo et al., 2007).
Acyclovir facilitates healing of VZV infections, has a
low rate of toxicity, and may help prevent postherpetic
neuralgia. In particular, immunocompromised patients
with VZV infection should be promptly treated with
high-dose acyclovir (800 mg 5 times per day orally, or
10 mg/kg 3 times per day intravenously). Treatment is
typically given for 7–10 days. Longer treatment or the
addition of steroids does not apparently improve the
outcome (Wood et al., 1994), and no randomized, con-
trolled trials have assessed the utility of corticosteroids
as an adjuvant to antiviral therapy in herpes zoster oti-
cus (Uscategui et al., 2008). An alternative to acyclovir
is famciclovir (500 mg 3 times daily in adults), although
the latter is more toxic. Especially during the first few
days, vestibular sedatives may help alleviate acute ver-
tigo when the eighth nerve is involved.
With severe peripheral facial paresis, a major consider-
ation is ensuring protection of the ipsilateral eye, especially
when the eyelid does not close fully, either volitionally or
during sleep. Such patients have poor reflex eye closure
and may have inadequate lacrimation; therefore, they are
susceptible to corneal abrasions and infections. An ophthal-
mic lubricant should be placed in the affected eye (a viscous
product is preferred especially at night). The eyelid can be
held closed with tape, or an inflexible convex eye shield can
be placed over the eye for protection. A hydrophilic soft
contact lens has also been used to bandage the cornea in
such cases to prevent injury (Yamane, 1980). It is potentially
dangerous to use flexible eye patches or to attempt to keep
the lid closed by applying a dressing held with pressure
and tape over the eye; in such cases, the eye often opens
under cover and is abraded by the patch or dressing.
Ototoxicity
A number of drugs are ototoxic, including aminoglyco-
sides, aspirin, furosemide, and alkylating agents used
in cancer chemotherapy. Aminoglycoside antibiotics can
cause both auditory and vestibular toxicity (Keene et al.,
1982; Bath et al., 1999; Lanska, 2013g)—gentamicin, strep-
tomycin, and tobramycin are relatively specific toxins for
the vestibular system, whereas kanamycin, neomycin,
netilmicin, and amikacin are more cochleotoxic (Bath
et al., 1999). Aspirin and loop diuretics typically cause
Disorders of the Special Senses in the Elderly 433
reversible cochleotoxicity, and alkylating agents uncom-
monly cause a mixed ototoxicity (Keene and Hawke,
1981).
Unlike other common antibiotics, aminoglycosides are
concentrated in endolymph and perilymph, which par-
tially accounts for their predilection for ototoxicity. Ami-
noglycoside toxicity has been thought to result from an
inhibition of mitochondrial protein synthesis because of
a similarity between mitochondrial ribosomes and bacte-
rial ribosomes (where aminoglycosides allow misreading
of mRNA during translation). A highly conserved region
of ribosomal RNA binds aminoglycosides, and mutations
in this region may result in increased susceptibility to
aminoglycoside-induced ototoxicity in humans (Prezant
et al., 1993; Hutchin and Cortopassi, 1994; Smith, 2000).
Other potential contributing factors include free radical
formation via binding of iron and subsequent formation
of oxidative compounds, reversible impairment of sen-
sory transduction by blocking calcium-sensitive potas-
sium channels, and excessive N-methyl-D-aspartate
(NMDA) receptor activation and excitotoxicity due to
aminoglycoside agonist activity at the NMDA subtype of
glutamate receptors (Basile et al., 1996; Ernfors et al., 1996;
Schacht, 1998; Smith, 2000).
Risk factors for aminoglycoside-induced ototoxic-
ity include older age, family history of ototoxicity, high
serum levels, higher total dose, longer duration of ther-
apy (beyond 7–10 days), intrathecal administration, pre-
vious exposure to ototoxins, concomitant use of other
nephrotoxic or ototoxic drugs (such as vancomycin, loop
diuretics, cis-platinum, or metronidazole), renal impair-
ment, and fever (Fee, 1980; Keene and Hawke, 1981;
Prezant et al., 1993; Fischel-Ghodsian et al., 1997; Triggs
and Charles, 1999; Peloquin et al., 2004; Lanska, 2013f).
Whenever possible, the following precautions should
be followed to minimize ototoxicity (Campbell and Dur-
rant, 1993; Matz, 1993; Triggs and Charles, 1999; Lanska,
2013g): document preexisting hearing loss or vestibular
dysfunction before prescribing vestibulotoxic or ototoxic
medications; administer aminoglycosides for no longer
than 1 week; avoid aminoglycosides in patients whose
calculated creatinine clearance is less than 1.2 L/h; moni-
tor peak and trough aminoglycoside levels, and adjust
dosing accordingly; use extended dosing intervals (such
as once daily instead of multiple daily administration);
avoid combinations of aminoglycosides with other neph-
rotoxic or ototoxic drugs; and discontinue ototoxic agents
when clinical vestibulotoxicity or ototoxicity is detected.
Aminoglycoside therapy should cease as soon as symp-
toms of either auditory or vestibular ototoxicity appear,
to avoid permanent impairment (Halmagyi et al., 1994).
If identified early, much of the symptomatic toxicity is
reversible (Wallner, 1949; Fee, 1980; Black et al., 1987).
Mutations in a highly conserved region of the mito-
chondrial 12S rRNA gene have been identified in a
434 Neurologic Conditions in the Elderly
significant proportion (17%) of patients with amino-
glycoside-induced ototoxicity, particularly in families
with aminoglycoside-induced deafness. Many of these
cases have a family history of aminoglycoside-induced
ototoxicity, suggesting that ototoxicity could have been
prevented with an adequate clinical interview (Fischel-
Ghodsian et al., 1997). Therefore, it is essential to obtain a
family history of drug-induced ototoxicity in all patients
before administering aminoglycosides. To prevent further
cases within the family, sporadic cases of aminoglycoside-
induced ototoxicity should be screened, with molecular
tests for the presence of known mutations (Casano et al.,
1999). In identified families, the inheritance pattern of
susceptibility to ototoxicity has matched that of a mito-
chondrially inherited trait (with maternal transmission)
(Prezant et al., 1993). Therefore, maternal relatives in fam-
ilies with known familial aminoglycoside-induced deaf-
ness or vestibular dysfunction should avoid aminoglyco-
sides (Prezant et al., 1993). Most familial cases received
aminoglycoside antibiotics for a much shorter period and
at a lower total dose than sporadic cases.
Hair cells do not regrow following ototoxic insults from
aminoglycosides. In addition, damage may progress for
months after the responsible drug is discontinued because
the drugs are bound to inner ear membranes. Damage is
usually complete by 6 months after aminoglycoside dis-
continuation.
Subjective tinnitus
Subjective tinnitus is a perceived sensation of sound that
occurs in the absence of external acoustic stimulation and
cannot be heard by the examiner (Lanska, 2013h). Sub-
jective tinnitus is usually described as ringing, buzzing,
roaring, or clicking. Subjective tinnitus is the most com-
mon form of spontaneous auditory phenomena, and it
is distinct from objective tinnitus (tinnitus heard by the
examiner) and more complex sounds characteristic of
auditory hallucinations (voices and music). The incidence
of subjective tinnitus increases with age. By age 70, at least
25% of patients experience constant tinnitus (Schwaber,
2003). Men are more often affected than women, perhaps
partly because of greater occupational and recreational
noise exposure.
Key clinical features of subjective tinnitus from the his-
tory include onset (insidious or sudden), duration, tem-
poral pattern (episodic or continuous, progression over
time), location (unilateral, bilateral, or nonlocalizable),
pitch (high or low), amplitude (loud or soft), rhythm
(steady, gradually fluctuating, or rhythmic), associated
symptoms (hearing loss, aural fullness, otalgia, vertigo,
insomnia, anxiety, depression, headache, and neurologic
dysfunction), as well as family history, previous head
injury, noise exposure, medication use, previous ear infec-
tions, and previous ear surgery (Ciocon et al., 1995; Peifer
et al., 1999; Rubak et al., 2008; Lanska, 2013h). Subjective
tinnitus is generally most apparent and most bothersome
at night, when the masking ambient noise is less.
Severe tinnitus is almost always associated with hear-
ing loss; tinnitus intensity levels established with loud-
ness-matching techniques correlate with hearing levels at
the frequency of the most severe hearing loss (Man and
Naggan, 1981; Ochi et al., 2003). It is helpful if the patient
can compare the sound of the tinnitus to an identifiable
sound in the environment. High-pitched tinnitus may
be described as ringing, steam- or windlike, or clicking,
whereas low-pitched tinnitus is often roaring, grinding,
or like the sound of a seashell held to the ear. The tin-
nitus associated with Ménière syndrome is typically low
pitched (below 1000 Hz, and usually 125–500 Hz). When
associated with middle-ear disease, it is typically low- or
midrange in frequency (250–2000 Hz). When associated
with acoustic trauma or noise exposure, it is typically
around 4,000 Hz. When associated with presbycusis,
ototoxicity, and other sensorineural causes, it is typically
high pitched (2000 Hz and greater). When associated
with normal hearing, subjective tinnitus of any frequency
can occur (Man and Naggan, 1981; Chung et al., 1984;
Campbell, 1998).
Subjective tinnitus is frequently associated with depres-
sion (in up to half of the patients), anxiety, annoyance,
anger, frustration, and insomnia (Nondahl et al., 2002;
Dobie, 2003; Zoger et al., 2006; Belli et al., 2008; Heinecke
et al., 2008). Although the causal direction is not always
clear, tinnitus may produce significant psychological
stress, anxiety, and depression. Patients may excessively
focus on their tinnitus, with detrimental effects on occu-
pational and social functioning; these patients often rate
their tinnitus as louder than nondistressed patients, even
though such reports are inconsistent with objective mea-
sures of tinnitus loudness using masking (Schleuning
et al., 1980). Perceived tinnitus severity correlates much
more strongly with sleep disturbance than with the loud-
ness of tinnitus as measured with a balance procedure
using external sounds that match the tinnitus pitch.
Clinical examination of patients with any form of tinni-
tus should include funduscopy, otoscopy, tests of hearing,
neurologic examination, auscultation for objective tinni-
tus (such as from arterial bruits or venous hums), obser-
vation for palatal myoclonus, palpation of the neck or oral
cavity for masses, examination of the temporomandibu-
lar joint, and audiometry. Otoscopy can identify impacted
cerumen, a perforated eardrum, middle ear fluid, and
various mass lesions. Blood studies should include a
complete blood count, serum lipids, blood sugar, thy-
roid stimulating hormone, ESR, Lyme titers, and syphilis
serologies (Ciocon et al., 1995; Peifer et al., 1999; Hannan
et al., 2005).
Audiometry is essential in the evaluation of subjective
tinnitus. In particular, at a minimum, a pure-tone audio-
gram should be performed along with an assessment of

speech reception thresholds and word recognition. The
pattern of hearing loss, when present, is helpful in identi-
fying possible causes. Several common configurations or
patterns of SNHL exist: a notched pattern (as with NIHL);
a symmetric bilateral downward sloping pattern (as with
presbycusis); and a low-frequency trough pattern (as with
Ménière syndrome). In elderly patients with bilateral sub-
jective tinnitus, NIHL and presbycusis are among the
most commonly identified causes. Retrocochlear lesions
in patients with subjective tinnitus should be suspected
when SNHL is asymmetric or when word recognition is
asymmetric or decreased out of proportion to threshold
hearing level. Tympanometry and acoustic reflexes are
sometimes recommended (Ciocon et al., 1995) but often
add relatively little to the evaluation of subjective tinni-
tus or retrocochlear hearing loss; they are less sensitive
and specific than BAER studies or MRI in the detection of
retrocochlear masses (Campbell, 1998). Otoacoustic emis-
sions can be helpful in differentiating between cochlear
and retrocochlear SNHL (Campbell, 1998). They gener-
ally reflect cochlear pathology (assuming no significant
conduction abnormality) and are relatively insensitive to
neurologic abnormalities. In particular, otoacoustic emis-
sions can be helpful in interpreting absent responses on
BAER testing (Campbell, 1998). If evoked responses are
absent and otoacoustic emissions are normal, the prob-
lem is neurologic and cannot be attributed to peripheral
hearing loss; if both are absent, hearing loss is probably
peripheral.
It is helpful to determine whether subjective tinnitus is
either unilateral or bilateral, to determine whether focal
neurologic findings exist, and to perform an audiogram to
distinguish cases with conductive hearing loss or SNHL.
Subjective tinnitus may result from a wide variety of
lesions of the external or middle ear, the cochlea or audi-
tory nerve, or the central nervous system, but a large pro-
portion are ultimately designated as “idiopathic” (Lech-
tenberg and Shulman, 1984). The most commonly identi-
fied causal factor is NIHL.
Subjective tinnitus may be bilateral or unilateral,
regardless of whether it is associated with conductive
hearing loss or SNHL. Subjective tinnitus associated
with conductive hearing loss may be caused by impacted
cerumen, osteomas, or serous otitis media. Bilateral sub-
jective tinnitus associated with SNHL may be caused by
ototoxic drugs, noise exposure, or presbycusis (Miller
and Jakimetz, 1984; Campbell, 1998; Rubak et al., 2008).
Subjective tinnitus is common with NIHL and may be
the most troubling symptom for some patients. Unilat-
eral subjective tinnitus associated with progressive SNHL
should suggest the possibility of an acoustic neuroma or
other eighth nerve lesion. Other causes of subjective uni-
lateral tinnitus associated with SNHL include Ménière
syndrome, labyrinthine concussion, neurolabyrinthitis,
autoimmune hearing loss, and perilymphatic fistula.
Disorders of the Special Senses in the Elderly 435
Microvascular compression of the cochlear and vestibular
nerves in the cerebellopontine angle or the internal audi-
tory canal has also been considered a potential cause of
various audiovestibular symptoms, including fluctuat-
ing, pulsatile, or continuous tinnitus (usually unilateral),
as well as hearing loss, hyperacusis, diplacusis, vertigo,
and imbalance. However, the existence of this disorder
remains controversial. A specific clinical presentation for
microvascular compression, if any, has not been clearly
defined, although proponents have considered associated
brief vertiginous spells and hemifacial spasm as sugges-
tive features. Acute-onset subjective tinnitus with sudden
deafness is often due to viral neurolabyrinthitis, labyrin-
thine ischemia, or labyrinthine concussion. Episodic sub-
jective tinnitus may occur with Ménière syndrome, peri-
lymphatic fistula, or lesions of the cerebellopontine angle
(Espir et al., 1997).
Central nervous system causes of subjective tinnitus
in the elderly are often associated with central neuro-
logic findings: head trauma, brainstem stroke, vascular
abnormalities (such as arteriovenous malformations),
palatal myoclonus, demyelination, mass lesions in the
posterior fossa, meningeal carcinomatosis, and menin-
gitis (Lechtenberg and Shulman, 1984; Espir et al., 1997).
Patients with subjective tinnitus and either focal neuro-
logic findings or progressive SNHL should have an MRI
with and without gadolinium contrast to exclude mass
lesions and brainstem stroke. BAER studies can be help-
ful in those with subjective unilateral tinnitus and either
normal hearing or unilateral SNHL of unclear dura-
tion and course; an increased wave I to wave V interval
should prompt MRI scanning to exclude a mass lesion
involving the internal auditory canal or the cerebello-
pontine angle.
Despite thorough evaluation, the cause of tinnitus is
not identified in many patients, particularly in those
with nonlocalized and continuous tinnitus or those with
normal hearing without neurologic findings. Referral to
an otolaryngologist should be considered for patients
with subjective tinnitus and either (1) conductive hear-
ing loss (not attributable to impacted cerumen or otitis
media), (2) mixed hearing loss, or (3) a retrotympanic
mass.
The pathophysiology of subjective tinnitus is poorly
understood, but a number of different mechanisms may
be responsible (Lanska, 2013h). With conductive hearing
loss, internal auditory signals (vascular noises and oto-
acoustic emissions) may be more apparent because of the
reduction of ambient sound. Cochlear damage (from noise
or ototoxins) or eighth-nerve damage may result in abnor-
mal afferent signals (altered rate or rhythm), which the
brain interprets as tinnitus. Pressure on the eighth nerve
may damage the myelin sheath, allowing ephaptic trans-
mission, or “crosstalk,” between axons (Espir et al., 1997);
this mechanism usually is considered with posterior fossa
436 Neurologic Conditions in the Elderly
tumors, but it has been argued that vascular anomalies
(such as a tortuous AICA or PICA) may also compress the
eighth nerve and cause tinnitus. Either absence or signifi-
cant decrement in afferent auditory nerve impulses may
also “release” central auditory pathways akin to VHs
with blindness, as well as “phantom limb” tactile and
kinesthetic hallucinations following amputations (Cogan,
1973; Ross et al., 1975; McNamara et al., 1982; Hammeke
et al., 1983; Lanska et al., 1987a; Arnold et al., 1996; Giraud
et al., 1999; Cacace et al., 2003; Moller, 2003; Weiss et al.,
2004, 2005; Saunders, 2007). In addition, most adults
experience tinnitus in anechoic environments, perhaps
because of such release mechanisms or because of per-
ception of otoacoustic emissions from the cochlea that are
normally masked by ambient noise (Pulec et al., 1978; Del
Bo et al., 2008). A variety of evidence supports the concept
that central auditory pathways participate maladaptively
in the pathophysiology of tinnitus: (1) tinnitus or periph-
eral origin can persist after recovery of cochlear func-
tion, labyrinthectomy, or eighth-nerve neurectomy; (2)
unilateral tinnitus can be suppressed by either homo- or
contralateral noise; (3) damage to the inner ear produces
substantial structural, neurochemical, and physiologic
neural changes in the auditory pathways of the brainstem
and cerebrum, including enhanced sound-driven activity,
increased spontaneous neural activity, altered neural fir-
ing (such as bursting discharges and neural synchrony),
reorganization of the tonotopic representation of fre-
quency in the brainstem and cerebral cortex, and exten-
sion of spontaneous cortical activity associated with tinni-
tus into nonsensory areas (Saunders, 2007). Studies using
positron emission tomography and magnetoencephalog-
raphy have suggested that tinnitus is related in part to
plastic changes in the auditory association cortex (Arnold
et al., 1996; Lockwood et al., 1998; Muhlnickel et al., 1998;
Giraud et al., 1999; Mirz et al., 1999; Cacace et al., 2003;
Moller, 2003).
Two-thirds of patients report tinnitus as annoying, yet
only about one-third seek professional help—and less
than 10% receive treatment (Sindhusake et al., 2003). The
prognosis depends heavily on the etiology. Most cases of
subjective tinnitus cannot be cured, and many are refrac-
tory to treatment, particularly those that are bilateral or
nonlocalizable. Symptomatic treatment of tinnitus, as
well as treatment of any associated depression, anxiety,
and insomnia, can be helpful, even if the associated tin-
nitus cannot be eliminated (Dobie, 2003). Symptomatic
treatment of tinnitus can include reassurance, various
psychological treatments (such as supportive psycho-
therapy, biofeedback, hypnosis, or habituation therapy),
masking techniques, drugs, electrical stimulation, and,
rarely, surgery (Andersson and Lyttkens, 1999; Berry et al.,
2002). The most widely employed treatments include
reassurance, masking techniques, and various drugs, but
many patients receive little apparent benefit from these.
Biofeedback does not reduce tinnitus loudness, but it
may reduce muscular tension and anxiety, may facilitate
coping with the tinnitus, and may be better accepted by
patients than psychological counseling. Removal of ceru-
men may help some patients with subjective tinnitus,
partly because it increases ambient sound and assists with
masking, and partly because cerumen on the tympanic
membrane can produce tinnitus through local effects on
the conduction pathway.
For patients who are particularly bothered by tinnitus
at night, a bedside radio (possibly with a pillow speaker)
tuned between stations can often provide effective mask-
ing and allow them to get to sleep. White noise genera-
tors, white noise tapes, and tapes of “ocean surf” produce
similar results. Similarly, a hearing aid may result in
improved hearing and communication and may decrease
the tinnitus by amplifying ambient sound and providing
some masking. Tinnitus-masking devices can be worn
like a hearing aid, and “tinnitus instruments” combine a
masking device with a hearing aid. Unfortunately, long-
term efficacy of tinnitus-masking units is, at best, variable
and, in some studies, poor; results in one small random-
ized trial were no better than placebo (Erlandsson et al.,
1987). In some patients, a high level of masking is required
(above 10 dB), and often the patient finds the masking sig-
nal to be too distracting (Campbell, 1998). In others, either
bilateral tinnitus is not relieved with masking devices or
the application of bilateral masking devices makes it diffi-
cult for patients to hear environmental sounds (Campbell,
1998).
Multiple drugs have been investigated in the hope
that a long-acting oral medication could be found to
effectively treat subjective tinnitus (Murai et al., 1992).
Unfortunately, in general, drug therapies have not been
successful, to date, for long-term tinnitus reduction
(Murai et al., 1992; Campbell, 1998; Hannan et al., 2005),
and available clinical trials of pharmacologic agents have
had significant deficiencies (Murai et al., 1992). Surgi-
cal treatment of subjective tinnitus has also generally
been disappointing. Nevertheless, a variety of surgical
procedures have been advocated, including cochlear
implantation, cochlear nerve section, and surgical
microvascular decompression. Surgical case series have
reported variable results, but many cases with subjective
tinnitus do not benefit from surgery with a reduction in
tinnitus, even if the surgery was necessary and helpful in
other ways; some actually worsen. Even ablation of the
cochlea or the eighth nerve may not substantially alter
the tinnitus in some patients with dysfunction of these
structures, suggesting that tinnitus may be maintained in
central auditory pathways, even if it had its genesis in the
dysfunction of peripheral auditory structures. Patients
most likely to develop postoperative tinnitus are those
with poorer hearing preoperatively or surgically induced
hearing loss.

Because no highly effective medical or surgical therapy
is available for subjective tinnitus associated with ototox-
icity or NIHL, prevention is essential. The patient’s pre-
scribed and over-the-counter medications, substance use,
and toxin exposures should be reviewed to identify possi-
ble sources of ototoxicity (such as salicylates, nonsteroidal
anti-inflammatory agents, aminoglycosides, furosemide
and other loop diuretics, anticancer drugs, and quinine)
and substances that may exacerbate tinnitus (such as ami-
nophylline, nicotine, caffeine, alcohol, and marijuana)
(Campbell, 1998). Hearing protection and environmental
controls should be utilized to control noise exposure.
Central hearing disorders
Cortical deafness, pure word deafness, and
auditory agnosia
The auditory cortex is located in the posterior superior
aspect of both temporal lobes, with the primary audi-
tory cortex located in the transverse temporal gyri of
Heschl. Rarely, cases of sudden deafness can be due to
cortical deafness from bilateral temporal lobe infarcts
(Kneebone and Burns, 1981; Buchman et al., 1986; Bahls
et al., 1988; Murray and Fields, 2001; Leussink et al.,
2005). Cases reported as cortical deafness (due to a pri-
mary sensory audiologic deficit) overlap clinically both
with cases of “pure word deafness” (or auditory verbal
agnosia, impaired ability to understand speech sounds,
even though the patient can hear them) and with cases of
generalized auditory agnosia (impaired ability to inter-
pret both verbal and nonverbal sounds, even though
the patient can hear them) (Buchman et al., 1986; Kaga
et al., 2004). Moreover, patients with diagnoses of word
deafness who had formal testing of linguistic and non-
linguistic sound comprehension and musical abilities
showed evidence of a more pervasive auditory agnosia
(Buchman et al., 1986). Some reported cases show evo-
lution of clinical features from one category to another
(Bahls et al., 1988; Murray and Fields, 2001). Because
common features can be delineated in reported cases of
pure word deafness, auditory agnosia, and cortical deaf-
ness, Buchman and colleagues suggested that these dis-
orders form a continuum rather than being three distinct
syndromes (Buchman et al., 1986). Although all reported
cases of word deafness have exhibited additional audi-
tory deficits, word deafness is the most distinctive deficit
on clinical examination; for this reason, patients with dis-
orders on this spectrum are categorized under the rubric
of “word deafness” (Buchman et al., 1986). Word deafness
most frequently stems from strokes causing bitemporal
cortico-subcortical lesions, presumably on a cardioem-
bolic basis (Buchman et al., 1986). Neurodegenerative
disorders (such as frontotemporal dementias and CJD)
can also produce cortical deafness and related syndromes
(Tobias et al., 1994; Otsuki et al., 1998; Kaga et al., 2004;
Jörgens et al., 2008).
Disorders of the Special Senses in the Elderly 437
Auditory hallucinations due to central nervous
system lesions
In humans, the primary auditory cortex is located deep
within the lateral fissure on a small patch of the trans-
verse gyrus of Heschl, on the upper surface of the tem-
poral operculum of the insula of the cortex, whereas the
lateral superior temporal gyrus is involved in processing
complex acoustic signals, including speech. Post-lesional
auditory (“release”) hallucinations can result from lesions
anywhere along the auditory pathway from the cochlea to
the auditory cortex, including the brainstem, akin to Bon-
net hallucinations with visual loss (Ross et al., 1975; Ham-
meke et al., 1983; Cascino and Adams, 1986; Lanska et al.,
1987a; Lanska and Lanska, 1993; Griffiths, 2000). Musical
hallucinosis in deafness may also involve widely distrib-
uted networks, distinct from primary auditory cortex, that
are responsible for perception and imagery of pattern in
segmented sound (Griffiths, 2000). Post-lesional auditory
hallucinations may be simple (as with subjective tinnitus)
or complex (voices or music). Such patients are likely to
be elderly and typically have hearing impairments such
as distortion, poor localization, hypoacusis, or deafness.
As with VHs, auditory hallucinations may have an irri-
tative basis. Electrical stimulation of the temporal cortex
(in either hemisphere) may produce reports of auditory
hallucinations (Penfield and Perot, 1963). Ictal auditory
hallucinations are most common in patients with tempo-
ral lobe epilepsy (but can occur less commonly with foci
in other lobes). Complex auditory hallucinations (voices
or music) are typically associated with temporal cortex
stimulation or irritation, while simple auditory hallucina-
tions (such as tinnitus with hissing, buzzing, or ringing)
can occur with cortical, subcortical, or insular stimulation
or irritation.
Auditory hallucinations are less common than VHs
in patients with PD (Inzelberg et al., 1998; Fénelon et al.,
2000; de Maindreville et al., 2005). Auditory hallucina-
tions in PD occur particularly in patients who have VHs
and are cognitively impaired or depressed (Inzelberg et
al., 1998). Auditory hallucinations occur repeatedly, and
the content is typically of human voices, which are non-
imperative, nonparanoid, and often incomprehensible
(Inzelberg et al., 1998).
The chemosenses: smell and taste
Disorders of the chemosensory senses, smell and taste,
are usually less disabling than disorders of the other spe-
cial senses (vision and hearing).
Smell
Olfactory impairment is a significant contributor to per-
ceived disability and lower quality of life among elderly
patients, and is a significant predictor of subsequent
438 Neurologic Conditions in the Elderly
cognitive decline (Miwa et al., 2001; Murphy et al., 2002;
Wilson et al., 2007b; Schubert et al., 2008). Patients with
olfactory symptoms generally report loss of olfactory
sensation (hyposmia or anosmia) and only rarely report
forms of distorted olfaction (dysosmia or parosmia).
When dysosmia is reported, the perception is almost uni-
versally unpleasant, a condition referred to as aliosmia
(the perception of unpleasant odors from nominally pleas-
ant odorants); it may involve a sensation either of fecal or
rotten smells (cacosmia) or of chemical or burned smells
(torquosmia). In addition, complaints of impaired “taste”
are often symptoms of olfactory dysfunction because
much of the flavor of a meal derives from olfactory stim-
ulation. Indeed, the complex sensory experience of “fla-
vor” during consumption of foods and drinks cannot be
constructed simply from combinations of the basic taste
qualities (sweet, salty, sour, bitter, and umami/savory).
Medications that can alter olfactory function in elderly
patients are numerous and varied, and include levodopa,
bromocriptine, lithium, opiates, various lipid-lowering
drugs, calcium-channel blockers, beta blockers, antimi-
crobials, and antineoplastics (Rollin, 1978; Schiffman,
1997; Spielman, 1998). Some medications interfere with
the process of sensory transduction (for example, by inter-
fering directly with the receptor or its components, such
as G-proteins, adenylate cyclase, or receptor kinase); oth-
ers interfere with neurotransmitters involved in olfactory
processing; and still others are directly toxic to olfactory
neuroepithelium or the nerves themselves. For example,
chemotherapy agents cause hyposmia by direct toxic-
ity to mucosa and nerves and by inhibition of mucosal
cell growth and replacement. In addition, zinc-induced
anosmia as a result of necrosis of nasal neuroepithelium
occurred with intranasal application of zinc gluconate gel
in commercial cold preparations, but this formulation has
been withdrawn (Alexander and Davidson, 2006; Smith
et al., 2009).
Conductive olfactory disturbances
Odorants reach the sensory receptors in the olfactory
neuroepithelium by two pathways: orthonasally through
the nostrils or retronasally through the nasopharynx
(Duffy et al., 1999). With retronasal olfaction, odorants are
delivered in a liquid or semiliquid phase during eating
or drinking, are volitalized, and are then combined with
gustatory and somatosensory sensations to form a com-
posite sensation of flavor. This process requires adequate
mastication to release volatile odorants, and sufficient
mouth and swallowing movements to effectively pump
the odorants retronasally.
Conductive (or “transport”) olfactory problems impede
the passage of odorants either orthonasally or retrona-
sally, and generally cause hyposmia (rather than anos-
mia) because the obstruction is usually incomplete. Some
common problems that produce conductive olfactory
disturbances include upper respiratory infections, chronic
rhinosinusitis, and nasal polyposis. In addition, elderly
patients with complete or palate-covering dentures have
lower olfactory sensitivity than those who are dentate or
who wear dentures that do not cover the palate, appar-
ently in part, because of impairment with chewing and
mouth movements, and interference with movement of
odorants retronasally (a conductive defect) (Duffy et al.,
1999).
Sensorineural olfactory disturbances
The olfactory receptors are located in the olfactory neuro-
epithelium on the superior-nasal septum and lateral wall
of the nasal cavity. The dendritic end of these bipolar sen-
sory cells projects into the overlying nasal mucous, while
the unmyelinated axons project through the cribriform
plate of the ethmoid bone via small bundles that comprise
the filaments of the short olfactory nerve to ultimately
synapse in the olfactory bulb.
With sensorineural olfactory problems, the odorants
contact the olfactory receptors of the bipolar neurons in
the olfactory neuroepithelium, but dysfunction of these
components prevents the information from being pro-
cessed. Sensorineural olfactory problems can be caused
by head trauma, tobacco smoking, other toxins, drugs,
nutritional disorders (including zinc deficiency, vitamin
A deficiency, cobalamin deficiency), influenza-like viral
infections, various comorbid medical conditions (hypo-
thyroidism, diabetes, Sjögren’s syndrome, renal failure,
and liver disease including cirrhosis), and structural
lesions involving the area of the cribriform plate (such
as subfrontal meningioma). Mechanisms of posttrau-
matic olfactory dysfunction include direct injury to the
olfactory epithelium (causing a sensory olfactory deficit),
shearing effect on the fragile olfactory fibers at the crib-
riform plate (causing a neural deficit), or potential brain
contusion or intraparenchymal hemorrhage (causing a
central olfactory deficit). Hyposmia in smokers is com-
mon, occurs in a dose-dependent fashion, and apparently
results from increased death of olfactory sensory neurons,
which eventually overwhelms the regenerative capacity
of the olfactory neuroepithelium (Collins et al., 1999; Vent
et al., 2004; Hummel and Lötsch, 2010). Hyposmia is com-
mon in hypothyroidism, occurring in about 20% of cases,
and contributes to anorexia and lack of interest in eating,
but it largely reverses with replacement hormone therapy
(McConnell et al., 1975). In the absence of local nasal dis-
ease, unilateral anosmia suggests a structural lesion of the
olfactory nerve filaments, bulb, tract, or stria. An olfactory
groove meningioma, for example, may cause ipsilateral
sensorineural anosmia, in conjunction with optic atrophy
in the ipsilateral eye (due to optic nerve compression) and
papilledema in the contralateral eye (due to increased
intracranial pressure), a constellation of manifestations
designated eponymically as Foster Kennedy syndrome.

Presbyosmia
Presbyomsia (literally “elderly olfaction” or “old age
olfaction”) is the gradual loss of olfactory abilities that
occurs in most people as they grow older. Age-related
losses of smell (presbyosmia) and taste (presbygeusia) are
common in the elderly and result from normal aging, cer-
tain diseases (especially PD, DLB), medications, surgical
interventions, and prior environmental exposures (Doty
et al., 1984c; Doty, 1989; Schiffman, 1997; Elsner, 2001a,
2001b; Murphy et al., 2002; Mackay-Sim et al., 2006; Raw-
son, 2006). Because chemosensory impairment is so prev-
alent among the elderly, many elderly people complain
that food lacks flavor and the elderly account for a dis-
proportionate number of accidental gas poisoning cases
(Doty et al., 1984c). The components related to aging, per
se, are relatively small (but significant), while the majority
of the age-related functional declines of the chemosenses
are attributable to accumulated insults to the sensory sys-
tem, smoking, medications, and comorbid disease (Mur-
phy et al., 2002; Mackay-Sim et al., 2006).
Olfactory senescence starts by the fifth decade and
accelerates with advancing years, preferentially involv-
ing pleasant odors (Doty et al., 1984c; Hawkes, 2006; Doty,
2008). Almost two-thirds of the patients aged 80 and older
have olfactory impairment (Murphy et al., 2002). Clini-
cally significant olfactory loss is common in the elderly
but frequently unrecognized, in part, because deficits
typically accumulate gradually over decades—indeed,
self-reported olfactory impairment significantly under-
estimates prevalence rates obtained by olfactory testing
(Murphy et al., 2002). The elderly have higher olfactory
thresholds, perceive suprathreshold odors less intensely,
and are less able to discriminate odors or to recognize
and identify common odors (Cain and Stevens, 1989;
Schiffman, 1997; Doty, 2008). Smell identification ability
declines markedly after the seventh decade—major olfac-
tory impairment is present in about one-third to one-half
of those aged 65–80, and in some two-thirds to four-fifths
of those over age 80 (Doty et al., 1984c; Murphy et al., 2002;
Doty, 2008; Lafreniere and Mann, 2009). Part of the decline
in olfactory abilities with age results from degeneration of
the olfactory bulb—the number of mitral cells and glom-
eruli in the olfactory bulb declines markedly with age, at
an approximate rate of 10% per decade, so that less than
30% of these elements remain by the ninth and tenth
decades (Meisami et al., 1998). Functional imaging shows
significantly lower activation among the elderly in brain
regions receiving primary olfactory projections (piriform
cortex, entorhinal cortex, and amygdala) (Cerf-Ducastel
and Murphy, 2003).
Male gender, current smoking, medications, cumula-
tive exposure to toxic fumes, prior head trauma, and
comorbid conditions (such as nasal congestion, upper
respiratory tract infection, sinusitis, systemic viral illness,
epilepsy, cerebrovascular disease, and neurodegenerative
Disorders of the Special Senses in the Elderly 439
diseases) are associated with an increased prevalence
of olfactory impairment in the elderly (Schiffman, 1997;
Elsner, 2001b; Murphy et al., 2002; Nguyen-Khoa et al.,
2007). Anosmia associated with chronic allergic rhinitis,
nasal polyposis, and chronic sinusitis may respond to
glucocorticoids, especially if administered systemically.
Results with zinc sulfate therapy, even in patients with
documented deficiency, have been mixed.
For patients with olfactory dysfunction, the prognosis
depends primarily on etiology and the degree of residual
function, but also secondarily on gender, parosmia, smok-
ing habits, and age (Hummel and Lötsch, 2010). Male
gender, initial presence of parosmia, smoking, and older
age are negative prognostic factors (Hummel and Lötsch,
2010).
Central olfactory disturbances
The olfactory bulb may constitute the “olfactory thal-
amus” (although it has also been suggested more
provocatively that the olfactory bulb may instead serve
as the primary olfactory cortex) (Haberly, 2001; Kay and
Sherman, 2007; Benarroch, 2010). Second-order neurons
from the olfactory bulb travel posteriorly as the optic tract
in the olfactory sulcus on the orbital surface of the fron-
tal lobes. The optic tracts divide into medial and lateral
striae, with fibers from the medial striae decussating in
the anterior commissure to terminate in the contralateral
cerebral hemisphere, while fibers from the lateral striae
project to the ipsilateral primary olfactory cortex, amyg-
dala, septal nuclei, and hypothalamus. Because of the
bilateral cortical representation for smell in the piriform
cortex, unilateral lesions distal to the decussation of the
olfactory fibers generally do not cause clinically impor-
tant olfactory dysfunction, although deficits in olfactory
discrimination and detection may be detected with major
unilateral damage to the frontal or temporal lobes. Dis-
orders that can interfere with central olfaction include
epilepsy, head injury (particularly with contusion of the
temporal tips against the anterior portion of the middle
fossa), and various neurodegenerative conditions (such
as PD, DLB, and AD).
Lewy body alpha-synucleinopathies
PD is a multisystem alpha-synucleinopathy, in which
Lewy bodies are the histologic hallmark. Lewy bodies
are composed of intraneuronal cytoplasmic aggrega-
tions of alpha-synuclein and ubiquitin, and are present
in pigmented neurons within the substantia nigra, the
locus ceruleus, the dorsal motor nucleus of the vagus,
and the substantia innominata. Olfactory deficits—
involving odor detection, identification, and discrimi-
nation—are common early in the course of PD and are
present in more than 90% of patients with early-stage
PD (Hudry et al., 2003; Doty, 2007b; Boesveldt et al.,
2008; Duda, 2010). Occasionally, patients with PD may
440 Neurologic Conditions in the Elderly
develop pleasant olfactory hallucinations (phantos-
mias) (Landis and Burkhard, 2008). Impaired olfac-
tion can predate the motor symptoms of PD by at least
4 years (Ross et al., 2008). Idiopathic olfactory dysfunc-
tion in first-degree relatives of PD patients is also asso-
ciated with an increased risk of developing PD within
2–5 years (Ponsen et al., 2010). Olfactory defects in PD
do not progress markedly with development of motor
manifestations (Doty, 2007b) and do not correlate well
with most other manifestations of the disease (Verbaan
et al., 2008), except with autonomic defects (Goldstein
et al., 2010) and cognitive dysfunction, including mem-
ory impairment (Baba et al., 2011). Anosmia in PD is
associated with autonomic failure, including baroreflex
failure and noradrenergic denervation of the heart and
other organs, independently of parkinsonism or stria-
tal dopaminergic denervation (Goldstein et al., 2010).
Olfaction in patients with PD does not improve with
levodopa therapy (Huisman et al., 2004; Rösser et al.,
2008), apparently at least in part, because dopamine
inhibits olfactory transmission in the olfactory glomer-
uli, and there is a paradoxical increase in the number of
periglomerular dopaminergic neurons in the olfactory
bulb in PD (Huisman et al., 2004).
DLB is closely allied with both PD and AD, and is char-
acterized anatomically by the presence of Lewy bodies
in both the neocortex and subcortical structures. There is
a loss of dopamine-producing neurons in the substantia
nigra similar to that seen in PD, and a loss of acetylcho-
line-producing neurons in the basal nucleus of Meynert
similar to that seen in AD. In DLB, as in PD, olfactory
dysfunction is nearly universal, develops early (before
any movement or cognitive disorder), and is often severe
(Hawkes, 2006). Nevertheless, addition of anosmia to the
consensus criteria for DLB did not significantly improve
overall diagnostic performance (McShane et al., 2001;
Olichney et al., 2005; Williams et al., 2009).
Odor identification is also impaired in patients with
REM sleep behavior disorder (RBD), a common and
very early feature of Lewy body alpha-synucleinopathies
(Stiasny-Kolster et al., 2005; Fantini et al., 2006; Miyamoto
et al., 2009; Postuma et al., 2009; Miyamoto et al., 2010).
Markedly reduced olfaction in a parkinsonian patient
is supportive of PD or DLB (Wenning et al., 1995), while
normal smell identification is rare with these conditions
and should prompt review of the diagnosis (unless pos-
sibly if the patient is female with tremor-dominant dis-
ease) (Hawkes, 2006). Preserved or mildly impaired olfac-
tory function in a parkinsonian patient is more likely
to be related to atypical parkinsonism such as vascular
parkinsonism, MSA, PSP, or corticobasal degeneration
(CBD) (Katzenschlager et al., 2004; Hawkes, 2006). How-
ever, these heuristic clinical rules are not absolute—some
patients with CBD, for example, have moderate or severe
impairment (Pardini et al., 2009).
Olfactory loss in PD and DLB is not due to damage to
the olfactory epithelium, but instead results from central
nervous system abnormalities (Hubbard et al., 2007; Witt
et al., 2009; Baba et al., 2011). Pathology of the olfactory
bulb and tract occurs prior to motor signs of PD (Hub-
bard et al., 2007). In synucleinopathies, olfactory dys-
function relates specifically to Lewy body pathology and
correlates with cardiac sympathetic denervation, inde-
pendently of striatal dopamine deficiency or parkinson-
ism (Goldstein and Sewell, 2009). Impaired olfaction in
PD is associated with the presence of Lewy bodies and
neuronal loss in the olfactory bulb and tract, with a strong
correlation between neuronal loss and disease duration
(Pearce et al., 1995). In PD, the olfactory bulb contains
numerous Lewy bodies, and severe neuronal loss is pres-
ent in the anterior olfactory nucleus (Kovács et al., 2003).
Immunolabeling for alpha-synuclein in the olfactory bulb
and tract occurs prior to clinical signs of parkinsonism in
DLB (Hubbard et al., 2007). The presence of Lewy body
alpha-synucleinopathy in the olfactory bulb accurately
predicts the presence of Lewy body pathology in other
brain regions (Beach et al., 2009).
The pathophysiology of hyposmia in Lewy-body
alpha-synucleinopathies is not well understood and
may have multiple components, including those result-
ing from degenerative changes in the olfactory bulb and
primary olfactory cortex, as well as limbic dysfunction
and possibly prefrontal dysfunction (Hudry et al., 2003;
Bohnen et al., 2008; Westermann et al., 2008; Bohnen et al.,
2010; Baba et al., 2011). Functional imaging indicates that
reduced neuronal activity in the amygdala, hippocampus,
and piriform cortex (uncus) contributes to olfactory dys-
function in PD (Westermann et al., 2008; Baba et al., 2011).
Hyposmia in PD is more closely associated with choliner-
gic denervation of limbic archicortex (hippocampus and
amygdala) than with nigrostriatal dopaminergic dener-
vation (Bohnen et al., 2010). However, because olfactory
threshold and odor identification in PD are not related to
duration of disease, to current therapy with levodopa or
anticholinergic drugs, or to “on” and “off” states, olfac-
tory impairment in PD likely involves mechanisms that
are not due to dopaminergic or cholinergic denervation
and that are not influenced by pharmacologic manipula-
tion of dopaminergic or cholinergic status (Quinn et al.,
1987).
Other age-associated neurodegenerative conditions
Although hyposmia is a frequent and early abnormality
in PD and DLB, this is not so in other forms of parkinson-
ism, including MSA, vascular parkinsonism, PSP, or CBD,
nor is hyposmia a feature of essential tremor (Wenning
et al., 1995; Katzenschlager and Lees, 2004; Shah et al.,
2008; Pardini et al., 2009). Most studies of olfaction in
CBD have reported relatively mild deficits, but olfactory
dysfunction can be moderate or severe in this disorder

(Pardini et al., 2009). A mild olfactory loss develops later
in the course of MSA (Katzenschlager and Lees, 2004),
associated with characteristic glial cytoplasmic inclusions
in the olfactory bulb and some degree of neuronal loss in
the anterior olfactory nucleus, but it is not clear that this is
of clinical significance (Kovács et al., 2003). Olfactory defi-
cits may also occur with motor neuron disease (MND),
but smell testing is not likely to be of clinical value in this
condition (Elian, 1991; Hawkes, 2006).
Some degree of olfactory loss has also been reported
in various other dementing disorders, including
AD and frontotemporal dementia (Doty et al., 1987;
Westervelt et al., 2007; Wilson et al., 2007a; Williams et al.,
2009). Olfactory impairment is more marked early in the
course of the disease in patients with DLB than in those
with either AD or frontotemporal dementia (Williams
et al., 2009). Nevertheless, olfactory deficits have been
reported in AD (Doty et al., 1987; Solomon et al., 1998;
McCaffrey et al., 2000; Li et al., 2010), and these deficits
may be detectable before the appearance of overt memory
loss (Li et al., 2010), increase with severity of dementia
(Murphy et al., 1990; Serby et al., 1991; Wilson et al., 2009),
and correlate with density of neurofibrillary tangles in the
entorrhinal cortex and hippocampus (Wilson et al., 2007a)
and with cortical Lewy body pathology (McShane et al.,
2001). It remains unclear, though, whether AD is associ-
ated with clinically meaningful hyposmia in the absence
of Lewy body pathology (McShane et al., 2001). Olfactory
dysfunction, if apparent in AD, can sometimes help in the
differential diagnosis with depression (Solomon et al.,
1998; McCaffrey et al., 2000). Frontotemporal dementia
is also associated with relatively mild olfactory deficits,
which are comparable to those seen in AD (McLaughlin
and Westervelt, 2008).
Taste
In patients with hypogeusia or dysgeusia, the medi-
cal history should address medication use, toxin expo-
sures, autoimmune disorders (particularly Sjögren’s
syndrome), local damage (such as burns), nutritional dis-
orders (such as cachexia, vitamin-deficiency-associated
glossitis, and zinc deficiency), depression, psychosis,
known cancer, and endocrine and metabolic disorders
(particularly hypothyroidism, but also diabetes, chronic
kidney disease, and hepatic cirrhosis) (McConnell et al.,
1975; Catalanotto, 1978; Frank et al., 1992; Heckmann
and Lang, 2006; Reiter et al., 2006; Doty et al., 2008). Oral
examination should exclude obvious local pathology,
such as candidiasis (thrush), gingivitis, xerostomia, glos-
sitis, burns (thermal, chemical, or radiation induced), and
oral cancer.
Medications that can alter taste in elderly patients
are numerous and varied, and include amitriptyline,
baclofen, carbamazepine, phenytoin, levodopa, and
propranolol, as well as various lipid-lowering drugs,
Disorders of the Special Senses in the Elderly 441
antihistamines, antimicrobials, antineoplastics, anti-
inflammatories, allopurinol, bronchodilators and other
asthma medications, antihypertensives and cardiac med-
ications, lithium, antidepressants, and antipsychotics
(Rollin, 1978; Frank et al., 1992; Schiffman, 1997; Spiel-
man, 1998). Possible mechanisms for medication-related
dysgeusia include disruption of zinc metabolism (e.g.,
by impairing absorption or facilitating chelation) and
alteration of ion channels, second-messenger systems,
and neurotransmitters involved in gustatory percep-
tion. Many medications produce a metallic dysgeusia
(aliageusia or, more specifically, torquegeusia), includ-
ing methimazole, captopril, and lithium carbonate, and
some (such as iron salts) appear to do this via olfactory
mechanisms (Hettinger et al., 1990; Frank et al., 1992).
Unfortunately, stopping a medication that may be caus-
ing dysgeusia is not always an easy option, particularly
when one is dealing with serious disabling or life-threat-
ening conditions such as seizures, cancer, infection, dia-
betes mellitus, and uncontrolled hypertension. Further-
more, although medication-related dysgeusia terminates
quickly after stopping the responsible medication, with
captopril and some other medications, dysgeusia may
persist for months (Frank et al., 1992).
Apart from obvious oral pathology, medication-
induced dysgeusias (metallic taste), hypothyroidism, and
depression- or psychosis-related taste complaints, most
“taste” complaints in the elderly are usually symptoms
of olfactory dysfunction. Altered gustatory thresholds
have been identified in groups of patients with various
systemic disorders (particularly endocrine, kidney, and
hepatic diseases), but as a rule, gustatory complaints
are seldom the basis for a separate evaluation in such
patients. Gustatory complaints are common in patients
with cancer, but toxicity due to chemotherapy or radia-
tion therapy or nutritional deficiencies (such as zinc) can
usually be readily identified.
Conductive gustatory disturbances
Conditions that impede or alter the contact of tastants
with the taste receptors produce conductive (or “trans-
port”) hypogeusia or dysgeusia. Such conditions can
include poor oral hygiene, dental caries, periodontal dis-
ease, denture use, gastroesophageal reflux, upper respira-
tory infections, oral candidiasis (thrush), and oral cancer.
With oral candidiasis, for example, the growth of yeast
produces a barrier that precludes contact of the tastants
with the gustatory receptors. Similarly, elderly patients
not infrequently develop a thick, whitish mucoid coat-
ing on the tongue (“tongue plaque”), which is evident
on arising and which can interfere with taste acuity. This
can be removed easily with a soft toothbrush, with a dry
gauze pad, or by eating so-called “detergent” foods (hard
bread, dry cereal, uncooked vegetables, or fibrous meats).
Tongue brushing should be encouraged twice a day, upon
442 Neurologic Conditions in the Elderly
rising and before bed, especially in elderly patients with
oral prostheses.
Conditions that interfere with chewing or salivation
are also likely to produce conductive hypogeusia. Dur-
ing mastication, food is crushed and ground by the teeth
(chewed), warmed, and mixed with liquid saliva. These
actions release tastants from the food and also facilitate
conveyance of tastants in a liquid or semiliquid state to
the gustatory receptors (among other actions such as
facilitating enzymatic breakdown of food components).
Therefore, conditions that interfere with chewing or
movement of the food bolus (such as lack of teeth, poorly
fitting dentures, temporomandibular joint dysfunction,
jaw claudication, and dysphagia) can lessen the experi-
ence of taste.
Because saliva is necessary to help soften the masticated
food and to convey tastants in a liquid state to the gusta-
tory receptors, disorders that interfere with saliva produc-
tion result in hypogeusia and/or dysgeusia. In addition,
saliva helps to prevent pathologic growth of bacteria and
fungi and to maintain oral pH and ionic composition at
proper levels; disruption of any of these can alter taste
sensation (Spielman, 1998). Saliva also has another role in
taste, which has only recently been elucidated and which
is also impaired by xerostomia—saliva modulates some
long-lasting flavors by trapping free thiols produced by
oral anaerobic bacteria (Starkenmann et al., 2008). Bacte-
ria convert odorless sulfur compounds in some fruits and
vegetables (grapes, onions, and bell peppers) into odorif-
erous thiols after the foods had been swallowed (the so-
called “retroaromatic effect”). The odoriferous thiols can
be perceived after 20–30 seconds and persist for several
minutes.
Xerostomia (dry mouth due to a lack of saliva, some-
times colloquially called “cotton mouth” or “dough
mouth”) is a common cause of conductive hypogeu-
sia in the elderly. Xerostomia can occur with the use of
various medications (such as anticholinergic medications
and diuretics) and with tobacco smoking, diabetes mel-
litus, radiation therapy for head and neck cancers, and
Sjögren’s syndrome (Spielman, 1998). Breath mints, sug-
arless chewing gum or lozenges, artificial saliva products,
citric acid mouthwashes, and systemic pilocarpine can
each be of modest symptomatic benefit in patients with
xerostomia.
Sensorineural and central gustatory
disturbances
Taste sensations are mediated by polarized neuroepithe-
lial cells that are clustered into taste buds scattered across
the dorsal surface of the tongue and are present to a lesser
degree on the soft palate, pharynx, epiglottis, larynx, and
the first third of the esophagus. The facial (via the chorda
tympani), glossopharyngeal, and vagus nerves transmit
taste signals from the taste receptor cells to the rostral
portion of the nucleus of the solitary tract in the dorsal
medulla. Chemesthetic (pungent) sensations in the oral
cavity are mediated separately via the trigeminal nerve
and also via free nerve endings in the chorda tympani,
glossopharyngeal, and vagus nerves. Such sensations are
considered to be a form of nociception distinct from taste
(Schiffman, 1997).
From the nucleus of the solitary tract, taste-responsive
axons project through the ipsilateral central tegmental
tract in the pons, decussate at a higher level (probably
in the midbrain), and project to the ventroposteromedial
nucleus of the thalamus and to other sites, including the
lateral hypothalamus and the amygdala (Lee et al., 1998;
Sánchez-Juan and Combarros, 2001). In the elderly, inter-
ruption of the central gustatory pathway in the brain-
stem most commonly results from lateral pontine strokes
(Sánchez-Juan and Combarros, 2001; Landis et al., 2006).
Gustatory neurons in the thalamus project to the primary
gustatory cortex, which in humans has been tentatively
localized to the transition area between the posterior
insula and parietal operculum and the central sulcus
(Kobayakawa et al., 2005). Cortical areas involved in pro-
cessing gustatory stimuli are located in the insula, the
frontal and parietal opercula, and the orbitofrontal cortex
(Small et al., 1999). In right-handed individuals, the left
cerebral hemisphere contains a gustatory representation
of both hemitongues, whereas only the right hemitongue
is represented in the right hemisphere (Sánchez-Juan and
Combarros, 2001; Mathy et al., 2003).
Severe symptomatic neural or central hypogeusia rarely
occurs as a clinical entity, particularly in isolation. Never-
theless, sensorineural or central gustatory disorders can
potentially result from damage to any part of the gusta-
tory neural pathway from the tastebuds via the cranial
nerves conveying gustatory sensation (the facial, glos-
sopharyngeal, and vagal nerves), through the brainstem
and thalamus to the cerebral cortex (Heckmann and Lang,
2006). Sensorineural and central gustatory disorders in
the elderly may be caused by drugs, toxins, and physical
agents; damage to the cranial nerves conveying gustatory
sensation (for example, isolated cranial mononeuropathy
as with Bell’s palsy, or cranial polyneuropathy); space-
occupying processes (particularly with tumors involv-
ing the cerebellopontine angle or the jugular foramen);
degenerative disorders (such as PD or AD); seizures; and
depression.
Presbygeusia
Presbygeusia (literally “elderly taste” or “old age taste”)
is the gradual loss of taste that occurs in most people as
they grow older. The elderly have higher detection and
recognition thresholds for taste than younger individuals,
and taste sensitivity is further compromised by medica-
tions and comorbid medical problems (Schiffman, 1997;
Spielman, 1998). Healthy elderly people have higher

thresholds for each taste category (sweet, sour, salty,
bitter, and umami/savory), particularly for bitter sub-
stances, with the average threshold for taste rising four-
fold in the elderly (Frank et al., 1992; Schiffman, 1997;
Spielman, 1998). The changes in taste sensitivity make
food seem relatively tasteless and contribute to difficul-
ties complying with dietary regimens (such as a low-salt
diet for management of hypertension) (Schiffman, 1997).
Chemosensory deficits reduce the pleasure obtained
from eating, and represent risk factors for nutritional
deficiencies and for nonadherence to dietary regimens
(Duffy et al., 1995; Schiffman, 1997). Lower olfactory per-
ception in elderly women is associated with lower inter-
est in food-related activities (such as cooking and eating
a varied diet), a lower preference for foods with either a
predominantly sour or bitter taste (such as citrus fruits) or
pungency (such as horseradish), a higher intake of sweets,
and a lower intake of low-fat milk products (Duffy et al.,
1995). Nutritional adequacy should be assessed in elderly
women with a self-reported or measured difficulty in
perceiving odors or flavor (Duffy et al., 1995). Flavor-
enhanced food can have a positive effect on food intake
and can increase enjoyment of food and improve the qual-
ity of life for elderly patients with chemosensory deficits
(Schiffman, 1997). Flavor enhancements with simulated
flavors can be used to amplify odor intensity, to improve
the enjoyment of eating, and to facilitate adequate nutri-
tion in the elderly with hyposmia (but not anosmia)
(Schiffman, 1997). Simulated flavors are mixtures of odor-
iferous substances that are either extracted from natural
substances (as with concentrated orange juice or vanilla)
or synthesized de novo (as with vanillin in artificial
vanilla).
Burning mouth syndrome
Burning mouth syndrome is an uncommon painful intra-
oral disorder affecting mostly postmenopausal women
(Spielman, 1998). The pain is described as an uncomfort-
able constant burning sensation in the mouth affecting
particularly the anterior tongue, palate, and lips. This
may be associated with paresthesias or a numb sensation
in the mouth or on the tip of the tongue, as well as a sensa-
tion of dry mouth and increased thirst, without associated
mucosal lesions. Approximately two-thirds of affected
individuals report dysgeusia or persistent abnormal taste
sensations (which might be termed “palingeusia”) (Spiel-
man, 1998). Most have alterations in sensations of salti-
ness, and some have alterations in sweet, sour, and bitter
tastes (Spielman, 1998). The persistent taste sensations are
most often described as bitter or metallic (torqugeusia)
(Spielman, 1998). Risk factors include older age, female
gender, menopausal status, status as a “supertaster”
(with a high-density of lingual papillae), upper respira-
tory infection, previous dental procedures, medications,
traumatic life events, and stress (Brailo et al., 2006). The
Disorders of the Special Senses in the Elderly 443
etiology of burning mouth syndrome appears to be multi-
factorial; various conditions have been associated with it,
including menopause, endocrine disorders (such as dia-
betes and hypothyroidism), nutritional disorders (such as
deficiencies of iron, zinc, thiamine, riboflavin, pyridoxine,
folate, and cobalamin), xerostomia (such as from Sjögren’s
syndrome or other causes), medications (especially anti-
convulsants and angiotensive-converting enzyme inhibi-
tors), gastroesophageal reflux, postnasal drip, oral can-
didiasis, tongue plaque, removable dentures, halitosis,
and mouth irritation (such as from overbrushing of the
tongue, mouthwash, or acidic drinks) (Spielman, 1998;
Salort-Llorca et al., 2008). Many cases, however, are idio-
pathic. Burning mouth syndrome can be disabling and
may cause a variety of complications, including anorexia,
weight loss, insomnia, irritability, depression, anxiety,
and impaired socialization. The treatment depends on the
etiology (if it can be identified). For primary (idiopathic)
burning mouth syndrome, saliva-replacement products,
oral rinses, clonazepam (applied topically or taken orally),
gabapentin, selective serotonin reuptake inhibitor anti-
depressants, alpha-lipoic acid, B vitamins, and capsaicin
have all been employed, with variable but limited success
(although high-quality trials are lacking) (Mínguez Serra
et al., 2007; Buchanan and Zakrzewska, 2008).
Cerebrovascular disease
Taste disorders are common, although underrecognized,
in acute stroke, with hypogeusia occurring in approxi-
mately 30% of cases (Heckmann et al., 2005). Stroke-
related hypogeusia is typically unilateral with brainstem
strokes (Landis et al., 2006) but is strictly unilateral in only
a minority of patients with cerebral infarction (Heckmann
et al., 2005). Risk factors for stroke-associated gustatory
loss include male gender, greater stroke-related func-
tional impairment, dysphagia, and anterior circulation
location, especially involving the periopercular frontal
lobe (Heckmann et al., 2005). Interruption of the gusta-
tory pathway in the brainstem usually occurs with lateral
pontine stroke (Landis et al., 2006). Thalamic hypogeusia
may be associated with a cheiro-oral syndrome (Sánchez-
Juan and Combarros, 2001). Stroke-related damage to the
left insula causes an ipsilateral deficit in taste intensity
but a bilateral deficit in taste recognition, suggesting that
the left insula is dominant for taste recognition (Pritchard
et al., 1999; Mathy et al., 2003). Stroke-associated dys-
geusia and hypogeusia often persist while other deficits
improve and can contribute to unwanted weight loss
poststroke (Mathy et al., 2003; Finsterer et al., 2004).
Lewy body alpha-synucleinopathies
Although less common than olfactory defects, impaired
taste appreciation is also present in about a quarter of
patients with clinically defined PD, independent of age,
disease severity, or olfactory deficits (Shah et al., 2009).
444 Neurologic Conditions in the Elderly
Given the sparing of the first- and second-order taste
neurons in PD, a disorder of taste may indicate involve-
ment of primary or secondary gustatory cortical areas,
although confounding by drug effects (such as anticho-
linergic drugs) and changes in salivary constitution are
possible (Shah et al., 2009).
Acknowledgments
The author thanks Phyllis Goetz, MLS; Erin McGinnis,
BSIR; Debra Alexander-Friet, MLIS; and Tammy Els-
ing, Tomah VA Medical Center Library, for assistance in
obtaining reference materials, as well as Anjela K. Krome,
OD, for reading sections of the chapter and for providing
constructive suggestions.
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 Chapter 18
Nervous System Infections
Ronald Ellis1, David Croteau1, and Suzi Hong2
1
Department of Neurosciences and HIV Neurobehavioural Research Center, University of California, San Diego, CA, USA
2
Department of Psychiatry, School of Medicine, University of California, San Diego, CA, USA

Summary
• Acute bacterial meningitis is among the most important neurologic emergencies and is diagnosed by blood cultures
and lumbar punctures (LPs) for cerebrospinal fluid (CSF) analyses. Viral meningitides are self-limited and less serious
conditions than bacterial meningitides. Mycobacterial and fungal meningitides are examples of chronic infectious
meningitides.
• Acute viral encephalitis is mostly caused by viruses such as herpes viruses, arboviruses, and enteroviruses.
CSF analysis is essential for diagnosis.
• Clinical manifestations of intracranial abscesses are fever, raised intracranial pressure (ICP), and focal neurologic deficit.
Brain imaging, particularly MRI and CT, are vital for diagnosis.
• Myelitis is diagnosed through spine MRI and CSF analyses. Spine MRIs usually have T2 hyperintense signal abnormality
and CSF usually shows lymphocytic pleocytosis with or without hyperproteinorachia, and normoglycorrhachia.
• Varicella zoster virus (VZV), septic encephalopathy, human immunodeficiency virus (HIV), and immunosenescence
effects in the elderly are further discussed.

Introduction pathogens is beyond the scope of this chapter, so refer-

ences for more comprehensive reviews are provided. We
Despite the availability of advanced antimicrobial thera- describe pathogens to which the elderly patient is more
pies, infectious diseases remain a major cause of morbid- susceptible, along with specific differential diagnostic
ity and mortality in the elderly. Infections of the central considerations in this patient population. In addition,
and peripheral nervous systems demand special consid- this chapter discusses appropriate treatments and tox-
eration in older individuals, for several reasons. First, icities to which the elderly patient is more susceptible.
age-related changes in immunity particularly impact the An anatomopathologic approach is employed whenever
central nervous system (CNS). Second, changes in the
Table 18.1 Infectious anatomopathologic syndromes and clinical
blood–brain barrier (BBB) and blood–cerebrospinal fluid
features specific to the elderly
barriers (BCB), particularly in glycoconjugates that serve
as bacterial receptors, may explain increased susceptibil- Infectious syndrome Clinical features specific to the elderly
ity to CNS infection by specific pathogens (Tuomanen, Acute bacterial Less acute onset (for example, days
1994; Shah and Mooradian, 1997). Third, as enumerated meningitides versus hours)
in Table 18.1, there are several important ways in which Predominant encephalopathy with variable
the clinical presentation of CNS infectious diseases in the (sometimes absent) meningeal irritation
elderly differs from that of younger individuals. Finally, and fever
systemic diseases in the elderly can masquerade as CNS Acute viral meningitides Encephalopathy present
infections, as for example, when fever in the context of Chronic infectious Predominant personality or cognitive
pneumonia or urinary tract infection “unmasks” preexist- meningitides changes, fever that may be minimal or absent
ing focal neurologic deficits, leading to a false impression Acute viral Altered consciousness not correlating
of focal CNS infection. encephalitides with overall disease severity, fever may be
minimal or absent
This chapter addresses common neurologic disorders
Intracranial abscess Encephalopathy more prominent than
related to specific bacterial, mycobacterial, fungal, and
focal features
viral pathogens, including human immunodeficiency
Other spinal canal Minimal or absent fever
virus (HIV) infection. Prion diseases are discussed in
infections
a separate chapter. An exhaustive review of specific

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

460

possible to facilitate syndrome recognition and differen-
tial diagnosis generation. Because clinical manifestations
of nervous system infections reflect complex interactions
between specific pathogens and the immune system, we
discuss pathogen-specific immune responses throughout
the chapter. Finally, at the end of the chapter, we review
immunosenescence (age-related changes in immune func-
tion) both generally and in the CNS specifically.
Infectious meningitis
Acute bacterial meningitis is among the most impor-
tant neurologic emergencies because early recognition,
prompt diagnosis, and rapid institution of therapy can
save lives and prevent permanent disability. Meningitis
is defined as any inflammatory process that involves the
meninges, including the pia, the arachnoid, and the dura
matter. Bacteria can reach the CNS through hematogenous
spread (for example, nasopharyngeal colonization and
blood stream invasion or bacteremia from any sources),
extension from paracranial structures (such as paranasal
sinuses, skull osteomyelitis, and mastoiditis, although
rare in the elderly), and by direct implantation through
intracranial surgeries, ventriculoperitoneal shunt, intra-
cranial hardware (such as deep brain stimulation devices
or intracranial electrodes), or, rarely, lumbar puncture
(LP). The clinical presentation of bacterial meningitis in
older patients differs from that of younger adults in sev-
eral ways. Whereas symptom onset is typically abrupt
in younger adults, symptoms may evolve over several
days in older patients. Also, whereas the cardinal clini-
cal manifestations in younger adults include headache,
fever, and nuchal rigidity, elderly patients often present
with encephalopathy (altered consciousness, behavior,
and cognition), less frequently accompanied by fever and
signs of meningeal irritation. Indeed, encephalopathy
with fever in older individuals should not be ascribed to
other causes until bacterial meningitis has been excluded
by cerebrospinal fluid (CSF) examination. Encephalopa-
thy may also be the result of raised intracranial pressure
(ICP) or ongoing nonconvulsive seizures, both caused
by the primary infectious process. Whereas younger
patients who develop acute bacterial meningitis exhibit
limited neck flexion (nuchal rigidity) that is more specific
for meningeal irritation, older patients with or without
meningitis frequently have degenerative cervical spine
disease that produces limitations also in neck extension,
lateral flexion, and rotation.
Other clinical findings that may be present, although
less frequently in the elderly, include nausea and vomit-
ing; photophobia; Brudzinski (knee and hip flexion asso-
ciated with passive neck flexion in supine position); and
Kernig (back and leg pain elicited by knee extension while
hips are flexed in supine position) signs, reflecting spinal
Nervous System Infections 461
nerve roots inflammation and reflex muscle spasm and
pain; seizures; focal deficits, which are usually the result
of an inflammatory or vascular complication such as arte-
ritis, septic venous thrombosis, cerebritis, or subdural
empyema; cranial neuropathy, particularly with Listeria
monocytogenes meningitis; or cutaneous rash with Neisseria
meningitidis. The differential diagnosis of acute bacterial
meningitis includes viral meningitis, viral encephalitis,
intracranial abscess, and subarachnoid hemorrhage. With
less acute meningitis presentations, etiologic consider-
ations include mycobacterial and fungal meningitis, as
well as carcinomatous or lymphomatous meningitis.
The symptomatic manifestations of bacterial men-
ingitis depend in part on the specific pathogen and the
immune responses to it. Extracellullar bacteria, such as
Staphylococcus and Streptococcus spp., N. meningitidis, and
Escherichia coli (gram-negative bacilli), replicate outside of
cells. These pathogens produce toxins and induce innate
immunity acutely (for example, phagocytosis by neutro-
phils and monocytes/macrophages, and cytokine pro-
duction), followed by adaptive immune responses (such
as antibody production) that aim to neutralize bacterial
toxins and eliminate the pathogens. These inflammatory
responses are often responsible for fever, edema, and
tissue damage at the site of the infection and, in severe
cases, for septic shock. A polymorphonuclear (PMN) CSF
pleocytosis reflects phagocytes recruited to the site of the
infection, and this response may be limited in immuno-
compromised individuals, such as those with HIV infec-
tion or transplant recipients. On the other hand, intracel-
lular bacteria such as mycobacteria and L. monocytogenes
are capable of surviving and replicating inside phago-
cytes, partly explaining their propensity to cause more
chronic or persistent infections. In the case of intracel-
lular pathogens, adaptive cell-mediated immunity (such
as T and B lymphocytes) plays a major role in resolving
infection. Such chronic infections caused by intracellu-
lar bacteria result in prolonged activation of the immune
system and may cause permanent, severe tissue damage.
Paradoxically, older individuals demonstrate greater and
more prolonged inflammatory responses but diminished
immune clearance of bacterial infections. As a result, early
diagnosis and treatment are key to obtaining optimal
outcomes.
The diagnosis of acute bacterial meningitis requires
blood cultures and urgent LP for CSF analyses. Anti-
biotic therapy must be started promptly because delay
may result in the formation or progression of purulent
exudates in the subarachnoid space and ventricles, with
consequent diffuse brain edema. Brain computed tomog-
raphy (CT) before LP is indicated when clinical evidence
of raised ICP or focal findings are present, such as with
papilledema (Kastenbauer et al., 2002). Brain imaging
also is indicated in patients with new-onset seizures or
immunocompromised states, to rule out cerebral mass
462 Neurologic Conditions in the Elderly

Table 18.2 CSF differential diagnosis in acute and chronic meningitisa

Pleocytosis Protein Glucose Meningitis type Selected investigation

PMN >1000/mm3 ↑ ↓ Bacterial Bacterial cultures, antigen testing

PMN <1000/mm 3 ↑ Normal Early viral Select viral PCR
Lymphocytes <1000/mm3 ↑ Normal Aseptic (viral or drug induced) Select virus PCR, acute and convalescent
serologies
Lymphocytes <1000/mm3 ↑ ↓ Partially treated bacterial, Bacterial antigen testing, India ink, fungal
fungal, mycobacterial, neoplastic, cultures and antigens, AFB, cytology, ACE
granulomatous (sarcoidosis)

PMN, polymorphonuclear; PCR, polymerase chain reaction; AFB, acid fast bacilli; ACE, angiotensin-converting enzyme.
aNote that these ranges are general guidelines only. Exceptions may arise in selected cases.

lesions that may precipitate brain herniation after LP.
However, because suspected bacterial meningitis is a
neurologic emergency, LP should be done immediately in
the absence of these risk factors, as a definitive microbio-
logic diagnosis is important to guide appropriate antibi-
otic selection. When the need for CT significantly delays
LP, blood cultures should be obtained and empiric anti-
biotic therapy administered based on the clinical setting.
Although antibiotic therapy takes a few hours to steril-
ize CSF, and culture results are often positive for the first
several hours after antibiotic administration, every effort
should be made to obtain CSF before or within 1–2 hours
of antibiotic therapy initiation.
CSF analyses are useful in distinguishing bacterial
meningitides from other types of meningitis (Table 18.2).
For bacterial meningitis, LP and CSF analyses may show
elevated opening pressure, hyperproteinorachia (high
protein; typically 100–150 mg/dL), and hypoglycorrha-
chia (low glucose), usually defined as a CSF-to-serum
glucose ratio of less than 0.5. However, clinicians should
bear in mind that this ratio assumes a normal serum glu-
cose. In diabetes mellitus, a frequent comorbidity in older
patients, the rule may be broken. Thus, in hyperglycemic
states, a CSF-to-serum glucose ratio substantially lower
than 0.5 may be normal, and appropriate adjustments
should be made using a nomogram (Skipper and Davis,
1997). Bacterial meningitis usually produces a PMN pleo-
cytosis (increased cell count) greater than 1000/mm3, but
if the pleocytosis is less than 1000/mm3, one should sus-
pect partially treated bacterial meningitis, immunosup-
pression, or a nonbacterial cause, such as an early viral
meningitis. As an exception to the rule of PMN pleocyto-
sis, Streptococcus spp. meningitis may occasionally pres-
ent with a lymphocytic predominance. Finally, paranasal
sinuses plain X-ray (or CT, if brain CT was performed)
and chest X-ray may be performed to document a pri-
mary infectious focus.
Table 18.3 summarizes current antimicrobial recom-
mendations for bacterial meningitis in the elderly, by spe-
cific bacterial pathogens. Antibiotic selection depends on
the clinical setting, with important considerations being
drug allergies, comorbid medical conditions, local antibi-
otic resistance patterns, and laboratory findings, includ-
ing CSF analyses results. When LP is delayed or the Gram
stain is nondiagnostic, empiric therapy is initiated (Fitch
and van de Beek, 2007). In the elderly patient, organisms
such as Streptococcus pneumoniae, L. monocytogenes, and
gram-negative bacilli (for example, E. coli, Klebsiella pneu-
moniae, and Pseudomonas aeruginosa) are the most com-
mon offenders and should be covered empirically. Until
recently, empiric coverage included ampicillin to cover
most S. pneumoniae and L. monocytogenes cases, plus a

Table 18.3 Specific therapy of bacterial meningitis in the elderly

Microorganism Antibiotic Comments

H. influenzae Third-generation cephalosporins Covers ampicillin-resistant H. influenzae; duration 7–10

days
S. pneumoniae Third-generation cephalosporins + Normally sensitive to penicillin G and ampicillin; duration
vancomycin (for penicillin-resistant strains) 10–14 days
L. monocytogenes Ampicillin + gentamicin Ampicillin only bacteriostatic; cephalosporins inactive;
gentamicin duration 14–21 days and 6 weeks for
cerebritis
Gram-negative bacilli Third-generation cephalosporins Ceftazidime or aminoglycoside for P. aeruginosa; duration
21 days
S. aureus Vancomycin Covers methicillin-resistant S. aureus

third-generation cephalosporin such as cefotaxime, cef-
triaxone, or ceftazidime for gram-negative bacilli. How-
ever, local resistance patterns influence empiric antibiotic
coverage in adults with community-acquired meningitis.
For example, with the emergence of ampicillin-resistant
S. pneumoniae in some regions, vancomycin is included
empirically until susceptibility is confirmed.
Although Haemophilus influenzae is infrequently observed
in the elderly, it should be considered and covered if there
is any comorbid immunosuppression. In the settings of
head trauma, neurosurgery, or ventriculoperitoneal shunt,
Staphylococcus spp. (including S. aureus) should be covered
with vancomycin and gram-negative bacilli with a third-
generation cephalosporin such as cefotaxime, ceftriaxone,
or ceftazidime. Ceftazidime, unlike other third-generation
cephalosporins, covers Pseudomonas spp. and is reserved
for situations in which this organism is suspected as or
proven to be the cause of the meningitis.
Adjunctive therapy with dexamethasone should be
strongly considered to reduce mortality and morbid-
ity, particularly if there is raised ICP or very high bac-
teria concentration in CSF. In a recent study in the
Netherlands, adjunctive treatment of S. pneumoniae men-
ingitis with dexamethasone in 84% of patients from 2006
to 2009 significantly improved favorable outcomes and
mortality compared with less widespread use of dexa-
methasone in 3% of patients from 1998 to 2002 (Brouwer
et al., 2010). However, if an infectious agent other than S.
pneumoniae or H. influenzae is suspected or proven, dexa-
methasone should be stopped, as benefit has not been
demonstrated for other organisms (de Gans and van de
Beek, 2002; Tunkel and Scheld, 2002). Dexamethasone
0.15 mg/kg body weight should be initiated at the same
time as or shortly before the first dose of antibiotics and
continued every 6 hours for 2–4 days. The rationale for
giving dexamethasone before antibiotic therapy is the
inhibition of production of tumor necrosis factor alpha
(TNF-α) mRNA before macrophages and microglia are
activated by bacterial cell wall components. Some authors
recommend the use of rifampin with dexamethasone,
as the reduction in inflammation with corticosteroids
may impair the penetration of vancomycin into CSF. In
treating penicillin-resistant S. pneumoniae meningitis, a
second CSF study after 24–48 hours is recommended to
document bacteriologic improvement because adjuvant
dexamethasone may mask clinical signs of poor antibiotic
response (Quagliarello and Scheld, 1997). Prophylactic
anticonvulsants are not indicated, as they have not been
shown to reduce seizure incidence, may cause significant
toxicity, and may alter antibiotic metabolism by hepatic
enzyme systems induction. However, any seizure should
be treated promptly with appropriate agents, including
benzodiazepine and fosphenytoin.
Worse prognosis in terms of morbidity and mortality
can be expected in the following settings: advanced age,
Nervous System Infections 463
altered level of consciousness, raised ICP, seizures and
focal neurologic deficits, and S. pneumoniae as the caus-
ative organism, because of its propensity to cause arteri-
tis. Residual sequelae in the elderly may include behav-
ioral and cognitive impairment, focal neurologic deficits,
and seizures.
Viral meningitides, also called aseptic meningitides,
are self-limited and less serious conditions than bacterial
meningitides. However, they have similar clinical mani-
festations, including fever, headache, nausea, photopho-
bia, and nuchal rigidity. Focal neurologic deficits, raised
ICP, and seizures are absent, but some encephalopathy
may be present, particularly in the elderly patient. As
with acute bacterial meningitides, viral meningitides
are diagnosed with CSF examination. Hyperproteinora-
chia, normoglycorrhachia, and a lymphocytic pleocytosis
less than 1000/mm3 are typically observed (Table 18.2).
However, in up to one-third of cases, viral meningitis will
present with a predominant, often transient PMN pleocy-
tosis. Bacteria will be absent from the CSF gram stain, bac-
terial cultures and antigen studies will be negative, and
no parameningeal infectious foci (such as abscess) will be
identified.
Enteroviruses (for example, coxsackieviruses and echo-
viruses) are the most common cause of viral meningitides,
followed by herpes simplex virus, HIV, arthropod-borne
viruses, also called arboviruses (such as the West Nile
virus), more commonly causing encephalitis and, less
commonly, lymphocytic choriomeningitis virus (LCMV).
Specific virologic diagnosis can be pursued with CSF real-
time polymerase chain reaction (PCR) (for DNA viruses)
and reverse transcriptase PCR (for RNA viruses) and other
methods (such as acute and convalescent specific serum
IgG), although the sensitivity and specificity of pathogen-
specific PCR vary (Debiasi and Tyler, 2004). Viral cultures
are difficult and have been largely replaced by PCR.
In patients with suspected viral meningitis, the fol-
lowing differential diagnoses should be considered in
addition to acute bacterial meningitis: viral encephali-
tis (especially herpes simplex virus); chronic meningiti-
des such as those due to mycobacteria, fungi, metastatic
neoplasms (carcinomatous or lymphomatous), and sar-
coidosis; and drug-induced meningitis. Infectious and
neoplastic chronic meningitides are similar to viral men-
ingitis, as they are associated with lymphocytic pleocyto-
sis; they also differ, in that the CSF glucose level is often
depressed (Table 18.2). Drug-induced meningitis in older
patients may be due to nonsteroidal anti-inflammatory
agents (such as ibuprofen) or sulfa-containing antibiot-
ics (such as trimethoprim-sulfamethoxazole). The latter
often are used to treat problems that are common in the
elderly, such as arthralgia and urinary tract infections
(Wambulwa et al., 2005; Periard et al., 2006).
Among patients with viral meningitis of undetermined
cause, empiric acyclovir therapy is prudent until PCR
464 Neurologic Conditions in the Elderly
can rule out herpes simplex virus meningoencephalitis.
Otherwise, given the self-limited nature of most viral
meningitides, treatment is mostly supportive with anal-
gesics and antipyretics. An exception is HIV serocon-
version meningitis, in which combination antiretroviral
therapy (cART) should be offered. Other antivirals may
also be used if a specific microorganism is identified or
suspected.
Innate immune responses during the early phase of
viral meningitis include immediate interferon (IFN)
production by virus-infected cells and killing of infected
cells by natural killer (NK) cells. These are followed by
antibody production to inhibit viral entry into host cells,
limiting virus spread (adaptive humoral immunity) and
killing of infected cells by virus-specific cytotoxic T lym-
phocytes (adaptive cellular immunity). Many viruses
(such as HIV and rhinovirus) present antigenic variation
to evade immune surveillance by virus-specific T lym-
phocytes, and the presence of varying serotypes results
in ineffective immunization against certain viral strains.
Decreased ability of the immune system to respond to
and resolve viral infections efficiently due to immunose-
nescence in the elderly can lead to chronic infection and
prolonged activation of the immune system and inflam-
mation.
Chronic infectious meningitides include mycobacterial
(such as Mycobacterium tuberculosis) and fungal menin-
gitides (such as Cryptococcus neoformans and coccidioi-
domycosis). Like mycobacteria, many fungi can reside
inside phagocytes and other cells, accounting for their
predilection to produce chronic and persistent infections.
Although clinicians frequently associate these disorders
with immunosuppressed hosts or those with comor-
bidities such as diabetes mellitus, they may occur also
in immunocompetent older patients. Diagnosis may be
delayed in the elderly due to a more indolent presenta-
tion, but suspicion should be high because these condi-
tions carry a grave prognosis if left untreated. Chronic
meningitis presents with subacute or chronic headache
and encephalopathy, including personality change and
cognitive impairment. Cranial mononeuropathies (IV, V,
VI, VII, VIII) are an important clue suggesting inflamma-
tion of cranial nerves in the subarachnoid space at the
base of the brain. Chronic meningitis differs from acute
meningitidis, in that fever and nuchal rigidity may be
absent or mild. In the elderly, encephalopathy can be
the major or only presenting clinical feature and may
be mistakenly ascribed to a depressive mood disorder
or degenerative dementia. If chronic meningitis remains
untreated, late neurologic complications can include sei-
zures, focal neurologic deficits due to arteritis and infarc-
tion (M.  tuberculosis), raised ICP from space-occupying
lesions (such as tuberculoma or cryptococcoma), or
hydrocephalus due to impaired subarachnoid CSF flow
or CSF reabsorption through arachnoid granulations.
Identification of a systemic infectious focus of disease
such as pulmonary tuberculosis or fungal infections or a
known cancer in many cases strongly points to a specific
pathogen or noninfectious etiology (such as carcinoma-
tous meningitis). M. tuberculosis typically reaches the CNS
through hematogenous spread of bacilli to the superficial
cortex or to subependymal regions–-sometimes in the set-
ting of a so-called miliary disease–-forming microtuber-
cles that rupture in the CSF. Occasionally, M. tuberculosis
meningitis results from a parameningeal abscess or osteo-
myelitis. Fungal microorganisms such as C. neoformans
and Coccidioides spp. typically access the CNS through
hematogenous spread from a primary site, such as lung,
gastrointestinal or nasopharyngeal mucosa, or skin.
Definitive diagnosis of chronic meningitis requires CSF
analyses. CSF analyses typically show a lymphocytic pleo-
cytosis with hyperproteinorachia and hypoglycorrhachia.
Occasionally, PMN pleocytosis may be observed in early
disease or in cases of superficial abscess/granuloma for-
mation, or may represent a hypersensitivity reaction to
microbial antigens, particularly those of M. tuberculosis.
A specific microbiologic diagnosis may be obtained with
the following: specific smear and staining, including
acid fast bacilli (AFB), India ink (facilitating cryptococ-
cus membrane polysaccharide capsule visualization),
and cryptococcal antigen; cultures; and PCR. In addition,
tuberculin testing or IFN-gamma release assays may be
useful in low-prevalence areas. Neuroimaging with mag-
netic resonance imaging (MRI) may show leptomeningeal
contrast enhancement, communicating or noncommuni-
cating hydrocephalus, and, uncommonly, space-occupy-
ing lesions. The meningeal contrast enhancement tends
to be located in the basal meninges. Over time, C. neofor-
mans can form small, gelatinous pseudocysts in Virchow–
Robin perivascular spaces in the basal ganglia, giving a
Swiss cheese or soap bubbles appearance best observed
on T2-weighted images. Systemic evaluation of chronic
meningitides should include at least a chest X-ray.
The differential diagnosis of chronic infectious men-
ingitides includes partially treated bacterial meningitis,
spirochetal meningitis with agents such as Treponema
pallidum (secondary syphilis) and Borrelia burgdorferi
(Lyme disease), and lymphomatous or carcinomatous
leptomeningeal metastases. If risk factors are present or in
endemic areas, serum should be tested for rapid plasma
reagin (RPR) and B. burgdorferi antibodies, and a CSF
venereal disease research laboratory (VDRL) titer should
be obtained. CSF should be collected and analyzed for
cytology in all patients, and suspicion should be particu-
larly high in cases with a known primary neoplasm.
The treatment of tuberculous meningitis is complex and
requires consideration of systemic disease, both pulmo-
nary and extrapulmonary. The input of an infectious dis-
ease specialist is invaluable. In general, initial treatment
should comprise a regimen of three to four drugs until

the patient’s clinical isolate is tested for drug susceptibil-
ity (Small and Fujiwara, 2001). Among these, isoniazid
and pyrazinamide are recommended, as they reach CSF
concentrations similar to plasma when meningeal inflam-
mation is present. Chemotherapy is continued for at least
6 months. Close monitoring should be performed for
side effects of antituberculous therapy because isoniazid,
ethambutol, and streptomycin can cause neurotoxicity.
To protect against sensorimotor axonal peripheral neu-
ropathy with isoniazid, pyridoxine supplements should
be given. In some patients, ethambutol causes optic and
sensory peripheral neuropathies, while streptomycin can
be ototoxic.
The cornerstone of cryptococcal meningitis therapy
remains amphotericin B with or without flucytosine for
CSF sterilization. In immunocompromised individuals
who show a clear clinical improvement with amphoteri-
cin B, fluconazole may be substituted after 2 weeks. Fluco-
nazole is then continued for 8–10 weeks of consolidation,
after which a chronic suppressive/maintenance phase is
begun (van der Horst et al., 1997). In immunocompetent
individuals, fluconazole may be stopped after 6–10 weeks
if symptoms have resolved, CSF glucose has normalized,
and repeat CSF cultures for C. neoformans have been nega-
tive on at least two consecutive taps. Additional manage-
ment considerations are treatment of the primary focus–-
most often the lung–-restoration of immunity if possible,
and therapy for neurologic complications such as hydro-
cephalus and seizures, if present.
Acute viral encephalitides
Viral encephalitis is a medical emergency requiring a
high index of suspicion to ensure prompt early treat-
ment initiation and the best possible prognosis. The term
encephalitis indicates inflammation of brain parenchyma
(cerebritis), but because some degree of leptomeningeal
inflammation is almost invariably present, meningoen-
cephalitis is usually the most appropriate descriptive
term. While many viral infections are asymptomatic in
the majority of affected individuals–-a feature known as
the “tip of the iceberg” phenomenon–-individuals who
express neurologic disease are likely to be older. Thus,
in one study, older individuals (60–79 years) were four
to five times more likely to suffer morbid and mortal
West Nile virus (WNV) disease than younger ones (30–49
years) Campbell et al., 2002.
Viral encephalitis typically causes fever and a rapidly
progressive encephalopathy with diffuse brain dysfunc-
tion that impairs the level of consciousness and cognitive
functions. Additional features overlap with those of viral
meningitis and include headache, meningismus, and
photophobia. In the elderly, these latter features may be
subtle or even absent. Additionally, although the degree
Nervous System Infections 465
of encephalopathy often correlates with the severity of the
encephalitis in younger patients, this relationship may be
less true in the elderly patient. Neuropsychiatric symp-
toms often predominate, including perceptual distur-
bances (illusions and hallucinations) and behavioral and
personality changes. Seizures, both partial and general-
ized, are common because of cortical involvement. Focal
neurologic deficits also may be present, as in the case of
receptive aphasia due to temporal lobe involvement by
herpes simplex virus 1 (HSV-1).
The frequent occurrence of delirium in elderly patients
with systemic infection can make the diagnosis of acute
viral encephalitis challenging. Thus, septic encepha-
lopathy (discussed later in a separate section), in which
delirium occurs despite the absence of brain parenchymal
involvement, is an important differential diagnostic con-
sideration in the elderly. Table 18.4 outlines other differ-
ential diagnostic considerations.
Viruses responsible for most cases of acute encephalitis
in immunocompetent individuals include herpes viruses,
arboviruses, and enteroviruses (Redington and Tyler,
2002). An exhaustive list of viral pathogens is beyond
the scope of this chapter and has been presented else-
where (Chaudhuri and Kennedy, 2002). Among the her-
pes viruses, HSV-1 is the most common cause of severe
sporadic viral encephalitis in adults in the United States,
followed by Epstein–Barr virus (EBV) and human her-
pes viruses 6 and 7 (HHV-6 and HHV-7). Herpes simplex
virus 2 (HSV-2) is a rare cause of encephalitis in adults.
Although cytomegalovirus (CMV) and varicella zoster
virus (VZV) can cause encephalitis, they more commonly
cause disease in immunocompromised individuals.
Arboviruses are arthropod-borne viruses; among them,
WNV has been the prototypical agent of epidemic viral
Table 18.4 Differential diagnosis of acute viral encephalitis
in the elderly
Fever and encephalopathy Encephalopathy without fever
Septic encephalopathy Metabolic disturbances
Viral or bacterial meningitides Nutritional deficiencies
Bacterial or fungal brain abscess Intoxication
Heat stroke Nonconvulsive status epilepticus
Drugs: anticholinergic intoxication, Cerebrovascular events: certain
neuroleptic malignant syndrome, strategically located ischemic
serotoninergic syndrome, and strokes, subarachnoid hemorrhage,
malignant hyperthermia CNS vasculitides, hypertensive
encephalopathy
Neoplasm (such as high-grade
supratentorial tumor)
Paraneoplastic disorders or
autoimmune encephalitides (such
as limbic encephalitis)
Demyelinating disorders
(such as acute disseminated
encephalomyelitis
466 Neurologic Conditions in the Elderly
encephalitis since the outbreak of summer 1999 in the
United States. Enteroviruses such as coxsackie- and echo-
virus can cause viral encephalitis, although they more fre-
quently cause epidemic aseptic meningitis.
Several diagnostic studies may help establish the diag-
nosis of acute viral encephalitis. A complete blood count
usually reveals a lymphocytic leukocytosis, although
lymphopenia may be seen with some viral infec-
tions. Although electroencephalography (EEG) is often
regarded as a nonspecific investigation, it may help dif-
ferentiate focal encephalitis such as HSV-1 from other
generalized encephalitides and from noninfectious causes
of encephalopathy. Periodic lateralized epileptiform dis-
charges (PLEDs), although seen in up to 50% of patients
with HSV-1 encephalitis, are of limited clinical utility
because they frequently do not appear until the later
stages of the illness. Cranial MRI is the imaging technique
of choice in acute encephalitis and may sometimes be
diagnostic (as with frontotemporal signal abnormalities
in HSV-1 encephalitis; see Figure 18.1). However, CT can
be obtained more rapidly and reliably in encephalopathic
patients and is useful to rule out other disorders, includ-
ing a cerebral space-occupying lesion, which would be a
contraindication to LP.
CSF analysis is an essential part of the investigation.
The CSF profile is indistinguishable from acute viral
meningitis and includes a lymphocytic pleocytosis, typi-
cally less than 500/mm3, normo- or hyperproteinorachia,
and normoglycorrhachia. PCR is the most sensitive viro-
logic study and is available for the most common viruses
(Debiasi and Tyler, 2004). For certain viruses (such as
HSV-1), PCR can provide results within a few hours and
may therefore be useful in guiding treatment or decid-
ing whether to continue antivirals. Acute and convales-
cent (4 weeks) specific serum IgG (more than fourfold
(a) (b)
Figure 18.1 Herpes simplex encephalitis. Axial T2-weighted image
showing hyperintense signal abnormality in the left mesial
temporal and basal frontal regions (a). Axial T1-weighted image
with gadolinium showing hypointense signal abnormality with
faint contrast enhancement in the same regions (b). Courtesy of
Dr. John Hesselink, MD, Department of Radiology, University of
California, San Diego.
increase) may occasionally be useful but is not commonly
used. CSF virus-specific IgM is indicative of intrathecal
synthesis and may also be useful. Viral cultures are dif-
ficult and have been largely replaced by PCR. Nowadays,
brain biopsy is reserved for when the diagnosis of HSV-1
encephalitis is doubtful or there is a need for surgical
decompression for raised ICP.
Specific therapy for viral encephalitis is limited to a
few specific pathogens. Thus, no approved therapy cur-
rently exists for enteroviruses or WNV (Diamond, 2009).
However, high-throughput screens of small molecules for
WNV and in vivo animal studies are ongoing. If HSV-1
encephalitis is suspected, empiric therapy with intrave-
nous acyclovir 10 mg/kg every 8 hours should be initi-
ated as soon as possible, and the need to continue this
should be reassessed based on clinical evolution and
specific virologic study results (Steiner et al., 2005). In
confirmed cases of HSV-1 encephalitis, acyclovir should
be continued for at least 14 days. Although acyclovir is
relatively safe, it requires dose adjustment for abnormal
renal function, a common problem in the elderly. Acyclo-
vir requires phosphorylation by viral thymidine kinase to
acyclovir triphosphate in order to inhibit viral DNA poly-
merase by competing with deoxyguanosine triphosphate.
The drug is effective due to the virus’s dependence on a
specific thymidine kinase that has high affinity for the
drug. The mortality rate for untreated HSV-1 encephali-
tis is approximately 70%, with less than 3% of the sur-
vivors returning to baseline neurologic status. Acyclovir
has reduced the mortality to 20–30%, but nearly half of
the survivors are left with significant neurologic disabil-
ity. Advanced age and altered level of consciousness at
presentation are poor prognostic factors.
Although acyclovir is not effective for the treatment
of CMV, HHV-6, and HHV-7, these viruses respond to
ganciclovir, a guanosine analog that requires triphos-
phorylation by three different kinases and that selec-
tively inhibits viral DNA polymerase. Ganciclovir is
given 5.0 mg/kg IV every 12 hours with or without
foscarnet, a pyrophosphate analog that does not require
any phosphorylation and inhibits directly viral DNA
polymerase, at a dose of 60 mg/kg every 8 hours (Ent-
ing et al., 1992).
With the exception of HIV infection (discussed in
the later section “HIV and the nervous system in the
aging population”), chronic infectious encephalitides
are uncommon in the elderly. These conditions include
subacute sclerosing panencephalitis (measles virus),
progressive rubella panencephalitis (rubella virus), and
progressive multifocal leukoencephalopathy (JC virus).
Although prion diseases including Creutzfeldt–Jakob
disease are often listed in this context, use of the term
encephalitis is not technically appropriate in this situation
because these disorders are not associated with brain
inflammation.

Intracranial abscesses
Intracranial abscesses are focal suppurative processes
that involve brain parenchyma or surround dura matter.
Determining the likely source or point of entry is essen-
tial, as it narrows the likely pathogens and, therefore,
dictates appropriate empiric antimicrobial treatment (Lu
et al., 2006). Intracranial abscesses arise from three pri-
mary sources: by contiguous spread from a paramenin-
geal focus, by direct contamination, or by hematogenous
spread. Contiguous spread likely occurs through valve-
less emissary veins, from an adjacent infected paracranial
structure such as the paranasal sinuses (causing frontal
lobe abscess), from the middle ear (causing temporal
lobe or cerebellar abscesses), or from teeth, oropharynx,
or bone (causing craniofacial osteomyelitis with epidural
abscess or subdural empyema). Risk factors for direct con-
tamination are open head trauma and neurosurgical pro-
cedures. Abscesses originating from contiguous spread
or direct contamination are usually solitary. In contrast,
hematogenous brain abscesses are often multiple, found
at the gray/white matter interface, and arise from a
remote source such as pyogenic lung disease, bacterial
endocarditis, intra-abdominal abscess, or urinary tract
infections. In addition to brain abscesses, bacterial endo-
carditis can lead to mycotic aneurysms through infected
emboli lodging into the vasa vasorum of the cerebral vas-
culature distal from the circle of Willis, resulting in vessel
wall weakening and aneurysm formation. Twenty per-
cent of brain abscesses remain occult without identifiable
sources. A variety of organisms can lead to brain abscess,
and mixed infections are present in 30–60%. Table 18.5
outlines specific etiologic considerations in the elderly.
Clinical manifestations of brain abscess include a clas-
sic triad of fever, raised ICP, and focal neurologic deficit.
Specific focal deficits depend on abscess location and
may range from aphasia (left temporal or parietal lobes)
to hemiparesis (frontal lobe or descending corticospinal
tracts), hemiataxia (cerebellar hemisphere), hemianop-
sia (occipital lobe or temporal isthmus), hemichorea, or
hemiballismus (basal ganglia). Manifestations of raised
ICP, including headache, emesis, altered level of con-
sciousness, and papilledema, are present in up to 70%
of patients. Fever, however, is not uniformly observed,
especially in the elderly, as only 30–50% of patients have
a temperature higher than 38.5°C. Elderly patients can
also exhibit a predominant encephalopathy, in addition to
focal neurologic deficit and raised ICP. Focal or general-
ized seizures occur in up to 50% of patients.
When a brain abscess is suspected, neuroimaging
is the key diagnostic study. The use of a contrast agent
is important, as there is often BBB disruption caused by
the accompanying inflammatory process. While MRI is
the most sensitive and specific modality, CT frequently
can be obtained more rapidly and provides helpful
Nervous System Infections 467
Table 18.5 Brain abscess microorganisms and portal of entry
Portal of entry Specific microorganisms
Contiguous spread
Paranasal sinus infections Streptococcus spp., Enterobacteriaceaea,
anaerobic organismsb
Odontogenic (oral) Streptococcus spp., anaerobic organismsb
infections
Direct contamination
Open head trauma Staphylococcus spp.,
Enterobacteriaceaea, anaerobic
organismsb, Clostridium spp.
Neurosurgical procedures Staphylococcus spp.,
Enterobacteriaceaea, Pseudomonas spp.
Hematogenous spread
Pulmonary origin Streptococcus spp., Nocardia spp.,
Actinomyces spp., anaerobic organismsb
Endocarditis S. viridans, S. aureus
Urinary tract origin Enterobacteriaceaea, Pseudomonas spp.
Intra-abdominal origin Enterobacteriaceaea, Streptococcus spp.
Special setting with
either contiguous or
hematogenous spread
Relative immunosuppression, M. tuberculosis, L. monocytogenes,
including diabetes mellitus Nocardia spp.
and advanced age T. gondii
Aspergillus spp., Mucormycosis,
Candida spp.
aIncludes gram-negative bacilli such as E. coli, K. pneumoniae, and
others.
bIncludes microorganisms such as Bacteroides spp., Peptococcus spp.,
Propionibacterium spp., and Fusobacterium spp.
diagnostic information. As outlined in Table 18.6, imag-
ing features depend on the stage of the bacterial abscess
at the time of imaging (Britt et al., 1981; Erdogan and
Cansever, 2008). Although a contrast-enhancing ring is
typical, this pattern may be absent during early abscess
evolution, and occasional multiloculated enhancement
is seen. Thickness, irregularity, and nodularity of the con-
trast-enhancing ring are suggestive of a neoplastic pro-
cess or a nonbacterial infectious etiology (such as fungal
or parasitic).
In addition to T1, T2, and fluid attenuated inversion
recovery (FLAIR) sequences, diffusion-weighted imaging
(DWI) can help differentiate brain abscesses from other
necrotic or cystic lesions, such as neoplasms (Chang et al.,
2002). DWI evaluates the movement (diffusion) of water
molecules in brain parenchyma. Restricted diffusion,
which appears hyperintense on DWI and hypointense
on corresponding apparent diffusion coefficient (ADC)
maps, suggests a bacterial abscess cavity (Figure  18.2).
Exceptions are fungal, tuberculous, and toxoplasmic
abscesses, in which restricted diffusion can be absent.
468 Neurologic Conditions in the Elderly

Table 18.6 Radiographic and pathologic correlation of bacterial brain abscess

Stage Histopathology Imaging

Early cerebritis Parenchymal softening, early necrosis, edema, vascular Low attenuation area on CT; T1 hypointense and T2
(1–4 days) congestion, and perivascular inflammation hyperintense signal abnormalities on MRI; absent or patchy
contrast enhancement

Late cerebritis Liquefaction, with necrotic debris (dead neutrophils, Similar to early cerebritis, with more mass effect and
(4–10 days) proteins) converted to pus contrast enhancement

Early capsule formation Fibroblasts from neovessels produce reticulin, which Same as cerebritis, but with formation of a new cavity and
(10–14 days) are converted to collagen in the capsule, which is highly a surrounding thin (thicker near cortex), smooth, contrast-
vascular, with a poorly developed BBB enhancing ring

Late capsule formation Abscess encircled by a vascularized, fibrotic capsule Enhancing ring better demarcated
(>14 days) and gliosis

Conversely, restricted diffusion is seen in some necrotic
tumors and cystic metastases, limiting the sensitivity and
specificity of DWI.
Screening investigation to identify the source of infection
is based on clinical history and physical findings but should
also include blood cultures, chest X-ray, and imaging of
Figure 18.2 Bacterial brain abscess. Axial T1-weighted without
(a) and with (b) gadolinium images shows a ring-enhancing
lesion in the left parieto-occipital region, with surrounding
hypointensity and mass effect. T2-weighted image shows
more extensive surrounding hyperintense signal abnormalities
reflecting edema (c). Diffusion-weighted image (d) shows a
hyperintense signal and the ADC map (e), a hypointense signal
indicating restricted diffusion. Reproduced from Bradley et al.
(2008), with permission from Elsevier.
paracranial structures, in addition to specific cultures and
imaging based on clinical suspicion. Definitive microbio-
logic diagnosis requires biopsy of the abscess, with evalua-
tion of purulent material by gram and AFB staining, as well
as aerobic, anaerobic, and fungal cultures.
The differential diagnosis of brain abscess depends
on the clinical circumstances and radiographic appear-
ance, including factors such as lesion stage and whether
solitary or multiple lesions exist. Etiologic considerations
include high-grade glioma, brain metastases, primary
CNS lymphoma, cerebral infarction, resolving cerebral
contusion or hematoma, cerebral radiation necrosis, and
demyelinating disease.
Cerebral abscesses are managed by aspirating the
purulent cavity or excising the entire abscess, followed
by parenteral antibiotic therapy for 6–8 weeks. Empiric
medical therapy is best avoided and should be reserved
for patients who have a microbiologic diagnosis from a
systemic source or who are too ill to undergo any surgi-
cal intervention (Moorthy and Rajshekhar, 2008). Small
abscesses and lesions at the cerebritis stage respond well
to medical therapy alone, however. Multiple abscesses
are best treated with aspiration of the largest lesion, fol-
lowed by antibiotic therapy. Excision may be required
if no imaging improvement is observed after aspiration
and/or medical treatment, as well as for mass effect relief
purposes. Typical empiric therapy, if required, should
include metronidazole to cover anaerobic organisms and
a third-generation cephalosporin to cover Enterobacteria-
ceae and Streptococcus spp., with or without vancomycin
to cover Staphylococcus spp. (in post-traumatic or neuro-
surgical settings). Corticosteroids may be used for tem-
porary mass effect relief. Prophylactic anticonvulsants
can be considered because up to 50% of patients will have
seizures in the acute period and up to 70%, following the
acute period (Lu et al., 2006). However, no randomized
controlled studies have been performed to study that
question. Anticonvulsant toxicities and hepatic enzyme
system induction potentially leading to interaction with
antimicrobial agents should also be kept in mind when
considering seizure prophylaxis and treatment.

Extraparenchymal abscesses are discussed briefly here.
Subdural empyema, defined as a suppurative process in
the virtual subdural space (between the dura matter and
subarachnoid membrane), is commonly the result of para-
cranial structures infections with contiguous spread, as
well as open head trauma and neurosurgical procedures.
Microorganisms are similar to those causing intraparen-
chymal brain abscesses but are less often mixed. Clinical
manifestations generally include fever, focal neurologic
deficit commensurate to location, and meningismus.
The treatment may include aspiration through a burr
hole or removal through craniotomy, along with appro-
priate antibiotics. Intracranial epidural abscess, a sup-
purative process taking place between the dura and the
skull, is similar to subdural empyema in terms of patho-
genesis, microorganisms (except for more frequent S.
aureus), clinical manifestations (except for meningismus,
which is uncommon), and treatment. Intraparenchymal
abscess, subdural empyema, and epidural abscess may
also occur simultaneously in the same patient.
Myelitides and spinal canal infections
Infectious myelitides are uncommon but must be differ-
entiated from other serious disorders. Myelitis is defined
as any inflammatory process involving the spinal cord
white matter, gray matter, or both. Infectious myelitis is
typically subacute, with clinical manifestations evolv-
ing over several hours or days, except for HIV vacuolar
myelopathy and human T lymphotropic virus (HTLV-1)
presenting with a chronic myelopathy. Various microor-
ganisms may cause myelitis, although the most common
offenders are viruses. Some viruses have specific tro-
pism for, or preferential involvement of certain anatomic
structures, which may help narrow the microbiologic
diagnosis, as outlined in Table 18.7. Acute viral myeli-
tis can present as acute flaccid paralysis (also referred as
poliomyelitis-like gray matter syndrome), particularly
Table 18.7 Myelitides microorganisms and clinical manifestations
Microorganism Anatomic structure tropism
VZV Dorsal root ganglia
HSV-2 Sensory roots
T. pallidum (meningovascular syphilis) No specific tropism
Poliovirus, coxsackieviruses, Anterior horn cells
enterovirus-70, 71, WNV
EBV No specific tropism
CMV Motor and sensory roots
HIV-1 Corticospinal tracts and dorsal columns
HTLV-1 Corticospinal tracts
Nervous System Infections 469
with enteroviruses or neurologic dysfunction due to
the involvement of the descending and ascending white
matter tracts (also referred as partial or complete white
matter syndrome), particularly with herpes viruses. The
latter usually affects only part of the transverse plane
of the spinal cord and manifests as asymmetric motor
and sensory symptoms. When both halves of the spinal
cord are affected, the entity is referred to as acute trans-
verse myelitis, and patients exhibit uniformly symmetric
weakness, sensory loss, and sphincter disturbances. The
presence of back pain should raise the suspicion for a
space-occupying lesion with spinal cord compression,
although it is also described with myelitides, particu-
larly postinfectious.
The diagnosis of infectious myelitis is established
by spine MRI and CSF analyses. Spine MRI typically
reveals a T2 hyperintense signal abnormality extending
over two to three segments or more extensive longitu-
dinal involvement, along with some mass effect from
edema, and contrast enhancement. The MRI may be ini-
tially normal and should therefore be repeated in sus-
pected cases of acute viral myelitides. CSF is obtained
to determine a microbiologic diagnosis. The CSF typi-
cally reveals a lymphocytic pleocytosis with or with-
out hyperproteinorachia, and normoglycorrhachia. A
PMN pleocytosis may be present with CMV and WNV
neuroinvasive infections. CSF real-time PCR (for DNA
viruses) and reverse transcriptase PCR (for RNA viruses)
for the various viruses outlined earlier and CSF VDRL
should be obtained based on clinical features. Viral
cultures are difficult and have been largely replaced
by PCR. Unfortunately, in most cases of isolated trans-
verse myelitis, a specific viral cause is never determined
(Kincaid and Lipton, 2006). The differential diagno-
sis of acute infectious myelitides includes spinal cord
compression, which must be ruled out with an urgent
spine imaging; demyelinating process either primary
(such as multiple sclerosis) or postinfectious; paraneo-
plastic; vascular disorders (such as ischemic infarction,
Distinguishing clinical manifestations
Radicular pain, dermatomal skin rash
Radicular pain, genital rash
None (isolated transverse myelitis)
Isolated flaccid paralysis
Mononucleosis symptoms or none (isolated
transverse myelitis)
Polyradiculopathy, cauda equina syndrome
Spastic paraparesis with sphincter disturbance
and sensory symptoms
Spastic paraparesis with sphincter disturbance
470 Neurologic Conditions in the Elderly
hematomyelia, dural vascular malformation, spinal
canal hemorrhage, and connective tissue diseases). The
differential diagnosis of chronic infectious myelitides is
much broader and encompasses degenerative disorders
(such as hereditary spastic paraparesis, spinocerebellar
ataxia, and primary lateral sclerosis), nutritional defi-
ciencies (such as vitamin B12 deficiency), and progres-
sive compressive myelopathies (such as spondylosis and
low-grade neoplasm). The treatment of acute infectious
myelitides is mainly supportive unless there is clinical
suspicion (such as genital or skin rash) or microbiologic
diagnosis of herpes virus infections or meningovascular
syphilis. Chronic myelitides are managed with specific
antiretrovirals or immunotherapy. Prognosis is variable,
but some degree of recovery usually occurs after acute
infectious myelitides.
Spinal canal infections are limited to epidural abscesses.
Spinal epidural abscesses tend to occur in the posterior
aspect of the spinal canal and in the thoracic region in
the majority of cases, but also in the lumbar and cervical
regions. In one-third of the cases, abscesses result from
contiguous spread from vertebral osteomyelitis or soft
tissue infection (such as retroperitoneal, mediastinal, or
paraspinal tissue), from penetrating trauma, and, rarely,
as the result of surgery, LP, or epidural anesthesia. In
another one-third, hematogenous spread from skin infec-
tion or parenteral drug use is the pathogenic mechanism.
The exact origin is unknown in another one-third. S.
aureus is the most common pathogen, followed by Strep-
tococcus spp. and gram-negative enteric bacilli. Other
pathogens such as M. tuberculosis and fungi may result in
more chronic abscesses. Cardinal clinical manifestations
include fever, localized back pain and tenderness, radicu-
lar pain, and myelopathy symptoms and signs, including
Lhermitte phenomenon (paresthesia often described as
an electric shock going down the back and limbs follow-
ing neck flexion). In addition, symptoms of bacteremia
are often present. Blood cultures are often positive, and a
peripheral PMN leukocytosis may be present. The diag-
nosis is established by neuroimaging with MRI or myelo-
gram combined with CT in patients unable to undergo
MRI. The myelogram should be performed at a different
level of the suspected abscess because of risk of infection
spread to the CSF and, less commonly, of spinal hernia-
tion. Urgent surgical decompression along with antimi-
crobial agents is the cornerstone of treatment. Micro-
biologic diagnosis is typically confirmed by material
obtained from surgery, but empiric antibiotic treatment
covering S. aureus, Streptococcus spp., and gram-negative
enteric bacilli with a third-generation cephalosporin and
vancomycin may be initiated before surgery. Corticoste-
roids should be considered if there are myelopathy signs,
but empiric antibiotic treatment must be initiated before-
hand or simultaneously, and surgical decompression
should be scheduled promptly.
Cutaneous herpes zoster and
complicated zoster syndromes
VZV is an exclusively human neurotropic virus. Primary
infection, typically in childhood, causes varicella (“chicken
pox”), after which the virus becomes latent in the sensory
cranial nerve ganglia, dorsal root ganglia, and autonomic
ganglia of the entire neuraxis. As VZV-specific, cell-
mediated immunity against VZV appears to diminish with
age and immunosuppression, VZV may reactivate, spread-
ing distally along the nerve and causing zoster, commonly
known as “shingles.” Although the exact mechanisms of
how VZV evades innate and adaptive immune responses
during reactivation remain to be uncovered, diminished
VZV-specific T lymphocyte responses (such as prolifera-
tion and IFN production in response to secondary expo-
sure to VZV) are observed in older individuals (Oxman,
2009). Among older individuals with shingles, up to half
develop postherpetic neuralgia (PHN), characterized by
persistent (more than 3 months) neuropathic pain in the
distribution of the affected dermatomes, despite resolu-
tion of the skin lesions. Given the ongoing VZV vaccina-
tion in children, the incidence of zoster syndromes later in
life may decrease over the next few decades.
Uncomplicated zoster is characterized by pain in the
distribution of the nerve(s) involved and a cutaneous
vesicular rash on an erythematous base. Prodromal dys-
esthesias and paresthesias described as itching, burning,
or tingling may be present. Zoster can develop anywhere
on the body but tends to be limited to one or, rarely, two
or more dermatomes. The most common dermatomes
are T5 to T10 and the V1 branch of the trigeminal nerve
(zoster ophthalmicus). The latter may be associated with a
keratitis that can lead to blindness and, therefore, should
be treated aggressively and monitored carefully. In most
patients, the resolution of the skin rash, usually within 2
or 3 weeks, is accompanied by pain reduction and, ulti-
mately, resolution within 4–6 weeks.
Diagnosis in most patients is based on the typical clini-
cal syndrome, including dermatomal pain and vesicular
rash. A Tzanck smear can further support the diagnosis
by demonstrating multinucleated giant cells, reflecting
virus-infected skin cells. CSF analyses are not usually nec-
essary but, if done, will show mild lymphocytic pleocy-
tosis, hyperproteinorachia, and positive VZV PCR. Occa-
sionally, occult zoster may be suspected clinically based
on reports of typical dermatomal pain in the absence of
rash, a condition known as zoster sine herpete. Definitive
diagnosis of such cases requires CSF analysis.
Complicated zoster syndromes include the following:
nonsensory cranial neuropathies (such as optic neuropa-
thy or ocular motor neuropathies), which occur due to
a meningitic reaction or direct perineural spread along
anastomotic pathways; zoster radiculitis, through mixed
spinal nerve involvement, causing segmental weakness

of limbs or abdominal muscles in 5% of cases; myelitis
(discussed earlier); encephalitis (discussed earlier); and
a thrombotic cerebral vasculopathy, presenting as an
ischemic cerebral infarction, 2–10 weeks after zoster oph-
thalmicus, through either direct viral invasion of arterial
walls innervated by V1 or an immune-mediated process
(Gilden et al., 2000). Specific antiviral treatment includes
oral nucleoside analogs such as acyclovir, famciclovir,
or valacyclovir. Intravenous acyclovir should be consid-
ered for any immunocompromised patient and for any
patients with complicated zoster syndromes. Early treat-
ment within 72 hours of rash appears to reduce the acute
pain and accelerate healing, but the effect on postherpetic
neuralgia (PHN) is less clear (Wood et al., 1994). Adjunc-
tive treatment with corticosteroids may help reduce the
incidence of PHN, although this question has not been
addressed in controlled clinical studies. Corticosteroids
are contraindicated in immunocompromised patients
(Gilden et al., 2000).
VZV prevention in patients 60 years and older may be
attained by giving live attenuated VZV vaccine, which
reduces the subsequent incidence of cutaneous zoster and
PHN (Oxman et al., 2005). PHN can occur after zoster in
any location, but is particularly common following zoster
ophthalmicus. It is characterized by constant pain, along
with superimposed lancinating exacerbations and some-
times other sensory disturbances at the site of the rash,
including hypesthesia and hyperesthesia. PHN appears
to be central in origin, with overactivity of some neu-
rons in the caudal trigeminal nucleus, possibly through
impaired segmental inhibition. Therefore, pain manage-
ment should include centrally active agents such as tri-
cyclic antidepressants (nortriptyline or amitriptyline),
gabapentin, or pregabalin (Dubinsky et al., 2004). Tempo-
rary opioids are sometimes necessary. Lidocaine patches
and topical high-concentration capsaicin patches are also
effective. Because the pain is of central origin, surgical
denervation is ineffective and should be avoided.
Septic encephalopathy
Septic encephalopathy is a relatively common and impor-
tant but under-recognized disorder in the elderly that is
associated with confusion and behavioral disturbances
such as agitation and hallucinations. Among critical
care patients with sepsis, approximately 25% develop
encephalopathy, even after excluding individuals whose
encephalopathy is attributable to severe coexisting
hepatic or renal dysfunction, endocarditis, pulmonary
failure, sedative or opiate medications, or other causes.
In a manner analogous to other organ system failures,
including cardiac, renal, and pulmonary, so-called “brain
failure” independently predicts poorer prognosis among
patients admitted to intensive care units (Knaus et al.,
Nervous System Infections 471
1991). Under-recognition is perhaps explained by the lack
of a specific treatment other than antimicrobial therapy
directed at the specific pathogen and by the exclusion-
ary nature of the diagnosis. The clinical manifestations of
septic encephalopathy reflect diffuse brain dysfunction
consisting of altered level of consciousness ranging from
somnolence, stupor, and coma to hypervigilance and
psychomotor hyperactivity; cognitive dysfunction and
behavioral disturbances ranging from agitation to catato-
nia; and perceptual disturbances such as hallucinations.
In a given patient, these disturbances may fluctuate in
severity and type over minutes to hours. Individuals with
preexisting CNS lesions, especially dementias, are more
vulnerable to septic encephalopathy. Symmetric para-
tonic rigidity or gegenhalten may be observed in some
patients, but focal neurologic functions are absent (Young
et al., 1990).
The diagnosis of septic encephalopathy is excluded
by the presence of any other condition that, in isolation,
could reasonably explain the encephalopathy, such as
certain CNS infections, structural lesions (such as isch-
emic stroke or hemorrhage), severe coexisting systemic
organ dysfunction, hypotension with reduced cerebral
perfusion, hypoxemia or hypercarbia, or other metabolic,
endocrine, or toxic derangements. Additional consider-
ations in the differential diagnosis include postictal state
or ongoing nonconvulsive status epilepticus. Investiga-
tions should include brain imaging without and with
contrast to rule out structural lesions. Because the clinical
features of meningitis and encephalitis in the elderly can
be subtle or atypical, as detailed earlier, clinicians should
have a low threshold to perform CSF analyses. In addition
to excluding ongoing nonconvulsive status epilepticus or
interictal epileptiform activity, EEG may also be useful
in identifying patterns consistent with toxic-metabolic
disturbances, such as diffuse slowing or triphasic waves.
A comprehensive metabolic, endocrine, and toxicologic
evaluation should be performed to evaluate, among other
things, sepsis-induced hepatic or renal failure, hyper- or
hypoglycemia, or hypo-osmolar states, such as the syn-
drome of inappropriate antidiuretic hormone (SIADH).
Potentially offending medications should be discontin-
ued, keeping in mind that even short-acting medications
can accumulate due to slower renal and hepatic clearance
in patients with sepsis and in the elderly. Management of
septic encephalopathy entails identification and specific
treatment of the systemic infection.
The underlying pathophysiology of septic encephalop-
athy remains a source of debate. Brief endotoxemia alone
does not explain the occurrence of septic encephalopathy,
as short-term systemic infusion of bacterial lipopolysac-
charides (LPS) to normal individuals results primarily in
an inflammation-mediated increase in cortisol and alert-
ness (van den Boogaard et al., 2010). On the other hand, in
animal models, administration of LPS increases cerebral
472 Neurologic Conditions in the Elderly
venous volume and ICP, which, in turn, reduces cerebral
perfusion pressure and oxygen extraction (Desai et al.,
1995). Other proposed mechanisms for sepsis-induced
brain dysfunction are altered hepatic amino acid metabo-
lism, altered serotonin metabolism, formation of endog-
enous benzodiazepine-like compounds, inflammatory
cytokine production, and microabscess formation (Streck
et al., 2008; Pytel and Alexander, 2009).
Human immunodeficiency virus and the
nervous system in the aging population
The worldwide burden of HIV and its tropism for the
nervous system makes this one of the largest single infec-
tious causes of neurologic disease worldwide. Across the
globe, approximately 36 million people live with HIV-1
infection. The greatest burden is in sub-Saharan Africa,
where there are 22 million infected individuals, account-
ing for two-thirds of the worldwide disease burden
(UNAIDS, 2008). In the United States, approximately one
million individuals are living with HIV infection, and the
epidemic is growing fastest in women, intravenous drug
users, and ethnic minorities. Although not commonly
viewed as a disease of aging, the CDC estimates that, by
2015, more than half of all HIV-infected individuals in the
United States will be 50 years and older (www.cdc.gov/
hiv/topics/over50).
HIV is a member of a family of retroviruses having a
propensity to cause CNS disease. The virus enters the ner-
vous system via a “Trojan horse” mechanism, piggyback-
ing on trafficking macrophages from the peripheral circu-
lation across the BBB into the CNS. This trafficking occurs
within days of initial infection and persists throughout
the disease. The virus does not directly infect neurons,
instead injuring them through “bystander” mechanisms
grouped into three categories: viral factors, host factors,
and cofactors. Viral factors include toxic proteins such
as gp120 and Tat. Host factors include cellular changes
that occur in response to viral infection and secondarily
injure neurons. Cytokines, chemical regulators of inflam-
mation and immunity, mediate injury through cell surface
receptors on neurons, microglia, astrocytes, and oligoden-
drocytes. Cofactors include comorbid conditions such as
drug use and hepatitis C infection, or social, nutritional,
or behavioral characteristics that contribute to or amplify
the pathogenicity of HIV.
These three mechanisms interact to damage neural
networks at the level of dendrites and synapses. Synap-
todendritic injury impairs higher-order neural systems
involved in information processing, leading to HIV-
associated neurocognitive disorders. Injury is diffuse, but
often particularly affects the basal ganglia, hippocam-
pus, and fronto-striato-thalamocortical circuits generally
(Langford et al., 2003). As with other causes of CNS injury,
neuroprotective and regenerative pathways are upregu-
lated in HIV. Successful protective and repair mechanisms
may explain why some HIV-infected individuals are
spared from CNS injury and neurocognitive impairment.
While the widespread use of cART since the mid-
1990s has led to a decline in the most severe neurologic
complications of HIV, including dementia, HIV-infected
individuals continue to experience mild and moderately
severe forms of nervous system diseases. Interactions
between aging and HIV are important because certain
age-related neurologic disorders and/or risk factors for
those disorders occur with a higher frequency in cART-
treated individuals, and because the symptoms and signs
of HIV-associated neurologic disorders may overlap with
those of age-related neurologic disorders. Additionally,
HIV and cART are responsible for premature metabolic
and atherosclerotic changes likely to contribute to neuro-
logic disorders common in older individuals.
The current gold standard for case definition of HIV-
associated neurocognitive disorders (HAND) is a recently
published, international expert consensus document
commissioned by the National Institute of Mental Health
and the National Institute of Neurological Disorders and
Stroke, often referred to as the Frascati criteria (Antinori
et al., 2007). These criteria integrate objective neuropsy-
chological (NP) performance with information about
changes in functional status and comorbid conditions, as
schematized in Table 18.8. HAND is diagnosed only in
the absence of another comorbid condition sufficient to
otherwise explain documented neurocognitive dysfunc-
tion. NP testing must document impaired performance
in at least two domains of cognitive functioning (such
as learning and speed of information processing) using
appropriate normative comparisons, adjusted for age,
education, and other demographic factors.
Among those meeting the criteria for global neuro-
cognitive impairment, three severity levels are defined.
HIV-associated dementia (HAD) describes individuals
with moderate-to-severe deficits in two or more domains
and substantial impairment in everyday functioning that
renders the individual incapable of employment and
frequently unable to live independently. Mild neurocog-
nitive disorder (MND) is diagnosed when there is mild
to moderate impairment in at least two domains and at
Table 18.8 Summary of diagnostic criteria HIV-associated
neurocognitive disorders (HAND)
Asymptomatic NP Mild neurocognitive HIV-associated
impairment (ANI) disorder (MND) dementia (HAD)
NP testing ≥ Mild ≥ Mild ≥ Moderate
impairment
Functional
None ≥ Mild ≥ Moderate
disability
NP, neuropsychological.

least mild interference in everyday functioning. Asymp-
tomatic NP impairment is assigned to individuals who
meet criteria for impairment in at least two domains, but
without any clear effect on everyday functioning. Crite-
ria for functional impairment are met when an individual
has developed dependence in instrumental activities of
daily living after becoming infected by HIV, when there is
inability to work or significantly reduced work efficiency
attributed to HIV-related cognitive changes, or when
there are complaints of increased cognitive difficulties
in the everyday life of an individual who does not have
clinically significant depression. Impaired functional per-
formance may be demonstrated by objective everyday
functioning tasks such as standardized work samples or
medication management.
A recent study applied the Frascati criteria to classify
1555 HIV-infected individuals at six university clinics
across the United States (CNS HIV Antiretroviral Therapy
Effects Research (CHARTER)) (Heaton et al., 2009). Most
study participants were middle-aged (mean 43 years),
nonwhite (61%) men (77%) who had received a diagno-
sis of AIDS (63%) by CD4+ counts below 200 cells/μL.
Most (71%) were on cART and had experienced substan-
tial immune reconstitution. At least mild NP impairment
was found in 52% of the cohort, and the most frequently
affected domains were learning, executive functioning,
recall, and working memory. After excluding individu-
als for whom diagnoses of HAND were confounded by
severe comorbid neurologic conditions such as traumatic
brain injury or residual deficit from prior CNS oppor-
tunistic infection, 46% of the remaining 1316 individu-
als were impaired. Rates of specific HAND diagnoses
were as follows: ANI, 32.7%; MND, 11.7%; and HAD,
2.4%. Extrapolating these figures to the larger population
of HIV-infected individuals, the estimated prevalence
of HAND nationwide is comparable to that of multiple
sclerosis.
Advanced HAD is now quite uncommon, being seen
principally among individuals who are severely immu-
nosuppressed due to late HIV diagnosis or because of
poor adherence to or resistance to antiretrovirals. Such
disabling dementia develops over a period of many
weeks or months. A more rapid onset raises suspicions
of other diagnostic possibilities. In the more advanced
stages, patients may have little insight into their disabili-
ties, requiring a knowledgeable informant to provide his-
tory on their functional status. Typical complaints include
slowed thinking; loss of spontaneity and initiative; slow-
ness or inability to complete multistep, sequential tasks
such as meal preparation; and slowed movements or
balance problems. Cognitive examination demonstrates
frontal/subcortical cognitive impairments without
apraxia, agnosia, or aphasia. Neurologic examination fre-
quently shows frontal release signs, diffuse hyperreflexia,
and a slow, unsteady gait. Anecdotally, antiretroviral
Nervous System Infections 473
treatment in some such patients can produce a remark-
able recovery of cognition and functional abilities that
takes place over many weeks to months.
Patients with MND, who are less disabled than those
with HAD frequently have insight into their difficulties
and are able to report slowness or difficulty in perform-
ing at work or in other activities at which they were
previously adept. Conventional bedside cognitive tests
such as the mini–mental state examination (MMSE) are
not useful. Even screening instruments designed for use
in HIV, such as the HIV Dementia Scale (HDS), are not
sufficiently sensitive, although better sensitivity and
specificity may be achieved through the use of appro-
priate normative corrections (Morgan et al., 2008). NP
testing is necessary to document impairment in these
patients. The neurologic examination is frequently
normal or may show an incidental distal sensory
polyneuropathy.
Because HAND remains a diagnosis of exclusion, cog-
nitive impairment presenting in an older HIV-infected
individual represents a true clinical conundrum. Potential
contributing factors include reversible endocrine distur-
bances, nutritional deficiencies, and infectious disorders.
These should be evaluated with thyroid function tests,
serum vitamin B12, and RPR. CSF analysis, including
mycobacterial and fungal cultures, AFB staining, India
ink, and cryptococcal antigen, is also warranted to rule out
subacute and chronic infections such as M. tuberculosis,
C. neoformans, and T. pallidum. Unfortunately, quantitative
HIV RNA polymerase chain reaction (PCR) performed on
CSF is not sufficiently sensitive or specific to serve as a
guide. Detailed NP testing is most useful to differentiate
HAND from common degenerative dementias such as
Alzheimer’s disease (AD) or pseudodementia associated
with depressive mood disorder, a common comorbidity
in the elderly. Imaging is quite useful in ruling out other
conditions that may be associated with neurocognitive
impairment. However, in HAND, conventional anatomic
MRI is nonspecific, usually showing only cortical and sub-
cortical atrophy with scattered, punctate T2 hyperintense
abnormalities. There is great interest in MR spectroscopy,
diffusion tensor imaging, and functional MRI, but at pres-
ent, these remain research tools that require validation for
clinical use (Gongvatana et al., 2009).
There is a general consensus based on studies performed
in both the United States and Europe that antiretroviral
treatment significantly improves neurocognitive function
in patients with HAND who start new regimens. How-
ever, Cysique et al. demonstrated that reliable cognitive
improvement is achieved only in about 40% of patients
treated for up to 1 year, with many individuals showing
slow improvement over 6–12 months (Cysique et al., 2009).
Among the factors considered as possible explanations
for limited neurocognitive recovery are irreversible neu-
ral injury during severe immunosuppression, persisting
474 Neurologic Conditions in the Elderly
neural injury due to dysfunctional immune reconstitution
(immune recovery disease), reduced penetration of anti-
retroviral drugs into the CNS, and the presence of comor-
bid conditions leading to neurocognitive impairment
(e.g., opportunistic infections). However, as noted previ-
ously, excluding individuals with major comorbidities
still leaves a marked excess of neurocognitive impairment.
Observational studies have demonstrated better
neurocognitive responses among individuals receiv-
ing antiretroviral regimens with superior predicted
CNS penetration, but not all studies are in agreement
(Letendre et al., 2004; Marra et al., 2009; Tozzi et al.,
2009). Superior penetration also is related to lower viral
loads in CSF. Letendre et al., have developed a clini-
cal scale that can be used to rank the expected relative
CNS penetration effectiveness of available antiretro-
viral medications (Letendre et al., 2008). An ongoing
controlled clinical trial is testing the use of this scale as
part of a strategy to improve neurocognitive outcomes
in HIV-infected individuals with HAND (see www.clini-
caltrials.gov). Adjunctive therapies such as central cho-
linesterase inhibitors, memantine, monoamine oxidase
inhibitors, and amphetamine-derived stimulants have
not been evaluated in randomized clinical studies or
have not shown significant benefit.
The exact mechanisms by which the immune system
contributes to brain dysfunction in HAND remain elusive.
Substantial additive-adverse effects of aging and HIV are
anticipated as the epidemic matures and individuals live
decades on cART. Aging leads to suppressed immunity
despite elevated inflammation, which is compounded
by accelerated, virally induced immunosenescence.
Immunosenescence is characterized by changes in the
composition of immune cell populations, particularly by
decreased naïve and central memory cells, with increased
terminally differentiated effector cells. Cellular expression
of CD28, a marker for naïve or central memory cells, has
been shown to be lower, especially on CD8 cells, among
HIV-infected individuals (Kalayjian et al., 2003; Cao et al.,
2009). With the use of cART, increases in naïve CD4 and
CD8 T cell counts are observed, but the degree of naïve
cell recovery is significantly smaller in older individuals,
who also show lower CD28 expression on CD8 cells com-
pared with younger individuals (unpublished data from
ACTG A5015 study). Given the pro-inflammatory nature
of terminally differentiated effector cells that readily traf-
fic to target tissues, it is reasonable to hypothesize that
an expansion of these cell types coupled with the lack of
naïve and central memory cells may contribute impor-
tantly to HIV-related CNS pathology in aging.
HIV-infected individuals on cART prematurely
develop metabolic disorders usually linked to aging, such
as arterial hypertension, dyslipidemia (elevated triglyc-
erides and reduced high-density lipoproteins), abdomi-
nal obesity, glucose intolerance/insulin resistance, and
a prothrombotic/inflammatory state (Grinspoon and
Carr, 2005; Aboud et al., 2007; Ances et al., 2009). Meta-
bolic syndrome has been associated with ischemic stroke
in HIV-infected individuals (Ances et al., 2009). Even in
the absence of stroke, these risk factors are associated
with cognitive impairment in older individuals (Kuusisto
et al.,  1997; Valcour et al., 2005; Valcour et al., 2006;
Cukierman-Yaffe et al., 2009; McCutchan et al., 2009).
Premature atherosclerotic changes have been observed
with HIV alone in the absence of other risk factors (Grun-
feld et al., 2009; Hsue et al., 2009). Atherosclerotic lesions
typically originate at sites such as the common carotid
bifurcation and bulb, carotid siphon, and middle cere-
bral artery stem, where complex flow patterns yield low
shear stress and flow reversal that promote monocyte
binding to endothelial cells. Increased transmigration of
monocytes across the endothelium at these sites results
in alterations of the intima and media that may promote
lipid deposition and platelet aggregation (Cunningham
and Gotlieb, 2005; Bui et al., 2009). These findings suggest
that management of HIV infection should include aggres-
sive control of atherogenic risk factors, earlier and more
aggressive viral suppression, and use of cART regimens
less likely to cause the metabolic syndrome.
Sensory neuropathy remains a frequent disorder in
HIV, with 38% of those in one study reporting neuropathic
pain that often interferes with daily activities, employ-
ment, and quality of life (Ellis et al., 2010). Its prevalence
increases greatly with age. The polyneuropathy is a sym-
metric, axonal, length-dependent syndrome, predomi-
nantly sensory, affecting small and large fibers and often
associated with painful dysesthesias and paresthesias. It
can be differentiated from dideoxynucleoside analogue-
induced (“d-drug”) neuropathy only by the latter’s
temporal relationship with drug initiation and improve-
ment following drug discontinuation. The differential
diagnosis includes paraproteinemia (such as monoclonal
gammopathy), vitamin B12 deficiency, diabetes mellitus,
toxins (such as alcohol, platinum compounds, vincris-
tine, taxanes, thalidomide, and pyridoxine), and inher-
ited sensory and autonomic neuropathies. Investigation
including serum protein electrophoresis and immuno-
fixation, serum vitamin B12, and glycosylated hemoglobin
is usually sufficient. However, the presence of significant
motor involvement warrants a more extensive investiga-
tion, including CSF analysis, nerve conduction studies,
and electromyography. Management of HIV-associated
neuropathy consists of minimizing neurotoxic agent
exposure and optimizing pain control (with a tricyclic
antidepressant (such as amitriptyline or nortriptyline),
a serotonin–norepinephrine reuptake inhibitor (such as
duloxetine or venlafaxine), an anticonvulsant (such as
gabapentin or pregabalin), or topical capsaicin). Anticon-
vulsants are particularly useful for pain with shooting or
stabbing characteristics.

Age-associated changes in immunity
The term immunosenescence refers to the gradual decline
and dysregulation of immune function that occurs in the
elderly. Immunosenescence is a double-edged sword,
in that whereas overall immunity is decreased, inflam-
matory responses are increased. The nature of immu-
nosenescence has not been thoroughly characterized
for all components of the immune system, but several
aspects are well established. First, neutrophils dem-
onstrate decreased phagocytic activity, particularly in
association with chronic comorbid conditions such as
diabetes mellitus. Monocytes and macrophages show
attenuated cytokine production upon stimulation by
pathogens. T cell clonal expansion is reduced, possibly
because of thymic involution. Effector memory T cells
are proportionately increased, and NK cell cytotoxic
activity and number are decreased (Castle, 2000; Agar-
wal and Busse, 2010). B cells demonstrate reduced naïve
subpopulations, but memory cells with limited diversity
are increased. Finally, aging individuals exhibit dimin-
ished antibody responses to vaccination, increasing their
susceptibility to specific pathogens such as H. influenzae
and S. pneumoniae. The relative impact on morbidity and
mortality of these distinct, age-related changes in vari-
ous components of the immunologic armamentarium
remains to be fully delineated.
• Markers of immunosenescence: Among the better-
described markers of immunosenescence are reduced
numbers of naïve CD4+ and CD8+ T cells and increased
numbers of more terminally differentiated T lympho-
cytes, such as effector memory cells. The decline in thy-
mic output of naïve T cells diminishes responses to newly
encountered pathogens, such as WNV. At the same time,
terminally differentiated cells that are not proliferative
or immunocompetent, yet are resistant to programmed
cell death, accumulate with aging. Such cells demon-
strate short telomeres and decreased telomerase activity,
another cellular marker of aging. The reduced function-
ality of these terminally differentiated memory T cells
correlates with persistent infection (Derhovanessian et
al., 2009). Certain latent viral infections, such as CMV,
accelerate immunosenescence by increasing numbers of
these cells. Other chronic viral infections, such as EBV
and VZV, appear to contribute to a lesser degree to this
effect (Pawelec et al., 2005).
• Aging and BBB alterations: A large body of literature
describes compromised function and permeability of the
BBB in aging individuals with and without a variety of
CNS pathologies such as AD and multi-infarct dementia.
Even among healthy asymptomatic individuals, aging
is associated with increased BBB permeability, assessed
by CSF/plasma albumin ratios or imaging (Farrall and
Wardlaw, 2009). In rodent models of aging, increased
BBB permeability is shown to be associated with learning
Nervous System Infections 475
or memory impairment and with microglial activation
(Popescu et al., 2009). Compromised function of the BBB
likely contributes to intraparenchymal deposition of com-
plement, leading to recruitment of pro-inflammatory im-
mune cells into the CNS.
• Brain-immune interactions and aging: Traditionally
considered as an “immune-privileged” site, it is now clear
that brain–immune interactions are part of necessary nor-
mal immunosurveillance (Schwartz and Shechter, 2010). In
mice rendered immunodeficient by genetic manipulation
or other means, impaired learning and memory can be re-
mediated by injection of immunocompetent T cells (Kipnis
et al., 2004; Kipnis and Derecki, 2008). Thus, normal T cell
immunity contributes to healthy brain function, and T cell
dysregulation during aging may impair cognition.
Aging-related neuroinflammation is characterized
by increased brain expression of IFN-γ, activation of
microglia and astrocytes, and elevated glial produc-
tion of pro-inflammatory cytokines such as interleukin
(IL)-1β, TNF-α, and IL-6 (Lynch, 2010). Elevated expres-
sion of major histocompatibility complex II (MHC II)
suggests increased interactions between microglia and T
cells and increased T cell infiltration into the CNS with
aging. In animal models, these features contribute to
impaired learning and memory. Either peripheral (intra-
peritoneal) or central (intrahippocampal) administra-
tion of inflammatory cytokine IL-1β or viral or bacterial
infections leads to poor performance during learning
and memory tasks. Elevated levels of pro-inflammatory
cytokines in the brain also lead to a reduction in synaptic
plasticity in rodents.
Aging glial cells express higher levels of activation
markers such as MHC II, CD80, and glial fibrillary acidic
protein. Peripheral immune activation and inflamma-
tion occurring in response to systemic infection can lead
to alterations in the brain microenvironment that impair
CNS function. Thus, sepsis or injection of an endotoxin
(such as bacterial LPS) activates microglia in rodent
models. Such activated microglia downregulate expres-
sion of neurotrophic mediators and upregulate neuro-
toxic ones. Aging is associated with amplification of
these deleterious responses to peripheral inflammation
(Dilger and Johnson, 2008). Accordingly, LPS injection in
older mice led to prolonged decreases in social explor-
atory behavior and locomotor activity, compared with
younger mice (Godbout et al., 2005). These behavioral
deficits were accompanied by a greater elevation in the
tissue expression of inflammatory cytokines such as IL-6
and IL-1β. The greater and prolonged decline in senso-
rium and cognitive function that occurs in older patients
with sepsis compared with those who are younger
is consistent with these animal models (Murray et al.,
2012). Future research will hopefully bring to light new
therapeutic strategies to address these pathophysiologic
alterations.
476 Neurologic Conditions in the Elderly
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 Chapter 19
Delirium
Alan Lerner1, Stefani Parrisbalogun2, and Joseph Locala3
1
Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
2
Rawson-Neal Psychiatric Hospital, Las Vegas, NV, USA
3
Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA

Summary
• There is a high prevalence of delirium in hospitals and specialty care units.
• Delirium is associated with a variety of causes, presumed to ultimately affect cerebral cortical processing. Hypotheses
concerning pathology include acute cholinergic deficiency, alterations in dopaminergic function, and changes in GABA.
• Common risk factors include underlying brain diseases, age, and dementia. Chronic medical illness, comorbidity,
severity, functional impairment, medication prescription, and polypharmacy can also cause delirium.
• Etiologies may be singular or multiple. A variety of laboratory tests can help identify the cause(s).
• The Confusion Assessment Method is a tool used to ascertain the presence of delirium.
• Clinical symptoms of delirium vary widely and investigators have proposed motoric subtypes including hypoactivity and
hyperactivity.
• Delirium is considered preventable and reversible. Prevention strategies include avoidance of anticholinergics and
inhibition of alcohol withdrawal. Initial treatment of delirium is often nonpharmacologic. Pharmacologic agents can
result in sedation. Haloperidol is often used.

Introduction shift of the United States (and other countries) to a larger

Delirium, also known as acute confusional state (ACS), is
best defined as a global disorder of cognition and behav-
ioral disturbance (Lipowski, 1987, 1989). This symptom
complex is common and may present in a dramatic fash-
ion, such as extreme postoperative confusion, or as a more
insidious process over days and weeks.
ACS is of clinical importance because it is, by definition,
due to an underlying medical problem that is often treat-
able. Thus, ACS should often be considered reversible. As
discussed here, dementia of various causes is a major risk
factor. Therefore, expectations for recovery may need to
be tempered by the presence of an underlying irreversible
condition, such as Alzheimer’s disease (AD) and other
types of dementia.
Delirium is a frequent and potentially preventable
source of morbidity and mortality for older hospitalized
patients. Based on 1994 data, delirium complicates hospi-
tal stays for more than 2.3 million older persons per year,
occurs during 17.5 million inpatient days, and accounts
for more than $4 billion of Medicare expenditures. Sub-
stantial additional costs accrue due to need for various
levels of post-acute care and treatment directly related
to the presence of delirium. Advancing age is an inde-
pendent risk factor for delirium. Given the demographic
percentage of geriatric patients, the incidence of delirium
will likely increase over time. This chapter reviews the
epidemiology, pathophysiology, diagnostic criteria, treat-
ment, and outcomes related to delirium.
Epidemiology
Delirium occurs in many age groups, from children to
older adults, and in many clinical settings, the commu-
nity inpatient hospital settings and long-term care facili-
ties. It also has multiple different clinical presentations.
Therefore, concisely summarizing the epidemiology of
delirium is difficult.
The prevalence within mixed community-based popu-
lations is estimated at 1–2%, but the overall prevalence
in hospitals at any time may be as high as 24% (Inouye,
1998). The incidence of delirium may be as high as 56%
in general medical wards, but conceivably higher in spe-
cialty care units such as palliative care, hospice, postop-
erative, or intensive care. Estimates of delirium incidence
in intensive care units have ranged as high as 87% (Pisani
et al., 2003).
Age is a major risk factor for delirium, so the incidence
rises with age in all settings. This problem is likely to

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

478

grow in absolute magnitude with the overall aging of the
population, particularly in the United States and other
developed countries.
Pathophysiology
Delirium has a wide assortment of causes, either alone or
in combination. For example, in DSM-IV, delirium may be
ascribed to various categories, such as a general medical
condition, substance abuse or withdrawal, or other con-
ditions (American Psychiatric Association, 2000). How-
ever, diagnostic nomenclature does not begin to cover the
myriad etiologic causes or underlying pathophysiology
of this complex disorder. Indeed, multiple studies have
suggested that, even in individual cases, as many as six
possible causes can be identified (Trzepacz et al., 1985;
Breitbart et al., 1996; Lang et al., 2006).
The underlying final pathophysiologic pathway pre-
sumably affects cerebral cortical processing, as indicated
by the wide array of effects on behavior and cognition,
perception and sleep, and slowing on the EEG (Jacobson
and Jerrier, 2000). One hypothesis regarding the neuro-
chemical changes present in delirium suggests that it is a
state of acute cholinergic deficiency, possibly with excess
dopaminergic tone (Blass and Gibson, 1999; Hshieh
et al., 2008). Other transmitter systems are almost cer-
tainly involved in many cases. This includes alterations
in GABAergic, serotonergic, and glutaminergic systems
(Trzepacz, 2000; Hshieh et al., 2008; Furuse and Hashi-
moto, 2010).
Part of the empirical basis for the hypothesis of cho-
linergic deficiency comes from the wide variety of medi-
cations and their metabolites that have anticholinergic
activities and are associated with delirium. An animal
model of delirium using atropine has also been reported.
This low cholinergic tone may be related to the increased
risk for delirium in individuals with AD and vascular
dementia. Lewy body dementia may also mimic delirium
and is associated with a severe loss of cholinergic inner-
vation (Blass and Gibson, 1999; McKeith et al., 2003; Jicha
et al., 2010).
Alterations in dopaminergic function are also associ-
ated with delirium. Many of the medications used to treat
parkinsonism and related disorders, including levodopa
and dopamine agonists, are associated with delirium.
Similarly, bupropion and cocaine usage, both of which
increase dopaminergic activity, may be linked with
delirium. Genetic polymorphisms in the dopamine trans-
porter gene and serotonin transporter genes have also
been associated with delirium, and opiates may mediate
increased dopamine release (Murray et al., 2007; Karpyak
et al., 2010; van Munster et al., 2010). Dopamine agonists
may cause slowing on the EEG, as can many of the neu-
roleptics and other medications that activate both D1 and
Delirium 479
D2 receptors. Nonspecific blockers of dopamine recep-
tors, such as haloperidol, are frequently used in treating
acute delirium.
Changes in other neurotransmitters, such as gamma ami-
nobutyric acid (GABA), have resulted in delirium, and Pre-
gabalin has been associated with delirium in patients with
multiple sclerosis (Solaro and Tanganelli, 2009). In particu-
lar, benzodiazepines and other GABAergic drugs, includ-
ing several drugs of abuse, such as “liquid ecstasy” drugs,
are associated with delirium (Supady et al., 2009; Galldiks
et al., 2011). Reduced GABA activity may be secondary to
withdrawal from ethanol and sedatives and may present
with catatonic symptoms (Hauser et al., 1989; Rosebush
and Mazurek, 1996). Both high and low levels of serotonin
have been associated with delirium. Hepatic encepha-
lopathy may result in increased serotonin activity, pos-
sibly related to increased tryptophan uptake in the brain,
but multiple neurotransmitter changes occur in hepatic
encephalopathy, raising some doubt about simple, direct
connections between clinical symptoms and neurotrans-
mitter changes (Lozeva-Thomas, 2004; Palomero-Gallagher
et al., 2009). Polymorphisms in the A9 allele of the dopa-
mine transporter gene may affect the course of delirium in
alcohol-dependent women (Limosin et al., 2004).
Changes in other neurotransmitters, including hista-
mine, glutamate, and opiates, have also been associated
with delirium. However, the complete relationship of
changes in these neurotransmitters to the pathophysiol-
ogy of delirium is not clear at this time.
Risk factors
Delirium mostly occurs as a result of multiple etiologies
and thus can be thought of as a multifactorial disorder
(Inouye and Charpentier, 1996). Risk factors for delirium
either increase the patient’s baseline vulnerability to
systemic disturbances or contribute directly to the distur-
bance (Elie et al., 1998). A patient’s vulnerability at hospi-
tal admission can include a history of cognitive decline/
impairment, low cognitive reserve, or noxious insults
prior to the time of hospitalization. More often than not,
factors that contribute to systemic disturbance are more
clinically significant, in that they may be treatable and,
therefore, preventable risks. Studies have shown that
patients with less baseline vulnerability or more cerebral
reserve were more resistant to possible systemic distur-
bances after hospital admission, and an increased likeli-
hood of delirium or an ACS was associated with more
baseline vulnerability.
The most commonly identified risk factors that increase
a patient’s baseline vulnerability are underlying brain dis-
eases as a result of dementia, stroke, Parkinson’s disease,
or central nervous system (CNS) injury/trauma; these
may be present in nearly half of the older patients with
480 Neurologic Conditions in the Elderly

Table 19.1 Medical causes of delirium systemic stressors is apparent in cortical hypometabolism
Heart disease Carbon tetrachloride markers such as low glucose, blood flow, and oxygen.
Heart failure As mentioned earlier, EEG activity slows, and there is
Hepatic encephalopathy Transient global amnesia an alteration or imbalance of neurotransmitters (Obrecht
Kidney failure Cerebral edema et al., 1979). Delirium is often comorbid with dementia
Renal failure, acute (Lerner et al., 1997). The prevalence of delirium super-
Endocrinopathies Infections imposed upon dementia documented in the literature
Pituitary apoplexy Urinary tract infection ranges from 22% to 89% (Fick et al., 2002). On average,
Cushing’s syndrome Surgical wound infection
patients with dementia have up to fivefold increased risk
Hyperthyroidism Legionnaires’ disease
for developing a superimposed delirium or ACS. Nearly
Hypothyroidism Malaria
Nutritional deficiency Brain abscess
two-thirds of cases of delirium occur in patients with
Vitamin B12 deficiency Meningitis some form of underlying dementia due to the increased
Folate deficiency Encephalitis baseline vulnerability or low cerebral reserve (Trzepacz
Nicotinic acid deficiency Viral hemorrhagic fevers and van der Mast, 2002; Cole, 2004; Inouye, 2006a).
Thiamine deficiency Plague The frequency of delirium also increases with severe
Respiratory failure Neuroleptic malignant syndrome medical disorders with and without CNS pathology such
Hypoxia as cancer (paraneoplastic syndrome or limbic encephalitis);
Hypothermia human immunodeficiency virus (HIV); other systemic
Electrolyte imbalance
or non-neurologic infections that can be symptomatic or
Hyponatremia
occult; and serious life-threatening conditions such as renal,
Hypercalcemia
hepatic, respiratory, and cardiac organ failure or insuffi-
ciency. Clinically, suspicion of an infectious process must
remain high, especially in older patients who may not be
delirium. Examples of other CNS pathology that may able to mount the appropriate immunologic response and
increase a patient’s baseline vulnerability include hyper- present with fever or leukocytosis. Cardiovascular events
tensive encephalopathy, intracranial hemorrhage, mass such as acute myocardial infarction, congestive heart fail-
lesions, infection, vasculitis, and seizure (see Tables 19.1 ure, cardiac arrest, and cardiogenic shock commonly pres-
and 19.2). Cerebrovascular disease predisposes to delir- ent with delirium. Low perfusion states, hypoxia, metabolic
ium in 24–48% of patients (Henon et al., 1999; Caeiro et al., disorders such as dehydration, hypo- or hyperglycemia,
2004). Subsequently, age becomes the most important risk hyper- or hyponatremia, hypercalcemia, and toxic confu-
factor in the development of delirium as the degree of cog- sional states such as alcohol or drug intoxication or with-
nitive impairment increases with age over 60 years. The drawal can also contribute to the development of delirium
aging brain’s diminished capacity to respond to metabolic (Kolbeinsson and Jónsson, 1993; Fick et al., 2002).
Chronic medical illnesses, comorbidity, severity, and
functional impairment also serve as predisposing factors to
Table 19.2 DSM-IV diagnostic criteria for delirium
delirium. Thyroid or adrenal dysfunction, alcohol depen-
A. Reduced ability to maintain attention to external stimuli and to dence, diabetes mellitus, burns, cancer, malnutrition with
appropriately shift attention to new external stimuli reduced plasma binding, vitamin B1 deficiency, vitamin B12
B. At least one of the following:
deficiency, and pellagra may also contribute to the develop-
Questions had to be repeated because attention wandered
Perseverated answers to previous questions
ment of delirium. Environmental factors that lead to altered
Disorganized thinking sensory perceptions, including sensory impairment (for
C. Confusion developed over a short period of time example, inadequate lighting, increased noise levels, blind-
D. Fluctuating level of confusion ness or poor hearing, sleep deprivation, stress, or major
E. At least 2 out of 6 of the following: environmental factors) contribute to the development of
Reduced level of consciousness delirium or the worsening of behavioral symptoms in a
Perceptual disturbances delirious state. Iatrogenic events such as surgery (notably,
Disturbance of sleep–wake cycle
emergency hip fracture, gastrointestinal surgery, coronary
Increased or decreased psychomotor activity
Disorientation to time, place, or person
artery bypass grafting, and lung transplant), anesthesia,
Memory impairment medications, ECT, transfusion reactions, and allergic reac-
F. Either of the following: tions can also cause ACS (Gleason, 2003). Functional impair-
Evidence that an organic factor initiated and maintained ment such as immobility including physical restraint use and
this confusion the use of indwelling bladder catheters greatly increases the
Confusion cannot be accounted for by any nonorganic mental disorder risk of delirium and functional decline. Psychological states
Source: Adapted from American Psychiatric Association (2000) with such as depression, anxiety, and pain may also predispose a
permission from APA. patient to ACS (Inouye et al., 2003; Inouye, 2006b).
 Delirium 481

Table 19.3 Drugs associated with delirium

Antipsychotic agents Cardiovascular Antibiotics Anticonvulsants

Phenelzine Antihypertensives Quinolones Barbiturates
Haloperidol Clonidine Isoniazid Ethosuximide
Quetiapine Guanethidine Phenytoin
Olanzapine Methyldopa Primidone
Propranolol Vigabatrin
Reserpine Bromide
Levetiracetam
Digoxin Carbamazepine
Amiloride Oxcarbazepine
Sedative–hypnotics Anticholinergics Anesthetics Antidementia drugs
Barbiturates Atropine Bupivicaine Donepezil
Benzodiazepines Chlorpheniramine General anesthetics Galantamine
Zolpidem Diphenhydramine Ketamine Memantine
Hydroxyzine Lidocaine Rivastigmine
Scopolamine Procaine
Stimulants Chemotherapeutic and Opiates and pain medications Antispasmodics
Amphetamine salts immunosuppresant agents Buprenorphine Baclofen
Methylphenidate Asparaginase Codeine Tizanidine
Atotmoxetine Prednisolone Fentanyl
Tacrolimus Diamorphine
Hydrocodone
Hydromorphone
Oxycodone
Tramadol
Ziconotide
Antidepressants and mood stabilizers Miscellaneous agents Anti-Parkinson’s agents Illegal and substances of abuse
Lithium Aspirin Amantadine Cocaine
Tricyclic antidepressants Iron compounds Bromocriptine Phencyclidine
Quinine L-DOPA Mescaline
Chloroquine Pramipexole Lysergic acid diethylamide
Aminophylline Ropinirole Tetrahydrocannabinol
Tolcapone Gamma hydroxybutyrate
Pergolide
Apomorphine

Likewise, a patient with adequate cerebral reserve may
develop delirium with singular or multiple exposures to
multiple risk factors.
One of the most common iatrogenic precipitants of
delirium is medication prescription and polypharmacy
(see Table 19.3). Although medications across many
classes have been noted to precipitate delirium, com-
monly used psychoactive drugs such as benzodiazepines,
sedative-hypnotics, narcotics, histamine H2 blockers, and
anticholinergic medications have been shown to increase
the risk associated with ACS (Brown and Stoudemire,
1998; Han et al., 2001; Pandharipande et al., 2006).
Causes
One of the most characteristic aspects of delirium is the
wide differential diagnosis of syndromes contributing to
the clinical presentation of delirium (refer to Table 19.1).
Although cerebral disorders are prominent, many other
systemic disorders affecting the CNS secondarily, as well
as multiple drugs and other exogenous substances, can
contribute to delirium.
Because of this wide range of causes producing a
limited number of clinical subtypes, it is best to focus
one’s attention on the identification of delirium (refer to
Table 19.2 for diagnostic criteria).
A single etiology is causal in fewer than 50% of cases,
with as many as six multifactorial etiologies identified in
others. Multiple causes occur particularly in the elderly
who may have a systemic illness, such as cancer or stroke,
and may be on medications affecting systemic organ func-
tion or that are psychoactive. Thus, the astute clinician
can often recognize a primary cause but should be aware
of multiple contributors to the clinical syndrome under
consideration in a given patient.
Particularly in individuals with underlying dementia,
the importance of polypharmacy cannot be overstated.
482 Neurologic Conditions in the Elderly
Frequently, the differential diagnosis includes progres-
sion of dementia, although the time course may suggest
more frequent etiologies, such as urinary tract infection or
drug-related toxicity.
Other causes that are less frequent in older adults but
should be considered in the appropriate context include
HIV and illicit drug use (Perry, 1990). Appropriate screen-
ing tests in delirium of unknown cause should include
consideration of these etiologies.
Evaluation
Knowledge of the wide differential diagnosis of delirium
should help guide the clinician in appropriate evaluation.
Typically, this includes comprehensive metabolic evalu-
ation, complete blood count, urine analysis, possible chest
X-ray or electrocardiogram, and imaging of selected body
parts as indicated. Combined with the history and physi-
cal examination findings, these laboratory tests can help
identify the singular or multiple causes of the patient’s
delirium. More extensive testing may be necessary to rule
out more rare causes of confusional states determined on
a patient-by-patient basis.
Diagnostic criteria
Various diagnostic criteria have been used for delir-
ium over the past 30 years, with varying sensitivity
and specificity, and optimized for different popula-
tions (inpatients versus outpatients, broad surveys
versus well-defined populations). The prevalence
and incidence of delirium has been estimated to affect
as many as 56% of inpatients on general medical
wards (Inouye, 1998). Clearly, this prevalence figure
is dependent on the diagnostic criteria and its applica-
tion to the study population in determining the pres-
ence of delirium.
A number of studies have compared DSM-III, DSM-IV,
and ICD-10 delirium criteria for their sensitivity and
specificity. Cole et al. (2003), reported a study of 322 medi-
cal inpatients stratified by the presence of delirium and
dementia (or neither), using clouding of consciousness
only, clouding of consciousness and inattention, clouding
of consciousness or inattention as criteria. When the crite-
rion was defined as clouding of consciousness or inatten-
tion, the sensitivity and specificity of DSM-IV, DSM-III,
and ICD-10 criteria were 100% and 71%; 96% and 91%;
and 61% and 91%, respectively, with similar results with
or without dementia present. The lower specificity of
DSM-IV was felt to be due to inclusion of patients without
disorganized thinking. However, DSM-IV has extremely
high sensitivity, which is key to delirium recognition and
subsequent treatment.
The confusion assessment method
Originally developed by Inouye et al. (1990), the Confu-
sion Assessment Method (CAM) is a widely used, reli-
able, and easy method for ascertaining the presence of
delirium. When validated against the reference stan-
dard ratings of geriatric psychiatrists’ ratings based on
comprehensive psychiatric assessment, the CAM had a
sensitivity of 94–100%, specificity of 90–95%, positive pre-
dictive value of 91–94%, and a negative predictive value
of 90–100%. The interobserver reliability of the CAM was
high (Kappa = 0.81–1.0). Because delirium is a fluctuating
condition by nature, test–retest reliability cannot be val-
idly assessed. Importantly, the CAM is significantly corre-
lated with the Mini-Mental Status Examination (Folstein
et al., 1975), the Visual Analog Scale for Confusion, and
the digit span test.
Although the CAM tool can be administered in less
than 5 minutes and closely correlates with DSM-IV crite-
ria for delirium, studies have shown a false positive rate
of 10%, and the instrument has not been widely tested as
a bedside tool for nurse raters. The tool identifies the pres-
ence or absence of delirium but does not assess the sever-
ity of the condition, making it less useful to detect clinical
improvement or deterioration. It also does not indicate
the etiology of the delirium, which is based on a thorough
history, physical examination, and a wide-ranging battery
of laboratory tests and imaging results.
Clinical presentations
Given the multitude of possible causes of delirium and
the multiple age groups affected, it should not be sur-
prising that the clinical symptoms can vary widely. One
model for thinking about delirium and clinical presenta-
tion is that the wide diversity of etiologies converges on
a final common pathway with disruption of brain struc-
tures and neurochemical systems to produce the clinical
symptomatology (Trzepacz, 1996, 2000).
Broad agreement does not appear to exist on what
might be “core symptoms” in delirium, although candi-
dates for this include memory impairment, attentional
deficits, disturbance of the sleep/wake cycle, thought
process changes, alterations in the motor system, and lan-
guage disturbances. Other associated symptoms include
perceptual disturbances such as illusions, hallucinations,
delusions, and mood changes.
Motoric subtypes have been identified by some investi-
gators as providing a biologic basis for different forms of
delirium. Although the motor system may not be involved
in an individual patient with delirium, different presenta-
tions of motor system dysfunction, both hypoactivity and
hyperactivity, have been recognized. Indeed, the word
delirious seems to connote a degree of motor hyperactivity.

Lipowski (1989) described three variants of delirium
based on motor activity termed hyperactive, hypoactive,
and mixed. However, no standardized definition exists,
and it is unclear what symptoms should be included in
each subtype.
Meagher and Trzepacz (2000) found that delusions,
hallucinations, mood changes, speech disturbances, and
sleep disturbances were more frequent in hyperactive
patients. It is recognized that the waxing and waning
nature of the symptoms and the sleep/wake cycle abnor-
malities also complicate our understanding and classi-
fication of motoric subtypes of delirium. Therefore, it is
also not surprising that many patients—in some studies,
a majority—are described as having a mixed motoric sub-
type. It is also not clear that the motoric subtypes have
distinct structural or neurochemical bases.
Numerous studies have indicated that patients with a
hyperactive subtype, however, experience a better out-
come, as determined by shorter hospital stays and lower
mortality rates and better recovery. The possibility of
selection bias in these studies cannot be fully ruled out. It
is also possible that hypoactive delirious patients may be
overlooked in many surveys.
Treatment
Although treatment of an underlying condition is rela-
tively straightforward and can contribute to resolution
of an episode of delirium, the multifactorial nature and
the need for a possibly offending medication need to be
considered. For example, individuals with preexisting
agitation due to dementia may develop delirium second-
ary to benzodiazepine or antipsychotic use. Withdrawal
of the drug entails neuropsychiatric risk of returning to
the patient’s baseline state that was judged to require the
medication in the first place.
Treatment of delirium can be roughly divided into pre-
vention strategies as well as symptomatic treatment. Fong
et al. (2009), estimate that as many as 40% of the cases of
delirium are preventable and that prevention is an effec-
tive strategy for minimizing the occurrence of delirium
and its negative outcomes. An example of delirium pre-
vention is avoidance of anticholinergic drugs in individu-
als known to be susceptible to the effects, such as a patient
underlying dementia. Strategies for prevention of alcohol
withdrawal are another example in which a common
cause of delirium may be easily prevented in an inpatient
setting.
A number of studies have examined the role of pharma-
cologic agents in delirium prophylaxis. Haloperidol may
reduce the incidence of delirium in patients undergoing
surgery; however, a larger study did not produce a sta-
tistically significant reduction in delirium. A randomized
controlled clinical trial of cholinesterase inhibitors has not
Delirium 483
shown benefit for preventing delirium in postoperative
patients, but these studies have generally been small case
series (Gleason, 2003; Overshott et al., 2008).
Treatment strategies
The first-line treatment for delirium in all patients should
consider nonpharmacologic interventions. This includes
behavioral approaches to improve orientation and behav-
ioral interventions by multiple health-care providers.
Attention to sensory impairments such as vision, hear-
ing loss, unilateral hemineglect, or tactile loss should be
minimized.
Physical restraints should be avoided whenever pos-
sible, as they lead to decreased mobility, increased agi-
tation, and risk of injury, sometimes resulting in death.
Adequately staffing hospital units and providing optimal
patient care settings with frequent human interactions,
appropriate lighting, and adequate nutrition may assist
in this regard. Minimal noise at night to allow an unin-
terrupted period of sleep at night is considered of crucial
importance in the management of delirium.
A recent review of pharmacologic strategies for treat-
ment of delirium indicates that there are few well-per-
formed, randomized, controlled studies; therefore, our
evidence base for treatment of delirium is relatively lim-
ited to recommendations based on case series and retro-
spective reports.
It needs to be recognized that the majority of medica-
tions that help calm agitated patients also can result in
sedation. This is true for benzodiazepines, many of the
tricyclic antidepressants, and many of the neuroleptics,
especially the atypical antipsychotics (Sipahimalani and
Masand, 1997).
Part of the paradigm of geriatric medicine is that phar-
macologic agents be initiated at the lowest starting dose
and that the “start low, go slow” heuristic be considered.
Modifications to this concept need to be individualized
because of the importance of preventing self-injury or
injury to staff or family members by the delirious patient.
Haloperidol is frequently used to treat delirium, and the
effectiveness of this drug has been studied in randomized,
controlled clinical trials. Haloperidol is available in par-
enteral formulations. Haloperidol use is associated with a
higher rate of extrapyramidal side effects and acute dys-
tonia, although it is less sedating than many of the newer
atypical antipsychotics. The long half-life of haloperidol
is frequently underestimated, particularly in older adults.
Especially in patients with cardiac issues, use of any of the
neuroleptics can result in prolongation of the QT interval.
Use of atypical antipsychotics has become common prac-
tice, but lack of parenteral forms limits use in ICUs and in
seriously agitated patients.
In the future, it is possible that large databases such as
those maintained by hospitals or other care organizations
or insurance companies may provide new methods of
484 Neurologic Conditions in the Elderly
understanding the relative efficacy of agents used in the
setting of delirium, to identify those associated with shorter
length of stay, reduced mortality, and better outcomes.
Future directions and research
The mediators of ACS are multiple, and additional
research is necessary to elucidate whether a “common
final pathway” in the brain is present in ACS. That is,
despite the panoply of causes, is there a common molecu-
lar mechanism, such as acute cholinergic failure, that is
present in a majority of ACS cases and represents a thera-
peutic target for the cognitive and behavioral changes?
We also need more robust data on long-term outcomes;
although complete recovery is present in the majority of
patients, suboptimal responses and incomplete recovery
to profound brain changes in delirium might be more
common than medical professionals generally assume
(Maclullich et al., 2009).
Additional research into tools necessary for rapidly
identifying delirium beyond staff education and frequent
independent assessments would be valuable. Depending
on methodology, delirium may be present in as many as
70% of acute hospital inpatients. Tools to assess its impor-
tance and to delineate who needs urgent assessment
and treatment would be useful in promoting good out-
comes and providing timely care in a complex health-care
environment.
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 Chapter 20
Headache in the Elderly
Brian McGeeney
Department of Neurology, Boston University School of Medicine, Boston, MA, USA

Summary
• Headache is one of the more common pain complaints encountered by practitioners and remains so in the elderly
population.
• Tension-type headache remains common though somewhat less so in the elderly.
• Secondary headaches are a much greater proportion but still a minority of elderly headache.
• Migraine is less common beyond the age of 70 and rarely ever has its onset in the elderly, with the possible exception
of migraine-type visual aura.
• Treatment of headaches is more challenging in elderly.

Introduction headaches taking analgesics, no matter what the indica-

tion for the analgesics. Sometimes simply eliminating
• Up to 20% of elderly headache sufferers may have a medication overuse does not solve the problem.
secondary headache, which is higher than in the general • Other medications associated with headache, which
population. again occurs more often in patients already suffering
from migraine, are dipyridamole, nitrates, sildenafil, bro-
PRIMARY HEADACHE DISORDERS
mocriptine, caffeine, and alcohol.
• Migraine is less common beyond the age of 70 and
• Giant cell (temporal) arteritis (GCA) or Horton’s
rarely ever has its onset in the elderly, with the possible
disease is the most common systemic vasculitis in the
exception of migraine-type visual aura. Triptans are used
elderly. Involvement of the posterior ciliary artery can
by most practitioners in its treatment, caution is needed
cause blindness. Biopsy with empirical commencement
in prescribing acetaminophen, nonsteroidal anti-inflam-
of steroid therapy is recommended.
matory drugs (NSAIDs), β blockers, and antidepressants.
• Other vascular causes of headaches include ischemic
• Tension-type headache remains common though some-
and more often hemorrhagic strokes, which need to be
what less so in the elderly. It is important to avoid daily
differentiated from venous sinus thrombosis, reversible
analgesic use especially for mild headaches.
cerebral vasoconstriction syndrome, intracranial hypo-
• Cluster headaches are more common in males (4–10:1),
tension, malignant hypertension, cough headache, and
and are characterized by bouts of unilateral short-lived
extension of sphenoid sinusitis.
headache usually in the early hours of sleep, accompa-
• Cervicogenic headache may occur in patients with ar-
nied by tearing and nasal discharge. Abortive treatment
thritis or cervical trauma. Diagnostic confirmation as well
relies on high-flow oxygen and steroids rather than trip-
as treatment relies on anesthetic blockade of the cervical
tans, and verapamil and lithium are used for prophylaxis.
sensory nerves involved.
• Hypnic headaches or “alarm clock” headaches occur in
• Trigeminal neuralgia (TN) typically presents as parox-
those over 50 years of age, mostly women, following the
ysms of severe unilateral shooting facial pain triggered by
onset of sleep.
touch, movement, or cold air. MRI, possibly with mag-
• Other uncommon headache disorders include paroxys-
netic resonance angiography (MRA) is warranted to rule
mal hemicranias, hemicrania continua and short-lasting
out intracranial pathology. Medical therapy is preferred
unilateral neuralgias with conjunctival tearing (SUNCT).
to nerve decompression or surgical ablation.
SECONDARY HEADACHE DISORDERS • Other possible etiologies to consider are acute glaucoma,
• Medication overuse headache (MOH), or rebound primary brain tumors and metastases, and controversially,
headache, actually occurs in individuals with primary obstructive sleep apnea.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

486

Overview
Headache is one of the more common pain complaints
encountered by practitioners and remains so in the
elderly population. One study of symptom prevalence in
the elderly noted that headache is the tenth most com-
mon symptom among elderly women and the 14th most
common symptom among elderly men (Hale et al., 1986).
What is notably different in the elderly headache popu-
lation compared to younger people is the prevalence of
secondary headaches; that is, conditions that are symp-
tomatic with headache, contributing a much greater pro-
portion but still a minority of elderly headache. Published
studies suggest that 2.2–20% of elderly headache suffer-
ers have a secondary headache problem (Edmeads and
Wang, 2006). Clinicians should approach all new head-
ache problems in the elderly as secondary until satisfied
otherwise, in contrast to evaluating young people with
headache. In one population study, of those with head-
ache, 16.9% had onset at or older than 65 years of age
(Prencipe et al., 2001). The majority of headache prob-
lems in the elderly are still primary; however, meaning
that they derive from a disturbance in the pain system of
the head alone (approximately) and include tension-type,
migraine, and cluster headache. As primary headache
is largely genetically predetermined, one would expect
symptomatic expression before the senior years, hence
one does not expect to make a new diagnosis in this age
group. Although a few common headache problems con-
stitute the majority of headache in the elderly, the differ-
ential diagnosis is wide because many medical disorders
are symptomatic with headache (see the following list).
Selected Etiologies of Headache in the Elderly,
Most of Which Can Manifest As Episodic or Chronic
Daily Headache
Primary Headache
Migraine
Tension-type
Cluster
Hypnic
Secondary Headache
More Common
Medication induced
Medication overuse
Alcohol induced
Cervicogenic
Severe hypertension
Stroke (including subarachnoid bleed)
Intracranial mass lesions
Respiratory failure
Depression
Less Common
Temporal arteritis
Meningitis
Headache in the Elderly 487
Acute eye syndromes, such as iritis
Vertebral/carotid dissection
Experimental studies in the 1930s and later on awake
individuals led to our present understanding of what
is pain sensitive in the head (Ray and Wolff, 1940). The
venous sinuses, larger arteries (especially at the base of
the brain), and parts of the dura were pain sensitive, while
the brain parenchyma, ependymal ventricular lining, and
pia are insensitive to pain. Headache can be experienced
with traction of these structures, in addition to local irri-
tation of trigeminal sensory endings. Direct pressure on
cranial nerves may also cause head pain. Overall, site of
headache has not been particularly useful in diagnosis,
less useful than patients might think.
A review of the more common primary headache dis-
orders and selected examples of secondary headaches is
presented.
Headache classification
Practitioners are greatly challenged by a lack of diagnostic
markers and pathognomonic features of the various pri-
mary headache disorders. Hence, diagnosis and classifica-
tion is a descriptive approach. The current International
Classification of Headache Disorders (ICHD) is based on
consensus opinion, which can and does change over time
(Headache Classification Subcommittee of the International
Headache Society [IHS], 2013). The classification is not based
on good scientific evidence, as there is little evidence avail-
able that can separate the different headaches. Clinicians are
encouraged to visit the website www.i-h-s.org and, under
“Guidelines,” download the ICHD-3, which is about 160
pages long. The guidelines are best suited for research pur-
poses, and in clinical practice, one does not have to strictly
follow the criteria. Out of necessity, in research, specificity
is weighted over sensitivity in an attempt to exclude “non”
cases from clinical study. In clinical practice, one does not
have to be so strict. The classification is a valuable resource
for how headache medicine practitioners approach the diag-
nosis of headache disorders and is a great reference point.
The clinical approach to headache
Evaluation of those with headache clearly requires a compre-
hensive history and examination. History about the amount
of impairment, independent of pain severity, is important to
consider, as there may be considerable disparity from one
patient to another. A background headache history from the
patient can change the level of concern or diagnosis, as can
(to a lesser extent) the family history of significant headache
problems. Two aspects of the examination require particular
mention: measurement of blood pressure and visualization
of the optic disks. Severe abnormalities may otherwise show
488 Neurologic Conditions in the Elderly
no signs, and these cannot be guessed. Neurologic abnor-
malities, even if transient, often result in brain imaging.
Signs on neurologic examination include visual field abnor-
malities, nystagmus, and a new or worsening gait problem,
among other concerning findings. Stigmata of arthritis in
the large or small joints may increase the likelihood of sig-
nificant cervical spinal disease, along with reduced range
of motion of the cervical spine. The eyes are examined for
signs of acute glaucoma. The threshold for radiologic inves-
tigation of the brain is much lower in new-onset headache
in the elderly, with either a CT scan or an MRI. In practice,
occasional headache presentations warrant cerebrospinal
fluid examination, with concern for infection among other
problems. Occasionally, occipital predominant headache
results in cervical spine imaging, and the normal degen-
erative disease present at this age presents a challenge to
attribute causality. Meningoencephalitis in the elderly is less
reliably accompanied by signs of meningism or fever, hence
a lumbar puncture and cerebrospinal fluid examination
may be warranted using a lower clinical threshold for new
headache disorders. Structures other than the brain itself are
important to review when imaging the head. Nasopharyn-
geal carcinoma can present with headache, hence scrutiny
of the head imaging for abnormalities in the nasopharynx
is advised. The management approach of elderly headache
when the etiology of the headache is not clear commonly
involves reducing or discontinuing nonessential medica-
tions, at least until the headache problem is under control.
Finally, somatic symptoms such as headache are more com-
mon with depression and may alert the provider to poor
mood (Mazzotta et al., 2003).
Primary headache disorders
Migraine
The propensity to migraine, largely genetically deter-
mined, is expressed to a lesser extent in the elderly. The
practitioner should not be making a new diagnosis of
migraine in the elderly, with the possible exception of
migraine-type visual aura, which can present as visual
phenomena only, without significant headache, and has
been termed late-life migraine accompaniments (Fischer,
1980). A minority of migraineurs continue to have attacks
into their 70s and beyond. Such attacks are mostly a
lighter version and are easier to treat than their migraine
attacks in earlier years. Often migraineurs in their older
years have learned how to micromanage their medication
doses down to smaller amounts, reflecting an improved
responsiveness to smaller doses and possibly an increased
concern about medication side effects and tolerability at
an older age. By the time they are much older, affected
people have developed a deeper understanding of their
symptoms and lack the exasperated, frustrated, and help-
less feelings that younger migraineurs may experience.
Migraine is mostly an episodic disorder, with at times
impairing headache and associated symptoms that can
include nausea, photophobia, and phonophobia (Goadsby
et al., 2002). Migraine can transform into a daily or near-
daily variety called chronic migraine, and this continues to
be seen in the elderly, although much less than in younger
years. Many conditions can worsen or expose migraine/
migrainous-type headache again, from medications to
severe hypertension. It is a matter of debate whether less
severe hypertension can worsen migraine, but this may
be the case. As mentioned earlier, aura may occur for the
first time in older individuals. This is typically visual,
such as scintillating scotomas, or “seeing stars,” but it can
also be accompanied by sensory symptoms. Such visual
symptoms often result in a workup for possible transient
ischemic attack (TIA) or even a focal seizure. Fischer
used the term “late-life migrainous accompaniments” to
describe such visual experiences (Fischer, 1980). Despite
this, the overall burden of aura in migraine is generally
reduced when compared to younger years in the minority
of migraineurs who experience aura.
Therapy of migraine in the elderly
Medical conditions common to the elderly often make
managing migraine more challenging. In addition, ther-
apy is rather individual, balancing the suffering and fre-
quency of the headache with the patient’s expectations
and appropriateness of various medications. Use of stan-
dard nonsteroidal anti-inflammatory drugs (NSAIDs), a
gold standard in headache treatment, may be inadvisable
due to peptic ulcer disease, renal failure, anticoagulation,
or just poor tolerability. Ergotamines are often avoided in
the elderly, due to their considerable vascular effects, and
triptans are used much less frequently for similar reasons.
Sumatriptan has been available since the early 1990s (the
first triptan), and many people continue to take this (and
other triptans) as they get older. In the absence of new
vascular concerns, clinicians commonly continue to pre-
scribe triptans to older individuals at an age when they
would not initiate new triptan therapy. Typical migraine
prophylactic agents such as β blockers and tricyclic anti-
depressants (TCAs) are more often accompanied by both-
ersome side effects in the elderly. In particular, TCAs
are generally avoided in this age group. The elderly are
particularly susceptible to the cognitive side effects of
medications, such as but not limited to topiramate and
gabapentin, which are also used in migraine prophylaxis.
Renal impairment may necessitate a reduction in the dose
of gabapentin also. Acetaminophen- or butalbital-contain-
ing compounds continue to be used successfully in the
elderly. Isometheptene-containing compounds have also
been used, although this medication has recently become
unavailable in the United States. Dopamine antagonists
such as promethazine remain useful when used with cau-
tion in the elderly.

Tension-type headache
Tension-type headache remains common, although less
so, in the elderly. This type of headache, the “common”
headache, is defined more by the absence of migrainous
features and is a mild or, at most, moderate, generally
global headache, with a sensation of tightness around
the head. Tension-type headache has a chronic form,
is present on most days, and contributes to the more
benign chronic daily headache population (IHS, 2013). As
with headache in general in the elderly, the practitioner
should reach this diagnosis by exclusion and then decide
whether the suffering element warrants medication use
or whether reassurance and an explanation are sufficient.
As this type of headache may be frequent, the provider is
alerted not to encourage daily analgesic use, especially for
mild and unimpairing headache.
Cluster headache
Cluster headache is a primary headache disorder with
a prevalence estimated at 2–6 per 10,000, and character-
ized by attacks of strictly unilateral short-lived headache,
mostly with autonomic features such as tearing and uni-
lateral nasal discharge. For most patients, the disorder is
characterized by periods of weeks (cluster periods) when
the patient is vulnerable to one or more attacks a day, fol-
lowed by longer quiescent periods that are cluster free.
Cluster headache is clearly a distinct entity of short-lived,
strictly unilateral pain, and generally there is not much
difficulty in making the diagnosis when the practitioner
is familiar with the symptoms and signs. Cluster periods
appear more likely in the spring and fall seasons. There
is an estimated male:female ratio of 4–10:1 from avail-
able data, hence cluster is much more common in men.
Patients can be quiescent for 10 years or more, with attacks
recurring when older. Seidler and colleagues describe
a 91-year-old patient with new-onset cluster headache,
the oldest new presentation of cluster headache (Seidler
et al., 2006). It is common for cluster headache to dis-
appear in older age, but for those afflicted, it is known
for the severity of the pain and remains intense in those
afflicted. The headache can last from 20 to 150 minutes,
hence a headache that lasts all day is not a cluster head-
ache. Up to 10% of new cluster headache may occur in
those over 60 years of age (Silberstein and Young, 1998).
The attacks are most commonly experienced at night in
the first 1–2 hours after falling asleep. Treatment involves
abortive agents for the actual attack and daily prophy-
laxis to induce and maintain a remission. Sumatriptan,
administered subcutaneously for a cluster headache
attack, is a treatment of choice and is often avoided due
to vascular risk factors in the elderly. With avoidance of
vasoactive agents, abortive treatment relies on high-flow
oxygen (10 L) administered with a nonrebreather mask
for about 20 minutes or intranasal lidocaine. Oral agents
for a short-lived headache attack are generally slow to
Headache in the Elderly 489
act. The quickest way to induce a remission of cluster
headache is to use steroids such as prednisone 60–80 mg
daily, tapering over 10 days to 3 weeks (Shapiro, 2005).
Steroids are usually well tolerated but carry a small risk
of osteonecrosis. The prophylactic agent of choice is vera-
pamil and has demonstrated efficacy, tolerability, and
safety in chronic prophylaxis (Leone et al., 2000). The
starting dose is 240 mg slow-release tablet daily or 80 mg
three times daily. Up to 720 mg daily are used. An electro-
cardiogram is suggested at doses above 240 mg daily, due
to slowed conduction across the atrioventricular node.
Constipation, hypotension, and dizziness are other side
effects. The other prophylactic agent with reasonable lit-
erature support is lithium (Stiener et al., 1997). Lithium
may be used in combination with verapamil. Monitor-
ing of blood levels of lithium is necessary along with
assessment of renal, liver, and thyroid status. Lithium is
administered three times daily or as a daily slow-release
preparation. Starting doses are 300 mg twice daily, with
a maintenance of 600–1200 mg daily in divided doses.
Other prophylactic options include the pineal hormone
melatonin, valproic acid, topiramate, and baclofen.
Paroxysmal hemicranias, short-lasting
unilateral neuralgias with conjunctival
tearing, and hemicrania continua
Paroxysmal hemicranias are different from cluster attacks
only by being of shorter duration and more frequent,
lasting 2–30 minutes and occurring 10–30 times a day. In
addition, they are less common than cluster headache.
Paroxysmal hemicrania is termed episodic when there are
remissions of at least a month and is chronic with a year of
no remission. The short-lasting unilateral neuralgias with
conjunctival tearing (SUNCT) syndrome is an uncommon
disorder, with attacks lasting 5–240 seconds, but is other-
wise similar to cluster. Attack frequency is up to 200 a day.
Hemicrania continua is a continuous headache that is oth-
erwise similar to cluster, in being strictly unilateral and
generally accompanied by unilateral autonomic features.
This headache type is thought to be under-recognized
and a considerable cause of refractory, unilateral, chronic
daily headache in the population. It is important to note
that, despite the continuous pain, there are clear exacerba-
tions of variable length. These disorders all share common
features of unilateral headache and autonomic features.
The autonomic features seen include unilateral lacrima-
tion, nasal discharge, and a blocked nasal passage. Good
studies are not available from which to guide treatment
decisions on these less common headaches. As currently
defined by the International Headache Classification, par-
oxysmal hemicranias should respond to prophylaxis with
indomethacin. In practice, some patients fulfill criteria
except for response to indomethacin. Otherwise, consid-
eration should be given to verapamil, celecoxib, acetyl-
salicylic acid, and topiramate. The treatment of SUNCT
490 Neurologic Conditions in the Elderly
syndrome is suggested to be lamotrigine, gabapentin, or
valproic acid. By definition, hemicrania continua is com-
pletely responsive to indomethacin. Failing that, vera-
pamil, valproic acid, or β blockers may be considered. All
these uncommon headache syndromes should be consid-
ered after head imaging, to rule out secondary cause.
Hypnic headache
Hypnic headache, sometimes called “alarm clock” head-
ache, is a rare headache syndrome first described in the
literature in 1988 and occurs by definition in those over
50 years of age upon awaking from sleep. It can be uni-
lateral or bilateral (Raskin, 1988). Hypnic headache is a
dull headache lasting from 15 to 180 minutes. About two-
thirds of the cases are women. Secondary causes must be
excluded, and most cases are mild to moderate in sever-
ity. Typical attacks awaken the patient between 1 am and
3 am, and there are generally no associated features, such
as photophobia or nausea. The pathophysiology of hypnic
headache is unknown. It has been suggested that this is
a rapid eye movement (REM) sleep-related disorder, but
recent evidence demonstrates that the onset of hypnic
headache was not associated with sleep stage (Holle et al.,
2011). There is no consensus on treatment. Aspirin or caf-
feine is suggested as initial nightly treatment, followed
by lithium 300–600 mg, melatonin 3 mg, or indomethacin
25–75 mg, all administered at night (Holle et al., 2010).
Secondary headache disorders
Medication-related headache
Overuse of analgesic medications in those with primary
headache disorders occurs commonly and can itself
induce headache. This type of headache is typically
termed medication overuse headache (MOH), sometimes
called rebound headache. The pathophysiology of this
problem is not well understood and can occur no mat-
ter what the indication for the analgesics. MOH is a com-
mon secondary headache, typically seen in the young
and early middle-aged migraineur. However, it can also
occur in the elderly, although the prevalence is much less
than those under 50 years of age. It is important to note
that this phenomenon occurs in individuals with primary
headache, especially with a big burden of a headache, and
should not occur in people taking daily analgesics with-
out a headache history. Sometimes eliminating medica-
tion overuse, after sufficient time for mechanisms to reset,
does not improve the headache problem.
In addition to MOH, medications by themselves cause
headache separate from analgesic overuse (Figure 20.1).
A critical point to recognize is that the propensity to do
so is much more common in those with a background
of migraine. The elderly patient with a background of
migraine during the younger years is more likely to
Medication-associated Headache
Vasodilators Histamine release
Dompamine agonist
Serotonergic agents
TNF inhibitors
Hormones
Immunomodulators
Raised ICP
Others
Figure 20.1 Medications capable of inducing headache,
independent of analgesic overuse.
present with medication-induced headache. Both caf-
feine and alcohol remain a common cause of headache in
the elderly, and one may miss the nightly alcohol intake
without a careful history. Medications commonly asso-
ciated with headache include dipyridamole, cyclospo-
rine, vasodilators like nitrates, and sildenafil. Dopamine
antagonists such as bromocriptine and tumor necrosis
factor (TNF) inhibitors such as etanercept also may cause
headache. Consideration should be given to stopping as
much medication as possible when working to improve a
headache problem.
Giant cell arteritis
Giant cell arteritis (GCA), otherwise known as temporal
arteritis or Horton’s disease, is the most common systemic
vasculitis in the elderly (Ward and Levin, 2005). (See the
following list for diagnostic criteria.)
International Headache Society Diagnostic Criteria for
Giant Cell Arteritis
A. Any new persistent headache fulfilling criteria C
and D
B. At least one of the following:
swollen, tender scalp artery with elevated erythrocyte
sedimentation rate (ESR) and/or C-reactive protein
(CRP)
temporal artery biopsy demonstrating GCA
C. Headache develops in close temporal relation to
other symptoms and signs of GCA
D. Headache resolves or greatly improves within 3 days
of high-dose steroid treatment
GCA presents with headache that is often daily; other
symptoms may be present, including jaw claudication
(which significantly increases the chance that headache is
from GCA), proximal limb pain characterizing polymy-
algia rheumatica, cranial neuropathies including optic

nerve ischemia, and less commonly, oculomotor palsy.
Examination can demonstrate tenderness and indura-
tion of the temporal arteries (Ward and Levin, 2005).
The headache has no particular features, and the feared
complication is involvement of the posterior ciliary arter-
ies that can easily result in blindness without recovery
from optic nerve ischemia. The gold standard of diagno-
sis is temporal artery biopsy, and some clinicians advise
bilateral biopsies to increase the likelihood of pathology.
Treatment involves steroid use and, much less commonly,
immunosuppressants for months. Starting doses are often
60 mg of prednisone daily, which is tapered gradually
over the next 4 weeks, then continued around 40 mg daily,
and reduced much more gradually over many months.
After initiation of steroids, the headache typically dis-
appears within a few days (helpful for diagnosis); this
generally commits patients to a few months of steroids.
Laboratory testing reveals ESR elevation in 97% of those
with GCA, often with an ESR over 100, an elevated CRP,
a platelet count of >375,000, and sometimes a normochro-
mic microcytic anemia. GCA may also affect the vertebral
and carotid arteries. Patients with GCA have a greater
proportion of vertebrobasilar territory infarcts and TIAs,
compared with carotid circulation events (Caselli et al.,
1988).
Other vascular diseases
Both ischemic and hemorrhagic stroke may be accom-
panied by headache, and generally other symptoms and
signs point to the diagnosis of stroke. A sudden-onset
severe headache is helpful in identifying a vascular catas-
trophe and is termed a “thunderclap” headache, with
pain maximal at onset. It is commonly associated with
subarachnoid hemorrhage from a cerebral aneurysm.
The patient should be questioned carefully, as severe
headache may also have onset in 5–10  minutes from
more benign etiologies instead of being true thunder-
clap. The differential diagnosis of thunderclap headache
is firstly primary and secondary. There are people with
apparent primary headache which can result in thunder-
clap headache, a diagnosis made after excluding other
disorders. Thunderclap headache can also occur second-
ary to intracranial hemorrhage, central vein/venous
sinus thrombosis, reversible cerebral vasoconstriction
syndrome, intracranial hypotension, acute hypertension,
and sphenoid sinusitis with extension. A sudden-onset
headache may occur with cough headache, a primary
headache syndrome triggered by a cough or the Valsalva
maneuver, and this headache can last 30 minutes or
more. Unruptured cerebral aneurysms are frequently
found on noninvasive imaging such as magnetic reso-
nance angiography (MRA) and are, for the most part,
asymptomatic; thus, their discovery on a workup for
Headache in the Elderly 491
headache is incidental. Subdural hematomas often have
a more subtle presentation and are not invariably associ-
ated with a trauma history, making the diagnosis more
difficult. As the blood pushes the brain aside, one may
find only subtle neurologic signs, if any. Small vessel dis-
ease that involves cranial nerves can result in dysfunc-
tion, such as ischemic optic neuropathy or oculomotor
neuropathy, particularly in diabetes. Such syndromes
can be associated with headache.
Although there is consensus that severe or “malignant”
hypertension is invariably accompanied by some head-
ache, most of the available studies suggest that lesser
degrees of hypertension are not associated with headache
(Gus et al., 2001; Hagen et al., 2002). Many medications
used to control hypertension have independent effects on
headache control, making the assessment more difficult.
The author’s opinion is that, in those with migraine, the
onset of essential hypertension or a significant worsening
of blood pressure control may be accompanied by more
headache.
Cervicogenic headache
Neck pain is well known to result in headache, and the
neck is often injured alone–-for example, in whiplash or
in conjunction with head injury (Packard, 2002; Bogduk,
2004). Many structures in the neck can produce referred
pain to the head, including the atlanto-occipital joint,
atlanto-axial joints, zygapophyseal joints, cervical and
vertebral ligaments, vertebral disks, and neck muscles.
Pain from neck structures often refers pain to the occipital
region, which also carries cervical root sensory innerva-
tion. Neck pain causing headache should be separated
from the common experience of neck pain in those with
migraine/headache, as trigeminal activation tends to
sensitize the upper cervical sensory system, at least inter-
mittently. Migraineurs often have considerable neck
pain–this is not cervicogenic headache. The same concept
applies to any headache that can sensitize the upper cer-
vical system. Admittedly, the cervical pain so generated
can then act as an irritant to headache. Those at risk for
cervicogenic headache are older individuals with arthritis
and those with post-traumatic headache (PTH). Younger
headache patients should be suspected of having cervi-
cogenic headache only if they suffered trauma, such as a
flexion–extension injury. Patients with rheumatoid arthri-
tis commonly have headache, thought to be associated
with extensive involvement of the upper cervical spine in
the arthritis.
Cervicogenic headache is best demonstrated by aboli-
tion of headache following diagnostic blockade of a cervi-
cal structure or its nerve supply. A variety of peripheral
procedures have been employed to treat cervicogenic
headache and PTH. Most rely on anesthetizing struc-
tures thought to be etiologic in the subject’s head and
neck pain. Chronic zygapophyseal joint pain is thought to
492 Neurologic Conditions in the Elderly
contribute to chronic neck pain post whiplash-associated
injury, in particular and has been the focus of interven-
tional treatments. An occipital nerve block may merely
change sensory input, which has a modulating effect cen-
trally and can result in benefit. Benefit obtained likely will
be short lived. Interventional procedures to anesthetize
neck structures may work in a similar way. A prolonged
positive outcome is likely due to successfully identifying
the source of nociception.
Unfortunately, tenderness in the neck is not a reliable
or valid feature for the source of neck or head pain, as this
finding is extremely common with head and neck pain.
Primary headache is often associated with an allodynic or
hyperalgesic state via peripheral and central mechanisms
that results in abnormal tenderness, as noted earlier. The
most compelling explanation for cervicogenic headache is
pain from the upper cervical joints. Convergence of spinal
afferents and occipital afferents easily explains referred
pain from the spine to the occipital region, but there is
also anatomic convergence between the cervical system
and the trigeminal system. Pain in the spine thus can be
referred not just to the occipital region, but to all regions
of the head.
The term cervicogenic headache is frequently used and
relies entirely on clinical criteria, by standard defini-
tion. This is controversial. The features are not specific,
and similar presentations may be seen with migraine.
Complete response to diagnostic blockage of cervical
nerves or structures is stronger evidence of true cervico-
genic headache. Post-traumatic neck pain with headache,
in particular, is thought to be caused by irritation of upper
cervical joints, particularly the C2–3 zygapophyseal joint.
This joint is innervated by the third occipital nerve, anes-
thetic blockage of which may result in the resolution of
headache. More long-term treatment is available with
radiofrequency neurotomy.
Other secondary headaches
Any intracranial mass lesion, which is common in the
elderly, can produce headache by raised intracranial
pressure and traction on blood vessels and meninges,
among other mechanisms, as noted earlier. Primary brain
tumors and metastatic disease to the brain are common
in the elderly and often, but not always, have headache
as a presenting complaint. Acute angle closure glaucoma,
more common in the elderly, can present with headache,
eye pain, blurry vision in the affected eye, and nausea.
Disease and disorders in the thoracic cavity may less com-
monly present with facial or head pain, including cardiac
ischemia, and, via the vagal nerve, lung carcinoma. Some
evidence suggests that those with obstructive sleep apnea
may experience morning headaches, although the litera-
ture is mixed.
Trigeminal neuralgia
Although not a headache, it is useful to review this facial
pain problem in the headache chapter. Trigeminal neural-
gia (TN) is a severe unilateral neuropathic pain syndrome,
resulting in brief (seconds), repeated paroxysms of uni-
lateral facial pain, often described as sharp and shoot-
ing from the back of the face forward (Rozen, 2004). TN
affects predominantly older age groups and, for the most
part, is idiopathic. Attacks are often spontaneous but may
be triggered by touching certain areas of the face or even
talking. A cold breeze on the face is a common trigger.
Mostly there is no sensory loss or neurologic findings on
examination. Eliciting neurologic deficits should trigger
a search for secondary causes of neuralgia in the distri-
bution of the trigeminal nerve. The clinical presentation
of apparent TN may be secondary to intracranial lesions,
and all patients warrant MRI imaging, generally with an
MRA as well. An MRA is performed, as it is thought that
some patients have TN due to compression of the trigemi-
nal nerve by an arterial vascular loop (microvascular com-
pression). Most patients are managed medically, although
there are surgical options. Older treatments such as carba-
mazepine, clonazepam, and baclofen provide reasonable
relief for most patients, but there are still many refractory
patients. The use of carbamazepine is most commonly
used for this purpose (for more than 40 years). Other
medications that are used for TN include oxcarbazepine,
valproic acid, lamotrigine, and gabapentin. A variety of
denervation procedures has been advocated, with vari-
able acceptance in the medical community. Side effects
include problems with pain in the area of anesthesia–
anesthesia dolorosa. Radiofrequency thermocoagulation
of the trigeminal nerve is the most common surgical treat-
ment in the United States for TN. This option requires an
appropriately trained surgeon and still leaves the patient
open to denervation-related complications such as pain.
Often patients regain their pain eventually. Microvascular
decompression has been advocated by Jannetta (Jannetta
and Bissonette, 1985). This requires a craniotomy and
placement of synthetic material between the trigeminal
nerve and an abutting arterial vessel. Initial outcomes are
good, although pain returns in some patients. The main
advantage of surgical decompression is that there is no
destruction of nervous tissue.
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 Chapter 21
Neuromuscular Disorders
Heber Varela and Clifton Gooch
Department of Neurology, University of South Florida College of Medicine, Tampa, FL, USA

Summary
• Motor neuron diseases (MNDs) are the result of degeneration of anterior horn cells in the spinal cord, motor neurons
of the brainstem, and the motor cortex. Mechanisms of motor neuron injury may be sporadic or hereditary.
• Amyotrophic lateral sclerosis (ALS) is the most common form of MND and is an incurable paralyzing disorder. It is a
clinical diagnosis and diagnosis of exclusion. Symptoms screened for is upper and lower motor neuron dysfunction.
Treatment is mainly supportive. Other MND include primary lateral sclerosis (PLS), progressive muscular atrophy
(PMA), focal MND, and post-polio syndrome.
• Nerve root diseases affect the peripheral nervous system, inflictions include radicular pain, dermatomal sensory loss,
decreased deep tendon reflexes. Lumbosacral radiculopathies more common than cervical. Assessments of nerve root
include MRI and CT myelography. Treatment of cervical radiculopathies through conservative approach to relieve pain,
and surgical approach if patient is unresponsive to other interventions.
• Diseases of brachial and lumbosacral plexus are very rare, and can be caused by plexus injury or metastatic tumors
and radiation treatment. Patients experience severe arm pain, weakness, and atrophy of muscles. MRI and EMG/NCS
are the diagnostic tools of choice. Radiation plexopathy is treated symptomatically, with pharmacologic and physical
therapy. Surgery is sometimes performed for neurolysis and removal of scar tissue.
• Neuropathy affects the peripheral sensory, motor, or autonomic nerves. it can occur symmetrically in the body or in
irregular distribution. A major diagnosis tool is a lumbar puncture, for autoimmune neuropathies.
• Guillain–Barré syndrome is an acquired neuropathy, that targets the peripheral nerves. The most common form is the
acute inflammatory demyelinating polyradiculoneuropathy (AIDP).
• Neuromuscular disorders include chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), paraproteinemic
polyneuropathy, paraneoplastic neuropathy, toxic neuropathies, diabetic neuropathies, idiopathic polyneuropathy,
hereditary motor and sensory neuropathy (HMSN), neuromuscular junction disorders, and disorders of muscle.

Introduction
The prevalence of most neuromuscular diseases increases
with advancing age, and many of these disorders are par-
ticularly common in the elderly. Any level of the periph-
eral nervous system may be affected, including the ante-
rior horn cell, the nerve roots, the plexi, the peripheral
nerves, the neuromuscular junction, and the muscle. This
chapter discusses the most common of these disorders,
including their history, physical examination, diagnostic
evaluation, and therapy.
brain stem, and the motor cortex. The clinical manifesta-
tions are those of amyotrophic weakness, atrophy, and
fasciculations and signs of corticospinal tract dysfunction
(weakness, spasticity) in various combinations. Amyo-
trophic lateral sclerosis (ALS) is the most common form
of MND. As it damages both the corticospinal tracts and
the anterior horn cells, it presents with progressive weak-
ness in concert with amyotrophy, spasticity, and upper
motor neuron (UMN) signs. Other forms of MND include
primary lateral sclerosis (PLS) and progressive muscular
atrophy (PMA), which selectively affect the corticospinal
tracts and the lower motor neurons, respectively.

The motor neuron diseases Pathophysiology

Diseases of the anterior horn cell, or motor neuron dis-
eases (MNDs), encompass a group of chronic, progressive
degenerative disorders affecting primarily the anterior
horn cells in the spinal cord, the motor neurons of the
MNDs are marked by pathologic loss of motor neurons in
either the UMN pathway (the corticospinal tract from the
cortex through the spinal cord), the lower motor neuron
pathway (the anterior horn cells), or both. Typically, these
disorders spare the sensory system. Mechanisms of motor

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

494

neuron injury may be sporadic or hereditary and include
excitotoxic and oxidative injury, inflammatory mediators,
disorders of cellular transport, mitochondrial dysfunc-
tion, support cell dysfunction (such as glial abnormali-
ties), and neurofilament dysfunction, among others. Most
cases of ALS are sporadic, and no specific trigger has been
found to date, although much has been learned about the
pathophysiology underlying its progression, once estab-
lished. About 10–20% of the cases are hereditary and typi-
cally transmitted as an autosomal dominant trait (familial
ALS), usually with younger onset than the sporadic form.
In some of these cases, disordered processing of superox-
ide dismutase (SOD) results in a toxic gain of function,
which causes the motor neuron injury.
Amyotrophic lateral sclerosis
ALS is the most common form of MND and presents,
with progressive weakness, in concert with amyotrophy,
spasticity, and UMN signs, due to damage to the cortico-
spinal tracts and the anterior horn cells.
Epidemiology and clinical features
ALS is a lethal, paralyzing disorder that most com-
monly affects adults in the fifth to seventh decades of life,
although it can impact both younger and older patients. It
affects men twice as often as women and is relatively rare,
with an incidence of 1 in 50,000 to 1 in 100,000. The dis-
ease most commonly begins with distal, focal limb weak-
ness, and atrophy, often accompanied by muscle cramps
and fasciculations, which then progresses to involve all
voluntary muscles, ultimately affecting the muscles of
respiration. Bulbar symptoms, such as dysarthria and
dysphagia, develop during the course of the disease, but
they may be a presenting feature. Bulbar-onset ALS has
a poorer prognosis, with earlier respiratory compromise.
Involvement of the corticospinal tracts is marked by spas-
ticity, hyperreflexia, and Babinski signs. Clinically, ALS
is a relatively selective motor neuron syndrome, with no
sensory symptoms. However, approximately one-third of
patients will have a mild frontotemporal dementia.
Diagnosis
ALS is a clinical diagnosis and a diagnosis of exclu-
sion; no single test is diagnostic of ALS. A careful his-
tory and physical examination is crucial and should
focus on symptoms and signs of combined upper and
lower motor neuron dysfunction. A series of serum
studies should also be performed to exclude disorders
of the nerve and muscle that might mimic ALS. Electro-
diagnostic testing (EDX) with electromyography and
nerve conduction studies (EMG/NCS) is the single most
important diagnostic test, as it provides detailed and
sensitive information regarding motor neuron injury
and also excludes potential mimics. NCS demonstrates
only motor axon loss with normal sensory responses,
Neuromuscular Disorders 495
while EMG reveals widespread denervation of muscles
throughout the body, ultimately including all extremi-
ties; the cervical, thoracic, and lumbosacral paraspinal
muscles; and the cranial muscles. EMG/NCS can also
help classify the level of diagnostic certainty at different
stages of the disease in a given patient (suspected, pos-
sible, probable, or definite ALS; Hammad et al., 2007).
Imaging studies of the brain and spine are also typically
indicated to rule out other lesions that might cause UMN
injury. Because ALS is a lethal disease, it is extremely
important to exclude mimics that are potentially treat-
able, particularly intercurrent cervical and lumbosacral
spondylotic myelopathy and polyradiculopathy, motor
neuropathies such as multifocal motor neuropathy with
conduction block (MMNCB), bulbar myasthenia gravis,
and inclusion body myositis.
Treatment
There is no cure for ALS, and treatment is primarily sup-
portive. Riluzole, an antiglutamatergic agent, has a mod-
est but definite therapeutic effect and prolongs survival
by 10–30% (an average of 2–3 months) when given in a
dose of 50 mg by mouth twice a day (Miller et al., 2009).
Other medications, such as gabapentin, have not shown
consistent benefit and are not approved for the treatment
of ALS. Stretching and range of motion exercises guided
by a physical therapist help improve mobility and avoid
contractures, with the appropriate use of mobility aids
and orthotic devices. Maintaining nutrition is of para-
mount importance and has been shown to clearly and sig-
nificantly prolong survival; it should be emphasized from
the beginning, with early assessment by a nutritionist. As
patients will eventually develop progressive dysphagia,
percutaneous endoscopic gastrostomy (PEG) tube place-
ment should be considered early, to maintain nutrition
and prevent weight loss and catabolic muscle deteriora-
tion (Miller et al., 2009). Dysarthria will also eventually
develop in most patients, and augmentative and alter-
native communication devices should be prescribed for
patients with severe dysarthria. Respiratory function
should be carefully followed (typically by serial forced
vital capacity measurements). Before respiratory compro-
mise begins to approach critical levels, noninvasive ven-
tilation should be offered. Tracheostomy and mechanical
ventilation should also be discussed with patients, with
the understanding that, although this will prolong life, it
will not prevent the progression of weakness, which will
ultimately lead to total quadriparesis and loss of cranial
nerve functions. The care of the ALS patient in a multi-
disciplinary clinic optimizes health-care delivery and
has also been shown to prolong survival. In this setting,
patients are evaluated by different health-care profes-
sionals, including a neurologist; physical, occupational,
respiratory, and speech therapists; and a social worker on
a single visit.
496 Neurologic Conditions in the Elderly
The mean duration of the disease is 3–5 years. Approxi-
mately one-third of patients die in less than 3 years and one-
third live longer than 5 years. About 10% of patients survive
more than 10 years. Younger age at onset and limb weakness
at onset correlate with slower disease progression (Magnus
et al., 2002). Bulbar-onset ALS has the poorest prognosis.
Primary lateral sclerosis
Epidemiology and clinical features
PLS is a form of MND characterized by the degeneration
of the corticospinal tracts, with sparing of the anterior horn
cells of the spinal cord and the brain stem. Whether PLS
and ALS are distinct disorders or simply part of a broader
spectrum of the same disorder remains a matter of debate,
as some patients with an initial diagnosis of PLS eventually
progress to ALS. There is also a well-recognized UMN–onset
form of ALS, but patients in this category develop lower
motor neuron symptoms and signs within a year of their
UMN symptoms, whereas true PLS remains restricted to
the UMNs. Gordon and colleagues (2006) proposed that the
definition of PLS includes the stipulation that pure upper
motor signs remain restricted for at least 4 years after symp-
tom onset. The clinical syndrome of PLS is rare, accounting
perhaps for 1–3% of all patients with MND, which extrapo-
lates to a prevalence rate of 1 in 500,000 to 1 in 1,000,000
(Mitsumoto et al., 1998). The age of onset is most commonly
between 50 and 55 years. The disease begins with a pure
spastic paraparesis, typically manifested as slowing of gait,
with spasticity predominating over weakness. Over the
years, the arms become involved, along with the bulbar
muscles, causing pseudobulbar palsy (emotional inconti-
nence), dysarthria, and dysphagia. About half the patients
develop spastic bladder. Sensory symptoms are rare and
should raise the question of another disorder.
Diagnosis
As with ALS, PLS is a clinical diagnosis and a diagnosis
of exclusion. The workup and evaluation parallels that
of ALS. Mimics include any disorder that can affect the
UMN anywhere along its path, as well as the myriad
causes of progressive paraparesis.
Treatment
As in the other types of MND, there is no cure for PLS.
Treatment is supportive, including physical therapy, with
particular emphasis on ambulation and spasticity man-
agement. Unlike ALS, true PLS is a syndrome of slow pro-
gression, with long maintenance of function and survival
up to several decades.
Progressive muscular atrophy
Epidemiology and clinical features
PMA is a pure lower motor neuron disorder seen more
commonly in men than in women. PMA comprises from
1% to 19% of motor neuron cases, with an estimated prev-
alence of 1 in 250,000 to 1 in 1,000,000. Onset is in the dis-
tal upper extremities and often asymmetric, with atrophy
of the intrinsic hand muscles and ultimate progression to
the proximal arms and the legs. Fasciculations, cramping,
and bulbar dysfunction are variably present, and deep
tendon reflexes are decreased or absent. It can occur at
almost any age but commonly manifests in the fifth and
sixth decades.
There is also a lower motor neuron form of ALS, with
the later appearance of UMN signs, which may be ini-
tially confused with PMA. A study of 962 patients found
UMN signs developed in 22% of patients with PMA
within 61 months after diagnosis (Kim et al., 2009). Some
patients with the clinical features of PMA frequently have
UMN pathology detected only with autopsy, and most
have ubiquitinated inclusions typical of ALS (Ince et al.,
2003), leading some to classify PMA as a variant of ALS.
Diagnosis
PMA, as with other forms of MND, is a clinical diag-
nosis, and the workup is similar to that of ALS, includ-
ing EMG/NCS, serum screens, and imaging studies to
exclude other disorders. Numerous emerging imaging
modalities, including diffusion tensor imaging, positron
emission tomography (PET), and transcranial magnetic
stimulation, have been used to determine which patients
with PMA actually have UMN dysfunction. However, no
method has proven to be sensitive or specific enough for
diagnosis.
Treatment
Treatment is supportive and focuses on physical therapy
and orthoses to maintain function. PMA is character-
ized by slower progression and longer survival than
ALS, ranging from 3 to 30 years, with a mean of 13 years
(Norris, 1992).
Focal motor neuron disease
Epidemiology and clinical features
Although most forms of MND initially present with focal
findings, the vast majority of them then follow a course
of inexorable progression and generalization. However, a
rare subset of the MNDs begin and progress regionally
but never generalize to other areas of the body. True focal
MND typically involves only the lower motor neuron,
and patients virtually never demonstrate UMN signs on
examination. The presence of UMN signs in a patient with
focal-onset MND is strongly predictive of future general-
ization. Focal MND can begin at any age, but the average
age of onset, as with ALS, is in the fifth and sixth decades.
Some forms of focal MND have been characterized as
specific syndromes, such as brachial amyotrophic diple-
gia. This syndrome begins with bilateral upper-extremity

weakness, but unlike ALS, it remains largely confined to
the arms, with no UMN signs. The age of onset is simi-
lar to that in ALS patients, but the male-to-female ratio is
9:1 in the brachial amyotrophic diplegia group, compared
with 1.5:1 in ALS. Bilateral arm weakness is a present-
ing symptom in 5–10% of ALS cases (Mulder, 1957; Katz
et al., 1999), but these patients develop both UMN signs
and more generalized weakness as the disease progresses.
Diagnosis
As with other forms of MND, focal MND is a clinical diag-
nosis, after excluding the many other disorders causing
regional denervation (such as radiculopathy, plexopathy,
and focal neuropathy). Although it is clinically supported
by evidence of denervation and reinnervation restricted
to one region on EMG examination, this diagnosis can be
confirmed only over time, with a lack of significant gener-
alization and a lack of UMN signs over at least 1–2 years.
Treatment
Management is supportive. Generally, these patients live
much longer than patients with typical ALS, and some
have a normal lifespan. However, in a minority of patients
with focal MND of the arms, respiratory involvement may
ensue. In the syndrome of brachial amyotrophic diplegia,
median survival is 57 months, compared with a median
survival of 39 months in ALS.
Post-polio syndrome
Epidemiology and clinical features
Polio is an enterovirus that causes focal injury to the
spinal cord and anterior horn cells, often in a segmental
pattern. Typically, the disorder causes acute-onset weak-
ness or paralysis with gradual recovery of strength over
1–2  years, but some patients with more severe infection
can be left with degrees of permanent weakness, ranging
from mild to complete paralysis. Poliomyelitis epidemics
in the United States ended with the introduction of the
polio vaccine in 1955. Some of these survivors develop
recurrent weakness after the age of 60 years, many
decades after the initial attack, due to a unique disorder
known as the “post-polio syndrome.” This disorder is pri-
marily a disease of the elderly.
The most prominent neurologic manifestation of post-
polio syndrome is a new slowly progressive weakness,
sometimes accompanied by atrophy, typically in a region
previously affected by poliomyelitis. However, post-polio
syndrome can also affect muscles not previously symp-
tomatic, including the respiratory and bulbar muscles.
Mulder et al., 1972 codified the diagnosis, identifying four
major criteria: (1) A prior episode of paralytic poliomyeli-
tis with residual motor neuron loss; (2) a period of neuro-
logic recovery followed by an interval (usually 15 years or
more) of neurologic and functional stability; (3) a gradual
Neuromuscular Disorders 497
or abrupt onset of new weakness or abnormal muscle
fatigue, decreased endurance, muscle atrophy, or gen-
eralized fatigue; and (4) exclusion of medical, orthope-
dic, and neurologic conditions that could be causing the
symptoms. Generalized fatigue is also common, as is pain
from joint instability, and these symptoms can sometimes
appear without the development of a new weakness.
Several mechanisms have been proposed to explain the
post-polio syndrome.
The prevalence of post-polio syndrome varies in
different studies from 22% (Codd et al., 1985) to 64%
(Windebank et al., 1991).
Pathophysiology
After the acute attack of polio, the remaining motor neu-
rons send out sprouts to take over degenerated muscle
fibers (collateral sprouting), creating enlarged motor
units five to ten times larger than normal. Some of these
new synapses may never fully stabilize (Wiechers and
Hubbell, 1981), ultimately resulting in the degeneration
of axonal branches, drop-out of motor neurons, and the
inability to fully activate muscles. However, most cases of
post-polio syndrome likely result from the normal loss of
motor neurons with aging. In healthy subjects without a
history of polio, this loss does not typically cause signifi-
cant functional weakness (though it can be quantitated
electrophysiologically and with quantitative strength
testing), but in patients with a substantially reduced pool
of motor neurons due to polio, this additional loss may
drive strength below a functionally significant threshold,
with continuing declines as aging progresses.
Diagnosis
The diagnosis of post-polio syndrome is a clinical one.
Electrodiagnostic studies cannot differentiate patients
with post-polio syndrome from asymptomatic post-polio
patients. However, these studies are important to exclude
other neuromuscular diseases, such as ALS, radiculopa-
thies, and myopathies. The needle examination demon-
strates diffuse neurogenic motor unit potentials indica-
tive of reinnervation, with little or no evidence of active
denervation (which helps to exclude severe and progres-
sive disorders such as ALS). Because of aggressive and
maximal collateral reinnervation, polio survivors typi-
cally demonstrate extremely large (“giant”) motor units
in previously affected myotomes, sometimes as large as
10–20 millivolts in amplitude, much larger and in greater
abundance than most other neurogenic disorders. Imag-
ing studies (MRI) are needed to exclude spine problems
such as spondylosis and stenosis.
Treatment
Most patients experience noticeable but mild additional
weakness and do not require specific intervention. For
those with more significant weakness, treatment is
498 Neurologic Conditions in the Elderly
supportive, including the institution of a nonfatiguing
strengthening exercise program, avoiding the overuse of
weakened muscles. Dysphagia can be treated with swal-
lowing techniques; respiratory dysfuncion, if present,
may be ameliorated by the use of noninvasive positive-
pressure ventilation. Most patients do not develop respi-
ratory symptoms, and in those who do, more invasive
ventilation is rarely required. Musculoskeletal pain and
joint instability are managed conservatively, with physi-
cal therapy, lifestyle changes, and the use of assistive
orthotic devices.
The natural course of post-polio syndrome is charac-
terized by slow progression with plateaus and is not
ultimately disabling in the majority of patients. One
study reported continuous progression of weakness over
12 years of follow-up (Mulder et al., 1972). A more recent
study demonstrated progression when patients were fol-
lowed for 15 years (Sorenson et al., 2005). Mechanical
complications from arthritis are common, and additional
bulbar weakness, though rare, may lead to aspiration
pneumonia.
Nerve root diseases
Epidemiology and clinical features
Diseases of the nerve root (radiculopathies) are among
the most common disorders affecting the peripheral ner-
vous system. With advanced age, degenerative disease of
the spine becomes an extremely common cause of cervical
and lumbar radiculopathy. Spondylosis is characterized
by osteoarthritic changes in the spine and osteophyte for-
mation, leading to compromise of the nerve root. In the
cervical region, nerve root compression in patients older
than 50 years is often caused by disc herniation super-
imposed on chronic spondylotic changes (Bradley et al.,
2003). Epidural spinal tumors, particularly metastasis,
can also compromise the nerve roots at any level but are
more common in the thoracic spine. Other less common
causes of radiculopathy include infections such as her-
pes zoster, cytomegalovirus (CMV), HIV, Lyme disease,
tuberculosis, and syphilis. Diffuse root involvement can
occur in inflammatory conditions, such as Guillain–Barré
and chronic inflammatory polyradiculoneuropathies and
carcinomatous meningitis.
Radicular pain is described as knifelike or aching and
typically is aggravated by coughing, sneezing, and strain-
ing. Dermatomal sensory loss or paresthesias referred to
the specific dermatome, weakness in the affected myo-
tome, and decreased or absent deep tendon reflexes
subserved by the affected root are characteristic clinical
features, which can present in varying combinations,
depending on the severity.
Lumbosacral radiculopathies are more common than
cervical radiculopathies. Disc herniations occur at the
L4–L5 or L5–S1 levels in 95% of lumbar radiculopathies,
typically compressing the L5 and/or S1 roots (Bradley
et al., 2003). At the cervical level, C7 radiculopathies are
the most common, followed by C6 (Yoss et al., 1957). In S1
radiculopathy, pain radiates to the buttock and down the
posterior leg, and paresthesias may be felt in the lateral
ankle and foot. The ankle jerk is frequently diminished or
absent, and weakness in the gluteus maximus (hip exten-
sion), knee flexors, and foot dorsiflexors may be present.
In L5 radiculopathy, the distribution of pain is similar, but
with paresthesias on the dorsum of the foot and the lateral
aspect of the calf. Weakness can occur in the L5 root inner-
vated muscles, including the gluteus medius (hip abduc-
tion), tibialis anterior (dorsiflexion), extensor hallucis lon-
gus (extension of the first toe) tibialis posterior (inversion),
and peroneus longus (eversion). The ankle reflex is spared
in L5 radiculopathy. The straight-leg raising test, in which
the examiner has the patient lie in the supine position and
then gently raise the leg at the hip while keeping the knee
straight to reproduce the symptoms of pain, paresthesias,
or numbness, can be a sensitive supportive sign of L5 or
S1 radiculopathy (Bradley et al., 2003).
Lumbar spinal stenosis deserves special consideration
here, as it is relatively common in the elderly population.
Spinal stenosis is associated with multilevel degenerative
spine disease, which narrows both the foramen through
which the nerve roots pass and the interior diameter of
the spinal column itself. Such narrowing of the spinal
canal is asymptomatic in 21% of cases (Boden et al., 1990)
but is frequently associated with low-back pain and can
cause symptoms and signs of focal nerve root injury. In
addition, it can give rise to the syndrome of neurogenic
claudication, in which prolonged walking reliably repro-
duces symptoms of pain and cramping in the legs, mim-
icking peripheral vascular disease. Patients may alter
their gait to help prevent the onset of symptoms, and one
study found that a wide-based gait among patients with
low-back pain had specificity exceeding 90% for lumbar
spinal stenosis (Katz et al., 1995).
Cervical radiculopathies typically cause symptoms in
the arms and hands. In C7 radiculopathy, pain radiates to
the shoulder, chest, forearm, and hand, and paresthesias
involve the middle finger. The triceps reflex is generally
reduced or absent. Weakness may be found in the tri-
ceps (elbow extension), extensor carpi radialis (extension
of the wrist), and extensor digitorium communis (fin-
ger extension). In C6 radiculopathy, pain radiates to the
shoulder, lateral forearm, and thumb. Paresthesias are felt
in the thumb and the index finger. Weakness may occur in
the biceps (elbow flexion and supination), pronator teres
(forearm pronation), and flexor carpi radialis (wrist flex-
ion). Biceps and brachioradialis reflexes are diminished
or absent.
Radiculopathies rarely occur in the thoracic spine.
However, conditions such as herpes zoster infections, as

well as its sequelae, postherpetic neuralgia, most com-
monly affect the thoracic region, and diabetes mellitus
can involve the thoracic roots as well. Discogenic pain
in the thoracic spine is relatively rare compared to the
cervical and lumbosacral areas. Symptoms of thoracic
radiculopathy may include chronic intermittent anterior
thoracic pain, acute nontraumatic thoracic radicular pain,
and tenderness in the medial scapular region. In diabet-
ics, the pain of thoracic radiculopathy is generally intense,
burning, or shooting pain that radiates to one side of the
chest or abdomen from the thoracic nerve root. The symp-
toms of thoracic radiculopathy can sometimes be con-
fused with cardiac pain, and a cardiac workup may some-
times be indicated. Herpes zoster radiculitis presents with
burning pain, itching, hyperesthesia, or paresthesias. The
pain may be mild to extreme in the affected thoracic der-
matome, often described as stinging, tingling, aching, or
throbbing, and can be interspersed with quick stabs of
agonizing pain. In most cases, after a few days, the initial
phase is followed by the appearance of the characteristic
erythematous and vesicular skin rash, limited to one or
two thoracic dermatomes on one side of the body without
crossing the midline.
Etiology and pathophysiology
Spondylosis is characterized by osteoarthritic changes in
the spine and osteophyte formation, leading to compro-
mise of the nerve root. In the cervical region, nerve root
compression in patients older than 50 years is often caused
by disc herniation superimposed on chronic spondylotic
changes (Bradley et al., 2003). Epidural spinal tumors, par-
ticularly metastasis, can also compromise the nerve roots
at any level but are more common in the thoracic spine.
Other, less common causes of radiculopathy include
infections such as herpes zoster, CMV, HIV, Lyme disease,
tuberculosis, and syphilis. Diffuse root involvement can
occur in inflammatory conditions, such as Guillain–Barré
and chronic inflammatory polyradiculoneuropathies and
carcinomatous meningitis. As mentioned previously,
lumbar spinal stenosis is caused by degenerative spine
disease, leading to narrowing of the intervertebral foram-
ina and the diameter of the spinal canal.
Diagnosis
The best methods for visually assessing the nerve root
and surrounding structures for mechanical compromise
are MRI and CT myelography. MRI is preferred because
it has equivalent diagnostic capacity to CT myelogra-
phy, high resolution, and the absence of ionic radiation.
However, EMG and NCS may detect damage when no
specific structural cause of nerve compression is visual-
ized by radiologic studies (as with diabetic radiculopathy,
polyradiculitis, and intermittent positional compression
not visualized in the supine position). In addition, EMG/
NCS provides localization of the root affected, as well as
Neuromuscular Disorders 499
the severity and evolution of the process, and also helps
to exclude other disorders. Sensory nerve conduction
studies (NCS) are generally normal in radiculopathies
because most radiculopathies occur at the level of the
intervertebral foramen, which is proximal to the dorsal
root ganglia, allowing integrity between the cell body
and the sensory axons to be maintained and precluding
detectable distal degeneration. Needle EMG examination
is the most important tool in the diagnosis of suspected
radiculopathy. Active denervation, manifested as fibril-
lation potentials or positive sharp waves (spontaneous
activity) in two or more muscles innervated by a given
root, identifies an active radiculopathy. As fibrillation
potentials typically do not appear until 2–3 weeks after
the onset of the nerve root compromise, information
regarding the timing of the lesion can also sometimes
be obtained. Chronic denervation–reinnervation change,
identified on needle EMG as motor unit remodeling due
to reinnervation (long duration, high amplitude, poly-
phasic motor unit potentials), typically does not appear
until 2 months after the initial injury.
Treatment
The treatment of cervical radiculopathies is divided into
conservative (nonsurgical) and surgical approaches.
Traditionally, physicians have used a number of conser-
vative measures with the intention of relieving the pain,
improving neurologic function, and preventing recur-
rences (Wolff and Levine, 2002). These include analgesics
such as opioids and nonsteroidal anti-inflammatory drugs
(NSAIDs), short courses of prednisone, epidural injections
of corticosteroids, immobilization with a hard or soft col-
lar, cervical traction, and exercise therapy. However, none
of the commonly recommended nonsurgical therapies
has been tested in randomized placebo-controlled trials
(Wolff and Levine, 2002). Thus, recommendations derive
largely from case series and anecdotal experience. The
preferences of patients should be taken into account in
decision making.
As most cervical radiculopathies will improve gradu-
ally over several months without surgical interven-
tion, conservative management is indicated as an initial
approach in most patients. However, if symptomatic
weakness appears; if the patient is in severe, intractable
pain and is unresponsive to other interventions; or if there
is evidence of intercurrent myelopathy, then surgery may
be indicated, provided that a clearly source of mechani-
cal compression can be identified and targeted with the
appropriate techniques. Category 1 data regarding the
efficacy or timing of surgery for cervical radiculopathy
is highly limited (Sampath et al., 1999; Heckmann et al.,
1999). Management of lumbar radiculopathy is similar. In
the absence of the cauda equina syndrome or progressive
neurologic deficit, patients with acute lumbar radiculopa-
thy should be treated nonsurgically with conservative
500 Neurologic Conditions in the Elderly
measures such as analgesics, physical therapy, and light
traction. Prolonged bed rest is ineffective and may make
worsen symptoms. Epidural corticosteroid injections
may offer temporary symptomatic relief for some patients
(Carette et al., 1997). In cases of spinal stenosis, nonsurgi-
cal therapy, including exercise bicycle or walking, is rec-
ommended, with brief rest when pain occurs (Hilibrand
and Rand, 1999). Analgesics, NSAIDs, physical therapy,
and epidural corticosteroids may be useful. Decompres-
sive laminectomy may be indicated in some patients with
severe intractable pain or progressive motor deficits.
Diseases of the brachial and
lumbosacral plexus
Brachial plexopathy
Epidemiology and clinical features
Disorders affecting the brachial or lumbar plexus (plexop-
athies) are much rarer than neuropathies and radiculopa-
thies. In younger patients, trauma is a common cause of
plexus injury. In the elderly, however, metastatic tumors
(such as those in the lung, breast, colon, and prostate)
involving the plexus may be the first indicator of a larger
cancer, and trauma can still occur, particularly with sur-
gical intervention such as cardiac bypass, which requires
thoracotomy. Brachial plexopathies are frequently caused
by trauma such as traction, compression, or stretch. Other
etiologies include ischemia, inflammatory disorders
(spontaneous or hereditary), neoplastic infiltration, and
radiation-induced and structural causes (such as neuro-
genic thoracic outlet syndrome).
Diseases involving the plexus typically produce severe
arm pain, weakness, and atrophy of the involved mus-
cles, with loss of deep tendon reflexes and sensory loss.
The pattern of weakness and sensory loss does not follow
the territory of a specific nerve or root, and plexopathy
should be suspected when the clinical findings cannot be
solely explained by the involvement of a particular root
or nerve. The upper trunk of the brachial plexus is par-
ticularly susceptible to stretch and other traumatic injury,
in addition to being a common site for metastatic disease.
Injury to the upper trunk of the brachial plexus may pro-
duce weakness of upper arm abduction, external rotation
of the shoulder, and elbow flexion, and supination with
loss of biceps and brachioradialis reflexes. Sensory loss in
upper trunk lesions, when present, may involve the lat-
eral aspect of the arm and forearm. Injury to the lower
trunk causes weakness of the wrist and finger flexors, as
well as the intrinsic hand muscles, with loss of the fin-
ger flexor reflex. Sensory loss may affect the medial arm
and forearm and the ulnar aspect of the hand. Horner’s
syndrome (ptosis, miosis, and anhidrosis) can be super-
imposed if the sympathetic fibers are involved and, when
present, should also raise suspicion of an apical tumor of
the lung.
Pathophysiology
The brachial plexus is a vulnerable structure because of its
relationship to surrounding structures, such as the lung
apex, lymph nodes, bones (clavicle and ribs), and major
vessels. In addition, the plexus is susceptible to traction
caused by the mobility of the neighboring shoulder joint
and neck.
Diagnosis
Evaluation includes careful history and physical exami-
nation, often followed by imaging studies of the plexus
(typically MRI with contrast) and, most importantly,
comprehensive EMG/NCS. As electrophysiologic assess-
ment of the brachial plexus is highly complex, it is best
performed in an academic electromyography laboratory
that is experienced in this area and capable of performing
advanced techniques such as Erb’s point stimulation.
Specific syndromes and treatment
Idiopathic brachial plexitis (neuralgic amyotrophy or
Parsonage–Turner syndrome) is an idiopathic, presum-
ably inflammatory, attack on the brachial plexus, often in
a multifocal distribution. An autoimmune mechanism is
likely. Patients typically present with acute shoulder pain,
followed within hours to days by numbness and weak-
ness of the arm or hand. These symptoms rapidly pla-
teau and are usually followed by gradual recovery over
months. Most patients recover completely, and recurrence
is rare, although some patients may have permanent defi-
cits. Electrophysiologic studies are of critical importance,
but nerve conduction abnormalities may not appear for
up to several days after onset, and needle EMG may not
become abnormal for 2–3 weeks. Imaging studies of the
neck and shoulder may be indicated, and serum studies to
assess for a broader autoimmune process may be needed.
The differential diagnosis includes stroke, acute radicu-
lopathy, and traumatic injury to the shoulder or plexus,
such as shoulder dislocation or rotator cuff injury. Most
patients recover without treatment. Physical therapy is
helpful for aiding recovery and preventing complications.
Within days of onset, a tapering course of corticosteroids
may be given, although the efficacy of this intervention
remains uncertain.
Tumors, such as breast cancer and lymphoma, usu-
ally reach the brachial plexus by direct extension from
axillary or supraclavicular lymph nodes, whereas supe-
rior sulcus bronchogenic carcinomas (Pancoast tumors)
spread directly to the adjacent plexus. Patients typically
present with pain that is relentlessly progressive and is
followed after a variable interval by weakness and sen-
sory loss in a pattern reflecting involvement of more
than one nerve root (Kori et al., 1981; Lederman and Wil-

bourn, 1984) The weakness affects mainly the muscles
innervated by the lower trunk of the plexus and can be
associated with Horner’s syndrome. Electrodiagnostic
studies in patients with brachial plexus tumors usually
demonstrate evidence of severe axonal loss, either diffuse
or predominantly affecting the lower trunk (Lederman
and Wilbourn, 1984). MRI appears to be more sensitive
than CT scanning in detecting a mass in or near the bra-
chial plexus (Thyagarajan et al., 1995). Radiotherapy pro-
duces significant pain relief in 40–70% of patients with
brachial plexus metastases from lung or breast carcinoma
(Kori et al., 1981). Fewer than one-third of patients have
improvement in focal motor or sensory deficits following
radiotherapy. In patients who received prior radiation
exposure to the brachial plexus and later develop metas-
tases, surgical neurolysis may improve pain but does not
improve neurologic deficit (Lusk et al., 1987).
Patients with cancer who have received radiotherapy
to the neck and chest may develop brachial plexopathy
due to radiation injury either acutely (rare) or, more com-
monly, delayed by several months or years. The most
common presenting symptoms of radiation plexopathy
are numbness and paresthesias of the hand and fingers,
with weakness tending to develop later in the course.
Most patients do not have pain at the outset, and approxi-
mately one-third of patients have minimal or no pain
throughout their entire course (Thomas and Colby, 1972;
Kori et al., 1981). Kori et al. (1981) reviewed 100 cases of
brachial plexopathy in patients with cancer and found
that severe pain occurred in 80% of tumor patients but in
only 19% of patients with radiation injury. In the majority
of cases, the radiation injuries affected the upper plexus
(C5–C6 roots), in keeping with the field of radiation. The
electrophysiologic abnormality that helps to best distin-
guish radiation injury from primary neoplastic brachial
plexopathy is myokymia, a specific electrical discharge
recorded during needle electromyography, consisting of
spontaneous, semirhythmic groups of motor unit poten-
tials, discharging in irregular bursts.
Treatment of radiation plexopathy is generally symp-
tomatic, with pharmacologic therapy for neuropathic
pain and physical therapy to improve strength and func-
tion and to reduce contractures. Occasionally, surgery for
decompression of the epineural sheath (neurolysis) and
removal of scar tissue may be tried to reduce the other-
wise intractable pain. However, neurolysis rarely relieves
motor or sensory deficits, and it is not clear whether sur-
gery can halt the progression of deficits.
Lumbosacral plexopathy
Epidemiology and clinical features
Lumbosacral plexopathies are less common than brachial
plexopathies, mainly because traumatic lesions are infre-
quent in this area. Surgical procedures on the abdominal
Neuromuscular Disorders 501
and pelvic organs and pelvic tumors, such as ovarian,
uterine, testicular, colon, and retroperitoneal lymphomas,
can implicate various parts of the lumbosacral plexus.
As in the case of the brachial plexus, it is sometimes dif-
ficult to differentiate tumor infiltration from radiation
injury. Diabetes mellitus (described shortly), retroperito-
neal hematomas (often associated with anticoagulation),
and aortic aneurysms extending into the pelvis are other
causes of lumbosacral plexopathy.
Insidious onset of pelvic or radicular leg pain, followed
weeks to months later by sensory symptoms and weak-
ness is characteristic. The main effect of upper lumbar
plexus lesions is weakness of flexion and adduction of the
thigh and extension of the leg, with sensory loss over the
anterior thigh and leg. Weakness of thigh adduction dis-
tinguishes this condition from femoral neuropathy. Lower
plexus lesions weaken the posterior thigh (hip extension),
leg, and foot muscles, and cause loss of the ankle reflex
and sensory loss over the posterior thigh and leg and the
entire foot. Weakness of hip extension differentiates lower
plexus lesions from sciatic neuropathy.
Diagnosis
As with brachial plexopathy, diagnosis rests upon history,
physical examination, imaging studies, and electrophysi-
ologic evaluation.
Specific syndromes and treatment
Treatment of lumbosacral plexopathy in general depends
upon successfully addressing the underlying etiology, as
neural regeneration cannot yet be facilitated beyond the
peripheral nerves’ natural mechanisms for recovery from
injury.
Diabetic lumbosacral plexopathy, also known as dia-
betic amyotrophy, is a syndrome of subacute, painful
unilateral or asymmetric multiple mononeuropathies,
which typically affects older patients with mild or clinical
unrecognized diabetes mellitus. The discomfort begins
in the lower back or hip radiating to the thigh and knee,
has a deep aching quality, and is more severe at night.
Weakness and later atrophy are more evident in the
pelvic girdle and the thigh muscles, focally at first and
then more generally as the disease progresses. The patel-
lar reflex is lost on the affected side. Sensation is intact
or mildly impaired. The EMG demonstrates a multifocal
axonal neuropathy with denervation typically in the L2
and L3 myotomes. An ischemic vascular mechanism has
been suggested, affecting the vasa nervorum. Complete
recovery is the rule, but it often requires months or years
and it may recur. Treatment is centered initially on pain
control with anti-inflammatory medications, tricyclic
antidepressants, anticonvulsants, and narcotics in severe
cases, along with physical therapy and assistive devices.
Immunomodulatory therapy, such as IVIG and steroids,
has been used experimentally, with reported successes in
502 Neurologic Conditions in the Elderly
some case series, but controlled trials are required (Dyck
et al., 2005). Good glycemic control is of paramount
importance, and physical therapy can improve functional
recovery.
Disorders of the peripheral nerve
Epidemiology and clinical features
Neuropathy is a disease of the peripheral sensory, motor,
or autonomic nerves. Neuropathy may be pure motor,
pure sensory, or mixed sensorimotor. It may occur sym-
metrically throughout the body (polyneuropathy), indi-
vidually in single nerves (mononeuropathy), or in multi-
ple, scattered nerves in an irregular distribution (multifo-
cal neuropathy). Autonomic neuropathy may accompany
a larger neuropathic process or occur independently.
Polyneuropathy has hundreds of potential etiologies.
Diabetes mellitus is the most common cause of polyneu-
ropathy in the United States, as it is in most of the West-
ern world, affecting at least 1–2% of the population. The
prevalence of polyneuropathy progressively increases
and is particularly common in patients over the age of 60,
at approximately 3.5% in the outpatient elderly popula-
tion. In geriatric patients, the incidence of idiopathic dis-
tal symmetric polyneuropathy is high and accounts for at
least 25–30% of cases.
Diagnosis
Evaluation of a patient with suspected neuropathy begins
with a careful history, to provide information about the
symptoms, distribution, and course of the neuropathy.
The medical and social history and review of systems
may alert the examiner to a possible systemic cause,
such as diabetes, inflammation, or cancer, or to a toxic
or nutritional etiology. A positive family history is sug-
gestive of hereditary neuropathy. A detailed neurologic
examination is required to confirm the presence of neu-
ropathy and to provide information regarding the func-
tional impairment, distribution, and severity of the dis-
ease. Potentially treatable conditions such as vitamin B12
deficiency, glucose intolerance, liver and renal disease,
vasculitis, and paraproteinemias are easily tested in the
blood. Other blood studies may also be indicated, includ-
ing assays for antibodies directed against specific nerve
or myelin components, some of which may be associated
with specific clinical syndromes, such as anti-GM1 anti-
body (acute motor axonal neuropathy (AMAN)), anti-
GQ1b (Miller Fisher variant of Guillain–Barré syndrome),
anti-Hu antibody (paraneoplastic sensory neuronopathy),
and antimyelin-associated glycoprotein (MAG) antibody
(multiple myeloma). Searches for other infectious pro-
cesses, particularly HIV and hepatitis, may also be indi-
cated. More rarely, serum cryoglobulins and serum and
urine heavy metal screening may be needed.
Lumbar puncture is especially important for the diag-
nosis of autoimmune neuropathies, such as acute inflam-
matory demyelinating polyradiculopathy and chronic
inflammatory demyelinating polyneuropathy, and may
provide additional information regarding infectious and
neoplastic diseases as well; however, it is not needed for
most neuropathy evaluations. EMG and nerve conduction
studies are the single most important diagnostic test for
the evaluation of neuropathy. The indications for nerve
biopsy are highly limited, and it should be used sparingly,
as harvesting of the sural nerve at the ankle (the most
common procedure) carries a 10–15% risk of chronic neu-
ropathic pain at the biopsy site. Biopsy can help to estab-
lish the diagnosis in suspected vasculitis, amyloidosis,
sarcoidosis, giant axonal neuropathy, and leprosy. More
refined diagnostic tools include quantitative sensory test-
ing, autonomic studies, and skin biopsy with staining and
quantitation of intraepidermal small sensory nerve fibers.
Acquired neuropathies
Guillain–Barré syndrome
Epidemiology and clinical features
Guillain–Barré syndrome refers to a group of immune-
mediated disorders targeting the peripheral nerves, hav-
ing an annual incidence ranging from 1 to 2 cases per
100,000 people and affecting all ages. The most common
form of Guillain–Barré syndrome, acute inflammatory
demyelinating polyradiculoneuropathy (AIDP), accounts
for 85–90% of cases. Less common variants of Guillain–
Barré syndrome include AMAN, also associated with
Campylobacter jejuni infection, and acute motor sensory
axonal neuropathy (AMSAN), which together account for
approximately 10% of Guillain–Barré cases.
AIDP often begins 1–3 weeks after an infection or incit-
ing event, such as surgery. Seventy percent of patients ini-
tially have paresthesias or vague numbness in their hands
and feet. Symmetric weakness appears a few days later
and progresses over days to a few weeks. Paralysis is max-
imal by about 2 weeks in more than 50% of patients and
by 1 month in more than 90%. If the disease progresses
longer, it is considered subacute or chronic inflammatory
polyradiculoneuropathy. Ascending weakness beginning
in the legs is typical, although descending paralysis with
predominant proximal muscle weakness rarely appears.
Facial weakness occurs in half of patients with AIDP, and
ophthalmoparesis and lower cranial neuropathies can
cause dysarthria and dysphagia.
Life-threatening respiratory paralysis may rapidly
appear as the disease progresses, necessitating intuba-
tion and mechanical ventilation. All patients with AIDP
must be identified as quickly as possible and carefully
monitored until the disease has stabilized. One quarter

of patients with AIDP require mechanical ventilation.
Another serious complication, more common in patients
with severe quadriparesis and often difficult to control, is
autonomic nervous system involvement, which can cause
dangerous fluctuations in blood pressure or precipitate
cardiac arrhythmia. Significant autonomic dysfunction in
AIDP carries a high mortality.
On examination, weakness is symmetric and ranges
from mild-to-severe flaccid quadriparesis. Sensation is
usually normal, despite sensory symptoms, although
mild distal vibratory loss may be found. Reflexes are
diminished or absent, but sphincter tone is normal.
Bedside pulmonary function testing (forced vital capacity
and negative inspiratory force) may reveal impending
respiratory failure. Patients with autonomic involvement
may demonstrate cardiac arrhythmia, fluctuations in
blood pressure, flushing and sweating, and abnormalities
of gastrointestinal motility.
Etiology and pathophysiology
Upper respiratory and gastrointestinal infections or non-
specific febrile illness precedes neurologic symptoms in
about 60% of Guillain–Barré syndrome patients, usually
by 1–3 weeks, and there is considerable evidence for
autoimmune-mediated demyelination as the cause of
this disorder. CMV, Epstein–Barr virus, Mycoplasma
pneumoniae, HIV, and hepatitis A and B infection have
all been associated with AIDP. Several other anteced-
ent events, including surgery, cancer, pregnancy, auto-
immune disease, and vaccinations (such as the swine
flu vaccine of 1976), have also been linked to AIDP. In
this disorder, there is significant segmental demyelin-
ation, disproportionately affecting the roots and proxi-
mal nerve segments at onset. AIDP demonstrates both
humoral and cell-mediated mechanisms of nerve injury.
Pathologically, demyelination begins in the proximal
nerves and then extends distally as the disease pro-
gresses. However, as in the cases of AMAN and AMSAN,
the primary immune-mediated attack is not against the
myelin, but rather against a component of the axon,
leading rapidly to axonal degeneration and subsequent
poor recovery. Although respiratory infections are the
most common precedent in AIDP, C. jejuni (a cause of
gastroenteritis) is the most frequently identified organ-
ism in cases of axonal GBS (AMAN). There is growing
evidence that cross-reactivity of C. jejuni epitopes and
peripheral nerve gangliosides may play a role in AMAN
via inducing autoimmune axonal attack.
Diagnosis
Imaging studies of the spinal cord may be necessary
to rule out a myelopathy. All patients with acute to
subacute onset of symmetric weakness and areflexia
should have a lumbar puncture after spinal cord dis-
ease has been excluded. CSF protein concentration
Neuromuscular Disorders 503
begins to rise a few days after onset of symptoms and
peaks in 4–6 weeks. The cell count typically remains
normal or shows only mild lymphocytic pleocytosis
(more common in patients with HIV infection). Appro-
priate evaluations for infection should be performed,
and electrocardiogram and chest radiographs should
be obtained.
In AIDP, nerve conduction studies demonstrate demy-
elination with slowed motor conduction velocities and
prolonged distal motor latencies within 3–5 days of
symptom onset, but they may be normal if performed
within the first few days of onset. Studies assessing
proximal demyelination (F-wave responses), an early
feature of Guillain–Barré syndrome, may be diffusely
abnormal at the time of clinical presentation. Sensory
conduction studies are often normal at presentation
but may be slowed. In early Guillain–Barré syndrome,
needle EMG may show a reduction in motor unit recruit-
ment. Evidence of axonal injury (denervation change
with fibrillations potentials), if present, usually does not
appear on EMG for 2–3 weeks. Prominent axonal change
on needle EMG supports significant axonal injury and
suggests a worse prognosis for complete recovery
(AMAN or AMSAN).
Treatment
Both intravenous immunoglobulin (IVIG; 0.4 g/kg/day
for 5 days) and plasmapheresis (five to six exchanges
over 1–2 weeks) appear equally effective when given
within the first 2 weeks after onset. Combination ther-
apy consisting of both does not seem to confer addi-
tional benefit. Plasmapheresis may be precluded in
hemodynamically unstable patients. These measures
generally increase the pace of recovery, although their
effects on the severity of the disease, the risk of respira-
tory and autonomic dysfunction, and ultimate disabil-
ity are less clear. Randomized trials of oral and intra-
venous corticosteroids (methylprednisolone and pred-
nisolone) have failed to show benefit in Guillain–Barré
syndrome.
Prognosis
Most patients with Guillain–Barré syndrome return
to normal function. After disease progression stops,
symptoms usually plateau for 2–4 weeks, followed by
gradual recovery. About 20–25% of patients require
mechanical ventilation, and 5% die, usually from the
complications of respiratory failure or autonomic dys-
function. Residual motor weakness is present in 25% of
patients after 1 year. Older age (60 years or older), ven-
tilatory support, rapid progression (<7 days), and low
motor amplitudes (suggesting axonal injury) on early
nerve conduction studies are poor prognostic factors
associated with a less than 20% probability of walking
independently at 6 months.
504 Neurologic Conditions in the Elderly
Chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP)
Epidemiology and clinical features
The prevalence of CIDP is estimated to range from 1.0
to 7.7 cases per 100,000 people. CIDP disproportionately
affects men and those older than 50 years of age. CIDP
can present in a stepwise progression with periods of pla-
teau, a steadily declining course, or a course with recur-
rent episodes. Most patients initially have predominately
motor symptoms, although examination typically reveals
both motor and sensory signs. Weakness may begin
focally but usually becomes bilateral or multifocal within
a few months of onset. As with Guillain–Barré syndrome,
CIDP is usually symmetric, and both proximal and distal
muscles are affected. Some degree of proximal hip flexor
weakness on examination (often unnoticed by the patient
at presentation) is considered by some authorities to be
an essential feature. Cranial neuropathies and respiratory
muscle weakness are rare.
Pathophysiology
The etiology of CIDP is unknown, and it is unclear
whether preceding vaccinations, infections, surgeries, or
other insults are implicated. A study of 92 patients with
CIDP found a history of preceding infection or some other
precipitating event in 32% of the cases, and there was a
significantly higher titer for CMV antibodies in the serum
of patients with CIDP than in controls (McCombe et al.,
1987).The presence of inflammatory infiltrates in periph-
eral nerves and much other experimental data supports
an autoimmune etiology. Epineurial and endoneurial
infiltrates consist mainly of T lymphocytes and macro-
phages expressing MHC class II molecules and chemo-
kine receptors (Schmidt et al., 1996).
Diagnosis
Nerve conduction studies typically reveal significant
demyelination with slowed conduction velocities, pro-
longed distal latencies, conduction block, and abnormal
late responses (such as F waves). Both motor and sen-
sory nerves may be affected. In severe cases, evidence of
secondary axonal injury may be seen. Lumbar puncture
reveals an elevated protein concentration, but the cell
count typically remains normal or shows only mild lym-
phocytic pleocytosis. Nerve biopsy, which carries a sub-
stantial risk of permanent focal neuralgia (10–15%), is no
longer routinely recommended.
Treatment
Most patients improve with immunomodulatory therapy.
Long-term therapy is often required, and complete remis-
sion is rare. The goals of treatment are to restore patients
to a level of function sufficient to enable them to go about
their daily activities while minimizing the adverse effects
associated with therapy. Some patients have persistent
symptoms despite aggressive combination therapy.
Oral prednisone therapy is effective in most patients.
Dosage is 1 to 1.5 mg/kg/day, titrated according to clini-
cal response after several weeks. Alternate-day therapy
(in equivalent weekly doses) may be instituted after
2–3  months in patients who improve, with subsequent
taper by 5–10 mg every 2–4 weeks thereafter. The side
effects of long-term corticosteroid administration may
limit their use, particularly in older patients. Some patients
respond incompletely to corticosteroids and require
adjunctive therapy or a switch to an alternate modality.
IVIG and plasmapheresis are both effective but often must
be continued indefinitely. The evidence shows that IVIG,
prednisone, and plasma exchange (PE) have similarly effi-
cacy. Disease severity, long-term side effects, concurrent
illness, cost of treatment, venous access, and age should
all be taken into consideration when selecting therapy.
A large trial of CIDP treatment demonstrated short-term
and long-term efficacy and safety of IVIG, supporting
use of IVIG as a therapy for CIDP (Hughes et al., 2008).
If IVIG and corticosteroids are ineffective, PE should be
considered. Two double-blind, randomized, controlled tri-
als showed that PE produces significant improvements in
about two-thirds of patients (Dyck et al., 1986; Hahn et al.,
1996). Other adjunctive immunosuppressive therapies,
such as azathioprine or mycophenolate, are often consid-
ered in patients with persistent symptoms, although there
is limited evidence of their benefit in CIDP. In patients with
disease that is refractory to all other modalities, cyclophos-
phamide (oral or intravenous) may be of benefit.
Paraproteinemic polyneuropathy
Epidemiology and clinical features
Abnormally elevated serum immunoglobulin levels can
cause a paraproteinemic neuropathy, sometimes because
of the production of antibodies targeted to myelin com-
ponents. Paraproteinemias typically affect men older
than 50 years of age, with an increasing prevalence with
each decade thereafter. Paraproteinemic neuropathies
are also associated with lymphoma, leukemia, amyloido-
sis, cryoglobulinemia, multiple myeloma, POEMS syn-
drome (polyneuropathy, organomegaly, endocrinopathy,
Monoclonal protein (M-protein), and skin changes), and
Waldenström macroglobulinemia.
In about two-thirds of patients, no underlying neoplasm
or other cause for the monoclonal spike is found (such as
MGUS). However, 20% of patients with MGUS ultimately
develop a malignant plasma cell disorder. IgG is the most
common paraprotein found in patients with MGUS, but
IgM is the most common in patients with neuropathy, fol-
lowed by IgG and, rarely, IgA. Patients with IgM gammop-
athy often present with large-fiber sensory loss, prominent

tremor, and sensory ataxia. Distal weakness and atrophy
can occur as the disease progresses. IgM gammopathy is
predominantly a demyelinating neuropathy, although
axonal loss may occur. Fifty percent of patients with IgM
neuropathy have antibodies to MAG, a protein found in
the periaxonal Schwann cell membranes. Anti-MAG anti-
bodies are associated with a discrete clinical syndrome
consisting of a slowly progressive, large-fiber neuropathy
with late distal weakness. IgG gammopathy can be either
axonal or demyelinating. Its clinical presentation is usu-
ally similar to that of IgM gammopathy.
Pathophysiology
The excess serum protein in these disorders (paraprotein or
M-spike) is usually a monoclonal immunoglobulin. It may
be an isolated abnormality or a by-product of a plasma cell
malignancy. The M-proteins are thought to cause neuropa-
thy through autoimmune demyelination and axonal attack,
corresponding to the antigenic specificity of the autoanti-
bodies. Deposits of anti-MAG M-proteins and compliment
are found on the affected myelin sheaths (Latov, 1995).
Diagnosis
Serum and urine protein electrophoresis may detect the
M-protein and are frequently used as a screening tool dur-
ing the initial evaluation of polyneuropathies. However,
immunofixation is a more sensitive technique in detecting
the M protein in some cases when protein electrophoresis
is unrevealing. Therefore immunofixation has become the
screening test of choice in cases of suspected monoclonal
gammopathy. EMG usually demonstrates demyelination
and axonal loss.
Treatment
One-third of patients with MGUS neuropathy improve
within days to weeks of IVIG therapy (0.4 g/kg/day for
5 days), plasmapheresis (220 mL/kg in four to five treat-
ments), or oral corticosteroids, often in combination with
other immunosuppressants. Patients with IgG or IgA mono-
clonal gammopathy–associated neuropathies respond
better than those with IgM monoclonal gammopathy. In
patients with osteoscherotic myeloma, including patients
with POEMS syndrome, the neuropathy usually improves
with resection of solitary bone lesions, focused radiation, or
chemotherapy with melphalan, cyclophosphamide, or pred-
nisone. Primary systemic amyloid neuropathy (nonfamil-
ial) responds poorly to melphalan and prednisone, despite
improvement in survival with these medications.
Paraneoplastic neuropathy
Epidemiology and clinical features
Paraneoplastic neuropathy may appear as the first mani-
festation of an occult neoplasm or may not appear until
Neuromuscular Disorders 505
after a cancer is diagnosed. As cancer is more common
with advancing age, these neuropathies are seen most
commonly in patients over the age of 60. Several different
paraneoplastic neuropathy syndromes exist. Paraneoplas-
tic sensory neuropathy is the most common and is often
associated with anti-Hu antibodies (type 1 antineuronal
nuclear autoantibodies, or ANNA-1). It is strongly associ-
ated with small cell lung cancer, but it is also seen in liver,
bladder, breast, and pancreatic cancers, as well as lym-
phoma and sarcoma. Antiamphiphysin antibody may also
be present in paraneoplastic sensory neuropathy, although
it is not as specific as anti-Hu for a sensory neuropathy.
Antiamphiphysin antibodies are also associated Lam-
bert–Eaton myasthenic syndrome (LEMS) and stiff-person
syndrome. Autonomic neuropathy is also sometimes seen
with anti-Hu-associated sensory neuropathy and may
cause gastroparesis, achalasia, dysphagia, and pseudo-
obstruction. Other paraneoplastic syndromes include sub-
acute sensory neuronopathy, demyelinating neuropathy
(usually a feature of paraproteinemic malignancies; see the
preceding discussion in Paraproteinemic polyneuropathy),
mononeuropathy multiplex, MND, and motor neuropathy.
Paraneoplastic sensory neuropathy is characterized by
numbness, painful paresthesias, and lancinating pain. It
may begin in one limb and then spread to the remaining
limbs, but it is usually generalized by the time of presen-
tation. All sensory modalities are lost, and propriocep-
tion is most severely affected. Strength is normal or only
minimally decreased, and tendon reflexes are reduced or
absent. Frequently, there is concurrent involvement of the
myenteric plexus, autonomic ganglia, spinal cord, brain-
stem, cerebellum, or limbic cortex.
Subacute sensory neuronopathy (Denny-Brown syn-
drome or dorsal root ganglionitis) appears to be distinct
from paraneoplastic sensory neuropathy; the dorsal root
ganglion is the site of primary injury. Women are affected
twice as often as men, and small cell lung cancer is, again,
the most common underlying tumor. Breast carcinoma,
ovarian cancer, and lymphoma are also frequently associ-
ated with this neuronopathy.
Paraneoplastic demyelinating neuropathy can mimic
either Guillain–Barré syndrome (usually associated with
Hodgkin disease) or a CIDP (non-Hodgkin lymphoma).
Multiple myeloma is also associated with a demyelinat-
ing neuropathy and can be associated with POEMS syn-
drome. Vasculitic neuropathy is associated with hema-
tologic malignancy, and these patients typically present
with mononeuropathy multiplex. A form of MND has
been described as part of paraneoplastic encephalomy-
elitis and may respond to treatment of an underlying
associated tumor; subacute motor neuropathy has also
been associated with malignancy. Finally, subacute para-
neoplastic autonomic neuropathy may be associated
with neuronal nicotinic acetylcholine receptor (AChR)
antibodies.
506 Neurologic Conditions in the Elderly
Pathophysiology
Peripheral neuropathies may develop in cancer patients
from one or more of three distinct pathogenic processes:
(1) Direct invasion of nerve roots by neoplastic cells; (2) a
remote effect of cancer on the peripheral nervous system—
that is, a paraneoplastic process; and (3) toxic side effects
from chemotherapy. Paraneoplastic sensory neuropathy
with associated autoantibodies is perhaps the best-defined
peripheral nerve disorder related to cancer. The role of the
autoantibodies in the pathogenesis of the neuropathy is
unclear. One hypothesis suggests that antibodies directed
toward tumor cell antigens cross-react with identical
neuronal nuclear proteins, resulting in cell damage and
neuronal death. Another possibility is that autoantibodies
may simply be generated during the evolution of the neu-
ropathy but not be related pathogenetically to the clinical
syndrome; some evidence suggests that an immune
response mediated by T cells may be important in mediat-
ing the nervous system injury (Dalmau et al., 1991).
Diagnosis
Anti-Hu antibodies are often associated with paraneo-
plastic sensory neuropathy, but their absence does not
rule it out. Nerve conduction studies show low-amplitude
or absent sensory nerve action potentials with preserved
motor amplitudes. Nerve biopsy is not usually needed
unless amyloidosis is suspected and cannot otherwise
be confirmed. CSF analysis may reveal elevated protein
concentration and mild pleocytosis, especially in patients
with associated lymphoma. Patients with subacute sen-
sory neuropathy in whom no underlying cause is found
should be screened for the presence of a malignancy.
Neoplastic screening may be indicated as well in other
instances of “idiopathic” neuropathy, depending on the
patient’s age, history, and risk factors. True paraneoplas-
tic neuropathies must be distinguished from other forms
of nerve injury associated with cancer and its treatments,
especially tumor invasion of the peripheral nerves and
the toxic effects of chemotherapy and radiation.
Treatment
Treatment of the underlying neoplasm is the mainstay
of therapy and offers the best chance of improvement,
although neuropathic symptoms may persist if the nerve
injury is well established. Treatment with corticosteroids,
immunosuppressants, and plasmapheresis is of question-
able benefit, although IVIG has been reported to be effec-
tive in some patients.
Toxic neuropathies
A wide range of toxins may cause neuropathies. Nerves
can be injured by industrial and environmental toxins
(such as aromatic hydrocarbons), heavy metals (such as
lead and arsenic), and medications. Antineoplastic drugs
are common offenders, causing a length-dependent sen-
sorimotor axonal neuropathy, pure sensory neuropathy,
or ganglionopathy. A symmetric stocking-glove distribu-
tion neuropathy is most often found with distal weakness
and hyporeflexia. Treatment consists of discontinuing the
offending agent.
The diabetic neuropathies
Epidemiology and clinical features
Diabetes mellitus is the most common cause of neuropa-
thy in the United States, and neuropathy is identified by
objective testing in two-thirds of diabetic patients. As with
cancer, the prevalence of diabetes increases with each
decade over 40 and is particularly common in patients
over the age of 60. Diabetic nerve injury produces many
clinical syndromes. Distal symmetric sensorimotor neu-
ropathy is most common and may appear in isolation as
the first manifestation of diabetes. Different syndromes,
however, can appear in virtually any combination.
Distal symmetric neuropathy begins with numbness,
paresthesias, or dysesthesias (alone or in combination)
in the feet. Over months or years, symptoms ascend up
the leg and eventually affect the upper extremities. Pain-
ful diabetic neuropathy may also develop at this early
stage. Loss of foot sensation in diabetic patients greatly
increases the chance of unrecognized cutaneous ulcer-
ation, which, along with impaired cutaneous healing,
can result in gangrene and limb amputation. Loss of light
touch, pain, and temperature typically occurs early, fol-
lowed by loss of proprioception, which may cause gait
ataxia. Distal weakness and atrophy follow, with gradual
subsequent ascension.
Pure small fiber diabetic neuropathy is also relatively
common. The small cutaneous nerve fibers that sense pain
and temperature are often damaged in diabetic patients,
resulting in loss of distal pinprick and temperature sen-
sation, sometimes accompanied by the development of
burning, electric, aching, stabbing, and pins-and-nee-
dles dysesthesias and pain, which can be incapacitating.
Patients may have allodynia (the perception of a nonpain-
ful stimulation as painful), especially at night, and foot
contact with bed sheets may interfere with sleep. Pain-
ful neuropathy spontaneously improves over months to
years in some patients, but becomes a chronic symptom
in others. Pure small fiber neuropathy may be reversible
if good control of serum glucose is achieved and main-
tained, but it often is followed by large fiber injury if the
diabetes is not adequately treated.
Autonomic neuropathy affects nearly 50% of diabetic
patients, commonly causing genitourinary dysfunction
(erectile dysfunction and neurogenic bladder), postural
hypotension, and gastrointestinal dysmotility. Autonomic

derangement can contribute to silent cardiac ischemia and
cardiac arrhythmia, the most common causes of death in
diabetic patients.
In addition to these neuropathies, patients with diabe-
tes are prone to many mononeuropathies resulting from
the occlusion of the vasa nervorum in individual nerves
secondary to diabetic small vessel disease. These mono-
neuropathies can occur in the cranial nerves (especially
the sixth and seventh) or in any peripheral nerve, creating
acute pain, weakness, and numbness. These syndromes
are often thought to be due to stroke on presentation,
and a full acute evaluation is often indicated. Some degree
of recovery may occur, though permanent deficit, ranging
from mild to severe, may persist.
Pathophysiology
The pathophysiology of the diabetic neuropathies is com-
plex and includes a combination of deleterious events.
Ischemic injury, due to disease of the small arterioles sup-
plying the peripheral nerves (the vasa nervorum), plays
a substantial role in human and animal models, but oxi-
dative injury, deficiency of nerve growth factors, activa-
tion of deleterious alternative metabolic pathways due
to insulin deficiency (the polyol hypothesis), nitric oxide
deficiency, and deficiency of insulin itself (as insulin has
important nerve growth factor properties) have all been
implicated. Maintenance of normal serum glucose levels
through insulin and antiglycemic measures can amelio-
rate most, if not all, of these problems in many patients
and in animal models.
Diagnosis
No single test can prove that the primary cause of nerve
injury is diabetes, as diabetic neuropathy is a clinical
diagnosis and a diagnosis of exclusion. Careful history
and physical examination may define patterns conform-
ing to a single diabetic syndrome or some combination.
Diabetic patients may develop neuropathy from a cause
other than diabetes, and at least one careful evaluation for
other potential causes is warranted. In patients who pres-
ent with neuropathy but no prior history of diabetes, a
3-hour glucose tolerance test may be useful when fasting
glucose measures or glycosylated hemoglobin are normal
or borderline.
EMG and nerve conduction studies define the type of
nerve injury and are also critical for identifying super-
imposed conditions such as carpal tunnel syndrome and
lumbosacral radiculopathy, to which patients with dia-
betes are more susceptible than the general population.
Distal symmetric diabetic neuropathy begins as an axonal
disorder, with decreased sensory and motor amplitudes.
Demyelinating change causing nerve conduction slow-
ing often follows, and patients frequently have both axo-
nal and demyelinative features at EDX. Pure small fiber
neuropathy, which does not produce nerve conduction or
Neuromuscular Disorders 507
EMG abnormalities, can be diagnosed through quantita-
tive sensory testing and quantitation of small nerve fiber
density via epidermal skin biopsies. When autonomic
symptoms are present, specific tests of autonomic func-
tion may be indicated. Cardiac symptoms require more
detailed cardiologic evaluation.
Treatment
Optimal glucose control is the most effective method
of preventing the development of diabetic neuropathy
and limiting its progression if it does develop. Inten-
sive control is less likely to reverse existing neuropathy.
Diabetic foot care is of critical importance, and patients
should undergo diabetic foot care education. If other
foot abnormalities (such as bony deformities, ingrown
nails, or corns) are present, referral to a podiatrist may
be necessary. Autonomic dysfunction may necessitate
assistance from the following specialists: urologist, gas-
troenterologist, and, especially, cardiologist. Physical
therapy, gait training, occupational therapy, and orthot-
ics are also important and should be appropriately
utilized.
Idiopathic polyneuropathy
The term idiopathic polyneuropathy is used in the 25% of
patients with distal polyneuropathy for whom no cause is
identified after extensive diagnostic evaluation. Patients
with idiopathic polyneuropathy are typically in their
sixth decade and have a slow progression of symptoms
over years. Distal sensory or sensorimotor symptoms and
signs are most common, and legs are affected more sig-
nificantly than the arms. Electrophysiologic testing shows
axonal polyneuropathy, and nerve biopsy reveals degen-
eration and regeneration of axons without inflammatory
changes. Rarely, vasculitic changes may be found on
biopsy examination in patients with idiopathic neuropa-
thy. Immunomodulatory treatment with corticosteroids,
IVIG, or plasmapheresis has not shown clear benefit.
(Vrancken et al., 2004).
Hereditary motor and sensory
neuropathy
Epidemiology and clinical features
Hereditary motor and sensory neuropathy (HMSN), or
Charcot–Marie–Tooth (CMT) syndrome, is one of the
most common neurogenetic disorders, with a prevalence
of 30 cases per 100,000. Genetically, it is divided into
autosomal dominant, autosomal recessive, and X-linked
types. Phenotypically, it is traditionally divided into those
types with very slow nerve conduction velocities; such
as CMT1 and demyelinating) and those with normal or
508 Neurologic Conditions in the Elderly
near-normal conduction velocities and low amplitudes
(such as CMT2 and axonal). For all types, onset is usually
in childhood, adolescence, or young adulthood. However,
though onset after the age of 40 years is unusual, symp-
tomatic onset in CMT2 may appear from midadulthood to
as late as the seventh decade (Bennett et al., 2008). Distal
muscle weakness and atrophy, with predilection for the
peroneal myotome, loss of distal muscle stretch reflexes,
and severe large fiber sensory loss, are characteristic. Pes
cavus and hammer toes are common, as are foot sores and
poorly healing ulcers.
Pathophysiology
The pathophysiology of the HMSNs varies according to
the specific mutation causing the variant. The most com-
mon varieties (such as CMT1) are associated with defects
resulting in disordered myelin formation and mainte-
nance, but the specific molecular mechanisms for most of
these diseases have yet to been worked out.
Diagnosis
History, family history, and physical examination are
highly important. Electrodiagnostic studies show axonal
injury in CMT2 and predominately demyelinative change
in CMT1. Genetic testing is available for many of the
HMSNs and is confirmatory when positive.
Treatment
Management is supportive and rehabilitation measures
are advised. Many patients with foot drop will benefit
from using ankle-foot orthoses to ameliorate foot drop.
Drugs that cause peripheral neuropathy should be
avoided. Genetic counseling is based on the inheritance
pattern of the disease. Occupational therapy is recom-
mended for strategies to assist with a variety of manual
activities, such as writing and eating.
Neuromuscular junction disorders
Myasthenia gravis
Myasthenia gravis is an autoimmune postsynaptic disor-
der of the neuromuscular junction characterized by fluc-
tuating weakness and fatigability. Most cases are caused
by autoantibodies directed against the nicotinic AChR in
the skeletal muscle membrane. Blocking of neuromuscu-
lar transmission due to interference with AChR function
produces the clinical weakness that is the hallmark of the
disease.
Epidemiology and clinical features
The disease onset has a bimodal distribution, appearing in
patients from 15 and 30 years old and also those between
60 and 75. Females predominate in the younger group,
whereas males comprise more of the older patients.
Though myasthenia has been eminently treatable since
the 1970s, natural history data from the years preceding
effective therapy demonstrated a mortality rate of 20–30%
due to respiratory failure (Oosterhuis, 1981).
The principal clinical manifestations of myasthenia
gravis are fluctuating weakness and premature fatigue,
affecting the ocular, bulbar, and peripheral muscles.
Prominent fatigability with diplopia and ptosis, worsen-
ing with sustained gaze and improving with rest, are char-
acteristic. With generalized disease, proximal weakness of
the arms and legs, as well as neck flexion and extension
weakness, are common and more severe after physical
activity, especially toward the end of the day. Dysarthria
with nasal speech can occur with sustained conversation.
Dysfunction of the swallowing muscles and respiration
is particularly dangerous because of the risk of aspira-
tion or respiratory failure. Diplopia and ptosis are early
primary features in 50–60% of patients. Isolated extra-
ocular and palpebral muscle weakness may be the only
initial manifestations in some patients (ocular myasthenia
gravis). However, 85–90% of patients presenting with
ocular symptoms will eventually develop more general-
ized weakness (Oosterhuis, 1988; Beekman et al., 1991).
However, those patients with pure ocular disease for at
least 2 years have only a 10% chance of further progres-
sion to generalized disease (Grob et al., 1987). A higher
prevalence of this form of the disease has been reported in
male patients older than 40 years (Grob et al., 1987).
The most serious complication of myasthenia gravis,
however, is respiratory muscle weakness, which may
progress to hypoventilation and respiratory failure. Dys-
pnea on exertion may be the initial manifestation, fol-
lowed by dyspnea at rest. Fatal respiratory dysfunction
may develop rapidly, over a matter of hours.
Myasthenia has been associated with a number of other
disorders. The best-known association is with thymoma,
and approximately 10–15% of myasthenics have a thy-
moma. The mean age of thymoma patients is 50 years.
Of thymomas, 90% are benign and easily treatable with
resection, whereas 10% are malignant and will spread to
local tissue, the lymphatic system, or the blood. The fre-
quency of autoimmune diseases is also increased in myas-
thenics. Hyperthyroidism is the most prevalent. Connec-
tive tissue diseases such as rheumatoid arthritis and sys-
temic lupus erythematosus, as well as sarcoidosis, have
also been described.
Pathophysiology
Myasthenia gravis is one of the best understood of all auto-
immune diseases. It is caused by autoantibodies directed
against epitopes on or around the AChR in the postsyn-
aptic membrane of the neuromuscular junction. These
antibodies can block the binding of acetylcholine (ACh)
to its receptors or cause receptor malfunction through
other mechanisms and may initiate immune-mediated

degradation of the receptors, reducing receptor numbers
and damaging the postsynaptic membrane. Decreased
number and malfunction of the ACh receptors results
in fewer miniature end plate potentials (MEPPs) and a
lower end plate potential (EPP), reducing the likelihood
of reaching the depolarization threshold necessary for
muscle contraction.
Diagnosis
Three ACh antibody assays are available for diagnostic
evaluation: the AChR binding, modulating, and blocking
antibodies. Binding antibody assays are widely available
and have an average sensitivity of 60–70%. Blocking anti-
bodies are found in only 1% of myasthenic patients with-
out binding antibodies. Although the modulating anti-
body assay may also be more sensitive in patients with
early, mild, or pure ocular disease, it is nonspecific and
prone to false positive results due to its technical com-
plexity. Some patients with symptomatic disease do not
have detectable AChR antibodies by theses assays and
have been traditionally termed seronegative myasthenia
gravis. However, between 40% and 70% of patients who
are seronegative for anti-AChR antibodies have antibod-
ies to muscle-specific tyrosine kinase (MuSK). Anti-MuSK
myasthenia gravis affects predominantly women and
involves mainly the neck, shoulder, and respiratory mus-
cles, with less limb weakness and rare ocular symptoms.
The molecular mechanisms underlying the interactions of
the anti-MuSK antibody in MG are not well understood.
Antistriated muscle antibodies are another class of anti-
bodies and can be found in up to 90% of patients with
myasthenia gravis and concurrent thymoma (Limburg
et al., 1983). Progressive rises in antistriational antibody
titers can be the first indication of thymic tumor recur-
rence following resection.
Two major electrodiagnostic tests are available to assess
neuromuscular junction function. Repetitive nerve stimu-
lation (RNS) studies of the peripheral nerve are widely
available and demonstrate significant decrements in the
CMAP amplitude in myasthenics, but have a sensitivity
of 60–70%. A second, more sophisticated test of neuro-
muscular junction function is single fiber electromyog-
raphy, a technique measuring the variability in the time
required for neuromuscular transmission at the level of
the single muscle fiber. Though technically complex and
not widely available, single fiber electromyography has
a sensitivity of 95% or greater in generalized and 90% or
greater in ocular myasthenia gravis when appropriate
muscles are tested (Howard et al., 1994). Because of its
high sensitivity, single fiber electromyography is mainly
indicated when the diagnosis of myasthenia is still sus-
pected and other confirmatory tests such as AChR anti-
bodies and RNS are unrevealing. This test is particularly
useful in cases of mild generalized, ocular, or seronega-
tive myasthenia gravis.
Neuromuscular Disorders 509
Intravenous administration of edrophonium (tensilon),
an acetylcholinesterase inhibitor, to a suspected myasthe-
nia gravis patient may transiently improve certain symp-
toms, providing supporting evidence for the diagnosis.
This test, known as the tensilon test, may be up to 90%
sensitive if an appropriate muscle is available for testing.
However, it can be technically challenging and carries a
risk of life-threatening cardiac arrhythmia, and it is rarely
performed in contemporary assessment of MG.
Treatment
Myasthenia gravis can be adequately controlled in the
vast majority of patients with appropriate immunomod-
ulatory therapies, and most patients lead normal lives.
Well-controlled MG should not decrease life expectancy.
However, if not properly treated, it can be disabling or
fatal.
Acetylcholinesterase inhibitors inhibit the enzyme that
metabolizes acetylcholine and, therefore, increase the
availability of acetylcholine at the neuromuscular junc-
tion. Acetylcholinesterase inhibitors do not effect lasting
changes in the primary disease process and are purely
symptomatic therapy. They have greatest utility in pure
ocular disease, in mild generalized disease, or as adjunc-
tive therapy in stable but symptomatic disease after an
appropriate course of immunosuppressive therapy.
Pyridostigmine is the most commonly used agent in the
United States and is typically started at 30 mg orally every
4–6 hours and titrated by clinical response. It takes effect
within 20–30 minutes and peaks at approximately 2 hours
in most patients. The main side effects are abdominal
cramps and diarrhea, although it is well tolerated by most
patients.
Because the myasthenic thymus demonstrates an
increased percentage of mature T-lymphocytes and thy-
mic B-cells, with active AChR antibody production,
removal of the thymus (thymectomy) may be of benefit.
Thymectomy should be considered in most patients with
new-onset myasthenia and is usually recommended in all
patients with thymoma or in myasthenics younger than
age 60 with generalized weakness. Patients with pure
ocular disease have not traditionally been treated with
thymectomy, and its benefits in this group remain ques-
tionable. The procedure has been discouraged in patients
older than 60 because of increased surgical risk, as well
the fact that the thymus significantly atrophies with
advancing age.
Corticosteroids have been particularly effective in
generalized and ocular myasthenia when symptoms
are disabling and not controlled with acetylcholinester-
ase inhibitors. Patients should be started at high doses
(60–80  mg) in severe cases, but lower doses, gradually
increasing over time, can be employed in particular
clinical circumstances. Some patients may experience a
brief, steroid-induced exacerbation within the first week
510 Neurologic Conditions in the Elderly
of high-dose therapy, lasting for 1–2 days, after which
improvement begins. After high-dose therapy is initi-
ated, sustained improvement appears in most patients
within 2  weeks, with substantial improvement within
4–12 weeks; after that time, patients on daily therapy may
be switched to alternate-day therapy. Maximal improve-
ment appears within 6 months in most patients, after
which the alternate dose is further reduced slowly until
the minimal effective dose is reached. If steroids cannot
be reduced to an acceptable level due to worsening symp-
toms, alternative immunosuppressive therapies should
be considered. Complications of steroid therapy include
weight gain, Cushingoid features, osteoporosis, cataracts,
GI symptoms, hypertension, diabetes, and increased sus-
ceptibility to infections.
Other immunosuppressive therapies are typically used
when steroid therapy fails or is contraindicated, or when
excessive steroid maintenance doses are required and a
steroid-sparing agent is needed as add-on therapy. Such
medications include azathioprine, cyclosporine A, cyclo-
phosphamide, and mycophenolate mofetil. Cyclophos-
phamide is effective but carries the risks of chemotherapy
and is poorly tolerated as long-term maintenance therapy,
as is cyclosporine. Azathioprine and mycophenolate are
typically considered first under these circumstances but
are slow acting; a response to these agents may not begin
for 3–12 months, and a maximal response may not appear
for 1–2 years. Consequently, they are not used as mono-
therapy in severe MG when a rapid response is critical.
PE and high-dose IVIG are temporizing therapies with
rapid onset of action and duration of action of 4–6 weeks.
They are particularly helpful in acute exacerbations,
severe myasthenia that is refractory to other immunosup-
pressive therapy, or as booster therapy prior to thymec-
tomy. Myasthenic crisis is defined as a rapid and severe
deterioration with worsening oropharyngeal weakness
and respiratory distress. Patients with rapidly worsen-
ing symptoms should be hospitalized and monitored
closely with serial measures of the forced vital capacity.
If impending respiratory failure is evident, endotracheal
intubation and mechanical ventilation are required. In
these instances, IVIG or PE hastens improvement and aid
in weaning from the ventilator.
Lambert–Eaton myasthenic syndrome
Epidemiology and clinical features
LEMS is an autoimmune disorder of the neuromuscular
junction caused by antibodies directed against the volt-
age-gated calcium channels (VGCCs) at the presynap-
tic nerve terminal. Blockade of these antibodies inhibits
release of acetylcholine from the presynaptic terminal,
resulting in failure of neuromuscular transmission and
clinical weakness. It is a rare disorder, with a prevalence
of between 1 in 500,000 and 1 in 1,000,000. Nearly 60% of
LEMS cases are paraneoplastic, and are most commonly
associated with small cell lung cancer (Gutmann et al.,
1992; Tim et al., 2000); occasionally, LEMS may be the first
manifestation of the malignancy. Because of this associa-
tion with lung cancer, it is more common in patients over
the age of 60.
Patients develop fluctuating proximal limb weakness
that begins in the legs and spreads to the arms. Symp-
toms of sympathetic or parasympathetic autonomic dys-
function are common, including dry mouth, impotence,
blurred vision, constipation, difficulty with micturition,
and reduced sweating. Sensory loss may be seen if there
is concurrent paraneoplastic sensory neuropathy. Deep
tendon reflexes are typically reduced but may transiently
normalize following brief (15-second) exercise of the
attached muscle (reflex facilitation or reflex augmenta-
tion). Strength testing usually demonstrates mild proxi-
mal weakness, most commonly affecting the hip flexor
muscles. Mild improvement in strength after exercise
(the warm-up phenomenon), which wanes with more
continuous activity, is characteristic. Though oculobulbar
symptoms may be subtle, careful cranial nerve examina-
tion reveals ptosis and/or diplopia, usually mild, in 25%
of patients. If a cancer patient has prolonged paralysis
following the use of neuromuscular blocking agents fol-
lowing surgery, LEMS should be strongly considered and
evaluated, with neurologic consultation and appropriate
diagnostic testing.
Pathophysiology
The primary pathophysiologic abnormality in Lambert–
Eaton syndrome is a reduction of the calcium-dependent
quantal release of acetylcholine triggered by a nerve
impulse. In paraneoplastic LEMS, it is believed that an
autoimmune response initially directed against tumor
cell antigens subsequently targets the same or antigeni-
cally related proteins at the presynaptic nerve terminal
of the neuromuscular junction. Eighty-five percent to
95% of patients with LEMS are seropositive for antibod-
ies directed at the P/Q type of VGCC in the presynaptic
neuronal membrane. Anti-VGCC antibodies reduce num-
bers of VGCC in motor nerve terminals. By decreasing
the influx of calcium triggered by each arriving action
potential, anti-VGCC antibodies ultimately impair the
calcium-dependent release of acetylcholine into the neu-
romuscular junction, causing clinical muscle weakness.
Parasympathetic, sympathetic, and enteric neurons are
all affected.
Diagnosis
History and physical examination are important, with
attention to reflexes, tests for reflex facilitation and also
proximal strength. Nerve conduction studies in LEMS
demonstrate low motor amplitudes due to neuromuscular
blockade, in contrast to MG, in which motor amplitudes

are usually normal on routine testing. RNS produces dec-
rement similar to that seen in MG when low-frequency
stimulation is used. However, brief exercise in LEMS
patients classically produces dramatic increases in CMAP
size (postexercise facilitation), typically exceeding 100%.
However, RNS has a sensitivity of around 70% when one
muscle is tested. Sensory nerve conductions are normal.
Needle EMG examination may reveal motor unit instabil-
ity and subtle myopathic change in the proximal muscles.
Neuromuscular junction function is typically abnormal
by single-fiber EMG, which has a high sensitivity of 90%
in LEMS. Antibodies directed at the P/Q type of VGCC
are also a sensitive indicator of disease and are seen in
85–95% of patients with LEMS.
In patients with confirmed Lambert–Eaton syndrome,
a neoplastic workup is indicated, with a special empha-
sis on the search for small cell lung cancer. Chest CT or
MR scanning with contrast should be performed and,
in some cases, FDG-PET scanning can detect the tumor
despite normal chest CT or MR (Linke et al., 2004; Younes-
Mhenni et al., 2004). Patients over 50 with a history of
chronic smoking and LEMS have a high probability of
an underlying lung cancer, and bronchoscopy should be
considered in these cases if chest CT or MRI is unreveal-
ing. It is not uncommon for initial evaluation for an occult
lung tumor to be unrevealing; in these cases, the workup
should be repeated at regular intervals. The diagnosis of
LEMS may be the presenting feature of cancer and pre-
cedes its diagnosis by two years or more. As LEMS may
also be associated with other tumors, the patient should
be brought up-to-date on all routine cancer screens, and
additional screens should be considered, depending upon
the specifics of the history.
Treatment
Paraneoplastic LEMS typically responds to successful
treatment of the underlying cancer, though symptoms
may return if the tumor comes back. In SCLC, chemother-
apy is the first choice and will have an additional immu-
nosuppressive effect. The presence of LEMS in a patient
with SCLC is associated with improved patient survival
from the cancer, perhaps because of earlier detection.
3,4-diaminopyridine (DAP) is a drug that blocks potas-
sium channel efflux in nerve terminals so that action
potential duration is increased, causing Ca2+ channels to
be open for a longer time, facilitating greater acetylcholine
release and partially overcoming the VGCC blockade. 3,4-
DAP in doses from 5 mg three times a day up to 25 mg
four times a day or more produces some degree of symp-
tomatic improvement in nearly all patients with Lambert–
Eaton syndrome, with or without an associated neoplasm.
Immunotherapy has little effect in improving strength
in patients with paraneoplastic LEMS if the underlying
tumor is not successfully treated. In patients with LEMS
who do not have cancer, aggressive immunotherapy may
Neuromuscular Disorders 511
be tried but is generally minimally effective. Case reports
suggest temporary benefit from PE and IGIV, but no con-
trolled trials have been performed and our experience
with these approaches has not suggested effectiveness
(Dau and Denys, 1982; Rich et al., 1997).
Lambert–Eaton syndrome is generally a chronic dis-
order in patients without tumor, although some patients
may experience clinical remissions. About 40% of patients
with LEMS will never develop a cancer.
Disorders of muscle
Dermatomyositis
Epidemiology and clinical features
Dermatomyositis is a common autoimmune disease
affecting the striated (voluntary) muscle, the skin, and
connective tissues. The exact incidence of dermatomyo-
sitis is unknown, but the inflammatory myopathies as
a group affect approximately 1 in 100,000 adults. Most
often, the skin changes precede the muscle weakness and
include a heliotrope rash (blue–purple discoloration) on
the upper eyelids with edema, a flat red rash on the face
and upper trunk, erythema of the knuckles with a raised
violaceous scaly eruption (Gottron’s papules), and sub-
cutaneous calcium deposits (subcutaneous calcinosis),
especially at the elbows. The erythematous rash can also
occur on other body areas, including extensor surfaces
such as the knees, elbows and malleoli, the neck and ante-
rior chest (often in a V-shaped configuration), or along the
back and shoulders (shawl sign). Dilated capillary loops
at the base of the fingernails are also characteristic of der-
matomyositis and suggestive of its pathophysiology as a
primarily vasculitic disorder. The cuticles may be irregu-
lar, thickened, and distorted, and the lateral and palmar
areas of the fingers may become rough and cracked, with
irregular, “dirty” horizontal lines, resembling a mechan-
ic’s hands. When the weakness develops, it takes the form
of a myopathy, with proximal leg and arm weakness,
developing over weeks to months.
Dermatomyositis can be seen in concert with connec-
tive tissue disorders such as systemic lupus erythemato-
sus, rheumatoid arthritis, Sjogren’s syndrome, and also
mixed connective tissue disease. Cardiac arrhythmias and
interstitial lung disease, particularly pulmonary fibrosis,
can also accompany the disease.
The incidence of malignancies is increased in patients
with dermatomyositis (Buckbinder et al., 2001; Hill
et al., 2001). Ovarian cancer is most frequent, followed
by intestinal, breast, lung, and liver cancer. A complete
annual physical examination, with breast, pelvic, and
rectal examinations (including colonoscopy in high-risk
patients); urinalysis; complete blood-cell count; blood
chemistry tests; and chest X-ray, is usually sufficient and
512 Neurologic Conditions in the Elderly
is highly recommended, especially within the first 3 years
after diagnosis.
Etiology and pathophysiology
No clear causative agent has been demonstrated in der-
matomyositis. An autoimmune mechanism is supported
by the association of dermatomyositis with other auto-
immune disorders, such as lupus and systemic sclerosis.
Various autoantibodies against nuclear and cytoplas-
mic antigens are found in patients with inflammatory
myopathies (Dalakas, 2001). In addition, 80% of derma-
tomyositis patients with the anticytoplasmic antibody
anti-Jo-1 develop interstitial lung disease. The primary
antigenic targets in dermatomyositis are components of
the endothelium of the endomysial blood vessels. The
antibody-triggered complement activation attacks the
endomysial microvasculature, leading to muscle fiber
destruction and inflammation. The endofascicular hypo-
perfusion is prominent distally and causes the perifas-
cicular atrophy typically seen in pathology sections. The
histologic picture of skin lesions in DM is characterized by
dermal perivascular infiltrates consisting mainly of CD4+
cells, followed by macrophages (Hausmann et al., 1991).
Diagnosis
The clinical diagnosis of dermatomyositis is suggested
by history and physical examination and confirmed by
serum muscle enzymes, electrophysiologic findings, and
muscle biopsy. Creatine kinase (CK) levels are typically
elevated, sometimes up to 50 times the normal level, and
frequently parallel disease activity. Needle EMG demon-
strates abundant spontaneous activity with fibrillations,
positive sharp waves, and complex repetitive discharges
reflecting the muscle membrane instability associated
with the inflammation in this disease. Myopathic motor
unit potentials are also abnormal, reflecting loss of muscle
fibers (characterized by short-duration, low-amplitude
and polyphasia), most clearly seen in the proximal mus-
cles. Electromyographic and nerve conduction studies are
also useful to exclude neuromuscular disorders. Muscle
biopsy is a definitive test to confirm the diagnosis. In con-
trast to necrosis of single fibers and endomysial infiltrates
seen in polymyositis, the classic histologic features of
dermatomyositis are perimysial and perivascular inflam-
matory infiltrates, as well as perifascicular atrophy. Skin
biopsy, performed in the vicinity of a characteristic rash,
may also confirm the diagnosis.
Treatment
Prednisone is the first-line therapy. A high dose of
80–100  mg/day as a single daily morning dose for an
initial period of 3–4 weeks is preferable. In patients with
aggressive disease, methylprednisolone 1 gm IV every
day for 3 days may be considered first, followed by the
oral steroid dose. Prednisone taper must be undertaken
cautiously, and high daily doses often must be continued
for 2–3 months, after which gradual taper is undertaken
over several months to low doses. If the patient devel-
ops intolerable side effects from prednisone or develops
repeated relapses during ongoing attempts at taper, a
steroid-sparing agent should be added. Azathioprine
(1.5–3 mg/kg/day) is usually effective after 3–6 months
of treatment. Methotrexate is also used and may be effec-
tive as a sole agent. It can be given orally starting at 7.5 mg
weekly for the first 3 weeks (given in a total of three doses,
2.5 mg every 12 hours), increasing gradually by 2.5 mg per
week up to a total of 25 mg per week. An important side
effect is methotrexate pneumonitis. Cyclophosphamide,
an alkylating agent, is also effective as monotherapy and
can be given intravenously at doses of 0.5–1 gm/m2, but
has significant deleterious side effects, especially with
prolonged usage. Cyclosporine has been used with lim-
ited success. A case series found mycophenolate effective
at controlling skin lesions, resulting in decreased steroid
dose required (Gelber et al., 2000). Plasmapheresis has
not been helpful, but IVIG has been shown to be effective
in a small double-blind study, improving strength and
dermatologic lesions and also clearing the underlying
immunopathology (Dalakas et al., 1993).
The natural history of dermatomyositis is unknown,
as no natural history studies were performed prior to
the advent of steroid therapy. Dermatomyositis typically
responds to immunotherapy more readily than polymyo-
sitis, but patients with interstitial lung disease (typically a
late complication) may have a high mortality rate, requir-
ing aggressive treatment with cyclophosphamide. Some
patients do not respond adequately to therapies and
become disabled.
Polymyositis
Epidemiology and clinical features
Polymyositis is an inflammatory disorder of muscles,
cause unknown, characterized by progressive proximal
and symmetrical weakness of the arms, legs, and neck
muscles appearing over weeks to months. Typically,
patients’ complaints are related to proximal weakness
and include difficulty combing their hair, climbing stairs,
and getting up from a low seated position. Deep tendon
reflexes are usually normal and sensation is intact. The
disease spares the ocular muscles, and the facial mus-
cles are rarely affected. Patients frequently complain of
myalgias, muscle tenderness, and fatigue, though pain is
absent in a significant minority of patients. Dysphagia can
also occur, and systemic complications can include dilated
cardiomyopathy and interstitial lung disease. It may be
associated with other connective tissue diseases, such
as systemic lupus erythematosus, rheumatoid arthritis,
and Sjogren’s syndrome. As mentioned previously, the
inflammatory myopathies as a group have an incidence

of approximately 1 in 100,000 adults, with peak incidence
in the fifth and sixth decades.
Pathophysiology
The cause of polymyositis remains unknown, but there
is ample pathologic evidence of autoimmune medi-
ated attack on the muscle fibers as the primary insult. It
may occur alone but may also be associated with a wide
variety of more systemic autoimmune diseases, and it
responds extremely well to aggressive immunomodula-
tory therapy.
Diagnostic tests
Polymyositis is a clinical diagnosis based upon history
and physical examination and supported by serum stud-
ies, electrophysiologic testing, and muscle biopsy. The
differential diagnosis includes muscular dystrophies; der-
matomyositis; metabolic myopathies; endocrinopathies;
electrolyte disturbances; mitochondriopathies; systemic
medical illnesses such as malabsorption syndromes, can-
cer, vasculitis, systemic infections, sarcoidosis, and granu-
lomatous disease; or toxic myopathies.
Serum CK levels may be increased up to 50 times the
upper limit of normal. Other enzymes, including ALT,
AST, and LDH, may also be increased and may some-
times lead to a diagnosis of primary hepatic disease, par-
ticularly if the CK level is not concurrently checked.
As with dermatomyositis, needle electromyography
demonstrates abundant spontaneous activity with fibril-
lations, positive sharp waves, and complex repetitive dis-
charges reflecting the muscle membrane instability asso-
ciated with the inflammation in this disease. Myopathic
motor unit potentials are also abnormal, reflecting loss of
muscle fibers and characterized by short duration, low
amplitude, and polyphasia, most clearly in the proximal
muscles. Electromyographic and nerve conduction stud-
ies are also useful to exclude neuromuscular disorders.
Muscle biopsy should be taken from an affected muscle
(most often the vastus lateralis) and may demonstrate
necrosis of single fibers and endomysial inflammatory
infiltrates. However, a normal muscle biopsy does not
exclude the diagnosis, as inflammation and necrosis can
be patchy and may be missed in the small tissue sample
taken. Consequently, EMG is a more sensitive test for
polymyositis because of its ability to assay large areas of
multiple muscles and also because of the typically wide-
spread changes wrought by muscle membrane instability
in this disorder.
Treatment
Polymyositis typically responds extremely well to
aggressive immunomodulatory therapy, with significant
improvement beginning within 1–2 months in most
patients. Treatment options are typically the same as
those for dermatomyositis.
Neuromuscular Disorders 513
As with dermatomyositis, the natural history of poly-
myositis is largely unknown, as no natural history studies
were performed prior to the advent of steroid therapy. In
general, older age, interstitial lung disease, and frequent
pneumonias due to esophageal dysfunction are associ-
ated with poor prognosis. A minority of patients still does
not adequately respond to immunotherapy and become
disabled. However, if there is no response to aggressive
immunotherapy, the diagnosis should be reconsidered,
with review of the history, neurologic examination, elec-
trophysiologic and biopsy data, and consideration should
be given to repeat and/or additional evaluations.
Inclusion body myositis
Epidemiology and clinical features
Inclusion body myositis is the most frequent myopathy
in patients over the age of 50, with a prevalence of over
50 per 1,000,000 (Needham et al., 2008; Mastaglia et al.,
2009). It affects males more often than females (3:1 ratio)
and is rare in people of African descent. There is also a
rare hereditary form, with onset in the second and third
decades.
Sporadic IBM produces painless muscular weakness
and atrophy, progressing gradually over many years.
Onset is often asymmetric, and the wrist and finger flex-
ors muscles are classically affected first and most severely,
with secondary progression to the quadriceps and foot
dorsiflexors. Hand weakness is an early manifestation in
most patients, producing difficulty with fine motor move-
ments such as grasping, pinching, or buttoning, followed
by falling and tripping due to leg weakness. Significant
dysphagia is a late feature in some patients, but some
degree of dysphagia may be present in up to 40% of the
patients by the time of diagnosis (Lotz et al., 1989). Mild
facial weakness and neck extensor weakness may also
be seen, but the extraocular muscles are spared. Tendon
reflexes may be normal, but patellar and ankle reflexes
are typically depressed early in the course of the disease.
Sensory examination is generally normal. The extremely
slow rates of progression, as well as the absence of fascic-
ulations, hyperreflexia, and UMN signs, helps distinguish
inclusion body myositis from ALS.
Diagnosis
CK is usually mildly elevated (two- to threefold) but may
be significantly increased (up to tenfold) or normal in
some patients. Electromyography can exclude important
mimics. Classic IBM patients demonstrate a pattern of pre-
dominately myopathic motor unit potential alteration with
early recruitment in clinically affected muscles (especially
the forearm flexor compartment and the distal legs, as
opposed to a primarily proximal distribution of myopathic
change in most acquired myopathies) on EMG examina-
tion, with an intermixed subset of neurogenic motor units.
514 Neurologic Conditions in the Elderly
Spontaneous activity may sometimes be present, though
it is typically mild (Joy et al., 1990). Muscle biopsy may
be definitive. Characteristic findings seen in IBM include
rimmed vacuoles, endomysial inflammation, and eosino-
philic cytoplasmic inclusions. By electron microscopy,
these eosinophilic inclusions appear to correspond to col-
lections of 12–18 nm intranuclear or cytoplasmic filaments.
However, the pathognomonic feature for IBM on muscle
biopsy is the presence of congophilic deposits of amyloid-
like material, which give apple-green birefringence on
polarized light microscopy after Congo red staining.
Pathophysiology
The trigger for this slowly progressive disorder is
unknown, but there is pathologic and other evidence of
combined mitochondrial, degenerative, and autoimmune
dysfunction as significant contributors to muscle fiber
injury and degeneration. However, the amyloid accumu-
lation so characteristic for this disorder appears to be a
marker of the degenerative process rather than a toxic
contributor to it (unlike the rare myopathy sometimes
seen in systemic amyloidosis).
Treatment
There is no effective therapy for inclusion-body myositis at
present. The disease is steroid resistant, and other immu-
nosuppressive agents, such as azathioprine, methotrexate,
cyclophosphamide, and total lymphoid irradiation, have
proven unsuccessful. The weakness progresses slowly
over years, and it is associated with worsening atrophy
of the weak muscles. Progression to disability appears to
occur more rapidly when symptoms begin after 60 years
of age (Peng et al., 2000). Both supportive and symptom-
atic therapies are essential in inclusion-body myositis
patients, including physical therapy, occupational ther-
apy, and the judicious application of assistive devices.
Close monitoring of dysphagia is important.
Toxic myopathies
Epidemiology and clinical features
A vast number of drugs and other chemicals are myo-
toxic and can produce muscle injury through a number of
mechanisms, including local trauma (intramuscular injec-
tions), electrolyte disturbances (hypokalemia), increased
metabolic demands (malignant hyperthermia), and toxic
effects on the muscle membrane and the internal appara-
tus of the cell. Several clinical features suggest a potential
toxic etiology for myopathic injury, including temporal
link between exposure to the toxin and the onset of symp-
toms, a lack of preexisting muscular symptoms, no other
identifiable cause, and complete or partial resolution of
the symptoms after withdrawal of the putative agent.
Toxic myopathies can appear at any age, but those due
to cumulative toxins and medication-induced injury are
more prevalent with advancing age.
Many drugs have been associated with myopathy,
but only a small number have been well documented as
clearly causative, including alcohol, amiodarone, chlo-
roquine, cholesterol-lowering agents, colchicine, cortico-
steroids, d-penicillamine, and zidovudine. Each of these
drugs acts through a different mechanism. Autophagic
degeneration and phospholipid accumulation in muscles
is seen in chloroquine-induced myopathy, while colchi-
cine causes disruption of the microtubule-dependent
cytoskeletal network. Zidovudine inhibits mitochondrial
function in the muscle, and D-penicillamine can produce
a syndrome that is clinically and pathologically indis-
tinguishable from polymyositis. Rhabdomyolysis has
now been associated with statin therapy and is a feature
of at least two other drug-induced disorders: neurolep-
tic malignant syndrome and malignant hyperthermia
(typically triggered by anesthetic agents).
Diagnosis
History and physical examination remain paramount in
the evaluation of toxic myopathies, with particular atten-
tion to known and potential exposures, including detailed
occupational, recreational and geographic history, current
and prior medication and recreational drug use, and any
similar illnesses in fellow employees, neighbors, or family
members.
Serum CK is one of the most sensitive indicators of
acute muscle damage. EMG may show myopathic change
and is more likely to be abnormal in moderate to severe,
acute or subacute cases. However, some toxins such as
steroids produce minimal electrophysiologic alterations.
Muscle biopsy may be helpful in some cases to confirm
the presence and degree of muscle damage, but rarely
provides data allowing identification of a specific toxic
agent.
Specific toxins
Cholesterol-lowering agents (“Statins”)
Epidemiology and clinical features
The incidence of myopathy is similar for all lipid-lowering
drugs and is in the range of 0.1–0.5% with monotherapy,
increasing to 0.5–2.5% with combination therapy (Hodel,
2002). However, the incidence of myopathy increases
dramatically when statins are given in combination with
fibrates such as gemfibrozil. Approximately one case of
rhabdomyolysis is reported for every 100,000 treatment-
years. The first-generation statins (lovastatin, pravastatin,
and simvastatin) are rarely associated with myopathy,
but the new synthetic drugs (atorvastatin, Fluvastatin,
and cerivastatin) are more frequently toxic. Cerivastatin
was the most commonly implicated statin and has been
removed from the market.

Symptoms range from mild muscular aches to severe
weakness and fatal rhabdomyolysis. Most patients with
this myopathy complain of muscle cramps and proximal
weakness. Myotonia is a common finding. Statin-associ-
ated necrotizing myopathy is a different and recently rec-
ognized disorder, likely immune mediated, characterized
by proximal muscle weakness occurring during or after
treatment with statins, which persists despite discontinu-
ation of the statin and improves with immunosuppressive
agents. The muscle biopsy shows necrotizing myopathy
without significant inflammation.
In addition to these clearly identified disorders, we
have anecdotally recognized at least mild proximal leg
weakness, often subclinical, in up to 50% of our patients
on chronic statin therapy, usually after many years of
treatment, which has no other apparent cause. This con-
dition appears to be nonprogressive and is often clinically
insignificant, but it can be problematic as a cause of addi-
tional weakness in patients with another cause of proxi-
mal weakness.
Pathophysiology
The mechanisms through which statins cause muscle
damage are poorly understood. An increase in “cell mem-
brane fluidity,” high blood lactate-to-pyruvate ratio (sug-
gestive of mitochondrial dysfunction), and depletion of
metabolites of geranylgeranyl pyrophosphate could be
potential causes.
Diagnostic tests
The diagnosis of statin myopathy is a diagnosis of exclu-
sion and is based upon history, physical examination, CK
measurements, and electromyographic and histologic
assessment. Drug challenge/dechallenge and rechallenge
may be confirmatory. EMG and nerve conduction studies
demonstrate classic myopathic findings, including fibril-
lation potentials, early recruitment, and short-duration,
low amplitude polyphasic motor unit potentials. Muscle
biopsy demonstrates atrophy and, in severe cases, necro-
sis of type I and II fibers.
Treatment
The elderly and female patients, as well as those already
on other potentially myotoxic medications or those with
impaired metabolism may be at particular risk for statin
myopathy and should be given extra consideration before
cholesterol-lowering therapy is initiated. Genetic analysis
for mutations identified as risk factors for statin myopa-
thy may also provide predisposition testing and is becom-
ing commercially available.
Because myotoxic events are more frequent at higher
doses, statins more likely to be effective at lower doses
should be used, if possible. If symptoms develop, imme-
diate discontinuation of statins usually results in rever-
sal of symptoms over days to weeks. Controlled trials of
Neuromuscular Disorders 515
coenzyme Q supplementation in statin myopathy have
yielded contradictory results.
If CK is elevated but the patient has no symptoms
(hyperCKemia) or signs, the medication can be continued
as long as the CK elevation remains in the low range (less
than two times the upper limit of normal) and does not
progressively increase.
Steroid myopathy
Epidemiology and clinical features
At least mild myopathy (as manifested by at least some
degree of detectable proximal muscle weakness on exam)
may be seen in up to 60% of patients receiving steroids
on a chronic basis (Batchelor et al., 1997). However, this
figure may be confounded by the fact that muscle injury
is caused by many chronic diseases for which steroids
are the treatment of choice, including systemic lupus
erythematosus, rheumatoid arthritis, bronchial asthma,
chronic obstructive pulmonary disease (COPD), and
polymyositis.
The prolonged use of corticosteroids can induce a pain-
less myopathy, manifested by a slowly evolving proximal
leg weakness. Although typically caused by oral steroid
therapy, other routes of administration, including inhaled
steroids, can induce myopathy in some cases. A specific
syndrome of acute myopathic injury and prolonged paral-
ysis can occur in the setting of high-dose steroid therapy
in critically ill patients, particularly those in whom depo-
larizing neuromuscular blocking agents are used to facili-
tate ventilation.
Pathophysiology
Corticosteroids seem to inhibit messenger RNA synthe-
sis that, in turn, influences the translation and synthe-
sis of muscle-specific proteins. Fast-twitching glycolytic
(type 2b) fibers are more susceptible to injury in steroid-
induced myopathy.
Diagnosis
Steroid-induced myopathy is a diagnosis of exclusion
and rests primarily on history and physical examination,
as there are no pathognomonic findings on diagnostic
workup. CK may be normal and EMG is frequently nor-
mal. Muscle biopsy may demonstrate atrophy of type 2b
fibers or may be normal. EMG in steroid myopathy asso-
ciated with critical illness may demonstrate fibrillation
potentials and myopathic motor units. Muscle biopsy in
these cases often demonstrates muscle fiber necrosis, vac-
uolation, and a striking loss of myosin filaments.
Treatment
Corticosteroid myopathy is usually reversible if the drug
is withdrawn or the dose is reduced. Corticosteroid-
induced muscle atrophy and weakness can often be
516 Neurologic Conditions in the Elderly
partially prevented or reversed by a program of physical
exercise. The prognosis of steroid-induced myopathy is
generally good and the symptoms subside after discon-
tinuation of the offending drug. In more advanced cases
of necrotic myopathy, residual muscle weakness, or paral-
ysis of the involved muscle may persist.
Late-onset hereditary myopathies
Most inherited muscle diseases typically manifest early
in life. However, a few hereditary muscle disorders may
present with onset late in life.
Welander distal myopathy (late-onset distal myopa-
thy) has an autosomal dominant inheritance pattern and
presents with weakness predominantly affecting the long
extensors of the hands and, later, the feet. Onset is usu-
ally in the fourth and fifth decades. CK values are nor-
mal or slightly elevated. Electromyography reveals both
myopathic and neuropathic motor unit change. Muscle
biopsy demonstrates myopathic change, often including
rimmed vacuoles.
Makesbery and colleagues reported a late-onset distal
myopathy in which weakness begins in the distal muscles
(tibialis anterior) and later spreads to the hands, with late
cardiac involvement. Tibial muscular dystrophy is a simi-
lar disorder, but with no cardiac involvement and symp-
tom onset ranging from the fourth to the eighth decades.
Few case reports of late-onset McArdle’s disease have
been described, manifesting as exercise-induced cramps
and exercise intolerance, with at least one late case with
onset as late as 60 years (Felice et al., 1992).
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Part 4
Therapeutics for the Geriatric
Neurology Patient
 Chapter 22
Neurosurgical Care of the
Geriatric Patient
David Fusco, Rasha Germain, and Peter Nakaji
Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

Summary
• Chronic subdural hematomas (SDHs):
• An accumulation of blood between the dura and brain as a result of trauma or brain atrophy.
• Large SDHs may mimic brain disorders such as dementia.
• Some chronic SDHs may resolve on their own, however, blood must be evacuated should enlargement occur.
Liquefied chronic SDHs are treated with drainage through one or two bur holes, twist-drill craniotomy, or a Subdural
Evacuating Port System.
• Aneurysms:
• An abnormal local dilation in the blood vessel wall due to defect, disease, or injury.
• Age considerations must be made when deciding whether the aneurysm should be treated and how it should
be treated.
• Computed tomography (CT) angiography, magnetic resonance angiography (MRA), and catheter-based digital
subtraction angiography (DSA) are used to study size, location, and morphology of the aneurysm.
• Treatment options include observation, craniotomy and clipping with or without bypass, and endovascular coil
embolization with or without stent assistance.
• Stroke:
• A sudden loss of blood circulation to an area of the brain resulting in loss of neurologic function.
• A noncontrast head CT distinguishes between ischemic and hemorrhagic infarction. An MRI with diffusion-weighted
imaging (DWI) may be used as well for improved sensitivity.
• Treatments for carotid occlusive disease, acute intracranial thrombotic stroke, spontaneous intracerebral hematoma,
and normal pressure hydrocephalus (NPH) are also reviewed.
• Neurooncology:
• Brain tumor diagnosis is based on clinical presentation, neuroimaging, and histology.
• Surgery to remove the tumor and obtain tissue for diagnosis is the initial treatment. Radiation therapy (RT) is also a
component of treatment, followed by chemotherapy.
• Odontoid fractures:
• A fracture through the second cervical vertebra resulting in neck pain. Injury is assessed with CT, magnetic
resonance imaging (MRI) and treated according to fracture classification (I, II, III).
• Nonoperative management (nonOP) includes rigid cervical orthosis or rigid immobilization in a halo vest; however,
prolonged immobilization may risk edema and other physical challenges.
• Surgical treatment includes either anterior or posterior fixation.
• Compression fracture:
• Often related to osteoporosis but may involve tumor infiltration or infection.
• Conservative management includes pain management, bracing, and rehabilitation.
• Surgery includes vertebroplasty and kyphoplasty.
• Pain: trigeminal neuralgia (TGN)
• Facial pain involving the trigeminal nerve. Pain is managed most commonly through carbamazepine.
• Surgical treatment options include percutaneous injury to the Gasserian ganglion, stereotactic radiosurgery, and
microvascular decompression (MVD).
• Parkinson’s disease (PD):
• Levodopa and carbidopa relieve symptoms by working to replenish dopamine in the brain.
• Deep brain stimulation (DBS) is a relatively safe option to treat movement disorders. The optimal target for DBS is
the subthalamic nucleus (STN). The globus pallidus interna may also be targeted.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

521
522 Therapeutics for the Geriatric Neurology Patient
As an organ system, the central nervous system (CNS)
holds up fairly well to the effects of aging. Only a
few diseases of neurosurgical importance that specifi-
cally affect older populations cannot also be found in
younger individuals. However, the impact of these
diseases changes as patients age. Furthermore, with
aging, the decision about not only how to treat but
whether to treat becomes important because the relative
risks of some conditions change as patients grow older.
For neurosurgical diseases, we must consider both
the absolute age of the patient and the remaining life
expectancy. For example, an unruptured aneurysm
with a 1% risk of rupture per year has a different impli-
cation for a 20-year-old patient with a 5% surgical risk
when compared with a 75-year-old patient with a 15%
surgical risk. That the former patient has a longer life
expectancy and 60 years of risk without treatment puts
him in a very different status than the latter patient,
with only a 13-year life expectancy. Actuarial analysis
is often necessary to provide optimal counseling.
Complete treatment of the entire range of neurosurgical
conditions affecting the geriatric population is impracti-
cal in this chapter. Therefore, we concentrate on selected
highlights of the most common conditions and those most
often overlooked in geriatric patients.
Chronic subdural hematoma
Chronic subdural hematomas (SDHs) are common in
the elderly. In its simplest form, an SDH is an accu-
mulation of blood between the dura and the brain.
These liquefied clots most often occur in patients of age
60 years and older who have brain atrophy and a loss
of cerebral parenchymal volume due to age or disease.
As the brain shrinks inside the skull over time, a poten-
tial space is created between the brain and the dura.
Minor head trauma can cause tearing of blood vessels
over the brain surface, resulting in a slow accumula-
tion of blood over several days to weeks. Because of
the space made available by the brain atrophy, these
liquefied blood clots can become quite large before they
cause symptoms.
Chronic SDH is a very different entity than blood that
occurs in a similar location on an acute basis as a result
of direct major head trauma. These latter patients are
most often affected by increased intracranial pressure
(ICP) and the damage caused by shear forces on the
brain, whereas chronic SDH patients often do not recall
any trauma and are more affected by the mass effect
of the blood clot than by increased ICP. In fact, fewer
than half of chronic SDH patients remember the trau-
matic event itself because even relatively trivial trauma,
such as a minor bump on the head, can produce these
slow hemorrhages. Other risk factors include alcohol
abuse, seizures, shunts that drain excess cerebrospinal
fluid (CSF) from the brain, bleeding diatheses such as
those due to hepatic or platelet dysfunction, and blood-
thinning medications such as warfarin.
The most common complaint of chronic SDH is head-
ache, seen in up to 80% of patients. Other symptoms
may include lethargy, memory impairment, confu-
sion, weakness, imbalance, nausea, vomiting, impaired
vision, and seizures. Patients with large hematomas may
develop varying degrees of paresis and coma. A chronic
SDH may mimic a number of other brain diseases and
disorders, including dementia, stroke, transient isch-
emic attack (TIA), encephalitis, and brain lesions such as
tumors or abscesses. An initial misdiagnosis of dementia
is particularly common in elderly patients when symp-
toms involve a steady decline in the overall mental func-
tion. An errant diagnosis at the time of hospital admis-
sion occurs in up to 40% of cases. Ultimate diagnosis
of these lesions involves computed tomography (CT)
and magnetic resonance imaging (MRI). Chronic SDHs
are often mixed density (CT) and intensity (MRI) due
to the presence of blood components of varying ages.
They may extend over a large portion of the surface of
the brain and often have multiple membranes and sep-
tations (Figure 22.1). When they are in their subacute
phase, they may be isodense to the brain and difficult
to visualize.
Chronic SDHs may begin as a subdural hygroma,
a separation in the dura–arachnoid interface that fills
with CSF. Dural border cells proliferate around this
CSF collection to produce a neomembrane. Fragile
new vessels grow into the membrane. These vessels
can hemorrhage with minor trauma and become the
Figure 22.1 Axial CT scan of the head demonstrating mixed-
density, chronic subdural hematoma (SDH). There is layering
of hemosiderin (arrow), effacement of the lateral ventricles,
effacement of the sulcal–gyral pattern, and significant midline
shift. © Barrow Neurological Institute.

(a)
Figure 22.2 Axial CT scans of the head
showing evolution and liquefaction of an
acute chronic subdural hematomas (SDHs)
1 week (a) and 3 weeks (b) after the initial
injury. © Barrow Neurological Institute.
source of acute blood into the space, resulting in the
growth of the chronic SDH (Kawakami et al., 1989).
Chronic SDHs also may evolve from liquefaction of an
acute SDH, particularly one that is relatively asymp-
tomatic. Liquefaction usually occurs after 1–3 weeks,
with the hematoma appearing hypodense on a CT
scan (Figure 22.2).
Patients with chronic SDHs that produce symp-
toms can be treated effectively and safely by multiple
means. In patients who have no significant mass effect
on imaging studies and no neurologic symptoms or
signs except mild headache, chronic SDHs have been
observed on serial scans and have been seen to remain
stable or to resolve in many cases. In some cases,
however, enlargement occurs, mandating evacuation
of the blood. Liquefaction of an acute SDH produces
a mass that has a thinner consistency but an unpre-
dictable volume. Furthermore, although spontaneous
hematoma resolution is well described, it cannot be
forecast reliably. No medical therapy has been shown
to be effective in expediting the resolution of acute
or chronic SDHs. Consequently, diligent surveillance
of all chronic SDH with serial imaging is essential. In
general, collections that cause neurologic signs or are
thicker than 1 cm and/or cause 5 mm or more of mid-
line shift are evacuated.
Various surgical techniques for the treatment of chronic
SDH have been described. Liquefied chronic SDHs are
commonly treated with drainage through one or two bur
holes in the skull overlying the hematoma. The bur holes
are placed so that conversion to a craniotomy is possible,
if needed. (Mori and Maeda, 2001) A closed drainage sys-
tem is sometimes left in the subdural space 24–72 hours
after surgery. Drainage via twist–drill craniotomy at the
bedside with placement of a drain to a closed bag system
has also been used frequently (Horn et al., 2006). Recently,
Neurosurgical Care of the Geriatric Patient 523
(b)
a new system, the Subdural Evacuating Port System
(Medtronic, Inc., Minneapolis, MN), has been introduced,
with encouraging results. This system involves screwing
a hollow bolt to the skull overlying the hematoma, enter-
ing the hematoma, and placing the bolt-to-bulb suction
(Lollis et al., 2006).
Under certain circumstances, craniotomy is recom-
mended for chronic SDH, depending on factors such as
recurrence, a thick consistency of the hematoma, and the
presence of membranes. Bilateral chronic hematomas
may require drainage from both sides, usually during the
same operation by means of bur holes placed on each side
of the head.
Recovery after treatment varies widely. Overall, 80–90%
of patients have significant brain function improvement
after drainage of a chronic SDH. However, the course of
such patients is not uniformly smooth. Despite its appar-
ent simplicity, chronic SDH is a complicated condition
that can confound neurosurgeons. Complications of treat-
ment can include seizures, acute SDH formation, infec-
tion, empyema, and pneumocephalus. Complication
rates tend to increase with age and medical comorbidi-
ties. Residual fluid may collect after treatment, and reop-
eration rates have been reported to range between 10%
and 25% (Stroobandt et al., 1995). Importantly, the fluid
does not have to be removed completely for symptoms
to improve and the clot may resolve eventually through
resorption.
Aneurysms
Aneurysms affect older patients just as they do younger
ones. As patients age, the risk of treatment typically
increases, leading to careful consideration of whether to
treat. For low-risk unruptured aneurysms, observation is
524 Therapeutics for the Geriatric Neurology Patient
often recommended. This is not because there is no risk of
rupture, but because the risk of treatment can be greater.
Nonetheless, with modern techniques, unruptured aneu-
rysms are often treatable, with excellent morbidity and
mortality rates. With ruptured aneurysms, the risk of no
treatment is so high that treatment is usually undertaken
despite the risks. Below we discuss the nature of cere-
bral aneurysms and the role of age in treatment decision-
making.
An aneurysm is an abnormal local dilation in the wall
of a blood vessel, usually an artery, due to a defect, dis-
ease, or injury. The three major types of true intracranial
(IC) aneurysms are saccular, fusiform, and dissecting.
The common causes of IC aneurysms include hemody-
namically induced vascular injury, degenerative vascular
injury (for example, from hypertension, tobacco use, or
arthrosclerosis), underlying vasculopathy (such as from
fibromuscular dysplasia), and high-flow states, such
as seen in association with an arteriovenous malforma-
tion (AVM) or arteriovenous fistula. Uncommon causes
include trauma, infection mycotic aneurysms, drug use,
and primary or metastatic neoplasms.
The classic cerebral aneurysm is the saccular or berry
type. Saccular aneurysms are rounded, balloon-like out-
pouchings that arise from arterial bifurcation points, most
commonly in the circle of Willis. The initiation, growth,
thrombosis, and even rupture of IC saccular aneurysms
can often be explained by abnormal hemodynamic shear
stresses at these bifurcation points. In the aneurysm, wall
shear stress caused by rapid changes in the direction of
blood flow (the result of systole and diastole) continually
damages the intima at the neck of an aneurysm. These
hemodynamic stresses work synergistically with the
degenerative insults noted previously to produce aneu-
rysm progression and ultimately rupture.
Congenital and developmental factors such as auto-
somal dominant polycystic kidney disease (ADPKD),
connective tissue disease, and fibromuscular dysplasia
contribute to aneurysm development as well. The true
incidence of IC aneurysms is unknown but is estimated
at 1–6% of the population, with a 5–40% incidence in
ADPKD patients (Wiebers et al., 2003; Yanaka et al., 2004).
IC aneurysms are multiple in 10–30% of cases, with a
strong female predilection for multiple lesions (between
5:1 and 11:1; Brisman et al., 2006).
Aneurysms typically become symptomatic in people
aged 40–60 years, with the peak incidence of subarachnoid
hemorrhage (SAH) occurring in people aged 55–60 years
(Greenberg, 2011). A substantial proportion of aneurysms
afflicts the elderly over 60 as well. Age is an important
consideration in the evaluation and treatment of all
cerebral aneurysms, whether ruptured or unruptured.
Whether to treat depends on both life expectancy and the
changing response of the aging brain to the available sur-
gical treatments. How to treat is also influenced strongly
by age because of the varying durability of the potential
treatments and the decreasing tolerance of the aging brain
to the neurologic impact of open surgery.
Approximately 86% of all IC aneurysms arise on the
anterior (carotid) circulation. Common locations include
the anterior communicating artery (30%), the internal
carotid artery (ICA) at the posterior communicating artery
origin (25%), and the middle cerebral artery (MCA) bifur-
cation (20%). The ICA bifurcation (7.5%) and the perical-
losal/callosomarginal artery bifurcation (4%) account for
the remainder. About 14% of all IC aneurysms arise on
the posterior (vertebrobasilar) circulation. Seven percent
arise from the basilar artery bifurcation, and 3% arise at
the origin of the posterior inferior cerebellar artery (PICA)
where it exits the vertebral artery.
Fusiform aneurysms are arterial ectasias that occur
because of a severe and unusual form of atherosclerosis.
Because they are often sequelae of atherosclerosis, fusi-
form aneurysms more often occur in the middle-aged and
elderly. These ectatic vessels may have more focal areas of
fusiform or even saccular enlargement. Intraluminal clots
are common, and perforating branches often arise from
the entire length of the involved parent vessel. The verte-
brobasilar system is commonly affected. Fusiform aneu-
rysms may thrombose, producing brainstem infarction
as small ostia of perforating vessels that emanate from
the aneurysm become occluded. They can also compress
the adjacent brain structures or cause cranial nerve pal-
sies. Dissecting aneurysms are the product of dissection of
arterial blood through the arterial wall to the level of the
subadventitial plane. They do not represent encapsulated
hematomas and thus must be distinguished from pseudo-
aneurysms. Most commonly, significant head trauma or
an underlying vasculopathy such as fibromuscular dys-
plasia is implicated in the origin of a dissecting aneurysm.
Extracranial (EC) vascular segments such as V2, V3, and
the mid- and terminal cervical ICA are most commonly
affected. Additional aneurysm subtypes that can fall into
any of the three major categories include traumatic pseu-
doaneurysms, mycotic aneurysms, oncotic aneurysms,
flow-related aneurysms, and vasculitic (true) aneurysms.
These aneurysm types are less common, and their treat-
ment is similar in geriatric and nongeriatric populations.
Most aneurysms do not cause symptoms until they
rupture; when they rupture, they most frequently cause
SAH and are associated with significant morbidity and
mortality. In North America, 80–90% of nontraumatic
SAHs are caused by the rupture of an IC aneurysm.
Another 5% are associated with bleeding from an AVM
or tumor, and the remaining 5–15% are idiopathic. How-
ever, as the overwhelming cause of SAH is trauma, it is
critical to obtain a good history. On presentation, patients
with nontraumatic SAH typically report experiencing the
worst headache of their lives. The association of menin-
geal signs should increase suspicion for this event. The

most widely used clinical method for grading the clinical
severity of SAH is the Hunt and Hess scale, which mea-
sures the clinical severity of the hemorrhage on admission
and correlates swell with outcome (Hunt and Hess, 1968):
Grade 0: Unruptured aneurysm
Grade 1: Asymptomatic or minimal headache and slight
nuchal rigidity
Grade 2: Moderate-to-severe headache, nuchal rigidity,
no neurologic deficit other than cranial nerve palsy
Grade 3: Drowsiness, confusion, or mild focal deficit
Grade 4: Stupor, moderate-to-severe hemiparesis, possi-
ble early decerebrate rigidity, and vegetative disturbances
Grade 5: Deep coma, decerebrate rigidity, and moribund
appearance
The Fisher grade, which describes the amount of blood
seen on noncontrast head CT, is also useful in correlating
the likelihood of developing vasospasm, the most com-
mon cause of death and disability from SAH. Vasospasm
is overwhelmingly most common in Fisher grade 3 and
rarely found in patients with no blood on CT (Fisher et al.,
1980):
Fisher 1: No blood detected
Fisher 2: Diffuse or vertical layers less than 1 mm thick
Fisher 3: Localized clot or vertical layer greater than or
equal to 1 mm
Fisher 4: Intracerebral or intraventricular clot with dif-
fuse or no SAH
Of patients with SAH, 10% die before reaching medi-
cal attention and another 50% die within 1 month. Fifty
percent of survivors have neurologic deficits. Ruptured
aneurysms are most likely to rebleed within the first day
(2–4%), and this risk remains very high for the first 2 weeks
(20–25%) if left untreated. Vasospasm, the leading cause
of disability and death from aneurysm rupture, is thought
to be secondary to a toxic relationship between subarach-
noid blood products and the vessel wall. Vasospasm
typically occurs 3–14 days after rupture, leads to neu-
rologic decline via ischemia and stroke if left untreated,
and correlates with the severity of the Fisher grade. Early
referral to a hospital with physicians experienced in treat-
ing IC aneurysms, early treatment (open surgery and clip-
ping or endovascular coiling), and aggressive treatment
of vasospasm are three factors that have been correlated
with improved outcomes over the last 20 years.
Signs and symptoms of aneurysms other than those
associated with SAH are relatively uncommon. Selected
IC aneurysms can produce cranial neuropathies. A com-
mon example is the third cranial nerve palsy related to
posterior communicating artery aneurysms. This condi-
tion is typically a pupil-involving, painless third cranial
nerve palsy. Other less common symptoms include visual
loss caused by an ophthalmic artery aneurysm that com-
presses the optic nerve, ophthalmoplegia from a large
cavernous sinus aneurysm, and seizures, headaches,
TIAs, or cerebral infarction related to emboli associated
Neurosurgical Care of the Geriatric Patient 525
with a large or giant partially thrombosed MCA aneu-
rysm. Giant aneurysms (diameter >2.5 cm) tend to be
symptomatic because of their mass effect.
The risk of rupture among aneurysms that have not
bled is unknown and, for many years, has been believed to
be 1–2% per year. The International Study of Unruptured
Intracranial Aneurysms (ISUIA)), published in 1998
(retrospective component) and 2003 (prospective com-
ponent), examined 2621 and 1692 subjects, respectively,
with IC aneurysms without intervention (The Interna-
tional Study of Unruptured Intracranial Aneurysms
Investigators, 1998). Its objective was to determine the
natural history of unruptured aneurysms and has since
challenged our understanding of aneurysm rupture risk.
Surprisingly, the study found that, for aneurysms smaller
than 7  mm and located in selected parts of the anterior
circulation in patients who had not had a prior aneurys-
mal SAH, the risk of subsequent rupture was extremely
small (0.05%  per year in the retrospective arm and a
5-year cumulative risk of rupture of 0% in the prospective
arm). Aneurysms at other locations (such as the basilar
tip and the posterior communicating artery), aneurysms
larger than 10 mm, and aneurysms found in patients who
had bled from a prior aneurysm had a higher risk (about
0.5% per year). The cumulative risk for aneurysms greater
than 7 mm in size was 0.8% (1998).
Critics of the ISUIA study emphasized that the selection
was biased because surgeons who entered patients into
the study thought that these aneurysms were less likely
to bleed. In fact, about 15,000 aneurysms that are 7 mm in
size or less rupture every year in the United States. Specif-
ically, smaller aneurysms that have not ruptured but have
manifested with other symptoms, such as a new-onset
third cranial nerve palsy or visual loss (caused by an
ophthalmic artery aneurysm), should be treated because
the natural history risk of rupture is believed to be sig-
nificantly higher (6% per year) than that of incidentally
discovered lesions.
The three primary modalities used to study the size,
location, and morphology of IC aneurysms are CT
angiography (CTA), magnetic resonance angiography
(MRA), and catheter-based digital subtraction angiog-
raphy (DSA). On noncontrast CT, the typical nonthrom-
bosed aneurysm appears as a well-delineated isodense
to slightly hyperdense mass located somewhat eccen-
trically in the suprasellar subarachnoid space or syl-
vian fissure. Enhanced images of the cerebral vascu-
lature can be obtained using rapid contrast infusion
and thin-section dynamic CT scanning. Various three-
dimensional (3D) display techniques, including shaded
surface display, volume rendering, and maximal inten-
sity projection complement the conventional transaxial
images. Such studies provide multiple projections of
anatomically complex vascular lesions and delineate
their relationships to adjacent structures. The accuracy
526 Therapeutics for the Geriatric Neurology Patient
of high-resolution axial CTA in the diagnosis of cere-
bral aneurysms 3 mm and larger has been reported to
be about 97%. The reported ability of CTs to reveal SAH
caused by ruptured cerebral aneurysms in the acute
phase is about 95%. This sensitivity decreases over
time. Acute SAH appears as high attenuation within
the subarachnoid cisterns.
Aneurysm appearance on MRI is highly variable and
may be quite complex. The signal depends on the pres-
ence, direction, and rate of flow, as well as on the presence
of clot, fibrosis, and calcification within the aneurysm
itself. Fortunately, MRA technology can overcome many
of the imaging challenges while precisely rendering the
pathology. MRA relies on the macroscopic motion of the
moving spins in flowing blood, together with background
suppression of stationary tissue to create images of the
cerebral vasculature. The images can be viewed as indi-
vidual thin sections (source images) or can be reprojected
in the form of flow maps.
DSA continues to be the standard for delineating the fea-
tures of an IC aneurysm. Recent advances in technology,
most notably 3D rotational angiography, have increased
the ability of catheter-based angiography to define aneu-
rysm anatomy. Infundibuli and vascular loops are now
well distinguished from aneurysms with such techniques.
Technically adequate cerebral angiography is considered
an important and indicated test in the assessment of non-
traumatic SAH, although some groups have reported
success with CTA as the only diagnostic test before treat-
ment. When angiography is performed, visualizing the
entire IC circulation, including the anterior and posterior
communicating arteries and both PICAs is important.
Multiple oblique, submental vertex, anteroposterior, and
lateral projections, as well as subtraction studies, are inte-
gral parts of the complete angiographic evaluation. If an
aneurysm is found, endovascular intervention to secure
the aneurysm can be performed in the same setting, if
appropriate.
Treatment decisions for ruptured aneurysms dif-
fer significantly from those for unruptured aneurysms.
Ruptured aneurysms should be treated urgently (within
72 hours of hemorrhage, and preferably within 24 hours)
to prevent rebleeding and to permit aggressive manage-
ment of vasospasm. Untreated ruptured aneurysms have
a very high risk of rebleeding after the initial hemorrhage.
The risk is estimated at over 20% in the first 2 weeks and
50% over the first 6 months, and such rebleeding carries a
mortality rate of nearly 85%. Unruptured aneurysms may
be treated electively.
There are three major options for treating IC aneu-
rysms: observation, craniotomy and clipping with or
without bypass, and endovascular coil embolization with
or without stent assistance. In the earlier days of aneu-
rysm treatment, surgery was delayed until the second or
third week after hemorrhage to avoid difficulty related
to brain swelling during surgery. Although this strategy
lowered surgical morbidity and mortality rates, manage-
ment results were not always good because of a high inci-
dence of rebleeding and morbidity from vasospasm. The
use of nimodipine and “triple-H” therapy (hypertensive
hypervolemic hemodilution) for prevention and treat-
ment of vasospasm, and ventriculostomy or lumbar drain
for treatment of SAH, intraventricular hemorrhage, and
hydrocephalus have become standard of care (Barker and
Ogilvy, 1996; Elliott et al., 1998).
The goal of open surgical treatment is usually to place
a clip across the neck of the aneurysm to exclude the
aneurysm from the circulation without occluding nor-
mal vessels (Figure 22.3). Microsurgical techniques are
used to dissect the aneurysm neck free from the feeding
vessels without rupturing the aneurysm. For aneurysms
that cannot be primarily clipped, wrapping with cot-
ton, muslin, or a synthetic patch and proximal occlusion
with bypass are additional surgical options. Intraopera-
tive angiography is now frequently used as an adjunct
to clipping and permits confirmation of aneurysm occlu-
sion and patency of nearby vessels. Recently, a new
technique called near-infrared indocyanine green (ICG)
videoangiography has become popular as a less inva-
sive way to assess aneurysm and blood-vessel patency
during aneurysm surgery. After intravenous injection
of the ICG, an operating microscope equipped with
appropriate software can detect blood flow within the
vasculature within seconds using near-infrared video
technology (Raabe et al., 2005).
The operative morbidity and mortality associated with
clipping depends on whether the aneurysm has ruptured:
ruptured aneurysms are more treacherous, and morbid-
ity is higher than that of unruptured aneurysms. The risk
of surgery for unruptured aneurysms is estimated to be
4–10.9% morbidity and 1–3% mortality (Solomon et al.,
1994; Cloft and Kallmes, 2004). Many factors affect the
morbidity rates, with larger aneurysms in certain loca-
tions and in older, less medically healthy patients faring
less well. Surgeons’ experience likely plays a role, with
high-volume surgeons working in high-volume institu-
tions having lower morbidity rates. In general, life expec-
tancy influences the decision strongly. An older patient
with a short life expectancy may not be a candidate for
surgery for an unruptured aneurysm because the remain-
ing lifetime risk is low. Conversely, due to the high mor-
tality associated with a ruptured aneurysm, treatment is
usually considered at any age if the patient is in good neu-
rologic condition.
After successful obliteration of a ruptured aneurysm,
the patient remains at significant risk for vasospasm,
hydrocephalus, and medical complications (including
hyponatremia, venous thromboembolism, infections,
and cardiac stun) and remains in an intensive care set-
ting for at least 7–10 days (Zaroff et al., 1999). Operative

(a)
Figure 22.3 Multiple CT scans of a 57-year- (c)
old woman with Fisher 3 subarachnoid
hemorrhage (SAH) secondary to rupture
of a 6 mm, right-sided middle cerebral
artery (MCA) aneurysm. (a) Axial CT
slice shows SAH, acute hematoma within
the right sylvian fissure, and right-to-left
midline shift. An external ventricular
drain is in place. (b) Axial and (c) coronal
CT angiogram slices show an MCA
bifurcation aneurysm (arrow) within a
focus of SAH. (d) Coronal CT angiogram
slice demonstrating clip occlusion of
the aneurysm via ipsilateral pterional
craniotomy. © Barrow Neurological
Institute.
complications represent only a small portion of the mor-
bidity and mortality rates associated with a ruptured IC
aneurysm. The major causes of morbidity and mortal-
ity include hydrocephalus, seizure, infection, and vaso-
spasm. As noted earlier, vasospasm refers to narrowing
of the IC vasculature in response to SAH. Management
protocols for vasospasm include daily nimodipine, tran-
scranial Doppler (TCD) trending, and balloon angio-
plasty with intra-arterial calcium-channel blocking
agents.
Over the past 15 years, endovascular methods to treat
IC aneurysms have been developed and refined. The use
of detachable platinum coils to embolize aneurysms has
become the primary treatment modality of aneurysms at
some centers. The purpose of the coil is to induce throm-
bosis at the site of deployment. Early limitations, such as
an inability to coil aneurysms with wide necks or com-
plex morphologies and high rates of recurrence second-
ary to coil compaction, are increasingly being addressed
with complex-shaped coils, balloon and stent technology,
and biologically active coils (Figure 22.4). In particular,
stent-assisted coiling for the treatment of wide-neck
aneurysms is increasing, although the complication rates
Neurosurgical Care of the Geriatric Patient 527
(b)
(d)
associated with this technique remain high. Two self-
expandable stents specifically designed for IC use (Neu-
roform and Enterprise) are approved by the Food and
Drug Administration for use in the United States.
More recently, both experimental and clinical evidence
suggests that stent placement across the neck of an aneu-
rysm causes a hemodynamic flow diversion that can
occasionally cause aneurysmal occlusion/thrombosis
without the need to introduce coils. A new stent with a
more tightly constructed mesh, known as the Pipeline
Embolization Device, designed to cause increased hemo-
dynamic diversion relative to the Neuroform or Enter-
prise, is undergoing experimental investigation (Fiorella
et al., 2006). The use of stent technology requires adju-
vant antiplatelet therapy with aspirin and clopidogrel for
6–12 weeks to prevent in-stent stenosis (incidence ~6%).
These additional medications carry their own set of risks
(Lylyk et al., 2009).
Obliteration of an aneurysm (ruptured or unruptured)
with coiling or clipping is a matter of significant con-
troversy. Currently, data suggest that whereas coiling
is somewhat safer than clipping for both ruptured and
unruptured aneurysms in the acute perioperative period,
528 Therapeutics for the Geriatric Neurology Patient

(a) (b) (c)

(d) (e)

Figure 22.4 Multiple angiographic images of a 65-year-old woman with an 11 mm, unruptured, right-sided V4 aneurysm. (a) Oblique view
demonstrating a wide-necked, irregular aneurysm. The aneurysm arises directly from V4, at about the level of the exit (arrow) of the
ipsilateral posterior inferior cerebellar artery (PICA). There is atherosclerotic dolichoectasia present in the ipsilateral proximal V4 as well.
(b) Intraoperative “roadmap” view demonstrating dual microcatheter technique. One catheter deploys an inflatable balloon (arrow) as a
buttress across the aneurysm neck, while a second catheter deploys coils into the aneurysm. (c) Unsubtracted lateral view demonstrating
partial coil occlusion of the aneurysm with residual at the neck. Final (d) lateral and (e) Townes views of the aneurysm showing complete
coil embolization and preservation of ipsilateral PICA. © Barrow Neurological Institute.

aneurysm obliterating via clipping is more durable and
more often complete. The well-publicized International
Subarachnoid Aneurysm Trial (ISAT) demonstrated
increased safety of coiling over clipping for the sub-
set of aneurysms considered suitable for either treat-
ment (Molyneux et al., 2002). In that study, 2143 patients
who presented with SAH and were deemed to have an
aneurysm that was considered treatable with coiling or
clipping were prospectively randomized to one of the
two treatments. The study was stopped prematurely
after a planned interim analysis found a 23.7% rate of
dependency or death in the coiling cohort versus a 30.6%
rate in the clipping cohort. The main criticism of the study
was that most of the aneurysms were thought to be bet-
ter treated by one modality over the other, and thus only
22.4% of all aneurysms screened were randomized. Of
those, the overwhelming majority were small and located
in the anterior circulation. Therefore, although the study
is important, generalizing the results to all ruptured aneu-
rysms is inappropriate. Ultimately, the decision to clip or
coil should be made on an individual basis and may often
involve difficult-to-quantify variables such as a patient’s

interest in one technique over the other or the experience
or availability of the physician operators.
Cerebral aneurysms are increasingly revealed before
rupture because of the ready availability of noninvasive
neuroimaging techniques. With our increased ability to
discover aneurysms comes the need to identify which
incidentally discovered aneurysms should be treated
and with what modality. A decision to treat is individu-
alized and should be made by a physician or group of
physicians who are capable of offering both modalities
of treatment, clipping or coiling, without bias. The risks
of any proposed treatment must outweigh the natural
history risks or risk associated with no treatment. Risks
of treatment and no treatment depend on many patient-
specific and aneurysm-specific factors, including aneu-
rysm size, location, and morphology and the patient’s age
and medical comorbidities. In general, life expectancy
of 12 years or more would warrant treatment of all inci-
dentally discovered aneurysms, with the exception of
very small aneurysms in elderly patients. Some patients
will choose conservative observation and forego surgery
and its risks (death and disability) in favor of the risk of
future rupture. On the other hand, some patients are so
frightened by knowing that they have an aneurysm that
they cannot function until it is repaired. This psychologi-
cal burden can be overcome in some patients with good
counseling. In other patients, only definitive treatment of
the aneurysm can provide relief. In the end, physicians
should review all the relevant data from trials and natural
history studies to help patients make their decision. Final
decisions take time, patience, and experience, and may
require repeated visits with patients.
Neurosurgical considerations for stroke
Stroke is characterized by the sudden loss of blood circu-
lation to an area of the brain, resulting in a corresponding
loss of neurologic function. Also previously called cere-
brovascular accident (CVA) or stroke syndrome, stroke is
a nonspecific term encompassing a heterogeneous group
of pathophysiologic causes, including thrombosis, embo-
lism, and hemorrhage. The neurosurgical options for
patients with stroke vary widely and are based on the
etiology of the stroke, as well as its severity. While most
patients with stroke will not benefit from surgery, many
need neurosurgical evaluation. Carotid endarterectomy
(CEA), carotid artery stenting, evacuation of intracerebral
hematoma, endovascular revascularization, external ven-
tricular drainage, and decompressive craniectomy are a
few of the neurosurgical interventions that may benefit
these patients.
Strokes are broadly classified as either hemorrhagic or
ischemic. Acute ischemic stroke refers to stroke caused
by thrombosis or embolism and is more common than
Neurosurgical Care of the Geriatric Patient 529
hemorrhagic stroke. A recent retrospective review found
that 40.9% of 757 strokes were hemorrhagic. The increased
percentage of hemorrhagic stroke may be due to improve-
ment of CT availability and implementation, unmasking
a previous underestimation of the actual percentage, or
it may be due to an increase in therapeutic use of anti-
platelet agents and warfarin causing an increase in the
incidence of hemorrhage (Shiber et al., 2010). In recent
years, significant advances have been made in stroke pre-
vention, nonsurgical supportive care, and rehabilitation.
Nonetheless, when the direct costs (care and treatment)
and the indirect costs (lost productivity) of strokes are
considered together, the cost to US society is $43.3 billion
per year (Roger et al., 2011).
On the macroscopic level, ischemic stroke is most often
caused by extra-cranial (EC) embolism or IC thrombosis,
but it may also be caused by decreased cerebral blood
flow. The risk of both types of stroke increases with age.
Embolic strokes are seldom of neurosurgical concern,
except for the possibility of endovascular lysis or hemi-
craniectomy. Thrombotic stroke can be divided into large
vessel, including the carotid artery system, and small ves-
sel, comprising the branches of the circle of Willis and the
posterior circulation. The most common sites of throm-
botic occlusion are cerebral artery branch points, espe-
cially in the distribution of the ICA. Arterial stenosis can
cause turbulent blood flow, which can increase the risk
for thrombus formation, atherosclerosis (for example,
ulcerated plaques), and platelet adherence. Each of these
then causes the formation of blood clots that either embo-
lize or occlude the artery. The open microsurgical as well
as endovascular management of thromboembolic large
vessel stenosis or occlusion is discussed in the next two
subsections.
Less common causes of thrombosis include polycy-
themia, sickle cell anemia, protein C or S deficiency,
Factor V Leiden, fibromuscular dysplasia of the cerebral
arteries, moyamoya disease, and prolonged vasoconstric-
tion from migraine headache disorders. Any process that
causes dissection of the cerebral arteries also can cause
thrombotic stroke (such as trauma or thoracic aortic dis-
section). Occasionally, hypoperfusion distal to a stenotic or
occluded artery or hypoperfusion of a vulnerable water-
shed region between two cerebral arterial territories can
cause ischemic stroke. Some of these processes (such as
arteritis, dissection, and hypercoagulability) are more likely
to have an initial presentation in elderly patients, while oth-
ers (such as moyamoya disease and sickle cell anemia) are
more likely in younger patients. Neurosurgical interven-
tion for stroke of these etiologies is usually limited to tem-
poral artery biopsy (giant cell arteritis) or superficial tem-
poral artery to MCA anastomosis for moyamoya disease.
The acute presentation of a potential stroke is a medical
emergency. Emergent noncontrast head CT is mandatory
for rapidly distinguishing ischemic from hemorrhagic
530 Therapeutics for the Geriatric Neurology Patient
infarction and may help determine the anatomic distri-
bution of stroke. Head CT is a fundamental branch point
in the evaluation of stroke because patients with acute
ischemic stroke may be triaged to receive thrombolytic
therapy, whereas patients with hemorrhagic stroke are
best served via a completely different diagnostic and
therapeutic pathway. CT may also rule out other life-
threatening processes, such as other forms of hematoma,
neoplasm, and brain abscess.
The changes on CT over the course of acute cerebral
infarction must be understood. The sensitivity of stan-
dard noncontrast head CT increases 24 hours after an
ischemic event (Adams et al., 2007). After 6–12 hours, suf-
ficient edema is recruited into the stroke area to produce a
regional hypodensity on CT (Wardlaw and Mielke, 2005).
A large hypodense area present on CT within the first
3 hours of reported symptom onset should prompt care-
ful review regarding the time of stroke symptom onset
(for example, determining when the patient was last seen
in usual health). The presence of CT evidence of infarction
early in presentation has also been associated with poor
outcome and increased propensity for hemorrhagic trans-
formation after thrombolytics (Hacke et al., 1995; The
National Institute of Neurological Disorders and Stroke
rt-PA Stroke Study Group 1995; Von et al., 1997). Other
radiologic clues to acute ischemic infarction include the
insular ribbon sign, the hyperdense MCA sign (MCA
occlusion), obscuration of the lentiform nucleus, sulcal
asymmetry, and loss of gray–white matter differentiation
(Adams et al., 2007). Noncontrast CT may be followed
by a CTA in certain centers. CTA may identify a filling
defect in a cerebral artery, thus localizing the lesion to a
specific portion of the causative vessel. In addition, CTA
can provide an estimation of perfusion because poorly
perfused cerebral tissue appears as hypodense areas of
tissue. Noncontrast head CT in combination with CTA
and CT perfusion imaging is more sensitive for detecting
small ischemic lesions, compared with any of the indi-
vidual imaging modalities alone. CT perfusion imaging
is a relatively new modality potentially useful in identify-
ing early areas of ischemia. By continuing to scan through
the brain after an initial bolus of intravenous contrast
dye, perfusion of different brain regions can be measured.
Areas of hypoattenuation on CT perfusion imaging corre-
spond well with ischemia and allow some determination
of viability and the ischemic penumbra (Klotz and Konig,
1999; Wintermark et al., 2002).
Various MRI protocols have utility in acute stroke.
Standard T1-weighted and T2-weighted MRI sequences
may be combined with other imaging protocols, such
as diffusion-weighted imaging (DWI) and perfusion-
weighted imaging, to yield improved sensitivity for the
detection of acute ischemic and hemorrhagic strokes
over standard noncontrast CT. Furthermore, subacute
intracerebral hemorrhage, while difficult to diagnose
via standard noncontrast CT, can be detected using MRI
with reliability approaching 100%. DWI can detect isch-
emia much earlier than standard CT or MRI sequences
and provides useful data in stroke and TIA patients
outside of the initial management window (Sorensen
et al., 1996; Gonzalez et al., 1999; Adams et al., 2007).
DWI can detect small areas of ischemia, particularly in
regions poorly visualized by noncontrast CT, such as
the cerebellum and the brainstem (Adams et al., 2007).
Acute stroke volume, as measured on DWI, correlates
well with final lesion volume and clinical stroke sever-
ity scales, suggesting a possible role in prognostication
(Lovblad et al., 1997; Barber et al., 1999). Carotid duplex
ultrasonographic scanning is indicated for patients with
acute ischemic stroke in whom carotid artery stenosis or
occlusion is suspected. TCD ultrasonography is useful
for evaluating more proximal vascular anatomy, includ-
ing the MCA, intracranial ICA, and vertebrobasilar
artery (Camerlingo et al., 1993).
The central goal of therapy in acute ischemic stroke is
to preserve the area of oligemia in the ischemic penumbra
(Roger et al., 2011). The area of oligemia can be preserved
by limiting the severity of ischemic injury (neuronal pro-
tection) or by reducing the duration of ischemia (restoring
blood flow to the compromised area). The ischemic cas-
cade offers many points at which such interventions can
be attempted, and multiple strategies and interventions
for blocking this cascade are currently under investiga-
tion. Several neurosurgical interventions have a defined
role in flow restoration, in the acute, subacute, and even
chronic phases of stroke.
Neurosurgical management of carotid
occlusive disease
As noted earlier, stenosis due to atherosclerotic dis-
ease at the carotid bifurcation in the neck is a common
cause of stroke. Most are due to embolism, with a much
smaller proportion causing acute ischemia. Character-
istically, plaque forms in the lumen of the Y-shaped
junction of the internal and external carotid arteries. As
the stenosis becomes more severe, the risk of fracture
of the plaque and subsequent embolization and stroke
increases commensurately. Asymptomatic disease is
often diagnosed through physical examination or diag-
nostic imaging. If mild, it is usually treated medically.
If severe, it is often treated surgically via CEA (carotid
bifurcation plaque removal; Figure 22.5). Symptomatic
disease presents with stroke, visual loss, or TIA. The
degree of stenosis determines whether treatment or
best medical therapy is employed. Age also plays an
important role in determining what treatment, if any,
is required. Patients with any degree of identifiable
stenosis should be considered for treatment at a mini-
mum with a single full-dose aspirin per day. Patients
with a higher degree of stenosis who are not surgical

(a)
(c)
Figure 22.5 CT angiogram of the neck
in an asymptomatic patient shows
severe calcified stenosis of the right ICA
bifurcation in (a) sagittal (arrow) and (b)
axial planes (arrow). CT angiogram of the
neck is repeated after a right-sided carotid
endarterectomy (CEA) confirms restoration
of flow in (c) sagittal and (d) axial planes.
© Barrow Neurological Institute.
candidates should be considered for stronger antiplate-
let agents, such as clopidogrel.
A number of high-quality prospective randomized tri-
als have compared CEA with best medical care. The North
American Symptomatic Carotid Endarterectomy Trials
(NASCET) I and II compared symptomatic patients and
conclusively showed improved benefit with endarterec-
tomy, as well as a very low procedural and periprocedural
complication rate. Symptomatic patients with stenosis as
low as 50% were seen to benefit from CEA (North Ameri-
can Symptomatic Carotid Endarterectomy Trial Collabo-
rators, 1991). Other trials, such as the VA Cooperative
Neurosurgical Care of the Geriatric Patient 531
(b)
(d)
Trial and European Carotid Surgery Trial (ECST), con-
firmed these results (European Carotid Surgery Trialists’
Collaborative Group, 1991; Hobson et al., 1993). In addi-
tion, asymptomatic patients have been similarly studied,
with a statistically significant benefit found for surgery
for patients with greater than 60% stenosis in trials such
as the Asymptomatic Carotid Atherosclerosis Study
(ACAS) (Executive Committee for Asymptomatic Carotid
Atherosclerosis, 1995). Because the benefit of endarter-
ectomy is much greater for symptomatic patients than
asymptomatic patients and for patients with high degrees
of stenosis versus mild stenosis, there is some debate
532 Therapeutics for the Geriatric Neurology Patient
about how strongly treatment should be recommended
for asymptomatic patients with lower degrees of stenosis.
Therefore, recommendation for surgery for asymptomatic
patients can be made for all degrees of stenosis over 60%
but should be made more strongly as the degree of steno-
sis rises from 60% to 99%. Although counterintuitive, the
older a patient is, the more likely he or she is to benefit
from CEA, because the risk of stroke rises faster than the
surgical risk.
Carotid angioplasty and stenting (CAS) has emerged
more recently as an endovascular treatment option for
carotid stenosis. Carotid stenting is an alternative treat-
ment for carotid stenosis in which the femoral artery is
catheterized, a catheter is passed up to the carotid artery,
a balloon is inflated to open the stenosis, and a metal stent
is placed. Although intrinsically appealing as a minimally
invasive option, data to support its use over CEA has
mostly been lacking. The SAPPHIRE trial, a comparative
noninferiority study of patients with a high cardiopulmo-
nary risk, showed no difference in the outcome of CAS
versus CEA (Yadav et al., 2004; Gurm et al., 2008). This
result has been interpreted to mean that patients with
high medical (cardiopulmonary) risk for surgery can be
considered for CAS as a first choice. It is important that
age not be conflated with high medical risk, as CEA has
been shown to have a better risk profile than CAS for
patients over the age of 70 (Bonati et al., 2010). Further-
more, because there is only a weak association between
medical risk and age, it is crucial to assess risk factors
independently of age when evaluating a patient’s global
medical risk profile.
A number of other recent trials have compared stent-
ing and endarterectomy. At present, all of these have
shown a very low risk for CEA. None of these large tri-
als have shown advantage for CAS, including SPACE
and EVA-3S in Europe and, most recently, the Carotid
Revascularization Endarterectomy versus Stenting Trial
(CREST) in North America (Mas et al., 2006; Ringleb
et al., 2006; Mas et al., 2008; Mantese et al., 2010; Silver
et al., 2011). A number of criticisms have been raised by
the endovascular community about these trials, includ-
ing concerns that distal antiembolism protection devices
were not used in enough patients and that the enroll-
ing endovascular surgeons were not skilled enough.
Nonetheless, no current trial has shown more benefit
for CAS in terms of the major endpoints of stroke and
myocardial infarction. Therefore, patients who have a
low or moderate cardiopulmonary risk should undergo
endarterectomy as a first choice. Patients who have a
higher risk can be considered for CAS or CEA, depend-
ing on the degree of that risk. Table 22.1 summarize the
indications and other factors that may influence deci-
sion making.
Complete closure (occlusion) of the carotid is typically
managed conservatively. For any chronic complete clo-
Table 22.1 Indications for carotid endarterectomy (CEA) or carotid
artery stenting (CAS)
Symptomatic stenosis >60%—high benefit
Low or moderate medical risk—CEA
High risk—CAS
Asymptomatic stenosis >60%—moderate benefit
Low or moderate risk—CEA
High risk—CAS
CEA favored
Age >80
Calcified plaque
CAS favored
Recurrent (postendarterectomy) stenosis
Postradiation therapy to neck
Contralateral carotid occlusion (relative)
Contralateral laryngeal nerve palsy
High (to C1 level) carotid stenosis
sure of the carotid, surgery to reopen the carotid artery
has shown no benefit. This is likely because the major risk
for stroke is at the time of closure, and thus surgical recan-
alization provides no reduction of stroke risk. However,
patients with ongoing stroke or TIA may be considered
for thromboendarterectomy if they are identified and
treated soon after the time of closure. This option may be
considered for patients with: (1) a zone of hypoperfusion
on MR or CT perfusion larger than the area of completed
diffusion change on MRI and (2) a luminal thrombus
that does not extend beyond the petrous carotid artery.
EC–IC bypass in the form of an STA-to-MCA anastomosis
was evaluated for carotid occlusion in the International
EC–IC Bypass Trial in the 1980s (EC/IC Bypass Study
Group, 1985) and, more recently, in the Carotid Occlusion
Surgery Study (COSS). In both trials, patients treated with
surgery did worse than those treated with best medical
care. While STA-to-MCA still has a place in the treatment
of moyamoya disease and complex aneurysms, its benefit
for ischemia seems doubtful.
Endovascular treatment for acute intracranial
thrombotic stroke
The endovascular treatment of acute IC thrombosis is
advancing rapidly. The major barrier to success in this
area appears to be the rapidity with which treatment can
be instituted. Endovascular options include direct intra-
arterial thrombolysis with enzymatic thrombolytics (strep-
tokinase, urokinase, tissue plasminogen activator (rt-PA))
and direct mechanical thrombectomy. A number of trials
with new thrombectomy devices are ongoing. In general,
endovascular thrombolysis or thrombectomy should be
attempted if it can be achieved within 3 hours of the onset
of stroke in patients without evidence of IC hemorrhage.
There is equivocal evidence of a time window up to 6
hours. Beyond this time window, such procedures should
be performed only as part of a clinical trial.
 Neurosurgical Care of the Geriatric Patient 533

Neurosurgical management of spontaneous Normal pressure hydrocephalus

intracerebral hematoma
As noted earlier, a significant number of patients present-
ing with acute stroke will be found to have suffered from
intracerebral hemorrhage. This group is not a candidate
for thrombolytic therapy, unless the hemorrhage is pre-
dominantly intraventricular. Most patients will be man-
aged conservatively. However, for some patients with
larger hemorrhages, surgical evacuation may be consid-
ered. Typically, those patients who do best with surgical
evacuation have superficially located hematomas in non-
eloquent areas of the brain.
The natural history of patients with substantial
intraventricular hemorrhage is much worse than that
of other patients with intracerebral hemorrhage. This
seems to be due largely to the sequelae of hydrocepha-
lus. External ventricular drainage and treatment with
intraventricular thrombolytics provide a gratifying
improvement in outcomes (Torres et al., 2008; Staykov
et al., 2009).
Decompressive hemicraniectomy
Decompressive hemicraniectomy in the treatment of
stroke has a controversial history. The purpose of the
treatment is to open the cranium ipsilateral to an ischemic
or hemorrhagic stroke to provide room for the brain to
swell. This mitigates the effect of the swelling tissue on
the surrounding brain, thereby reducing brain shift and
reducing the potential for increased ICP (Figure 22.6).
The benefit for elderly patients seems to be less than for
younger patients, for reasons that are not immediately
clear. If practiced, it should be done before herniation
occurs and only as a life-saving measure.
Normal pressure hydrocephalus (NPH) is a clinical symp-
tom complex characterized by abnormal gait, urinary
incontinence, and dementia and is described in more
detail in Chapter 20. It is an important clinical diagnosis
because it is a potentially reversible cause of dementia.
First described by Hakim in 1965, NPH describes hydro-
cephalus in the absence of papilledema and with normal
CSF opening pressure on lumbar puncture (Hakim and
Adams, 1965). Clinical symptoms result from distortion
of the central portion of the corona radiata by the dis-
tended ventricles. This distention may also lead to inter-
stitial edema of the white matter and impaired blood
flow, as suggested in nuclear imaging studies. Hakim first
described the mechanism by which a normal or high–
normal CSF pressure exerts its effects—increased CSF
pressure over an enlarged ependymal surface applies con-
siderably more force against the brain than the same pres-
sure in normal-sized ventricles. It is thought that NPH
may begin with a transient high-pressure hydrocephalus
that produces subsequent ventricular enlargement, which
persists despite ultimate pressure normalization.
NPH is predominantly a disease of the elderly. Patients
present with a gradually progressive disorder. Although
the classic triad is noted, gait disturbance is typically the
earliest feature and considered to be the most responsive
to treatment. Furthermore, this is an apraxia of gait—it
is characteristically bradykinetic, magnetic, and shuf-
fling. True weakness or ataxia is typically not observed.
The dementia of NPH is characterized by prominent
memory loss and bradyphrenia. Frontal and subcorti-
cal deficits are particularly pronounced. Such deficits
include forgetfulness, decreased attention, inertia, and

(a) (b) (c)

Figure 22.6 (a) Axial CT angiogram of the head demonstrating contrast block in the right distal M1 segment in a patient with acute onset of
left-sided weakness (arrow). (b) Noncontrast CT scan of head obtained hours later demonstrates edema within the right middle cerebral
artery (MCA) territory suggestive of infarction, as well as midline shift and ventricular effacement. (c) A decompressive hemicraniectomy
was performed to mitigate brain shift and prevent herniation. © Barrow Neurological Institute.
534 Therapeutics for the Geriatric Neurology Patient
generalized cognitive slowing. The presence of cortical
signs such as aphasia or agnosia should raise suspicion
for an alternate pathology such as Alzheimer’s disease
(AD) or vascular dementia (Bech-Azeddine et al., 2007).
However, comorbid pathology is not uncommon with
advancing age. The index of suspicion for NPH should
remain high, given its better response to treatment com-
pared with other forms of senile dementia (Golomb
et al., 2000).
NPH may occur due to a variety of secondary causes
but may be idiopathic in approximately 50% of patients.
Secondary causes of NPH include head injury, SAH,
meningitis, and CNS tumors. Another potential cause
may be previously compensated congenital hydroceph-
alus. Multiple other illnesses, including Alzheimer’s
dementia, Pick’s disease, Lewy body dementia, Wilson’s
disease, and vascular dementia, may present similarly to
NPH and should be considered in the differential diag-
nosis. In particular, Parkinson’s disease (PD) and NPH
may present in a similar, yet subtly distinct manner. Start
hesitation and freezing episodes can occur in NPH, often
mimicking the gait in PD. In contrast to PD, however,
rigidity and unilateral rest tremor are less commonly
observed.
CT and MRI findings in NPH include the following: ven-
tricular enlargement out of proportion to sulcal atrophy,
prominent periventricular hyperintensity consistent with
transependymal flow of CSF, and a prominent flow void
in the aqueduct and third ventricle. This last finding rep-
resents the so-called “jet sign,” a dark aqueduct and third
ventricle on a T2-weighted image where the remainder of
CSF is bright. A specific MRI cineradiographic study can
be ordered to assess flow through the aqueduct. A value
(a) (b)
Figure 22.7 (a) Axial CT scan of the head showing typical ventriculomegaly out of proportion to volume loss in a patient with normal
pressure hydrocephalus (NPH). (b) Ventriculoperitoneal shunting can use either a right frontal or right parietal approach. (c) Bone windows
demonstrate intraventricular drainage sites (black arrow) and flow-regulating valve (white arrow). © Barrow Neurological Institute.
of >100 μL per cardiac cycle is thought to correlate with
shunt responsiveness, though the correlation is not strong.
Absence of flow through the aqueduct, especially in the
setting of enlarged lateral and third ventricles and a small
fourth ventricle, should prompt consideration of the diag-
nosis of aqueductal stenosis. This condition is responsive to
endoscopic third ventriculostomy. Prominent medial tem-
poral cortical atrophy favors a diagnosis of hydrocephalus
ex vacuo and is often related to AD or vascular dementia.
Radionuclide cisternography has been used in the
diagnosis of NPH. A radionuclide such as 99-Technicium
diethylene triamine pentaacetic acid (99Tm-DTPA)
is introduced into the lumbar spinal fluid, and the neur-
axis is imaged at intervals over the first 24–48 hours. A
normal study demonstrates flow of spinal fluid over the
cerebral convexities and absorption of most of the dose
within 24 hours. A study consistent with NPH shows
reflux of the fluid back into the ventricles. The use of this
test is controversial, as some patients without hydroceph-
alus show similar findings. However, a clearly positive
radionuclide cisternogram has predicted a response to
shunting in some studies as high as 75%.
All patients with suspected NPH should undergo diag-
nostic CSF removal (either large-volume lumbar puncture
and/or external lumbar drainage (ELD)), which has both
diagnostic and prognostic values (Williams et al., 1998).
When the CSF opening pressure is greatly elevated, other
causes of hydrocephalus should be considered, although
CSF pressures may be transiently elevated in NPH. Surgi-
cal CSF ventricular shunting remains the main treatment
modality (Figure 22.7).
Detailed testing is performed before and after
CSF drainage. Initially, patients are given a baseline
(c)

neuropsychological evaluation (such as the Folstein test
or more formal neuropsychological testing) and a timed
walking test/fall risk assessment, such as is included in
the Tinetti Gait and Balance Scale (Tinetti et al., 1986).
Patients then undergo a lumbar puncture with removal
of approximately 25–50 mL of CSF. Testing is repeated
3 hours later. A clear-cut improvement in mental status
and/or gait predicts a favorable response to shunt surgery.
The effect of the lumbar puncture does not persist beyond
48 hours. While large-volume lumbar puncture was the
earliest invasive diagnostic test in predicting response
to shunt surgery, ELD is being used with increased fre-
quency. In this method, clinicians use an indwelling CSF
catheter in lieu of repeated lumbar punctures (Hebb and
Cusimano, 2001).
Patients with a good response to predictive testing
should be considered for ventriculoperitoneal shunt-
ing. The best results are reported in patients who have
no adverse surgical risk factors, have responded favor-
ably to a large-volume lumbar puncture, have pre-
dominantly gait disturbance with mild dementia, and
have appropriate CT or MRI findings and a normal
CSF cellular and chemical profile at lumbar puncture.
While a significant proportion of patients will achieve
substantial functional benefit from shunting, the over-
all prognosis of NPH remains poor, due to both a lack
of improvement in some patients following surgery
and a significant complication rate related to shunting
(Pujari et al., 2008). In patients who develop recurrent
symptoms after initial improvement, shunt malfunction
should be suspected and an evaluation for mechani-
cal failure should be pursued. The incidence of shunt
complications of all degrees of severity is estimated in
30–40% of patients (Vanneste et al., 1992). These include
anesthetic complications, IC hemorrhage from place-
ment of the ventricular catheter, infection, CSF hypo-
tensive headaches, SDHs, shunt occlusion, and catheter
breakage. Rapid reduction in ventricular size following
the shunt favors complications such as subdural hema-
toma, which may occur in 2–17% of patients. Shunt
valves, which prevent siphoning of CSF from the head,
and programmable valves, which can adjust the pres-
sure at which fluid drains, may reduce the incidence of
this complication.
Neurooncology
Brain tumors, whether benign or malignant, affect the
elderly at a higher rate in the general population. Malig-
nant brain tumors, both primary and metastatic, are asso-
ciated with considerable morbidity and mortality. The
overall incidence of brain tumors continues to increase,
with the highest increase noted in patients over 60 years
of age. The attitude of the medical community toward
Neurosurgical Care of the Geriatric Patient 535
offering treatments to elderly patients with malignancies
is changing, and more elderly patients with brain tumors
are now treated aggressively. Advances in understanding
the molecular biology of brain tumors and the genetics of
brain tumors in older patients have resulted in treatments
that are more effective or better tolerated in this age group
(Nayak and Iwamoto, 2010). The overall prognosis for
malignant tumors remains poor, and the search for more
effective therapies is ongoing.
Malignant brain tumors can be primary or meta-
static. Metastatic tumors to the brain are most common,
accounting for greater than 50% of all brain tumors in the
elderly. Adenocarcinoma of the lung and breast most fre-
quently metastasize to the brain, followed by melanoma
and carcinoma of the kidney and thyroid. Among pri-
mary brain tumors, malignant gliomas, particularly glio-
blastomas multiforme (GBMs), are most commonly seen
in the elderly. Age is a strong prognostic factor affecting
survival for all brain tumor patients (Davis et al., 1999).
The 5-year survival rate for patients with a GBM is about
20% in patients younger than 35 years, 10% in patients
aged 35–54, and only 1% in patients 55 years and older.
This is now known to at least partially reflect fundamen-
tal differences in tumor biology (Burger and Green, 1987;
Roa et al., 2009). The age-based survival data parallel
the survival rates based on performance status, as mea-
sured by the Karnofsky performance scale, indicating the
importance of this preoperative variable.
Additional tumor types commonly seen in older
patients are meningioma, acoustic neuroma, and CNS
lymphoma. Meningiomas are the most common benign
tumor and are often seen in the elderly (mean age 59), with
a female predominance. The 5-year survival rate is 92%
for patients aged 45–74 and 70% for patients aged 75 and
older (Nayak and Iwamoto, 2010). Acoustic neuromas are
predominantly benign tumors of the vestibular division
of the eighth cranial nerve. They should be suspected in
patients with unilateral hearing loss or vertigo that does
not resolve with medical treatment. Depending on the age
of the patient, the severity of symptoms, and the size of
the tumor, management of meningioma and acoustic neu-
roma can be conservative (with symptomatic treatment
and follow-up with serial scans) or more definitive (with
surgery or stereotactic radiosurgery). CNS lymphoma is
a primary CNS malignancy with poor overall prognosis.
The median survival is about a year. These tumors can be
multifocal, are associated with immune compromise, and
are most commonly treated with a combination of intra-
venous and intrathecal chemotherapy.
The diagnosis of brain tumors is based on clinical pre-
sentation, imaging studies, and histology. In the older
population, intellectual decline over a brief period, gait
disturbances, and short-term memory deficits are clini-
cal signs that may indicate the presence of a brain tumor
and must be differentiated from “normal” aging signs
536 Therapeutics for the Geriatric Neurology Patient
and cerebrovascular disease. The symptoms and signs
are dependent on tumor location. The majority of malig-
nant glioma and metastatic lesions in the elderly occur
in the cerebral hemispheres. Headaches and seizures are
the most common symptoms at presentation. The pres-
ence of focal neurologic deficits helps to localize the lesion
(Mahaley Jr. et al., 1989). Tumors in the anterior frontal
lobes, the anterior temporal lobes, or the base of the skull
can grow to a large size with few or no symptoms or with
nonspecific symptoms often ascribed to the aging process
(such as memory loss, personality changes, or some gait
difficulties). The diagnosis of tumor can be suspected if
the symptoms develop over a short period of time (less
than 6 months). The presence of any history of cancer,
however remote, must greatly raise the index of suspicion
for metastatic lesions.
Neuroimaging studies are valuable tools in localizing
tumors and may suggest the diagnosis and malignant
character of a tumor. Contrast-enhanced MRI of the brain
is now the most utilized imaging modality. It allows
visualization of the tumor in axial, coronal, and sagittal
planes, thereby providing a 3D view of the tumor and its
relationship with the surrounding structures. MR spec-
troscopy and MR perfusion can help differentiate recur-
rent tumor from treatment effect in patients who have
received prior radiation therapy (RT). Stereotactic MRI
scans can be coregistered with high-resolution micro-
scopes, allowing for intraoperative navigation around a
tumor and its surrounding structures as seen on the MRI.
Neuroimaging studies such as DWI sequences can differ-
entiate between tumor and stroke when the lesion does
not respect a vascular distribution. They can also help to
differentiate between hemorrhage due to hypertension
and hemorrhage into a tumor. When the scan reveals
peripherally enhancing lesions, the differential diagno-
sis is often primary malignant tumor, metastatic tumor,
or abscess. If the chest radiograph is normal, the highest-
yield procedure will be a biopsy of one of the lesions for
tissue diagnosis. In this age group, infectious or vasculitic
lesions are less common than in younger patients.
The pathologic examination of the tumor specimen on
frozen section and fixated material defines the type of
tumor and the histologic grade. Primary brain tumors are
classified histologically based on the World Health Orga-
nization (WHO) classification. The grade of malignancy
is based on the cellularity, presence of mitoses, vascular
endothelial proliferation, and necrosis. For an accurate
grading, the pathologist needs to know whether the
patient received RT or chemotherapy prior to the surgi-
cal procedure. Tissue necrosis can be caused by RT and
chemotherapy, as well as by some malignant tumors,
particularly GBM (Roa et al., 2009). On the subcellular
level, recent research has focused on defining the genetic
alterations and interactions among tumor-suppressor
genes, oncogenes and their products, growth factors, and
enzyme systems. The goal of this research is to determine
the mechanisms of oncogenesis, cell resistance, and repair
mechanisms and to develop new treatment modalities
based on the molecular biology data. The p53 tumor sup-
pressor gene, found on chromosome 17p, is frequently
altered in gliomas, as it is in systemic cancers. The PTEN
gene, located on 10q23, has also been identified as a
putative tumor suppressor gene and is often mutated in
gliomas.
The treatment of brain tumors is determined by the
histologic type and the location in the cranial cavity, as
well as the patient’s performance status, neurologic sta-
tus, age, coexisting medical problems and life expectancy.
In the elderly, treatment of brain tumors raises particular
challenges. Benign tumors such as meningiomas, acoustic
neuromas, or pituitary adenomas can often be managed
conservatively in older patients unless the symptoms
and tumor size warrant a more aggressive approach. For
gliomas and metastatic tumors, the conventional therapy
involves surgery, RT, and chemotherapy. Most primary
brain tumors and metastatic tumors have surrounding
vasogenic edema, which contributes to the neurologic
symptoms (Figure 22.8). Vasogenic edema is controlled
most often with corticosteroids. Dexamethasone is com-
monly used, and it may need to be tapered slowly fol-
lowing tumor resection to treat persistent edema. Side
effects with long-term corticosteroid use include gastric
irritation, corticosteroid myopathy, Cushingoid appear-
ance, and, in some patients, osteoporosis, depression, and
corticosteroid psychosis. Hence, an effort is made to taper
the steroids as quickly as the clinical situation allows.
Surgery is the first therapeutic intervention for most
brain tumors, with the goal of obtaining tissue for diag-
nosis and, whenever possible, debulking the tumor
to relieve mass effect and bring about rapid clinical
improvement. In the elderly, surgery is considered to
carry a higher risk of morbidity and mortality compared
with younger patients. When feasible, complete resection
of malignant glioma (WHO grade III and IV) has been
shown to significantly increase the rate of survival by
providing cytoreduction, with a better chance of response
to subsequent therapy. Outcome studies further show
that patients who undergo resection have a better qual-
ity of life and are less likely to become depressed than
patients who undergo only biopsy (Pietila et al., 1999).
For patients with unresectable lesions (most often due to
the anatomic location being associated with an unaccept-
able risk of neurologic deficit) or with associated signifi-
cant medical comorbidities, a stereotactic biopsy for tis-
sue diagnosis is sufficient. At present, the most important
prognostic factors for overall survival are preoperative
performance status for malignant glioma and the extent
of resection for low-grade glioma (WHO grade II; Nayak
and Iwamoto, 2010). For metastatic lesions, surgical resec-
tion for patients with one to three lesions has been shown
 Neurosurgical Care of the Geriatric Patient 537

(a) (b)

Figure 22.8 (a) Sagittal T1-weighted MRI

with gadolinium and (b) axial T2-weighted
MRI of the brain demonstrate a large right
frontal dural-based tumor consistent with a
meningioma. The T2-weighted image also
shows a large component of surrounding
vasogenic edema, visible as a bright
signal within the white matter. © Barrow
Neurological Institute.

to improve both clinical performance status and overall RT. Some patients experience headaches, likely related to
survival, with most patients ultimately succumbing to edema, or a worsening of the neurologic deficits. Fatigue
systemic disease burden rather than their CNS disease is another complaint. Depending on the tumor location,
(Suh, 2010). patients may experience nausea, sore throat, hearing loss,
All malignant brain tumors, whether they are primary or blurred vision. These symptoms are transient and can
or metastatic, single or multiple, benefit from RT as a be controlled with corticosteroids and reassurance. Early
component of standard treatment. RT can also be used delayed effects, which appear in the first 3 months after
as an alternative to surgery in low-grade glioma patients completion of RT, include somnolence, loss of appetite,
with multiple medical comorbidities. Most intensity- and apathy. These effects are self-limiting and seem to
modulated radiation treatment (IMRT) schedules deliver be more severe in older patients (Roa et al., 2009). Late-
the total radiation dose over a series of weeks. Hyperfrac- delayed radiation injury occurs months or even years
tionation schedules allow the RT dose to be delivered in after completion of radiation. Patients experience short-
two or three daily treatments, while hypofractionation term memory loss and cognitive decline. CT or MRI
schedules use a once-weekly treatment (Roa et al., 2009). shows white matter changes bilaterally or may show focal
While hyperfractionation allows for larger total radiation radiation necrosis (Figure 22.9).
dose with less toxicity to the normal brain, hypofraction- Chemotherapy has been established as an accepted
ation helps to reduce acute RT side effects. Stereotactic adjuvant treatment for malignant primary brain tumors.
radiosurgery is a noninvasive technique that allows deliv-
ery of high-dose single fractions of radiation to small,
well-circumscribed tumors; it is often used in patients
with meningioma, acoustic neuroma, and some cerebral
metastases such as nonsmall cell lung cancer. It is occa-
sionally used as a primary tumor treatment or to treat
a surgical resection bed as a means of preventing local
recurrence. The treatment is low risk and effective, and
because it is done in one single dose or a few fractionated
doses in an outpatient setting, stereotactic radiosurgery
is convenient for the patient and cost-effective. The mor-
bidity associated with this approach is primarily related
to increased peritumoral edema, which can be controlled
with corticosteroids (Patil et al., 2010).
Regardless of the radiation modality used, RT may
cause side effects in the elderly patient that need to be dis-
cussed and monitored. The reactions to RT are more sig-
Figure 22.9 Axial FLAIR MRI of the brain demonstrating profound
nificant when RT is administered to a large portion of the postradiation changes in a patient who previously underwent
brain. The effects can be acute or delayed. Acute effects both IMRT and stereotactic radiotherapy for cerebral metastases
occur during treatment or shortly after completion of from breast carcinoma. © Barrow Neurological Institute.
538 Therapeutics for the Geriatric Neurology Patient
It is traditionally used after completion of RT. The addi-
tion of chemotherapy to RT in malignant glioma has
been shown to prolong survival by up to 6 months.
Temozolomide (Temodar), an alkylating agent, is cur-
rently the most effective chemotherapy for treatment of
malignant glioma. Clinical trials are currently under-
way to assess the adjunctive use of other chemotherapy
agents such as bevacizumab (Avastin), although the
efficacy of this use has not yet been established. Pri-
mary CNS lymphoma is another malignant primary
brain tumor whose management combines systemic
and intrathecal chemotherapy with RT. Methotrexate is
often employed. In some cases, an Ommaya reservoir
may be of benefit. Clinical studies show that elderly
patients tolerate intensive chemotherapy well, although
prognosis remains poor, with an average survival of
only 1 year (Nayak and Iwamoto, 2010). Chemotherapy
can also be considered for control of both CNS and
active systemic metastatic disease.
The decision to initiate treatment for a brain tumor in
an elderly person should be based not only on age, but
also on life-expectancy, performance status, the presence
or absence of neurologic deficits, the extent of systemic
disease, if any, and coexistent chronic illnesses. These fac-
tors determine the surgical risk in deciding for resection
or biopsy, as well as whether to consider radiosurgery in
addition to standard external beam RT. Given the impact
of the brain tumor and its treatment on both the cognitive
and physical abilities of the patient, the goals of therapy
must always include improving performance status and
minimizing treatment side effects. For elderly patients
with malignant glioma who have a poor long-term prog-
nosis, conventional fractionation or hypofractionation RT
provides palliation and can improve the quality of life
over the short term. Furthermore, physical therapy and
occupational therapy can be utilized to help support a
patient’s ability to perform activities of daily living. At all
stages, the nature of the tumor and the prognosis must be
Figure 22.10 The classification system of Anderson and D’Alonzo. Type I: Fracture through the tip, above the transverse ligament. Rare;
represents less than 5% of cases. Type II: Fracture through the base of the neck. Most common; occurs in >60% of cases. Type III: Fracture
through the body of C2. Occurs in 30% of cases. © Barrow Neurological Institute.
discussed with the patient and the family in a manner that
would neither discourage therapy nor raise false hope.
The involvement of the patient and family in the manage-
ment decision process creates a support system for the
patient. After options are discussed, the patient should be
allowed to make the informed choice whenever possible.
Odontoid fractures
Odontoid fractures are the most common cervical frac-
tures in the elderly. Gait and balance problems, as well
as decreased bone density predispose older patients to
these types of fractures. An odontoid fracture is a fracture
through the second cervical vertebra (also known as C2 or
the axis). In younger patients, this type of injury is usually
sustained in a motor vehicle accident or other high-force
mechanism. In the elderly, however, a simple fall in which
the patient strikes the forehead and sustains a hyperex-
tension injury may produce this type of fracture. Patients
often present with neck pain and, barring other injuries,
are neurologically intact.
Odontoid, or dens, fractures are classified into three
types, with Type I fractures occurring through the tip of
the dens, Type II fractures occurring at the base of the
dens, and Type III fractures occurring through the body
of the axis (Figure 22.10) (Anderson and D’Alonzo, 1974).
Type IIA fractures, described by Hadley and colleagues
(1988) involve a comminution at the base of the odontoid
process. Type II fractures are by far the most common and
represent 8–15% of all cervical fractures. Type IIA frac-
tures represent 5% of all Type II fractures, are considered
highly unstable, and are usually managed with early pos-
terior surgical fixation.
CT and plain radiographs are standard in the initial
diagnosis of bony injuries such as odontoid fractures
(Figure 22.11a). For the complete diagnostic work-up,
as well as for treatment planning, MRI is essential in

(a)
Figure 22.11 (a) CT of cervical spine,
sagittal view, demonstrating a Type II
fracture through the dens with posterior
displacement. (b) MRI of cervical
spine, gradient echo sequence, axial
view, demonstrating the transverse
atlantal ligament (TAL). It appears as a
homogenous, thick, low-signal intensity
structure (arrow) that extends between the
medial portions of the lateral masses of C1.
© Barrow Neurological Institute.
assessing the spinal cord, as well as for evaluating the
status of ligamentous structures such as the transverse
atlantal ligament (TAL) (Figure 22.11b). TAL disruption
occurs in 10% of patients with odontoid fractures (Greene
et al., 1994) and the integrity of this structure is important
in selecting the appropriate treatment. For example, ante-
rior odontoid screw fixation will not provide stability if
the TAL is disrupted. In addition, odontoid fractures have
been seen in association with occipitoatlantal dislocation,
and MRI will assist in evaluating for this type of injury.
Finally, when a C2 fracture is identified, it is important to
evaluate the subaxial spine, as 16% of patients will have a
noncontiguous fracture.
Type I and III dens fractures are stable injuries that can
be treated with a hard collar. Treatment paradigms for Type
II fractures, however, remain controversial. Nonoperative
management (nonOP) options include rigid cervical ortho-
sis (hard collar) or rigid immobilization after reduction in
a halo vest. Studies, however, have revealed a nonunion
rate of 35% with nonOP of Type II fractures. Risk factors for
nonunion include increasing age, subluxation greater than
5 mm, and any significant posterior subluxation.
Elderly patients are uniquely susceptible to the com-
plications of conservative management because of the
morbidities associated with prolonged immobilization in
a halo vest, as well as the physiologic hurdles associated
with the injury. These include edema of the upper cervical
region, resulting in difficulties with swallowing and air-
way protection, and subsequent pulmonary compromise
or aspiration. Risks also are associated with prolonged bed
rest, pin site care, personal hygiene, pressure sores under
the vest, balance and gait impairment, and increased falls
(Tashjian et al., 2006). Finally, halo vest usage can signifi-
cantly limit respiratory function by impairing total vital
capacity (Lind et al., 1987). Recent studies revealed higher
rates of pneumonia, cardiac arrest, and death in patients
treated with a halo vest, as compared to patients treated
with cervical orthosis or operative fixation (Tashjian et al.,
Neurosurgical Care of the Geriatric Patient 539
(b)
2006). In addition, halo vest-treated patients had morbid-
ity and mortality rates of 66% and 42% versus rates of 36%
and 20% in nonhalo vest-treated patients (Tashjian et al.,
2006).
External immobilization is considered as a treatment
option in the initial management of all odontoid frac-
tures. Next, consideration is given to the factors involved
in determining whether a patient will benefit from
operative management. Advanced age and significant
comorbidities usually deem a patient as too high risk for
operative intervention. Hence, conservative management
is selected. After discharge, patients are evaluated on
an outpatient basis for evidence of fusion and are main-
tained in either a rigid cervical orthosis or a halo vest until
successful fusion is achieved. If there is no radiographic
evidence of fusion after a period of several months (aver-
age 3–4 months), operative fixation is considered.
For patients with dens displacement of greater than
5 mm, comminution of the odontoid fracture (Type IIa),
disruption of the TAL, or inability to achieve or maintain
fracture alignment with external immobilization, conser-
vation management is unlikely to be successful. Surgical
management must be considered instead (Greene et al.,
1997).
Surgical fixation can be performed through either an
anterior or posterior approach. Options for posterior fixa-
tion include C1–2 wiring, C1–2 transarticular fixation, or
C1 lateral mass–C2 pars/pedicle screw fixation. Though
extremely effective in the treatment of odontoid fractures,
posterior fixation also leads to loss of C1–2 axial rotation.
For this reason, many surgeons use the posterior approach
only when the anterior approach is contraindicated.
Anterior odontoid screw fixation has several advan-
tages over posterior fixation. Immediate stabilization
is achieved with single screw placement (Figure 22.12).
No bone graft is required and there is no need for post-
operative halo immobilization. Contraindications to the
procedure include osteoporosis or osteopenia, barrel
540 Therapeutics for the Geriatric Neurology Patient
Figure 22.12 Schematic of a Type II odontoid fracture repaired
through anterior odontoid screw placement. © Barrow
Neurological Institute.
chest from severe chronic obstructive pulmonary disease
or emphysema, and cervicothoracic kyphosis. It is not
recommended in patients with nonreducible fractures,
nonunion longer than 3 months, fractures associated
with transverse ligament rupture, fractures that require
flexion for reduction, and oblique fractures oriented from
anterior–inferior to posterior–superior.
After discharge from the hospital, patients are seen
in clinic on a regular basis and assessed for progress of
fusion with radiographic imaging. A recent study reported
a fusion rate of 77% with anterior screw fixation in the
(a) (b)
Figure 22.13 Various constructs for posterior fixation. (a) C1–2 interspinous wiring. (b) C1–2 transarticular fixation with wiring. (c) C1 lateral
mass–C2 pars/pedicle screw fixation. © Barrow Neurological Institute.
elderly; mean time to fusion was noted at 17.1  weeks
(Collins and Min, 2008).
Complications of anterior odontoid screw fixation
include tracheal or esophageal injury, vascular injury,
hemorrhage, infection, significant dysphagia, and the
operative morbidity and mortality related to general
anesthesia and surgery in an elderly and compro-
mised population. In one study, up to 25% of patients
required feeding-tube placement, and 19% developed
aspiration pneumonia in the immediate postoperative
period (Dailey et al., 2010). Furthermore, there are the
possibilities of nonfusion, suboptimal screw place-
ment, inadequate fracture reduction, poor capture of
the distal fracture fragment, and screw breakout (due
to poor bone density, the screw fractures through the
cortex of the dens). In these cases, a posterior fusion is
required.
In a systematic review of the literature, the most
commonly reported medical complications following
odontoid fracture surgery in the elderly included cardiac
failure (6.8%), deep venous thrombosis (3.2%), stroke
(3.2%), pneumonia (9.9%), respiratory failure (7.7%), liver
failure (6.7%), and severe infection (3.2%) (White et al.,
2010). The overall mortality rate after surgery was noted
at 10.1% (in hospital 6.2%; postdischarge 3.8%). Similar
mortality rates and rates of airway complications were
reported following both anterior and posterior surgery.
Notably, however, there were higher rates of site-specific
complications, including nonunion, technical failure, and
need for revision surgery, following anterior surgery as
compared with posterior surgery.
For posterior fixation, several procedures can be
employed successfully, depending on the patient’s anat-
omy. Options, as mentioned previously, include C1–2 wir-
ing, C1–2 transarticular fixation, and C1 lateral mass–C2
pars/pedicle screw fixation (Figure 22.13). These tech-
niques require the harvest of bone graft, either from the
iliac crest or a posterior rib, and each leads to the loss of
C1–2 axial rotation. Considerations prior to posterior fix-
ation include evaluation for aberrant or ectatic vertebral
arteries, dysmorphic C1–2 anatomy, or previous vertebral
(c)

artery injury or occlusion. Studies in elderly patients
65 years and older report an 86% rate of successful fusion
after posterior C1–2 arthrodesis (Campanelli et al., 1999;
Andersson et al., 2000).
Complications with posterior fixation include malalign-
ment, poor screw position, vertebral artery injury, spinal
cord or nerve root injury, infection, hemorrhage, and the
risks associated with anesthesia and surgery in an elderly
and compromised population.
Several studies have analyzed the different properties
and outcomes between patients who underwent surgical
fixation versus those who received conservative treatment,
to establish a definitive treatment paradigm for odontoid
fractures in the elderly. One recent study reviewed the
management of 108 elderly odontoid fracture patients
(Fagin et al., 2010). The patients were classified as either
“early operative management” (<3 days, early OP), “late
operative management” (>3 days, late OP), or “nonOP”.
The nonOP patients were predominantly treated with cer-
vical orthosis (64 of 68). These patients were found to be
significantly older than the patients within the OP groups
(mean 82.4 years vs. 77 years) and had shorter hospital
lengths of stay and fewer ventilator days than their oper-
ated counterparts. This was thought to be related to (1)
increased edema around the airway and esophagus fol-
lowing surgery, resulting in longer ventilator times and
problems with dysphagia after extubation, and (2) longer
periods of time before mobilization. Furthermore, both
operative groups underwent tracheostomy and percu-
taneous endoscopic gastrostomy (PEG) two times more
frequently than the nonOP patients and had an increased
risk of deep vein thrombosis (DVT). Otherwise, there
were no differences between the two groups in the devel-
opment of urinary tract infection or pneumonia, or per-
centage of patients discharged to skilled nursing facility
after treatment.
Drawing conclusions on the proper management of
the elderly with odontoid fractures is difficult because
study findings across the board have been extremely
variable, with some groups actually reporting increased
mortality with nonOP treatment of odontoid fractures
(Muller et al., 1999; Smith et al., 2008; Pal et al., 2010).
In addition, the study groups tend to be small and the
follow-up in most studies has been lacking. As an exam-
ple, in the study reviewed, clinical or radiographic fol-
low-up was available on only 50% of the patients (Fagin
et al., 2010). Although complication profiles for nonOP
patients appeared better than for OP patients, the out-
comes for nonOP patients were often not ideal. In Fagin
et al. (2010), two (2.9%) nonOP patients subsequently
required posterior fixation for fracture instability, 16
(23.5%) patients had increasing angulation and narrow-
ing of the spinal canal on follow-up, and four (5.9%)
patients had persistent nonunion. This is compared
with three (7.5%) OP patients whose surgeries were not
Neurosurgical Care of the Geriatric Patient 541
completed and who continued with nonOP manage-
ment and one (2.5%) OP patient who required a halo vest
after surgical fixation.
Thus, the jury is still out on the appropriate management
of odontoid fractures in the elderly. A reasonable treat-
ment algorithm is for placement in a collar for (1) fragile
patients with numerous comorbidities for whom surgery
would pose a grave risk, and (2) patients with adequate
alignment and intact ligamentous structures. If the frac-
ture is unstable or unlikely to fuse in proper alignment,
surgical management is preferred. Halo vest placement
should be approached with caution in the elderly popula-
tion, given the risks noted earlier.
Compression fracture
Along with odontoid fractures, vertebral body com-
pression fractures are extremely common in the elderly
population. Because the vast majority are associated with
osteoporosis, often very little force is required to gener-
ate these painful fractures. Collapse of the vertebral body
can lead to loss of height, progressive kyphotic defor-
mity, and, if a fragment of bone is dislodged posteriorly,
spinal cord or nerve root compromise. With progressive
kyphotic deformity, patients can develop a “dowager’s
hump” and impaired respiratory function in the form of
decreased vital capacity.
Osteoporotic compression fractures most commonly
involve the lower thoracic or upper lumbar vertebral lev-
els. Occasionally, they are asymptomatic and incidentally
discovered on routine imaging. At other times, the pain
has been present for years and is disabling. Most often,
however, patients report an acute onset of pain that is
localized at the midline within the thoracolumbar region;
the pain is exacerbated by standing, sitting, or walking;
and is relieved by lying down. The pain is aching or stab-
bing in quality and very severe. On physical examination,
patients may also complain of moderate point tenderness
to palpation along the spinous process.
In addition to those related to osteoporosis, vertebral
compression fractures in the elderly can be due to tumor
infiltration. Most commonly, metastatic disease from the
breast, lung, kidney, or prostate is responsible. Mela-
noma, multiple myeloma, or lymphoma can also manifest
as spinal pathologic fractures. In the event that the pri-
mary tumor is unknown, a biopsy is often required before
definitive treatment is undertaken.
Lastly, vertebral compression fractures can result from
infection. Systemic infection can seed the intervertebral
disc and then spread to the bone, leading to osteomy-
elitis. Severe pain is the hallmark symptom. With spinal
tuberculosis, or Pott’s disease, the disc spaces are usu-
ally spared and a compression fracture can be the initial
presentation.
542 Therapeutics for the Geriatric Neurology Patient
With regard to the diagnostic workup, most thoraco-
lumbar pain is initially evaluated with either plain radio-
graphs or CT of the spine (Figure 22.14a). CT can reveal
the degree of cortical bony disruption and deformity
due to the fracture and is useful in treatment planning.
In many patients, imaging can reveal several compres-
sion fractures. It is important to elucidate exactly which
compression fracture is the source of the pain—or, rather,
which fracture is “most acute.” For this purpose, MRI is
very valuable, and either T2-weighted images or short-
tau inversion recovery sequences (STIR) may be used
(Figure 22.14b). In these sequences, the unhealed or acute
fractures appear hyperintense. In addition, MRI provides
the best visualization of the neural and ligamentous
structures. In the case of suspected pathologic fracture
(tumor involvement) or possible infection, postcontrast
sequences are important for the complete workup. For
patients with pacemakers who cannot undergo MRI, the
test of choice is the bone scan. Acute fractures will show
increased uptake of the tracer as compared with healed
fractures.
The physical examination is essential in formulat-
ing the treatment plan. It is important to determine the
degree of disability that the fracture confers on patients
and their ability to perform activities of daily living. The
interview should aim to address these concerns, as well as
assess the patient’s level of pain. Next, a thorough assess-
ment of the patient’s lower extremity, bowel, and bladder
function must be made. Lastly, in the case of osteoporotic
fractures, it is important to confirm that the patient is on
(a) (b)
Figure 22.14 (a) CT of the thoracic spine, sagittal view. T7 compression
fracture with loss of height. (b) MRI, STIR sequence, sagittal view. T7
compression fracture. STIR demonstrates edema within the vertebral
body, suggesting an acute fracture. © Barrow Neurological Institute.
appropriate medical treatment for the osteoporosis. Med-
ications can include bisphosphonates, selective estrogen
modulators, antiosteoporotic agents such as calcitonin,
and recombinant parathyroid hormone.
Several options exist for the management of acute,
painful compression fractures. Surgical treatment is nec-
essary in the case of neurologic compromise, instability, or
severe deformity. Surgery is also indicated if conservative
management has failed and there is continued disabling
pain or progressive kyphotic deformity on serial imaging.
The goals of treatment are pain control and restoration of
mobility.
Nonoperative treatment consists of pain manage-
ment, bracing, and rehabilitation. Pain management can
be achieved with a variety of medications. Though pain
control is essential, in the elderly, it is important to avoid
overmedicating patients, as this can result in sedation,
respiratory depression, severe disorientation, and con-
stipation. Patients are frequently placed into customized
thoracic–lumbar–sacral orthoses (TLSO) to help with pain
control during mobilization. If pain control is adequate,
some patients can be treated in less restrictive corsets or
abdominal binders. Lastly, and most importantly, patients
are mobilized as quickly as possible. Physical and occu-
pational therapists are heavily involved in treatment;
if necessary, patients undergo a course of therapy in an
acute inpatient rehabilitation center before transitioning
to outpatient therapy. Weight-bearing exercises are the
main types of exercises involved and are believed to slow
the progression of osteoporosis. A strong focus is made
on keeping the patient as mobile and independent as pos-
sible, to avoid the complications associated with immo-
bility. These complications include pneumonia, DVT,
pulmonary embolism, skin breakdown, and gastric ulcer-
ation. The brace is worn for 1–3 months, and follow-up
plain radiographs are obtained during this period. If pro-
gressive kyphotic deformity is noted in comparison with
prior images, or if the patient continues to have uncon-
trolled pain and impaired quality of life, surgical inter-
vention is indicated.
Vertebroplasty and kyphoplasty are minimally inva-
sive, percutaneous procedures in which a biologic cement
is injected into a pathologic vertebral body to relieve pain
and disability. Vertebroplasty was first introduced in
France in 1984 and used as a technique to treat symptom-
atic vertebral hemangiomas (Galibert et al., 1987). It was
found that the support provided by the hardened poly-
methylmethacrylate (PMMA) resulted in substantial pain
relief. Surgeons expanded the use of this technology to
include the treatment of pain from myeloma and meta-
static neoplasms of the spine. Today in the United States,
the primary use of vertebroplasty is the treatment of pain
from osteoporotic compression fractures. Kyphoplasty
was introduced in 1999 by Kyphon, Inc. It involves intro-
ducing an inflatable balloon into the collapsed vertebral
 Neurosurgical Care of the Geriatric Patient 543

(a) (b)

Figure 22.15 (a) AP and (b) lateral

fluoroscopic views during L1 vertebroplasty.
The needle has been introduced through
the right pedicle into the vertebral body
for injection of the cement. © Barrow
Neurological Institute.

body. After inflation of the balloon, the cement is injected Inflation continues until (1) the kyphotic deformity is
directly into the balloon, with the goal of restoring verte- corrected, (2) the balloons reach the cortical margins,
bral body height and spinal alignment. or (3) the system reaches a maximum pressure of 300
The indications for either procedure are for the treat- psi or maximum balloon volume. The balloons are then
ment of painful, unhealed compression fractures. Con- deflated, and the cement is carefully injected under fluo-
traindications to treatment include systemic or spinal roscopic imaging.
infection, uncorrected bleeding disorder, inability to tol- Prognosis is very good with both procedures, with
erate sedation or general anesthesia, inability to tolerate many patients reporting excellent relief of pain in the
the prone position, and fracture instability. Spinal canal recovery room (Gill et al., 2007; Tang et al., 2010). Both
compromise due to the fracture is also a contraindication procedures have very low risks of mortality and morbid-
to the procedures. Even if there is no clinical evidence of ity. Careful attention to bony landmarks is essential, as
radiculopathy or myelopathy, the risk is increased that one is working near the spinal cord and aorta. Cement
even a small leakage of cement posteriorly during injec- leakage is common and must be monitored carefully
tion will lead to neurologic compromise. (Figure 22.16). If the leakage results in nerve root compro-
For either procedure, medical clearance is necessary to mise, patients can initially be treated with a short course
ensure that the patient can tolerate sedation and/or gen- of steroids or nerve root block. If symptoms do not abate,
eral anesthesia. The patient is placed in the prone position surgical decompression is necessary. If leakage results in
on a padded operating table. The correct vertebral level spinal cord compromise, decompression is mandatory. If
is identified, and a needle is used to pierce the skin and the cement leaks into perivertebral veins, there is a very
enter through the pedicle into the vertebral body. Next, small risk of pulmonary embolus (Radcliff et al., 2010).
the PMMA cement is mixed with sterile barium sulfate
powder so that it is radio-opaque, and is injected under
continuous visualization (Figure 22.15). Posterior leakage
of cement is to be avoided, as is intradiscal or venous
leakage. The endpoints for injection are (1) leakage of
cement beyond the marrow space, (2) cement reaching
the posterior quarter of the vertebral body, and (3) the
cement filling the vertical height of the vertebral body
and extending across midline. The patient is monitored
in the recovery room for 2–3 hours and then allowed to
attempt ambulation. If there is no increased pain or dis-
ability, the patient is discharged home with instructions
to limit activity for 3 days.
The kyphoplasty procedure is similar, although, due to
its longer duration, it is almost always performed under
general anesthesia. A large cannula is introduced into
the pedicle, and a small hand-operated drill bit is used
to drill into the vertebral body. A deflated balloon is then
advanced into the created cavity and slowly inflated with Figure 22.16 Lateral fluoroscopic view demonstrating anterior
iodinated contrast. Usually this procedure is performed leakage of cement after L4 vertebroplasty. © Barrow Neurological
bilaterally, and both balloons are inflated simultaneously. Institute.
544 Therapeutics for the Geriatric Neurology Patient
Other procedure risks include infection, hematoma, and
pedicle fracture.
An analysis of the natural history of vertebral com-
pression fractures has revealed that the majority will
heal within 6–12 months with conservative management.
Klazen et al. found that, with bracing and pain man-
agement, 63% and 69% of patients had significant pain
relief at 6 and 23 months, respectively. However, nearly
one-third of patients still had severe pain at 23 months.
In studies comparing vertebroplasty with conservative
management, vertebroplasty-treated patients consis-
tently had significantly reduced pain scores, decreased
use of analgesics, more rapid return to normal function,
and lower rates of hospitalization, as compared with con-
servatively treated patients (Diamond et al., 2006; Klazen
et al., 2010; Wang et al., 2010). However, the differences
in status between the two treatment groups were lost by
12 months of follow-up.
These findings are logical in light of the natural history
of compression fractures. Nonetheless, many clinicians
are moving away from the initially published guidelines
recommending 3–6 weeks of conservative therapy in
favor of early intervention. For patients in severe, dis-
abling pain, vertebroplasty and kyphoplasty are safe
treatment modalities that can be used to immediately
reduce pain, facilitate early mobilization, and minimize
the risks of immobility in the elderly population afflicted
with these fractures.
Pain: trigeminal neuralgia
Facial pain can be a challenging problem to both diagnose
and treat. The most common and treatable form is trigem-
inal neuralgia (TGN). Although facial pain syndromes
are prevalent in both younger and geriatric populations,
the medical comorbidities of older patients often lead to
greater consideration of the full spectrum of conserva-
tive treatment options before surgical management is
proposed.
Natural history
Facial pain syndromes have been described throughout
history. One of the earliest descriptions was written in the
eleventh century by the Arab physician Jurjani (Ameli,
1965). In 1829, Bell delineated the anatomy of the fifth
cranial nerve which was recognized as responsible for
facial sensation and innervation of the muscles of mas-
tication. Treatment options for facial pain were limited
and ranged from various ointments to cleansing of the
gastrointestinal tract. In 1853, Trousseau noted the par-
oxysmal nature of a particular kind of facial pain, which
he likened to a seizure of the trigeminal nerve. Thus, for
a time, the disorder was known as neuralgia epilepti-
form. The introduction of antiepileptic medications in
the mid-1900s provided the first effective medical treat-
ment for TGN.
Patients with TGN tend to present with the following
symptoms: (1) paroxysmal, “electric” pain in the trigemi-
nal distribution on one side of the face; (2) trigger points
on the face that, when stimulated, initiate this type of
pain; (3) periods of remission and exacerbation; (4) pain
that is worse in the mornings and absent during sleep;
and (5) temporary pain relief when treated with an ade-
quate dose of carbamazepine. Wind on the face, talking,
eating, brushing of the teeth, and shaving often precipi-
tate symptoms along one or more divisions of the trigemi-
nal distribution.
TGN predominantly occurs in people over the age of 50,
although the younger population can also be affected. Some
reports suggest a female predominance as high as 2:1. The
condition can affect either side of the face and any division
of the trigeminal nerve, though most often the V2 (max-
illary) or V3 (mandibular) division, or both, are involved
(Figure 22.17). Findings on the neurologic examination and
imaging studies are usually unremarkable. However, vas-
cular anomalies, multiple sclerosis, and tumors of the cer-
ebellopontine angle can also produce TGN. Therefore, MRI
of the brain, with and without contrast, is an essential part
of the diagnostic workup for facial pain.
The exact mechanism underlying TGN is unclear.
Autopsy studies reveal demyelination of the large-diameter
Trigeminal (Gasserian) ganglion
Figure 22.17 Schematic of the trigeminal nerve and its three
divisions, V1, V2, and V3, and their respective sensory territories.
Ophthalmic (blue V1); maxillary (red V2); mandibular (pink V3).
© Barrow Neurological Institute. (For a color version, see the
color plate section.)

A fibers found at the root entry zone of the fifth cranial
nerve into the brainstem. One hypothesis is that demyelin-
ation leads to erratic signal transduction to poorly myelin-
ated A delta and unmyelinated C fibers, which results in
paroxysmal facial pain. It is thought that the demyelination
is most often related to compression at the root entry zone
by a vascular structure, either an artery or a vein. Nonethe-
less, autopsy studies have demonstrated both the absence
of compression in patients with TGN and instances of obvi-
ous compression in patients without TGN.
Diagnosing TGN can be difficult, especially when it
manifests with atypical features that do not conform to
the usual presentation. The differential diagnosis of facial
pain includes entities that range from postherpetic neu-
ralgia, to multiple sclerosis, to head and neck cancers, to
giant cell arteritis. Hence, it is important to secure a clear
description of the pain from the patient before initiat-
ing any form of treatment. After the diagnosis of TGN is
made, several options are available for treatment.
Medical therapy
Carbamazepine, a tricyclic drug related to the antidepres-
sant imipramine, is currently the drug of choice for man-
aging TGN. The initial response of TGN to carbamazepine
is fairly universal; hence, a lack of response to the drug
should lead to a reassessment of the diagnosis. Initially,
most patients respond well to carbamazepine. Some
patients, however, are unable to tolerate the side effects,
which include somnolence, dizziness, nausea, impaired
memory, peripheral neuropathy, and nystagmus. These
side effects occur most commonly in the elderly and
with increases in dosage. Dermatologic reactions occur in
5–10% of patients and include rash, erythema multiforme,
and Stevens–Johnson syndrome. Hematologic side effects
of carbamazepine are rare but include aplastic anemia.
Hence, regular hematologic studies are recommended
for monitoring while on this medication. Very rare side
effects include hyponatremia, hepatotoxicity, and conges-
tive heart failure.
Long-term studies have shown a gradual decline in the
efficacy of carbamazepine over time. The initial response
rate is almost 80%; however, 10 years after the start of
therapy, only about 50% of patients note any relief with
treatment. After carbamazepine is ingested, peak blood
levels are achieved within 2–8 hours. At first, there is a
linear relationship between dose and plasma level; with
chronic treatment, however, there is auto-induction of the
hepatic metabolic system. Hence, the elimination half-
life reduces from 20 to 40 hours to as short as 11 hours in
the blood stream. This leads to fluctuations in the serum
concentration of the drug, which, in turn, influences drug
efficacy and side effects.
If carbamazepine therapy fails, other options include
phenytoin, baclofen, clonazepam, sodium valproate,
oxcarbazepine, pregabalin, and a combination of these
Neurosurgical Care of the Geriatric Patient 545
medications. The drugs should be titrated until pain relief
is achieved or until side effects become intolerable. If
medication therapy is ineffective or poorly tolerated, neu-
rosurgical referral should be considered.
Surgical treatment
A range of surgical options must be tailored to the indi-
vidual patient. These options include direct percutaneous
injury to the Gasserian ganglion (such as thermal rhi-
zotomy, glycerol rhizolysis, or balloon compression), ste-
reotactic radiosurgery, and microvascular decompression
(MVD). Percutaneous rhizolysis and stereotactic radio-
surgery are the treatments most often offered to older
patients for whom medical therapy has failed. However,
for patients with good life expectancy and low medi-
cal risk for surgery, retrosigmoid craniotomy for MVD
remains the preferred option.
Percutaneous procedures
In 1965, the first modern percutaneous modality for the
treatment of TGN was developed. It involved using a
probe to thermocoagulate the trigeminal nerve rootlets
to differentially injure the pain fibers. In this manner, the
overall sensory input to the demyelinated root entry zone
is reduced, resulting in pain relief.
For the procedure, patients lie supine on the operating
table and are sedated only to a degree such that they can
awaken rapidly during the procedure. A spinal needle is
placed through the cheek using standard landmarks and
directed toward the foramen ovale (Figure 22.18). Once
engaged, the fibers are stimulated with the patient awake
to determine the exact area to be targeted. The patient is
then resedated and a series of lesions are made with the
thermocoagulation probe. The goal of the procedure is not
complete analgesia, but rather dense hypalgesia. Patients
should still be able to feel that a safety pin is sharp against
their skin, but the sensation should be dulled. During the
procedure, the presence of the blink reflex, both direct and
consensual, is assessed repeatedly. Loss of the blink reflex
is associated with a risk of corneal ulceration.
Complications or problems with the procedure include
confusion and difficulty in communicating with the
elderly, sedated patients, and loss of the airway. In addi-
tion, complete facial sensory loss, diminished corneal
reflex, keratitis, and, rarely, visual loss, are also risks of
the procedure. In general, the success of the procedure is
related to the level of analgesia achieved. The rate of initial
and immediate pain relief is high—almost 99%. However,
several large studies have shown that the durability of
pain relief is highly variable, with results as good as 90%
or as poor as 40% at 5 years of follow-up (Broggi et al.,
1990; Taha and Tew Jr., 1996; Kanpolat et al., 2001; Tatli et
al., 2008). Glycerol rhizotomy is now regarded by many
546 Therapeutics for the Geriatric Neurology Patient
Trigeminal (Gasserian)
ganglion
V1
V2
Foramen ovale
V3
Stylet entry into the cheek
Figure 22.18 For the percutaneous procedures, a spinal needle
or cannula is introduced through the cheek using standard
landmarks: 2.5 cm lateral to the angle of the lip, 3 cm anterior to
the external auditory meatus, and just below the medial aspect of
the pupil. When the foramen ovale is engaged, the patient usually
winces, and the surgeon can feel the cannula enter the foramen.
© Barrow Neurological Institute.
as the first-line percutaneous treatment modality after
failure of medical therapy in the elderly. For this proce-
dure, a spinal needle is introduced through the cheek into
the foramen ovale. A mixture of sterile glycerol and tan-
talum (for permanent marking of the cistern) is injected.
The patient is kept seated upright with the head slightly
flexed for 1 hour. Afterward, the glycerol is evacuated.
The rates of early pain relief are high, at nearly 90%,
with 50% of patients achieving immediate pain relief and
the other 50% achieving pain relief within 2 weeks. None-
theless, the median time to recurrence of pain is noted at
16–36 months.
Finally, percutaneous balloon compression is consid-
ered a secondary treatment option for those who have
failed both medical treatment and other percutaneous
modalities. The procedure is performed under general
endotracheal anesthesia or, rarely, with intravenous anes-
thesia as well as local anesthesia at the level of the gan-
glion. A cannula is advanced through the cheek toward
the foramen ovale. The cannula stylet is then removed
and replaced with a balloon catheter. The balloon is
inflated to 1.3–1.5 atmospheres for 60–120 seconds. The
balloon is then deflated, and the needle and catheter are
removed simultaneously. The entire procedure takes less
than 20 minutes and is usually performed on an outpa-
tient basis.
After the procedure, patients must be warned of the
risk of herpetic eruptions, be instructed on eye care, and
be tapered off the anticonvulsant medications for their
TGN. The initial success rate ranges from 78% to 100%,
with a mean time to recurrence of 3.5 years (Lichtor and
Mullan, 1990; Skirving and Dan, 2001).
In the older population, many factors must be con-
sidered, such as anticoagulation for atrial fibrillation,
coronary disease, and stroke prevention. For these per-
cutaneous procedures, the risk of hemorrhage is very
low. Thus, patients may not need to be reversed off their
medications for very long periods of time. These consid-
erations must be made in conjunction with the patient’s
cardiologist or internist.
Stereotactic radiosurgery
Stereotactic radiosurgery is an excellent, noninvasive
alternative treatment for elderly patients, especially for
those with cardiovascular disease that necessitates antico-
agulation, as they may continue taking their medications.
First described by Lars Leksell in 1951, radiosurgery is
now a major modality for treating TGN, targeting the root
entry zone of the fifth cranial nerve adjacent to the pons
and minimizing irradiation of the brainstem. The most
established modality is gamma knife radiosurgery, which
delivers precise radiation using intersecting beams from
multiple radioactive cobalt sources. A number of other
commercially available linear accelerator-based systems
are available. Treatment planning is performed jointly
by a radiation oncologist, neurosurgeon, and medical
physicist.
For the procedure, the patient’s head is placed into a ste-
reotactic coordinate frame, and contrast-enhanced T1- and
T2-weighted MRIs of the brain are obtained. The trigemi-
nal nerve root entry zone is visualized, and a single 4-mm
isocenter is placed adjacent to it, usually 2–4 mm anterior
to the junction of the root and the pons (Figure  22.19).
A median prescription dose of 75 Gy (range 70–85 Gy,
35–42.5  GY at the 50% isodose line) is then delivered to
the nerve root entry zone. The brainstem receives less
than 20% of the dose delivered. Patients are discharged
the same day and informed that pain relief may take up
to 10 weeks. Tapering of pain medications begins once
adequate pain relief is achieved. The best results for ste-
reotactic radiosurgery are obtained with continued use
of pharmacotherapy; consequently, it may not be the best
option for patients who cannot tolerate their medication.
Few publications have reported the long-term follow-up
(average 5 years) of patients who have undergone gamma
knife treatment for TGN. Urgosik et al., presented their out-
comes in 107 treated patients (Urgosik et al., 2005). Initial
pain relief was achieved in 80% of patients after a median
latency of 3 months. However, pain recurred in 25% of
 Neurosurgical Care of the Geriatric Patient 547

(a) (b)

Figure 22.19 (a) Axial and (b) coronal MRIs of

the brain delineate the location (circle) of the
trigeminal nerve entry zone at the level of
the pons. © Barrow Neurological Institute.

patients after a median latency interval of 3 years. In 2009,
Dhople et al., analyzed their long-term results with gamma
knife surgery for TGN (Dhople et al., 2009). Of 95 patients,
initial pain relief was achieved in 81%, with a median time
to pain relief of 2 weeks (range 0–12 weeks). Initial response
rates for patients with no prior surgeries were the same as
those for patients who had undergone prior invasive pro-
cedures (81% vs. 77%, p = 0.42). With long-term follow-up,
however, the authors noted that the rates of freedom from
treatment failure at 1, 3, 5, and 7 years were 60%, 41%, 34%,
and 22%, respectively. Furthermore, response duration was
significantly better for patients with no prior invasive treat-
ment than for those with prior treatment (32 vs. 21 months,
p < 0.02).
The major complication from this procedure is both-
ersome facial numbness, which is reported in 6–20% of
patients. Patients with recurrences may be offered repeat
gamma knife radiosurgery, MVD, or a percutaneous treat-
ment option.
adhesions, and then pieces of shredded Teflon are used
to elevate compressive vascular structures away from the
trigeminal nerve. The most common offending vessel is
the superior cerebellar artery.
The complications of MVD include cerebral or cerebellar
infarction, hearing loss, facial paresis, facial dysesthesia,
CSF leakage, and pseudomeningocele formation. Usual
complication rates are in the middle single digits. Success
rates are very high, with 90% of patients reporting excel-
lent pain relief at 1 year and with 70% remaining pain-
free at 10-year follow-up. Success rates seem to be greater
for patients who have their disease treated earlier in its
course (Barker et al., 1996; McLaughlin et al., 1999; Sindou
et al., 2006).

Microvascular decompression

Posterior fossa exploration with MVD of the trigeminal

nerve is generally considered the best operation for medi-
cally fit patients with TGN. Advantages of MVD include
consistently higher long-term success rates and signifi-
cantly lower rates of facial dysesthesias. Preoperative
testing includes audiometry and otologic examination, as
well as MRI.
For the procedure, a small craniotomy is performed at
the junction of the transverse and sigmoid sinuses, in the
retrosigmoid region (Figure 22.20). The dura is incised
and, under direct microscopic visualization, the cerebel-
lopontine angle is explored (Figure 22.21). The trigemi- Figure 22.20 Left retrosigmoid craniotomy performed at the
nal nerve is visualized and inspected for any evidence of junction of the transverse and sigmoid sinuses. © Barrow
structural compression. The nerve is freed of arachnoid Neurological Institute.
548 Therapeutics for the Geriatric Neurology Patient
Atypical pain
Patients who have progressed to the point at which
they have constant pain that is less “shock-like,” but
rather more burning in character, with associated sen-
sory changes, have developed atypical facial pain.
Some patients begin with pain in this fashion. Whether
chronic or de novo, this type of pain is less likely to
respond to medical or surgical therapy. Atypical facial
pain can be an endpoint for a small number of patients
who have resistant TGN that requires multiple treat-
ments. A final complication of TGN is anesthesia dolo-
rosa, a condition in which the patient is both numb and
subject to constant pain. This condition is highly resis-
tant to treatment of any kind. Motor cortex stimulation
is being explored on an experimental basis for the treat-
ment of this kind of pain; early results appear mixed,
at best.
Many factors must be considered in the care of elderly
patients with TGN. Most importantly, the treatment
modality selected must afford the highest success rate
at the lowest overall risk to the patient. In the absence of
significant medical comorbidities, MVD is an excellent,
durable option. Alternatively, the percutaneous treatment
modalities offer high rates of pain relief with relatively
lower risks, minimal hospital time, and significantly
lower cost. Neurosurgical referral for patients who are
not easily managed with medication alone should be con-
sidered, as many good and effective surgical options are
available.
Figure 22.21 Left retrosigmoid approach.
View of neurovascular structures after
the dura has been opened. Once the
compressive vessel is identified, a Teflon
pledget is placed between the nerve and
offending vessel to achieve decompression.
TS, transverse sinus; SS, sigmoid
sinus; SCA, superior cerebellar artery;
AICA, anterior inferior cerebellar artery.
© Barrow Neurological Institute.
Neurosurgical treatment of
Parkinson’s disease
Movement disorders, including Parkinson’s Disease
(PD) and tremor, have physiologic underpinnings that
are increasingly understood. They frequently affect the
elderly and are amenable to surgical treatment in many
cases. A variety of surgical targets can ameliorate or abol-
ish symptoms with either lesion placement or deep brain
stimulation (DBS). Patient and procedure selection are the
key factors in achieving success.
PD is a motor disorder caused by the loss of dopami-
nergic cells in the substantia nigra pars compacta. Gener-
ally, PD affects people over the age of 50. Symptoms are
initially subtle and progress gradually. Most people pres-
ent with tremor that worsens and begins to affect daily
activities. The four primary symptoms of PD include
(1)  tremor of the hands, arms, legs, jaw, and/or face;
(2) rigidity, or stiffness of the limbs and trunk; (3) bradyki-
nesia, or slowness of movement; and (4) postural instabil-
ity, or impaired balance or coordination. With progressive
disease, patients can develop difficulty with swallowing,
chewing, and speaking; urinary problems or constipa-
tion; skin problems; sleep disturbances; and depression
or emotional changes.
Patients are treated with a variety of medications
that work to either replenish or mimic dopamine in the
brain, often providing dramatic relief from symptoms.
Levodopa and carbidopa help relieve symptoms in 75%

of cases, although not all symptoms respond equally to
treatment. In general, bradykinesia and rigidity are well
controlled with medications; on the other hand, tremor
is often only mildly reduced, and balance issues may not
be affected at all. Other common medications include
anticholinergics, bromocriptine, pramipexole, ropinirole,
amantadine, and rasagiline.
PD is progressive, with symptoms that worsen as more
dopaminergic cells are lost. Medications are often initially
effective. However, as dosages increase to control symp-
toms, so do associated adverse effects. Problems include
dyskinesias, or involuntary excessive movements;
sleepiness; nausea; hallucinations; confusion; cognition
problems; lightheadedness; and behavioral/personality
changes. At some point, when adequate management
with medication is no longer possible, patients consider
surgical options.
The neurosurgical treatment of movement disorders
has been a strong focus of research and effort for more
than a century. Early attempts achieved some success at
symptom control, but at the cost of significant permanent
morbidity and mortality.
Over the last several decades, the techniques for surgi-
cal treatment of movement disorders have continued to
evolve. Surgeons have discovered that (1) bilateral tha-
lamic lesions are associated with significant complications
and (2) electrical stimulation, which is frequently used
for target localization, can itself be used to arrest tremor
and treat bradykinesia and rigidity. With the introduc-
tion of CT and MRI, target localization has become very
precise. Finally, with continued advancements in research
and microelectrode recordings, the targets for stimula-
tion have become more defined. Although much about
how DBS helps to control movement disorders remains
unknown, it is now an accepted and relatively safe treat-
ment option for patients who are failing medical therapy
for their disease.
The single most important factor in ensuring the suc-
cess of DBS is patient selection. To this end, the neuro-
surgeon, neurologist, and neuropsychologist must work
together to ensure that all criteria are met. The ideal can-
didate is a patient with levodopa-responsive idiopathic
PD. Patients should have disabling symptoms, including
bradykinesia, rigidity, and tremor, as well as significant
side effects from medications, such as dyskinesias and
on/off fluctuations.
In the early stages of the disease, it is relatively easy
to achieve periods of good symptom control and mobil-
ity (“on” periods) with medication. However, as the dis-
ease progresses, patients must increase their medication
dosages to maintain control over their symptoms, as well
as take additional medications. At some point, compli-
cations such as increased “off” periods (periods of poor
symptom control), dyskinesias, and troubling side effects
such as sleepiness, nausea, hallucinations, confusion,
Neurosurgical Care of the Geriatric Patient 549
lightheadedness, and behavioral or personality changes
become overbearing. A neurologist with experience in
treating movement disorders must ensure that a patient
has undergone appropriate medical management before
considering surgical intervention. Patients are asked to
keep a diary of their “on/off” periods during the day and
must chart the relationship of these symptoms to the tim-
ing of their medications. The following patient selection
criteria are generally accepted by most movement disor-
der treatment centers:
• Patients should have significant disability despite max-
imal medical therapy.
• Patients should be in generally good health without
significant cardiac, pulmonary, or renal risk factors. In ad-
dition, some centers use the age of 70 years as a cutoff.
• Patients must not be demented or have significant cog-
nitive impairment. They also may not have uncontrolled
psychiatric illness, anxiety, or mood disorders.
• Patients must be able to comprehend the risks of sur-
gery and have reasonable expectations regarding out-
come from surgery.
• Patients should not have severe atrophy or white mat-
ter disease on preoperative imaging, as these findings
may indicate increased risk of intracerebral hemorrhage
or postoperative cognitive impairment.
• Patients who are no longer levodopa-responsive or
who have Parkinson plus syndromes (progressive supra-
nuclear palsy, multisystem atrophy) are poor candidates
for surgery.
Last, with the exception of tremor, symptoms that do
not respond to levodopa are not likely to improve with
DBS.
After patients are accepted as candidates for surgery,
they must undergo medical clearance for the procedure.
Once cleared, the surgery can be scheduled. At many
institutions, a neurosurgeon, a neuroelectrophysiologist,
and a neuroanesthesiologist are present for the entire
procedure.
On the day of surgery, a stereotactic head frame and
base ring and localizer are affixed to the patient’s head
using local anesthetic (Figure 22.22). Next, an MRI is
obtained and targeting is performed using a stereotactic
targeting system and software. The anterior commissure
(AC) and posterior commissure (PC) are identified on
axial images, as well as several other midline structures.
The target coordinates are calculated based on fixed rela-
tionships to these structures. The software then super-
imposes the target onto the corresponding axial, sagittal,
and coronal image slices. Modifications are made if the
target appears too close to critical structures such as the
internal capsule.
When target planning is completed, the surgery
commences. Lead implantation is performed under local
anesthetic, with light sedation administered by the anes-
thesiologist (Figure 22.23). Following the cranial procedure,
550 Therapeutics for the Geriatric Neurology Patient

hardware migration, or erosion of hardware through the

scalp or skin. The incidence of IC hemorrhage ranges from
1% to 5%, although, fortunately, most are small and cause
minimal symptoms. Infection rates range from 3% to 13%.
Superficial infections can often be treated with antibiotics.
Deep infections involving the hardware, however, must
often be treated with debridement and explantation of the
system. Rare complications include death, coma, paralysis,
and medical problems involving the cardiac, respiratory,
or circulatory systems.
A separate operative procedure is usually scheduled
for implantation of the internal pulse generator(s), which
is performed under general anesthesia (Figure 22.24).
Most patients are discharged directly from the recovery
room within a few hours of surgery completion. Patients
are seen in clinic for a wound inspection by the neurosur-
geon 2 weeks following surgery, and by the neurologist
thereafter for programming of the DBS system.
Optimal programming of the DBS system can be time
consuming, as both stimulation parameters and medi-
cation dosage adjustments must be performed concur-
rently. Hence, at most institutions, programming is solely
performed by the neurologist. This allows for a single
physician to be in control of all adjustments and reduces
the number of office visits for the patient. For the initial
Figure 22.22 Patient with head secured in Leksell stereotactic head
programming session, patients are asked to hold their
frame/base ring and localizer. © Barrow Neurological Institute.
medications for at least 12 hours. A baseline motor assess-
ment is then performed, evaluating the patient for tremor,
rigidity, bradykinesia, gait, and postural stability. The
patients remain in the hospital overnight and are released
the following day if they meet discharge criteria. Operative
mortality is less than 1%; overall incidence of complica-
tions is 30%, but most are minor. Complications include IC
hemorrhage, infection, hardware fracture or malfunction,

Figure 22.23 The deep brain stimulation (DBS) lead is inserted

into position using the Leksell stereotactic head frame and the
preoperatively determined coordinates. The final position is Figure 22.24 Schematic of the DBS system, including the
confirmed using microelectrode recordings and intraoperative intracranial stimulation lead, connector cable, and internal
patient assessment. © Barrow Neurological Institute. pulse generator. © Barrow Neurological Institute.

electrodes are then evaluated and programmed. When an
effective program is established, patients are given a dose
of levodopa and observed for dyskinesias. Further adjust-
ments are then made to treat drug-induced dyskinesias.
The goal of programming is to provide maximal thera-
peutic benefit with minimal side effects and with the least
amount of power drain on the battery possible. A wide
range of stimulus parameters is possible, and the device
is externally programmable. Generally, battery life ranges
from 3 to 5 years. Consideration of battery life is impor-
tant, as replacement of the generator requires surgery, and
with each surgery there is risk of infecting the system.
The targets for DBS are continually evolving
(Figure  22.25). Ablation of the ventral intermediate
nucleus (VIM) of the thalamus has been used as a treat-
ment for both essential tremor and parkinsonian tremor
for more than 50 years. As high-frequency stimulation
(>100 Hz) in the same location can also effectively sup-
press tremor without creating many of the deficits associ-
ated with thalamotomy, VIM DBS is now the preferred
treatment for tremor. Long-term results of VIM DBS for
essential tremor reveal an 80% improvement in tremor
and nearly 70% improvement in handwriting (mean
follow-up 56.9 months) (Zhang et al., 2010). Studies also
reveal a slight decrease in effect over time (Blomstedt
et al., 2007), as well as a gradual increase in stimulation
parameters to maintain efficacy of treatment (Zhang et al.,
2010). In general, resting tremor is better controlled with
DBS than action tremor, distal better than proximal/axial
tremor, and upper-extremity tremor better than lower-
extremity tremor. VIM DBS does little to improve rigidity
or bradykinesia in PD patients.
Figure 22.25 Schematic of the commonly
used targets for DBS, including the globus
pallidus interna, subthalamic nucleus,
and ventral intermediate nucleus of the
thalamus and adjacent structures. © Barrow
Neurological Institute. (For a color version,
see the color plate section.)
Neurosurgical Care of the Geriatric Patient 551
The target of choice for PD is the subthalamic nucleus
(STN). STN stimulation can potentially improve all the
motor symptoms of PD, including rigidity, bradykine-
sia, postural instability, and gait. Studies have revealed
a 70–80% reduction in tremor in the off state as well.
Improvements in overall motor function in the off medi-
cation state range from 50% to 74% in most series, but
improvements in the on medication state show little
change (0–26%; Rodriguez-Oroz et al., 2000; Deep Brain
Stimulation for Parkinson’s Disease Study Group, 2001).
Hence, it is important to counsel patients that the results of
DBS will likely be equivalent to their best on conditions, as
most of the benefit from STN DBS comes from reductions
in off states and on/off fluctuations. Finally, STN DBS sig-
nificantly increases on time without dyskinesias, an effect
that may be related to the reductions in levodopa require-
ments after STN stimulation. Studies cite a reduction in
daily levodopa dose by 40–60% after DBS placement
(Rodriguez-Oroz et al., 2000; Deep Brain Stimulation for
Parkinson’s Disease Study Group, 2001; Liang et al., 2006).
Parent et al., recently evaluated the relevance of age
and disease duration in the treatment of PD with STN
DBS (Parent et al., 2010). Forty-six patients were evalu-
ated prior to surgery and at 1-year follow-up. At one
year, patients with both short and long duration of dis-
ease showed significant reductions in dyskinesias: 64%
and 70%, respectively. However, patients with shorter
disease duration (<10 years) demonstrated a significant
reduction in rigidity, whereas those with longer disease
duration (>10 years) failed to show significant improve-
ment (45% vs. 31%, respectively). Both younger and older
patients showed significant improvements in dyskinesias,
552 Therapeutics for the Geriatric Neurology Patient
but those older than age 70 failed to show any significant
change in rigidity at one year follow-up. Hence, in regard
to rigidity, performing early DBS in younger patients may
maximize the benefits of this technology.
Another commonly used target for PD, as well as for
dystonia, is the globus pallidus interna (GPI). With stimu-
lation, improvements in the off state range from 33% to
50% (Ghika et al., 1998; Deep Brain Stimulation for Par-
kinson’s Disease Study Group, 2001). The length of the on
period without dyskinesias increases and on/off fluctua-
tions decrease. Improvements are significant for tremor,
rigidity, bradykinesia, gait, and postural instability. In
regard to comparisons between STN versus GPI DBS for
PD, most studies find both modalities to be effective in
improving motor scores, although anti-PD medications
are reduced only in the STN groups (Anderson et al.,
2005; Moro et al., 2010). Cognitive and behavioral com-
plications, however, are noted only with STN stimulation.
DBS is an accepted, safe treatment for PD, as well as
for essential tremor and some forms of dystonia. To deter-
mine whether a patient is a good candidate for surgery, a
full evaluation by a neurologist who specializes in move-
ment disorders, a neurosurgeon, and a neuropsycholo-
gist must be performed. If all the criteria are met, patients
stand to gain many years of improved function and better
quality of life through this treatment modality.
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 Chapter 23
Treatment of Dementia
23.1 Evidence-Based Pharmacologic Treatment of Dementia
Jasmeet Singh1, Marwan N. Sabbagh2, and Anil K. Nair1

23.2 Immunotherapy for Alzheimer’s Disease

Michael Grundman3, Gene G. Kinney4, Eric Yuen5, and Ronald Black6

1
Alzheimer’s Disease Center, Quincy Medical Center, Quincy, MA, USA
2
Banner Sun Health Research Institute, Sun City, AZ, USA
3
Global R&D Partners, LLC, San Diego, CA, USA
4
Prothena Biosciences, Inc., South San Francisco, CA, USA
5
Janssen Alzheimer Immunotherapy Research & Development, South San Francisco, CA, USA
6
Probiodrug AG, Halle, Germany

Summary
Evidence-Based Pharmacologic Treatment of Dementia
• There are few preventative treatments available in geriatric neurology due to a lack of ability to predict risk and time
frames for each individual.
• Symptomatic treatment is typically effective for a few years.
• Drug treatments for dementia:
• Alzheimer’s disease: Tacrine, donepezil, rivastigmine, galantamine, and memantine.
• Frontotemporal dementia (FTD): No FDA-approved medications currently available. FTD patients are more likely to
use antipsychotics, antidepressants, and sedatives/anxiolytics.
• Dementia with Lewy bodies: No FDA-approved medications currently available. Treatment focuses on hallucination
and agitation management.
• Vascular dementia: No FDA-approved treatments currently available. Prevention of risk factors such as hypertension
is important.
• Parkinson’s disease dementia (PDD): Rivastigmine and donepezil are the widely accepted medications for treatment
of PDD.
• Pseudobulbar affect (PBA): Nuedexta.
Immunotherapy for Alzheimer’s Disease
• Alzheimer’s disease (AD) may be due to a disrupted balance between Aβ production and clearance. Anti-Aβ
immunotherapy may help facilitate clearance using either active or passive immunization.
• Studies show that AD mice treated with anti-Aβ antibodies shown greater cognitive performance compared to control
AD mice. Antibodies against both soluble and insoluble Aβ have been generated and studied.
• AN1792, a full-length Aβ, has been used for active vaccination in clinical studies (phase 1 and phase 2 trials). Subjects
who developed sufficient antibody responses showed a slowing of decline; however, there was an occurrence of
meningoencephalitis (ME). Follow-up studies showed that despite a high degree of plaque clearance in some subjects
at autopsy, progressive dementia still continued. There is also evidence of potential long-term benefits from sustained,
low levels of anti-Aβ antibodies.
• Immunotherapy may be active or passive, each with relative advantages and disadvantages.
• Proposed mechanisms of anti-Aβ immunotherapy include microglial activation, catalytic disaggregation, and the
“peripheral sink.”
• Bapineuzumab is a passive immunotherapy that has completed clinical trials. Many other immunotherapies are also
currently in clinical trials and in development.
• Vasogenic edema (VE) was observed as a side effect. Immunotherapy may be more effective when started earlier
during the preclinical and prodromal phases of AD.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

556
 Chapter 23.1
Evidence-Based Pharmacologic Treatment
of Dementia
Jasmeet Singh, Marwan N. Sabbagh, and Anil K. Nair
Introduction
Lack of effective therapy for geriatric neurologic diseases
such as Alzheimer’s disease (AD) may bankrupt the US
health-care system. Age is a major risk factor for demen-
tia, with risk doubling approximately every 5 years after
age 65—by the age of 85, one’s chances of having demen-
tia due to AD range from 25% to 50% (Alzheimer’s Asso-
ciation, 2010). Prevalence of AD may double every 20
years, due the increase in the average expected life span.
Thirty-five million people worldwide have AD today, and
more than 100 million individuals will have AD by 2050
(Alzheimer’s Disease International, 2010).
For all practical purposes, diagnosing AD is achieved
using clinical criteria, as pathologic criteria cannot be
confirmed in vivo and brain biopsy to achieve diagno-
sis is impractical (Dekosky et al., 1992) due to lack of
FDA-approved biomarkers. Moreover, preclinical AD
criteria defined in 2011 are not yet applicable for clinical
treatment. The DSM clinical criteria focus on the require-
ment for multiple cognitive deficits, including memory
loss, aphasia, apraxia, agnosia, and impaired executive
functioning (Cummings and Benson, 1983). In addi-
tion, functional impairment is a mandatory criterion for
the diagnosis of probable DAT. The positive predictive
value of the National Institute of Neurological and Com-
municative Disorders and Stroke and the Alzheimer’s
Disease and Related Disorders Association (NINCDS-
ADRDA) probable AD category and that of the AD diag-
nosis by DSM-III-R is very high and ranges from 89%
to 100% when validated against an autopsy diagnosis
(Nagy et al., 1998). This makes these tools suitable for
research purposes. The combination of the NINCDS-
ADRDA categories for possible and probable dementia
of the Alzheimer type has a high sensitivity (91–98%) but
lower specificity (40–61%; Knopman, 2002). NINCDS-
ADRDA and DSM criteria incorporate a differential
diagnosis to exclude other conditions presenting similar
clinical symptoms. Computerized tomography (CT) or
magnetic resonance imaging (MRI) scans are used to aid
the physician in assessing the presence or risk of vas-
cular disease (Richter and Richter, 2002). The Hachin-
sky Ischemic Scale (HIS) and Geriatric Depression Scale
(GDS) have been used in key dementia trials to exclude
patients with dementia caused by or complicated by
vascular lesions and depression, respectively (Rosen et
al., 1980). The medical history from the patient (when
possible) and caregiver, laboratory assessments (chem-
istry, hematology, and urinalysis panels), and physical
examination aid the physician in both the diagnosis and
the differential diagnosis. Shorter screening instruments
such as the Mini–Mental Status Exam (MMSE) and the
Montreal Cognitive Assessment (MOCA) are also useful
in a clinical diagnosis of dementia but may lack rigor for
use in research (Olson et al., 2011).
Several key aspects of the pathogenesis of a disease
such as AD remain unknown, but scientific advances
over the last 25 years have provided a growing rationale
for potentially disease-modifying therapies that target
the suspected pathology of the disease. Multiple agents
using cholinergic agonism and partial antagonism of
N-methyl-d-aspartate (NMDA) receptors have gained
FDA approval. Novel strategies with agents addressing
the initiating role of amyloid β–protein (Aβ) aggregates,
tau protein modification, histamine receptor antagonism,
and nicotinic receptor agonism are in clinical trials pres-
ently. Current trial design involves treatment of clinically
symptomatic patients, a setting in which failure to show
efficacy may be even more likely, given the advanced
pathologic state of the disease. Moreover, unclear ratio-
nale for drug therapy, preclinical testing, and the actual
testing of the drug in human clinical trials have been
barriers to effective new drug development over the last
decade.
Types of treatments
Treatments can be divided into primary (preventive
therapy used before onset of clinical symptoms or in the
preclinical stage), secondary (after onset of clinical symp-
toms, subdivided into symptomatic, disease modifying,
or curative), and tertiary (palliative, used to contain the
ravages of the disease and to improve quality of life). In
geriatric neurology in general and dementias in particu-
lar, curative and disease-modifying treatments have been
rare, with most available secondary treatments in the
symptomatic realm.
557
558 Therapeutics for the Geriatric Neurology Patient

Primary prevention or treatment in the
preclinical state
Few preventive treatments are available in geriatric neu-
rology. Moreover, identifying precise disease onset is
problematic using current clinical information, which
may preclude the development of effective preventive
agents. For example, using anti-Aβ therapy in patients
with clinically diagnosed AD may be comparable to treat-
ing patients with myocardial infarction and heart fail-
ure with a statin to lower cholesterol and expecting the
current cardiac function to noticeably improve. In these
late clinical settings when end organs have already been
damaged, treating the pathophysiologic process that is
protracted or triggering the disease is not likely to dem-
onstrate efficacy. Such a treatment trial design would be
akin to measuring mortality as the endpoint for a statin
drug to show efficacy. We now know that statins clearly
lower cholesterol, but it is still challenging to demonstrate
improvement in cardiovascular morbidity and mortality
with these agents. Primary treatments targets in geriatric
neurology face a similar dilemma.
For instance, in AD, despite advances in the ability to
diagnose preclinical AD (Natrini, 2010), a move toward
primary prevention depends on advancing our ability to
predict who is at very high risk for AD and in what time
frame they might develop observable pathology and,
subsequently, clinical symptoms. Age, cardiovascular risk
factors, diabetes, African American race, history of head
injury, APOE E4 genotype, low cerebrospinal fluid (CSF)
Aβ42, and increased positron emission tomography (PET)
amyloid tracer binding in the brain may all increase risk for
the progression of preclinical AD to mild cognitive impair-
ment (MCI) and MCI to AD (Romas et al., 1999; Blennow,
2004; Storandt et al., 2009; De Meyer et al., 2010). But these
risk markers do not provide information regarding onset
of disease pathology, which makes timing of preventive
treatments difficult. Not surprisingly, multiple preventive
interventions in the past have failed in AD (Table 23.1).
Phase 2 and phase 3 trials in geriatric neurology are com-
plicated and resource intensive and have low probabilities
for success. They consume an estimated 48% of the costs
for each drug launched (Paul et al., 2010). Prevention trials
are even more expensive. Due to the prohibitive cost of an
AD prevention trial, only one such industry trial has been
sponsored: a ginkgo biloba extract study in France involv-
ing about 2800 patients over 5 years (Vellas et al., 2006).
Most of the prevention trials (Table 23.1) were sponsored
by the NIH or similar government bodies, leading to the
comparably large ADAPT (Leoutsakos et al., 2012; Breitner,
2007) and ginkgo biloba extract (GEM) study (DeKosky et
al., 2008) studies that have received approximately $44 mil-
lion and $28 million, respectively, of total funding.

Table 23.1 Alzheimer’s disease prevention studies

Age Sample Length
Study Inclusion criteria (years) size (years) Outcomes Status

ADAPT/naproxen, celecoxib (Meinert First degree ≥70 2,528 5–7 AD, cognitive Early termination
et al., 2009) relative with AD decline
GEM/ginkgo biloba (Snitz et al., 2009) Asymptomatic ≥75 3,072 5 AD, cognitive No significant effects
60%, MCI 40% decline,
cardiovascular
GUIDAGE/ginkgo biloba (Vellas et al., Memory >70 2,854 4 AD No significant effects
2006) complaints
Physicians Health Study-II/vitamin E, Asymptomatic >65 10,000 9 Telephone Ongoing
folate, β-carotene (Christen et al., 2000) cognitive
testing
Heart Protection Study/vitamins E, Asymptomatic 40–80 20,536 5 AD, telephone No differences
C, β-carotene, simvastatin (Heart with interview
Protection Study Collaborative Group, cardiovascular for cognitive
2002) risk factors status (TICS)
PreAdvise/selenium, vitamin E (Kryscio Asymptomatic, ≥60 10,400 9–12 Dementia Terminated
et al., 2004) males only onset,
cognitive tests
HERS/estrogen medroxyprogesterone Asymptomatic, Mean 1,060 4.2 Cognitive tests Improvement on one test
(MPA) (Grady et al., 2002) females = 67
WHIMS/estrogen and MPA (Craig et al., Asymptomatic, 65–80 4,532 4–5 AD and MCI, Increased risk for MCI/AD, worse
2005) female cognitive scores with hormone replacement
scores (add-on) therapy (HRT)
WHIMS/estrogen alone (Craig et al., Asymptomatic, 65–80 2,497 4–5 AD and MCI, Increased risk for MCI/AD, worse
2005) female cognitive scores with HRT
scores (add-on)

Source: Adapted from Golde et al. (2011) with permission from Elsevier.
 Evidence-Based Pharmacologic Treatment of Dementia
Despite the cost, primary prevention for most geriat-
ric neurologic conditions, including dementias, is devel-
oping into an exciting new field in which we can expect
rapid advances. Recent advances in amyloid imaging
may allow smaller clinical trials, decreasing the cost. The
Alzheimer’s Disease Neuroimaging Initiative has allowed
investigators to identify which markers best track change
over time, thus allowing for developing clinical trials that
are more efficient with lower cost, shorter durations, and
smaller sample sizes.
Increased knowledge of the mechanisms of neural injury,
the best targets for neuroprotection, and improved animal
models (such as transgenic mice that exhibit more neurode-
generation and the full spectrum of AD pathologies) may all
lead to more successful translation of neuroprotective drugs,
from the preclinical to the clinical phase in the near future.
The second generation of prevention trials are underway or
in development. The Alzheimer’s Prevention Initiative (API)
targets the use of the monoclonal antibody crenezumab in
subjects that are PS1 carriers (Reiman et al., 2011). The Dom-
inantly Inherited Alzheimer’s Network (DIAN) study will
investigate multiple different drugs as a secondary preven-
tion in subjects with autosomal dominantly inherit AD risk
(Morris, 2012). Other prevention studies will deploy meta-
bolic-based targets in at-risk people (e.g., TOMM40) or will
select subjects for immunotherapy treatment on the basis of
the presence of amyloid by PET imaging.
Secondary prevention or treatment after
clinical symptom onset
The current annual worldwide costs of care for those
with AD are approximately 1% of the world’s GDP, or
$604 billion. However, regulators across the world are ill
prepared to meet the growing need for early stage treat-
ments. For example, the Food and Drug Administration
(FDA) regulatory guidelines require that a drug “show
benefit for patients with dementia on cognition and a
clinical benefit demonstrated either by global or staging
assessment or in activities of daily living (ADL).” Almost
all trials for mild or for mild-to-moderate AD used the
Alzheimer’s Disease Assessment Scale-cognitive subscale
([ADAS-cog] cognitive measure) and the Clinical Demen-
tia Rating or an ADL scale (clinical benefit) (Schneider and
Sano, 2009). The trials for MCI used the onset of AD as the
primary outcome (Raschetti et al., 2007). These cognitive
and functional measures as required now lead to expen-
sive and long trials that may be inadequately powered
and add significant costs. Changes in regulatory point of
view from these measures to biomarker-based measures
that show “delay in the onset of clinical AD or attenuate
the course of cognitive impairment” may be possible once
regulators recognize and validate at-risk state or markers
and accept them as legitimate outcomes. In the absence
of such regulatory vision, we are left with symptomatic
therapy for most geriatric neurologic conditions.
559
Symptomatic therapy
Currently in geriatric neurology, the norm is symptomatic
treatment that lasts for a few years in effectiveness. For
example, in the typical AD patient, current symptomatic
therapies (acetylcholinesterase inhibitors and meman-
tine) demonstrate only modest symptomatic benefit that
is sustained for a period of 6 months to a few years. More-
over, there is no clear evidence that these treatments sig-
nificantly alter disease progression (Schneider et al., 2011).
Although there is renewed effort to develop novel cog-
nitive-enhancing agents that target different pathways,
only a few, such as the mitochondrial agent dimebon
(Doody et al., 2008) and histamine receptor antagonists,
have entered phase 3 efficacy studies in humans. Results
from the several phase 3 studies of dimebon, unfortu-
nately, showed conflicting evidence of efficacy (Jones,
2010). Studies of the drug in subjects using donepezil as
an add-on agent are ongoing.
Symptomatic effect is measured in two domains: wors-
ening on a cognitive measure (such as ADAS-cog) and a
clinical (or global) measure (such as Clinical Dementia Rat-
ing [CDR], Clinician’s Interview-Based Impression of
Change [CIBIC], or CIBIC with caregiver input [CIBIC-
plus]). Experience based on longitudinal studies of ambu-
latory patients with mild-to-moderate AD suggests that
scores on the ADAS-cog increase (worsen) by 6–12 points
per year. However, smaller changes may be seen in
patients with very mild or very advanced disease because
the ADAS-cog is not uniformly sensitive to change over
the course of the disease. The annualized rate of decline in
the placebo patients participating in donepezil trials was
approximately two to four points per year. Overall clinical
effect is measured using CIBIC or CIBIC-plus. The CIBIC-
plus is not a single instrument and is not a standardized
instrument like the ADAS-cog; therefore, it captures the
clinical variability. Clinical trials for investigational drugs
have used a variety of CIBIC formats, each different in
terms of depth and structure. The FDA presently requires
effectiveness on both domain scales (cognitive as well as
improvement in function) to approve a drug for AD. In a
meta-analysis of the treatment trials in AD using ADAS-
cog, the pooled analysis showed a diagnostic odds ratio
(DAR) of 0.56 (95% CI 0.42–0.74). However, significant
heterogeneity was seen. ADAS-cog variability in each
study accounted for 89.6% of the treatment effect. Strati-
fying by treatment class (choline esterase inhibitors vs.
others) or by the disease state (MCI vs. AD) did not elimi-
nate the heterogeneity of reported treatment effects using
ADAS-cog. Similar DAR was seen with CIBIC, without
significant heterogeneity (Figures 23.1 and 23.2).
In the last 20 years, the FDA has approved five drugs
for the treatment of dementia, and all have been approved
specifically for AD: tacrine, donepezil, rivastigmine,
galantamine, and memantine. Tacrine, donepezil, riv-
astigmine, and galantamine have been approved for an
560 Therapeutics for the Geriatric Neurology Patient

Diagnostic OR (95%)
Tacrine_160 mg 0.30 (0.19–0.48)
Rivastigmine—high dose 0.43 (0.28–0.64)
Rivastigmine—low dose 0.58 (0.38–0.89)
Galantamine_AD_24 mg 0.46 (0.30–0.70)
Galantamine_AD_32 mg 0.50 (0.33–0.76)
Galantamine_AD_8 mg 0.85 (0.56–1.29)
Galantamine_AD_16 mg 0.49 (0.35–0.71)
Galantamine_AD_24 mg 0.54 (0.38–0.77)
Galantamine_AD_18 mg 0.47 (0.22–0.99)
Galantamine_AD_24 mg 0.53 (0.23–1.24)
Galantamine_AD_36 mg 0.38 (0.15–0.97) Figure 23.1 Changes from baseline in mean
Donepezil_AD 0.43 (0.27–0.68) ADAS-cog score in studies of galantamine,
Galantamine_24–32 mg 0.45 (0.28–0.72)
donepezil, tacrine, and rivastigmine.
Positive changes from baseline on the
Random Effects Model MMSE indicate improvement; negative
Pooled Diagnostic Odds Ratio = 0.49 (0.43–0.56) values indicate deterioration. Data based
Cochran-Q = 13.27; df = 12 (p = 0.3500) on various randomized clinical trials
0.001 1 100.0 Inconsistency (I-square) = 9.5 % (RCTs) conducted through 2004–2010 after
Tau-squared = 0.0058
Diagnostic Odds Ratio applying the CONSORT quality criteria.

identical indication: the treatment of mild-to-moderate
dementia of the Alzheimer’s type. Memantine has been
approved for the treatment of moderate-to-severe demen-
tia of the Alzheimer’s type (MMSE < 14).
Tacrine
The first drug the FDA approved to treat AD was tacrine,
or tetrahydroaminoacridine (THA), a centrally active
anticholinesterase (Summers et al., 1986). In six stud-
ies with 994 subjects with mild-to-moderate AD, signifi-
cant improvement occurred in one trial with the largest
sample size. Two other trials were not blinded and had
an additional 425 subjects. Significant improvement was
seen among subjects who received the drug, on the global
assessment (p = 0.003), the Orientation Test (p = 0.004),
the Alzheimer’s Deficit Scale (p = 0.003), and the Names
Learning Test (p = 0.001). Symptomatic improvements
occurred and no serious adverse effects (SAE) attribut-
able to THA were observed, but significant adverse effects
(AE) (up to 55% withdrawal rates) limited its use. GI and
elevated hepatic transaminase occurred in approximately
25% of patients.
Donepezil
The next drug approved (1993) for AD was donepezil
hydrochloride (Aricept) (Rogers and Friedhoff, 1996),
a reversible inhibitor of acetylcholinesterase, which did
not have the hepatic toxicity of tacrine. It is available for
oral administration in film-coated tablets containing 5, 10,
or 23 mg of donepezil hydrochloride and in ODT (orally
dissolving tablet) formulation that contains 5 or 10 mg of
donepezil administered once daily usually in the evening
(if patients recall dreams, it may be switched to morn-
ing). Donepezil is postulated to exert its therapeutic effect

Diagonostic OR (95%)
Tacrine_AD_160 mg 0.50 (0.33–0.76)
Physostigmine_AD 0.56 (0.36–0.88)
Rivastigmine_AD_high dose 0.60 (0.38–0.95)
Galantamine_AD_24 mg 0.11 (0.06–0.19)
Galantamine_AD_32 mg 0.11 (0.06–0.19)
Galantamine_AD 0.45 (0.28–0.72)
Choline Alfoscerate_AD 0.13 (0.07–0.26)
Galantamine–11_MCI 0.86 (0.64–1.15)
Donepezil_MCI 0.86 (0.58–1.27)
Donepezil_MCI 1.0.2 (0.53–1.96)
Galantamine–18_MCI 0.86 (0.65–1.13)
Vit.E_MCI 0.96 (0.65–1.40)
Rofecoxib_MCI 1.38 (1.01–1.87)
Rivastigmine_MCI 0.86 (0.65–1.13)
Trifusal_MCI 0.58 (0.30–1.16)
Galantamine_MCI 0.54 (0.37–0.79)
Donepezil_MCI 0.47 (0.23–0.93)
Ginkgo Giloba_MCI 1.03 (0.85–1.25)
Figure 23.2 Existing dementia treatments
Random Effects Model show effectiveness in a meta-analysis of
Pooled Diagnostic Odds Ratio = 0.56 (0.42–0.7) multiple treatments in mild cognitive
Cochran-Q = 163.96; df = 17 (p = 0.0000) impairment and Alzheimer’s dementia,
0.01 1 100.0 Inconsistency (l-square) = 89.6 % using clinical trials meeting the CONSORT
Tau-squared = 0.3252
Diagnostic Odds Ratio 2010 quality criteria (CIBIC).
 Evidence-Based Pharmacologic Treatment of Dementia
by enhancing cholinergic function. This is accomplished
by increasing the concentration of acetylcholine through
reversible inhibition of its hydrolysis by acetylcholines-
terase. No evidence indicates that donepezil alters the
course of the underlying pathologic process.
Pharmacokinetics of donepezil is linear over a dose
range of 1–10 mg given once daily. The rate and extent
of absorption of donepezil tablets are not influenced
by food. The elimination half-life of donepezil is about
70 hours, and a steady state is reached within 15 days. It
is 96% bound to human plasma proteins, mainly to albu-
mins. Other protein-bound agents, such as furosemide,
digoxin, and warfarin, do not affect donepezil binding to
albumin. It is excreted in the urine intact and extensively
metabolized to four major metabolites, two of which are
known to be active by glucuronidation using CYP 450 iso-
enzymes 2D6 and 3A4. CYP2D6 genotype affects elimi-
nation, with poor metabolizers having a 31.5% slower
clearance and rapid metabolizers a 24% faster clearance.
Liver impairment can reduce elimination, while renal
impairment does not seem to affect clearance. In addi-
tion, advancing age reduces clearance. When compared
with 65-year-old subjects, 90-year-old subjects have a 17%
decrease in clearance.
The effectiveness of donepezil as a treatment for mild-
to-moderate AD is demonstrated by 10 randomized,
double-blind, placebo-controlled trials in 3239 patients
with AD (diagnosed by NINCDS and DSM III-R criteria;
Farlow et al., 2010). The mean age of patients participat-
ing in donepezil trials was 73 years; 62% were women.
The racial distribution was white 95%, black 3%, and
other races 2%. After 24 weeks of treatment, the mean
differences in the ADAS-cog change scores for donepe-
zil-treated patients compared to the patients on placebo
were 2.8 and 3.1 points for the 5 mg/day and 10 mg/day
treatments, respectively. The beneficial effects of donepe-
zil wash out over 6 weeks following discontinuation of
treatment. There was no rebound effect after abrupt dis-
continuation of therapy. Similarly, on the CIBIC, the mean
drug–placebo differences for these groups of patients were
0.35 points and 0.39 points for 5 mg/day and 10 mg/day,
respectively, once again significantly different from pla-
cebo. Each treatment arm was significantly different from
placebo on both tests, but there was no between-dose sig-
nificance. The significant treatment effects continued into
moderate and severe disease states while using donepezil.
Withdrawal due to adverse events ranged from 0–11%
for placebo to 0–18% for donepezil. The most common
side effects of donepezil are diarrhea, nausea, vomiting,
insomnia, muscle cramps, fatigue, and anorexia. Done-
pezil can also rarely increase the chance of ulcers and
GI bleeding. In people with heart problems, it can rarely
cause slow heartbeat and fainting, especially when used
with beta-blockers. Very unusual side effects include uri-
nary retention, worsening asthma, and seizures.
561
Galantamine
Galantamine hydrobromide (Razadyne), a tertiary alka-
loid, is a competitive and reversible inhibitor of acetyl-
cholinesterase that the FDA approved in 2000 for mild-to-
moderate AD. As with donepezil, the precise mechanism
of galantamine’s action of improving memory in demen-
tia is unknown.
It is postulated to exert its therapeutic effect by enhanc-
ing cholinergic function. The oral bioavailability is 90%,
with an elimination half-life of 7 hours and linear phar-
macokinetics. It is also glucuronidated by hepatic CYP
450 enzymes 2D6 and 3A4 and excreted unchanged in
the urine (Ago et al., 2011). Unlike donepezil, this agent
accumulates in subjects with renal impairment. Accumu-
lation can also occur with advancing age and inhibitors
of 2D6, such as paroxetine, erythromycin, amitriptyline,
fluoxetine, fluvoxamine, and quinidine; it does not affect
the levels of other drugs.
The FDA approved the drug after reviewing the results
of six randomized, double-blind, placebo-controlled tri-
als in 3530 patients with probable AD (NINCDS-ADRDA
criteria, with MMSE 10–24 and mean participant age 75
years), with doses of 8–32 mg/day given as twice-daily
doses (immediate-release tablets). On the ADAS-cog at
21 weeks of treatment, galantamine-treated patients were
better by 1.7, 3.3, and 3.6 units for the 8, 16, and 24 mg/
day treatments, respectively. On CIBIC-plus, the galan-
tamine–placebo differences for these groups of patients in
mean rating were 0.15, 0.41, and 0.44 units for the 8, 16,
and 24 mg/day treatments, respectively. The 16 mg/day
and 24 mg/day treatments were statistically significantly
superior to placebo and 8 mg/day treatment in both out-
come measures.
The AE profile is similar to donepezil, except that is has
more GI side effects (Table 23.2). The most common side
effects were diarrhea, nausea, vomiting, insomnia, muscle
cramps, fatigue, and anorexia.
Velnacrine
Two of the three studies evaluating 774 AD subjects with
this medication showed benefit. However, hematologic
and hepatic adverse events (up to 40%) kept the FDA
from approving it (Birks and Wilcock, 2004).
Rivastigmine
Six studies evaluated 2071 subjects (three limited to AD)
on rivastigmine before the FDA approved it in 2000. Doses
varied from 1 to 12 mg given for 14–26 weeks.
Evidence indicates that cognitive function improves
with rivastigmine at the 12-mg dose, but efficacy results
were mixed at lower doses. In two trials, results were
inconsistent (between cognitive measures). However,
there is consistent benefit for global function—but the
effective dose to achieve benefit was variable among the
trials. Caregiver burden outcomes were not evaluated.
562 Therapeutics for the Geriatric Neurology Patient

Table 23.2 Summary of the adverse events observed with various medications used in the treatment of Alzheimer’s disease
Adverse effects Placebo Donepezil (Aricept) Galantamine (Razadyne) Rivastigmine (Exelon) Memantine (Namenda)
(Percentage/ranges (N = 3819) (N = 2682) (N = 1040) (N = 2439) (N = 940)
indicate multiple trials) (%) (%) (%) (%) (%)

Bradycardia 0–1 2
Fatigue 0.6–3 0–1 5 0.8–2 2
Syncope 0.2–1 0–1 2 0–1
Confusion 0.3–5 0–1 6
Dizziness 0.3–6 0.4–1 9 1.7–7 7
Headache 0.8–5 0.6–1 8 1.1–6 6
Tremor 0.1–2 3 0.4–2.8
Constipation 0.5–3 0–1 5
Nausea 0.5–9 0.6–1.5 24 4–23
Vomiting 0.7–4 0.6–1.6 13 2.6–19 3
Diarrhea 0.4–7 0.8–2 9 1.6–10
Abdominal pain 0.6–4 5 1–4
Dyspepsia 0.5–2 5 0–1
Weight decrease 0.3–2 0–1 7 0.3–8
Anorexia 0.4–3 0.4–1.6 9 1.4–9
Depression 0.4–5 0–1 7 0.5–4
Insomnia 0.8–4 0.3–1.2 5 0.8–4
Somnolence 0–3 0–1 4 0.4–1.1 3
Anemia 0–2 3
Rhinitis 0–3 4 0–1
Urinary infection 0–7 8 0–2
Hematuria 0–2 3

Withdrawal rates were 4–11% for placebo and 11–27% for
the rivastigmine group, with side effects of dizziness, nau-
sea, vomiting, anorexia, and headache (Birks et al., 2000).
Memantine
Memantine has been available since 1982 in Germany
(originally approved for the treatment of organic brain
syndrome) and was available outside the United States in
42 countries before its FDA approval in 2003. In 2013, an
extended release formulation was approved by the FDA,
which allows a dosing of 28 mg once daily. Even though
the precise mechanism of action in AD is uncertain,
memantine is thought to be a low-to-moderate affinity,
uncompetitive NMDA receptor antagonist with strong
voltage dependency and rapid blocking/unblocking
kinetics. These pharmacologic features “appear to allow
memantine to block the sustained activation of the recep-
tor by glutamate that may occur under pathologic con-
ditions and to rapidly leave the NMDA receptor channel
during normal physiologic activation” (McKeage, 2009).
In humans, memantine is 100% bioavailable after an
oral dose, undergoes minimal metabolism, and exhibits a
terminal elimination half-life of 60–80 hours (75% or more
of the dose is eliminated intact in the urine). It rapidly
crosses the blood–brain barrier with a CSF/serum ratio
of 0.52. Memantine does not inhibit cytochrome P-450
(CYP 450) isoenzymes in vitro, and its pharmacokinetics
are not affected by food, sex, or age (Micuda et al., 2004).
Memantine demonstrated efficacy in the treatment of
moderate-to-severe AD (MMSE 3–14) using a dose of
up to 20 mg/day in two key double-blind, placebo-con-
trolled trials of 6-month duration. As the patients were
more advanced, Severe Impairment Battery (SIB) and
the 19-item version of the Alzheimer’s Disease Coopera-
tive Study–Activities of Daily Living Inventory (ADCS-
ADL19), which is modified for more advanced AD
patients, were used as the indices of cognitive and func-
tional change. The clinician made a global clinical assess-
ment of change using CIBIC-plus (Schmitt et al., 1997;
Orgogozo, 2002; Reisberg et al., 2003).
AE reported frequently (>5%, memantine greater than
placebo) were dizziness, confusion, headache, and consti-
pation. This agent did not get FDA approval for use in
mild dementia or vascular dementia due to inconsistent
effects on cognitive and global measures.
Medical foods
Medical foods undergo a different approval process than
drugs. As these agents are considered to be derived from or
parts of food already consumed widely, the expectation is
they are not harmful. Currently these agents can be brought
to market with much less oversight by the FDA. The first
medical food for Alzheimer treatment approved by the FDA
in 2012 was Axona. It is derived from triglycerides moieties
in coconut milk. As coconut milk is consumed extensively,
the general expectation is that of low side effect profile.
 Evidence-Based Pharmacologic Treatment of Dementia 563

Frontotemporal dementia
No FDA-approved medications for frontotemporal
dementia (FTD) exist, and the pharmacologic treatment of
clinical symptoms is mostly based on clinical judgment.
Large-scale, placebo-controlled clinical trials of treatments
are not available to determine effectiveness on measures
of clinical progression. Psychiatric drugs are more com-
monly used in FTD than AD. See Table 23.3 for a summary
of all studies. See Chapter 9.5 for additional details.
Compared to AD, FTD patients are generally younger,
with higher MMSE and neuropsychiatric inventory (NPI)
scores (p < 0.001). FTD patients are less likely to be pre-
scribed dementia medications, donepezil (27% vs. 53%),
and memantine (35% vs. 42%, p < 0.001). FTD patients are
more likely to use antipsychotics (10% vs. 5%, p = 0.013),
antidepressants (59% vs. 39%, p < 0.001), and sedative/
anxiolytics (17% vs. 8%, p < 0.001), adjusted for age, onset
age, MMSE, education, and CDR. Higher aberrant motor
(odds ratio [OR] 1.6, p = 0.009) and appetite (OR 1.6, p =
0.011) scores were associated with increased antipsychotic
use, while higher depression (OR 0.482, p = 0.016) and dis-
inhibition (OR 0.635, p = 0.025) were associated with lower
use. Antidepressant use was increased with higher agita-
tion (OR 1.3, p = 0.048) and depression (OR 1.6, p = 0.003),
but decreased with higher irritability (OR 0.76, p = 0.040).
Dementia with Lewy bodies
Currently, only rivastigmine is FDA-approved medica-
tions exist for treatment of Parkinson-related dementias
(e.g., Lewy body dementia).
Clinical trials did not show significant efficacy of medi-
cations currently used in the management of AD (Ferman
et al., 2004) (Table 23.4). Some improvement of motor
function, global clinical status, and behavioral symptoms
on NPI scores was noted on these medications. Treatment
of dementia with Lewy Bodies (DLB) focuses on manag-
ing hallucinations and agitations. Acetylcholinesterase
inhibitors are thought to be beneficial to most. Rivastig-
mine may alleviate apathy, anxiety, hallucinations, and

Table 23.3 Summary of published open-label and randomized clinical trials and case reports in patients with frontotemporal dementia (FTD)
through 2009

Number of
Study Medications Study duration subjects Main findings

Kertesz et al. (2008) Galantamine 18 weeks 36 No improvement in FTD.

Lebert et al. (2004) Trazadone 12 weeks 26 Improvement in neuropsychiatric symptoms. No effect on cognitive status.
Mendez et al. (2007) Donepezil 6 months 24 No difference in cognitive function between treated and untreated.
Neuropsychiatric impairments worse, reversible after drug removal in
33% treated subjects.
Moretti et al. (2004) Rivastigmine 12 months 20 Improvement in neuropsychiatric symptoms and caregiver burden, while
cognitive function declined.
Mendez (2009) Sertraline 6 months 18 Decreased stereotypical movements.
Moretti et al. (2003b) Olanzapine 24 months 17 Improved agitation, misconduct, delusions. Decreased caregiver distress.
Ikeda et al. (2004) Fluvoxamine 12 weeks 16 Improved stereotyped and other behaviors.
Moretti et al. (2003a) Paroxetine 14 months 16 Improvement in neuropsychiatric impairments and caregiver stress. Few
adverse events.
Diehl-Schmid et al. (2008) Memantine 6 months 16 No improvement in behavior. Worsening of cognitive dysfunction.
Swartz et al. (1997) SSRIs 3 months 11 Improvement in neuropsychiatric impairments in more than half of patients.
Deakin et al. (2004) Paroxetine 6 weeks 10 No improvement in neuropsychiatric impairments. Mild worsening in
cognitive function in treated group.
Rahman et al. (2006) Methylphenidate One dose 8 Decreased risk-taking behavior on gambling task.
Swanberg (2007) Memantine 3 months 3 All three patients had improved NPI scores, especially for apathy,
agitation, and anxiety.
Ishikawa et al. (2006) Fluvoxamine NA 2 Improved stereotyped behaviors, fewer pain complaints.
Goforth et al. (2004) Methylphenidate NA 1 Partial normalization of quantitative electroencephalogram (EEG) pattern.
Anneser et al. (2007) Sertraline NA 1 Decrease in inappropriate sexual behavior and physical aggression in
FTD–amyotrophic lateral sclerosis (ALS) patients.
Cruz et al. (2008) Topiramate 6 months 1 Reduction in alcohol abuse, but no change in other compulsive behavior.
Curtis and Resch (2000) Risperidone NA 1 Improved behavior.
Fellgiebel et al. (2007) Aripiprazole 1 month 1 Stabilization of clinical symptoms. Improved frontal glucose metabolism
on PET.

Source: Adapted from Boxer and Boeve (2007) and Vossel and Miller (2008) with permission from Lippincott Williams & Wilkins.
564 Therapeutics for the Geriatric Neurology Patient

Table 23.4 Summary of published open-label and randomized clinical trials and case reports in patients with Lewy body dementia
Number of
Study Medications Study duration subjects Main findings

McKeith et al. (2000a) Rivastigmine 20 weeks 120 Clinically significant behavioral effects in patients with Lewy body dementia.
Wesnes et al. (2002) Rivastigmine 20 weeks 92 Benefits of the cognitive functioning, as well as improvement in MPI
scores.
Grace et al. (follow-up of Rivastigmine Up to 96 29 Improved MMSE at 12 and 24 weeks, with no change at 36 weeks reported.
McKeith et al., 2000a) weeks Decreased NPI scores at weeks 12 and 24, baseline at weeks 36 and 96.
Levin et al. (2009) Memantine 16 weeks 23 Reductions in the severity of fluctuations in mental state, aggressivity,
lack of spontaneity, and disinhibition.
Lebert et al. (1998) Tacrine 14 weeks 19 Increased cognition in Mattis Dementia Rating Scale (MDRS) in 11 cases.
Mori et al. (2006) Donepezil 12 weeks 12 Significant improvements in NPI-11 scores. Significant improvement in
ADAS-J-cog until week 4. Deterioration in Unified Parkinson’s Disability
Rating Scale (UPDRS) scores.
McKeith et al. 2000b (follow- Rivastigmine 12 weeks 11 No change in cognition—MMSE. NPI scores decreased 47%.
up of McKeith et al., 2000a)
Shea et al. (1998) Donepezil 8–24 weeks 9 Improved cognition—MMSE and ADL. Decreased fluctuations.
Maclean et al. (2001) Rivastigmine 3–24 weeks 8 Decreased NPI. Improved ADL. Improved sleep reported.
Lanctôt and Herrmann Donepezil 8 weeks 7 Improved MMSE (two out of three cases). Decreased NPI scores at
(2000) 4 weeks. Three out of seven cases discontinued.
Grace et al. (2001) Rivastigmine 12 weeks 6 Cognition improved. MMSE increased from 18.5/30 to 23/30 at week 12.
Decreased sleep.
Querfurth et al. (2000) Tacrine 24 weeks 6 Increased cognition in DLB responders: MDRS memory subscale and
Functional Assessment Scale (FAS) Fluency task.
Samuel et al. (2000) Donepezil 6 months 4 Improved cognition noted.
Coulson et al. (2002) Donepezil 6 months 1 Increased cognition. MMSE 23/30 at baseline and 27/30 6 months
post-baseline.
Rojas-Fernandez et al. (2001) Donepezil 3 months 1 Increased cognition. Increased ADL. Decreased fluctuations.
Aarsland et al. (1999) Donepezil 7 weeks 1 Increased cognition. MMSE 23/30 at baseline and 30/30 at three and
seven weeks post-baseline.
Skjerve and Nygaard (2001) Donepezil 14 weeks 1 Improved cognition. MMSE 11/30 at baseline and 20/30 at 6 weeks, as
well as 21/30 at 14 weeks.
Geizer and Ancill (1998) Donepezil 10 weeks 1 Improved cognition. 25/30 at baseline and 27/30 at 2 and 10 weeks
post-baseline.

delusions (McKeith et al., 2000a; Fernandez et al., 2003).
Memantine may also help improve cognition and behav-
ioral symptoms (Emre et al., 2010). Atypical neuroleptics
are also prescribed, but clinical trial results have been
nonsignificant. Selective serotonin reuptake inhibitors
(SSRIs) are the treatment of choice in managing depres-
sion. Levodopa/carbidopa (Sinemet) may improve
motor function, but the results are limited by sample size
(Lucetti et al., 2010). Low doses of Zonisamide may be
effective in managing behavioral symptoms such as apa-
thy and aggression (Odawara et al., 2010; Sato et al., 2010).
See Chapter 9.3 for additional details.
Overall approach to
pharmacotherapy of dementia
Although it is hard to generalize treatment to diseases
other than AD, the volume of evidence suggests at least
that an empirical trial of medications approved for AD
be used as off label in Lewy body dementia and even
more selectively in FTD. The role of approved medi-
cations is even more limited in rapidly progressive
dementias.
It is advisable to start with one of the acetylcholin-
esterase inhibitors (ACHEIs) and titrate up to a toler-
able dose, based on an individualized approach to each
patient. A geriatric neurology consultation for careful
titration of medication is required to safely manage the
medications. Frequent neurologic evaluations (biweekly
or monthly) until the dose is titrated up to a tolerable dose
are required. Once the patient is on a stable dosing, serial
follow up every 3–6 months with a geriatric neurologist
is highly recommended for continued patient safety. In
addition, a short-form neuropsychological test measure
(such as the MOCA test, available at http://mocatest.org)
is also recommended, to document decline, two to three
times a year.
Table 23.5 summarizes current medications with their
dosages, precautions, and interactions.
Table 23.5 Pharmacotherapy of dementia
Drug Starting dose Contraindications Precautions Interactions

Donepezil 5 mg PO once daily (start at night; Hypersensitivity, Chronic Seizures, asthma, sick sinus syndrome, or other Increases effects of succinylcholine, cholinesterase
(Aricept) if excessive dreaming, may switch Obstructive Pulmonary supraventricular conduction abnormalities. Peptic ulcer inhibitors, or cholinergic agonists. Counteracts effects of
to morning dosing). Increase by Disease (COPD). disease. anticholinergics used for bladder control.
5 mg every 30 days till diarrhea
limits further dosing increase.
Rivastigmine 1.5 mg PO twice daily. Increase by Documented hypersensitivity. Significant nausea, vomiting, anorexia, and weight Reduces effects of anticholinergics. Increases effects
(Exelon) 1.5 mg every 30 days till diarrhea loss, history of peptic ulcer disease, sick sinus of cholinergic agonists and neuromuscular blockers.
limits further dosing increase. syndrome, urinary obstruction, COPD, bradycardia or May lead to bradycardia when used with beta-blockers
supraventricular conduction conditions. Some cases of without ISA.
worsening of motor features of PD or exacerbation of
bradycardia have been reported but have not yet been
clinically proven.
Galantamine 8 mg PO once daily. Increase by Documented hypersensitivity. Decrease dose in moderate renal insufficiency or When given with other cholinesterase inhibitors, may
(Razadyne) 5 mg every 30 days till diarrhea Not to be prescribed in moderate-to-severe hepatic impairment. Use caution increase toxicity. CYP2D6 or CYP3A4 inhibitors may
limits further dosing increase. patients with severe renal in asthmatic patients; may cause bradycardia or AV decrease elimination and increase serum levels.
dysfunction (i.e., <10 mL/min block, or syncope may occur with doses >24 mg/day.
creatinine clearance). Also use caution in patients with sick sinus syndrome
or other supraventricular conduction. Some cases of
worsening of motor features of PD or exacerbation of
bradycardia have been reported but have not yet been
clinically proven.
Clozapine 12.5 mg once daily. Documented hypersensitivity. May cause serious agranulocytosis. May worsen Epinephrine and phenytoin may decrease effects.
(Clozaril) WBC count <3500 cells/μL confusion and EPS. Possibly may increase lethargy and Tricyclic antidepressants (TCAs), neuroleptics, CNS
before or during therapy. cause tachycardia, dizziness, and increased sweating. depressants, guanabenz, and anticholinergics may
Never stop abruptly. Must perform WBC testing q2wk increase effects.
for duration of therapy.
Quetiapine 25 mg PO twice daily. Documented hypersensitivity. May induce orthostatic hypotension associated with May antagonize levodopa and dopamine agonists.
(Seroquel) dizziness, tachycardia, and syncope. Neuroleptic Phenytoin, thioridazine, and other liver enzyme inducers
malignant syndrome and tardive dyskinesia have been may reduce levels. CYP450 3A inhibitors (such as
associated with treatment. Hyperglycemia may occur. ketoconazole and fluconazole) may increase serum
concentrations. (Also discussed in Chapter 24)
Aripiprazole 10–15 mg PO, once daily. Documented hypersensitivity. Common AE include headache, anxiety, somnolence, CYP450 3A4 and 2D6 isoenzyme substrate inhibitors
(Abilify) or insomnia. Rare reports of tardive dyskinesia and (for example, ketoconazole, quinidine, fluoxetine, and
neuroleptic malignant syndrome have been noted. May paroxetine) or inducers (such as carbamazepine) may
cause orthostatic hypotension, seizure, dysphagia, or increase or decrease serum levels. (Also discussed in
suicidal ideation. Chapter 24)
Venlafaxine 75 mg per day, PO. Documented hypersensitivity Patients may experience hypertension. Fatal reaction Cimetidine, MAOIs, sertraline, fluoxetine, class IC
(Effexor) with monoamine oxidase may occur if taken concurrently with an MAOI. Use antiarrhythmics, TCAs, and phenothiazine may increase
inhibitors (MAOIs) within caution in patients with cardiovascular disorders. effects. (Also discussed in Chapter 24)
Evidence-Based Pharmacologic Treatment of Dementia

14 days.
(continued)
565
Table 23.5 (continued)
566

Drug Starting dose Contraindications Precautions Interactions

Paroxetine 10 mg per day, PO. Documented hypersensitivity Use caution with a history of seizures, mania, renal Phenobarbital and phenytoin decrease effects. Alcohol,
(Paxil) with MAOIs within 14 days. disease, cardiac disease, or hepatic impairment. Must cimetidine, sertraline, phenothiazines, and warfarin
discontinue MAOIs at least 14 days before initiating increase toxicity. (Also discussed in Chapter 24)
therapy.
Sertraline Start 12.5 mg PO once daily. Documented hypersensitivity May increase confusion and agitation. May increase Increases toxicity of MAOIs, diazepam, tolbutamide, and
(Zoloft) Increase by 12.5– 25 mg every when used concurrently with sleepiness or cause insomnia. May be associated with warfarin. (Also discussed in Chapter 24)
3–7 days. MAOIs. weight gain or weight loss. Must discontinue MAOIs at
least 14 days before initiating therapy.
Fluoxetine 20 mg/day PO, once daily in the Documented hypersensitivity Known or suspected history of mania or hypomania. Inhibits CYP450 isoenzymes 2C9, 2C19, 2D6, and
(Fluzac) morning. when used concurrently with Use caution in hepatic impairment and history of 3A4. Increases toxicity of diazepam and trazodone
MAOIs or in the last 2 weeks, seizures. MAOIs should be discontinued at least by decreasing clearance. Increases toxicity of MAOIs
coadministration with 14 days before initiating fluoxetine therapy. and highly protein-bound drugs. May cause serotonin
thioridazine. syndrome, which pertains to myoclonus, rigidity,
confusion, nausea, hyperthermia, autonomic instability,
coma, and eventually death, occurs with simultaneous
use of other serotonergic agents (such as tramadol or
buspirone). (Also discussed in Chapter 24)
Clonazepam 0.25 mg PO, once at night. Documented hypersensitivity, Use caution in chronic respiratory disease or impaired Phenytoin and barbiturates may reduce effects.
(Clonopin) Increase by 0.25 mg nightly, not severe liver disease, and renal function. Withdrawal symptoms can result from Coadministration of CNS depressants increases toxicity.
Therapeutics for the Geriatric Neurology Patient

to exceed 1 mg.
Levodopa/ 25/100 mg tablet. Start with half
Carbidopa tablet PO; twice daily, titrate by
(Sinemet) half to one tablet per dose every
week until tolerated or effect.
Nuedexta Quinidine 10/dextromethorphan
20 mg combination tablet. Start
one tablet PO once daily. Increase
to twice daily after 1 week.
Memantine Start XR 7 mg PO once daily.
(Namenda) Increase by 7 mg every week till
28 mg once daily.
(IR formulation is not approved at
doses above 20 mg)
acute narrow-angle glaucoma. abrupt discontinuation.
Documented hypersensitivity,
narrow-angle glaucoma,
malignant melanoma, or
undiagnosed skin lesions.
Concomitant use with
quinidine, quinine, or
mefloquine is contraindicated.
Thrombocytopenia,
hepatitis, hypersensitivity to
dextromethorphan, within
14 days of stopping an MAOI.
Documented hypersensitivity.
Not to be prescribed in
patients with severe renal
dysfunction (i.e. <10 mL/min
creatinine clearance).
May increase agitation, lethargy, dyskinesias,
postural hypotension, hallucination, and confusion.
Psychiatric symptoms (such as hallucinations) may be
exacerbated.
Congenital long QT syndrome, prolonged QT
interval, torsades de pointes, heart failure, complete
atrioventricular (AV) block without implanted
pacemaker.
Decrease dose in moderate renal insufficiency,
dizziness or moderate-to-severe hepatic impairment.
Use caution in seizures and alkaline urine (high pH) due
to any condition.
(Also discussed in Chapter 24)
Hydantoins, pyridoxine, phenothiazine, and hypotensive
agents may decrease effects. Toxicity increases when
administered concurrently with antacids or MAOIs. (Also
discussed in Chapter 12)
Drugs that both prolong QT interval and are metabolized
by CYP 2D6 (e.g., thioridazine). MAOIs.
No drug interactions systematically studied. Combination
with cholinesterase inhibitors recommended.
 Evidence-Based Pharmacologic Treatment of Dementia 567

Vascular dementia
Currently, no treatment is approved to treat vascular
dementia (VaD).
Preventing vascular risk factors associated with an
increased risk of dementia, including hypertension,
hypercholesterolemia, diabetes mellitus, smoking, obe-
sity, and lack of physical exercise (in midlife and, to a
lesser extent, in later life), is important. Preventing fur-
ther strokes by antiplatelet agents is the mainstay of treat-
ment. (Table 23.6 shows some commonly used treatments
for VaD.) Silent cerebral infarcts and white matter lesions
increase the risk of future dementia. Aspirin has been
found to slow progression of VaD, along with the use of
various antiplatelet drugs and modification of vascular
risk factors (Devine and Rands, 2003). See Chapter 9.4 for
additional details.
Most available evidence from randomized, controlled
clinical trials comes from cardiovascular studies using
stroke, coronary heart disease, or mortality as primary
outcome measures, and assessing cognitive function or
incident dementia as a secondary endpoint. Hyperten-
sion is the strongest risk factor for VaD (Sharp et al., 2011).
Only the Syst-Euro trial reported 55% absolute risk reduc-
tion in incident VaD with anti-hypertensive use over
3.9 years (Staessen et al., 2004). A meta-analysis including
four randomized clinical trials (RCTs) conducted with BP-
lowering therapy revealed a hazard ratio of 0.87 (95% CI
0.76–1.00) for incident dementia.
Two RCTs did not show cognitive effects of cholesterol-
lowering therapy with statins. Another RCT on a diabetic
subset to evaluate the effect of intensive glycemic control
versus standard control did not show cognitive improve-
ment and incident dementia. A third RCT conducted to
compare multicomponent interventions and regular care
against vascular risk factors in an AD patient population
with cerebrovascular lesions on MRI did not find any sig-
nificant effect on cognitive decline, but the treatment arm
decreased progression of the white matter lesions as com-
pared to control group (Staessen et al., 2004).
Cognitive decline after stroke is more common that
stroke recurrence (Alvarez-Sabín and Román, 2011).
Cognitive decline risk doubles after stroke. Post-stroke
VaD affects 30% of stroke survivors, and the incidence
of new-onset dementia increases from 7% one year after
stroke to 48% after 25 years.
Use of citicoline (CDP-choline) and choline alfoscer-
ate has been observed through various RCTs to be asso-
ciated with improved memory and attention for choline
alfoscerate, whereas improved memory, behavior, and
clinical global impression were associated with the use
of CDP-choline. CDP-choline enhances cognitive, neuro-
logic, and functional recovery. Compared with placebo,
CDP-choline-treated patients with acute ischemic stroke
with an NIHSS score of >8 were more likely to have a full
recovery (García-Cobos et al., 2010; Alvarez-Sabín and
Román, 2011).

Table 23.6 Commonly used treatments, side effects, interactions, and contraindications for managing vascular dementia (VaD)

Drug Dose Contraindications Precautions Interactions

Aspirin 325 mg PO qd Documented hypersensitivity,
(Anacin, liver damage,
Ascriptin) hypoprothrombinemia,
vitamin K deficiency, bleeding
disorders, asthma, use in
children (<16 years) with
flu (associated with Reye
syndrome).
Ticlopidine 250 mg PO bid Documented hypersensitivity,
(Ticlid) neutropenia or
thrombocytopenia, liver
damage, active bleeding
disorders.
Clopidogrel 75 mg PO qd Documented hypersensitivity,
(Plavix) active pathologic bleeding
(e.g., peptic ulcer), intracranial
hemorrhage.
Pentoxyfylline 400 mg bid Documented hypersensitivity,
(Trental) cerebral or retinal hemorrhage.
May cause transient decrease Action may decrease with antacids and urinary
in renal function and aggravate alkalinizers. Corticosteroids decrease salicylate
chronic kidney disease. Avoid use serum levels. May lead to increased bleeding
in patients with severe anemia, time when used with anticoagulants. May
patients with history of blood antagonize uricosuric effects of probenecid
coagulation defects, or patients and increase toxicity of phenytoin and valproic
on anticoagulants. acid. Doses >2 g/day may potentiate glucose-
lowering effect of sulfonylurea drugs.
Discontinue if absolute neutrophil Effects may decrease with coadministration of
count decreases to <1200/μL or if corticosteroids and antacids. Toxicity increases
platelet count falls to <80,000/μL. when taken concurrently with theophylline,
cimetidine, aspirin, and NSAIDs.
Use caution in patients at Coadministration with naproxen is associated
increased risk of bleeding with increased occult GI blood loss. Prolongs
from trauma, surgery, or other bleeding time. Safety of coadministration with
pathologic conditions. Also use warfarin not established yet.
caution in patients with lesions
with propensity to bleed (such as
ulcers).
Renal impairment. Coadministration with cimetidine or
theophylline increases effects and
toxic potential. Increases effect of anti-
hypertensives.
568 Therapeutics for the Geriatric Neurology Patient
In a double-blinded, placebo-controlled, multicenter
study, treatment with pentoxifylline (European Pentoxi-
fylline Multi-Infarct Dementia Study, 1996) was found
to be beneficial for patients with multi-infarct dementia.
Significant improvement was observed in areas of intel-
lectual and cognitive function (Black et al., 1992). Also, the
extent to which neuroprotective drugs such as nimodip-
ine, propentofylline, and posatirelin can be useful is
currently underway and may be useful for VaD when
ongoing studies are complete. Preliminary studies have
showed a decrease in cognitive deterioration in patients
with cerebrovascular disease with the use of Nicardipine
(dihydropyridine calcium channel blocker).
Cerebrolysin, a neuropeptide earlier used in the treat-
ment of AD-related dementia, has been shown to be
an effective therapy in managing VaD. Cerebrolysin
(daily dose of 20mL) used in combination with Aspi-
rin in a multicenter, randomized, double-blind clinical
trial for 24 weeks reported positive primary outcomes
for ADAS-cog and CIBIC scores, as well as improved
scores on MMSE and ADAS-ADL (secondary efficacy
measures). In the treatment group, 75.3% of the patients
had improved CIBIC scores, whereas only 37.4% had
improved scores in the placebo arm (Guekht et al., 2010).
Parkinson’s disease dementia
Cognitive impairment and dementia are common features
of Parkinson’s disease (PD). Estimated point prevalence
for dementia in PD population (usually elderly with more
severe extrapyramidal signs) is about 30% (Aarsland and
Kurz, 2010). Parkinson’s disease dementia (PDD) mani-
fests with impairment of executive function and attention
at first, whereas memory and visuoconstruction impair-
ment develop at a later stage. See Chapter 12.1 for addi-
tional details on how to treat motor aspects of PD.
Significant neuropsychiatric burden accompanies cog-
nitive decline, as well as fluctuation in attention. Mean
duration for the development of dementia through
inception is around 10 years. Various RCTs have deter-
mined that 48% of patients with PDD develop visual hal-
lucinations in the first year of the disease.
The main neurochemical impairment in PD is dopa-
mine, but significant deficits in cholinergic transmission
are also in these patients. These deficits are largely local-
ized to the cholinergic system of the basal forebrain and
brainstem, in contrast to patients with AD, where cholin-
ergic deficits are primarily seen in the hippocampus. In
patients with PDD, cholinergic deficits may be greater
than in AD patients with similar levels of cognitive impair-
ment (Poewe et al., 2008). Because no approved medica-
tion can stop or reverse disease progression, efforts have
been focused on delivering symptom-oriented treatments
(Emre, 2007). Significant cholinergic deficits are evident
in these patients; hence, appropriate treatment strate-
gies can be initiated using anti-cholinesterase inhibitors.
Cholinesterase inhibitor drugs (ChEIs) improve choliner-
gically mediated cognitive and neuropsychiatric symp-
toms in PDD. Various randomized studies have shown
the association between functional imaging and use of
ChEIs to treat PDD (Kramberger et al., 2010). Increased
regional cerebral glucose metabolism and blood flow has
determined the positive as well as significant effects of
ChEIs in PDD. Use of rivastigmine, donepezil, and galan-
tamine has been most widely seen in studies conducted
in this disease state, but use of tacrine has also been dis-
cussed in a few small studies. Rivastigmine and donepe-
zil are now the most widely accepted and used medica-
tions for PDD, although the use of memantine has been
discussed in the literature to some extent. Various studies
(mostly RCTs) have shown an improvement in behavioral
and psychotic symptoms (hallucinations) with the use of
anti-cholinesterase inhibitors. (See Table 23.7 for a sum-
mary of published open-label and RCTs and case reports
in patients with PDD.)
Rivastigmine
The most widely used and approved medication for treat-
ment of cognitive impairments associated with PDD is
rivastigmine. Various randomized studies have shown
the safety and efficacy of this medication in its ability to
treat the disease state.
Significant treatment differences have been noted in
ADAS-cog and MMSE scales when the patient popula-
tion with PDD was treated with rivastigmine. One of the
largest RCTs conducted by Emre and Colleagues noted
improvement in cognition by 2.1 points on the ADAS-cog
scale as compared to the control group, which saw dete-
rioration by 0.7 points. Similar improvements were noted
on other cognitive assessment measures (ADCS-ADL,
CDR, MMSE, and NPI) when this subset was treated with
rivastigmine. Nausea, vomiting, worsening tremors, and
death were noted in some instances. Various studies are
underway evaluating the benefits of capsule formulation
versus a transdermal patch.
Donepezil
Donepezil is another widely used medication in clini-
cal trials for the treatment of cognitive deficits associ-
ated with PDD, but regulatory authorities have not yet
approved it. Treatment benefits have been assessed on the
basis of various cognitive measures (ADAS-cog, CIBIC,
NPI), and significant improvements have been reported.
Several clinical trials are underway to confirm the safety
and efficacy of donepezil in the management of PDD. Of
particular interest is one of the largest clinical trials, by
Dubois et al.; results are eagerly awaited.
Memantine
Memantine is postulated to modulate the glutamater-
gic neuronal transmission and, hence, could potentially
 Evidence-Based Pharmacologic Treatment of Dementia 569

Table 23.7 Summary of published open-label and randomized clinical trials and case reports in patients with PDD
Study duration Number of
Study Medications (weeks) subjects Main findings

Dubois et al. (2007) Donepezil 24 550 Improvement in MMSE and CIBIC-plus. No significant changes in
ADAS-cog, NPI, or motor symptoms.
Emre et al. (2004) Rivastigmine 24 541 Improvement noted in ADAS-cog, MMSE, ADCS-ADL, NPI, and CDR.
Poewe et al. (2006) Rivastigmine 24 334 Improvement in ADAS-cog, MMSE, and NPI. No change in motor
symptoms.
Thomas et al. (2005) Donepezil 20 40 Improvement on MMSE and NPI. No change in motor symptoms.
Dujardin et al. (2006) Rivastigmine 24 28 Improvement noted in total MDRS score.
Giladi et al. (2003) Rivastigmine 26 28 Improved ASAS-cog and attention component of MMSE.
Müller et al. (2006) Donepezil 12 24 Improvement in MMSE. No change in Clinician Global Impression
(CGI) or motor symptoms.
Rowan et al. (2007) Donepezil 20 23 Improvements on power of attention and reaction time. No
significant improvement in continuity of attention or cognitive
reaction time.
Ravina et al. (2005) Donepezil 10 22 Improvements on MMSE and CGI. No change in ADAS-cog or MDRS.
Leroi et al. (2004) Donepezil 18 16 Improvement in memory component of MDRS. No change in MMSE.
Reading et al. (2001) Rivastigmine 14 15 Improvement noted on MMSE and NPI.
Minett et al. (2003) Donepezil 20 15 Improvement on MMSE after 20 weeks noted. Improvement in
behavioral symptoms.
Aarsland et al. (2002) Donepezil 20 14 Improvement on MMSE and CIBIC-plus.
Werber and Rabey (2001) Donepezil and 26 11 (7 on tacrine, Improvement on ADAS-cog. No significant change in MMSE or
tacrine 4 on donepezil) motor symptoms.
Fabbrini et al. (2002) Donepezil 6 8 Improvement on PPRS. No change in MMSE.
Bergman and Lerner (2002) Donepezil 6 6 Improvement on CGI and NPI. No change in MMSE.
Bullock and Cameron (2002) Rivastigmine 20–52 5 Improved cognition and visual hallucinations.
Kurita et al. (2003) Donepezil 2–56 3 Improvement in hallucinations. Some improvement in cognition.

prevent the toxic effects of raised concentrations of glu-
tamate. Memantine has been shown to be clinically effi-
cacious in AD and VaD. Various small and large RCTs
have been and are being conducted, but results from
small RCTs have shown that, in PDD, memantine was
well tolerated; results are limited due to a sample size,
however (Aarsland et al., 2009). Results of larger RCTs are
still awaited, and its potential use in combination with
ChEIs is highly debated. One of the studies on the use of
memantine and ChEIs reported enhanced neurotoxicity
in the rat brain, so the use of this regimen needs further
studies and clarification.
Additional agents are in phase 2 and phase 3 trials,
including pimavanserin, a 5-HT2A inverse agonist/
antagonist being studied for its effects in patients with
PDD.
Pseudobulbar affect
There is increasing recognition of pseudobulbar affect
(PBA) among geriatric neurologic diseases and the diag-
nosis is being made more often, now that the first FDA-
approved treatment Nuedexta (quindine sulfate 10 mg
and dextromethorphane HBr) is available for PBA. The
typical PBA episode is about 45 seconds with an abrupt
onset and end. It can be characterized as “laughter without
mirth” or “crying without sadness.” Historically, several
terms were been used to describe PBA: pathologic laugh-
ing and crying, emotional lability, emotional dyscontrol,
emotional incontinence, excessive emotionality, post-
stroke emotionality, and so on. While families and profes-
sional caregivers are negatively affected by this behavior,
the patient typically does not have a change in affect or
active tearing when crying occurs. This lack of affective
disturbance differentiates it from depression. Utilizing
psychoactive agents in this subset of patients, who are
often misdiagnosed as having depression can potentially
have significant side effects and is best avoided. Center
for Neurologic Study-Lability Scale (CNS-LS) is a seven-
question validated scale (Moore et al., 1997; Smith et al.,
2004; Phuong et al., 2009) that can provide a score for total
PBA frequency and severity and possibly help in differen-
tiating from depression symptoms.
Nuedexta
In 2010, the FDA approved Nuedexta, a combination
product containing dextromethorphan hydrobromide 20
570 Therapeutics for the Geriatric Neurology Patient
mg (an uncompetitive NMDA receptor antagonist and
sigma-1 agonist) and quinidine sulfate 10 mg (a cyto-
chrome P450 (CYP) 2D6 inhibitor) that is indicated for the
treatment of PBA. Pivotal studies to support the effective-
ness were performed in patients with underlying amyo-
trophic lateral sclerosis (ALS) or multiple sclerosis (MS).
The typical starting dose is one capsule daily by mouth
for 7 days after which 1 capsule is used every 12 hours if
tolerated. As the quinidine content in Nuedexta is only
one-tenth of the lowest dose of quinidine tablets, con-
comitant use with quinidine, quinine, or mefloquine is
contraindicated. Avoid using this drug in patients with
a history of quinidine, quinine or mefloquine-induced
thrombocytopenia, hepatitis, hypersensitivity reactions to
dextromethorphan, within 14 days of stopping an MAOI,
prolonged QT interval, congenital long QT syndrome,
history suggestive of torsades de pointes, or heart failure,
complete atrioventricular (AV) block without implanted
pacemaker, patients at high risk of complete AV block and
patients using concomitant drugs that both prolong QT
interval and are metabolized by CYP2D6 (e.g., thiorida-
zine). The agent is used with caution in left ventricular
hypertrophy (LVH) or left ventricular dysfunction (LVD).
In patients with dizziness take precautions to reduce falls.
SSRIs or tricyclic antidepressants increases the risk of
serotonin syndrome, discontinue the SSRI if this occurs.
Anticholinergic effects of quinidine can worsen myasthe-
nia gravis and other sensitive conditions. The most com-
mon adverse reactions (incidence of ≥3% and twofold
greater than placebo) in patients taking Nuedexta are
diarrhea, dizziness, cough, vomiting, asthenia, periph-
eral edema, urinary tract infection, influenza, increased
gamma-glutamyltransferase, and flatulence.
Conclusion
Increasing geriatric neurologic diseases such as AD can
make the US health-care system unviable. An aging
population is a major risk factor for dementia, with
more than 100 million individuals projected to have AD
by 2050 (Alzheimer’s Disease International, 2010). Only
five approved drugs for AD exist, and no FDA-approved
medications are available for other dementias, except for
the treatment of PBA. There is an urgent need for more
clinical trials and effective medications.
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 Chapter 23.2
Immunotherapy for Alzheimer’s Disease
Michael Grundman, Gene G. Kinney, Eric Yuen, and Ronald Black
Introduction
Alzheimer’s disease (AD) and other dementias affect
approximately 36 million individuals worldwide.
Unless successful treatments or preventives are found,
it is expected that the number of individuals with
dementia will increase to 66 million by the year 2030
and to 130 million by 2050 (Wimo and Prince, 2010).
For an individual, the risk of developing AD doubles
with every 5–6 years of advancing age (Ziegler-Graham
et al., 2008), with some estimates of disease prevalence
surpassing 40% after age 85 (Hebert et al., 2003). Once
affected, patients with AD suffer an unrelenting decline
of cognition associated with behavioral abnormalities,
ultimately leading to loss of functional independence
and death. There is an urgent need to discover and
develop effective treatments and preventive strategies,
both to reduce current AD morbidity and to preempt
the predicted increase in disease prevalence as the
world’s population ages.
The pathologic hallmarks of AD include synaptic and
neuronal loss, extracellular amyloid deposition, and
intraneuronal neurofibrillary tangles. Extracellular amy-
loid deposition may be found (1) in neuritic plaques—
amyloid plaques surrounded by dystrophic neurites,
activated microglia, and gliosis; (2) in diffuse plaques—
extracellular amyloid deposits without dystrophic neu-
rites and gliosis; and (3) within cerebral blood vessels
(cerebral amyloid angiopathy (CAA)). The major protein
component of deposited amyloid is Aβ, a 40–42 amino
acid peptide that is generated by the proteolytic process-
ing of the amyloid precursor protein (APP). Soluble amy-
loid and amyloid deposits may play a pivotal initiating
role in the development of AD. This hypothesis is based
partly on the observation that certain autosomal domi-
nant genetic mutations lead to overproduction of Aβ,
amyloid deposition, and early onset of dementia. Addi-
tional genetic evidence for the importance of Aβ comes
from studies of apolipoprotein E, a cholesterol carrier that
is commonly expressed in three different allelic forms (ε2,
ε3, and ε4) that differ from each other by a small number
of critical amino acid substitutions. Individuals who carry
the apolipoprotein E ε4 allele tend to develop amyloid
plaques and CAA with associated clinical symptoms of
dementia earlier than those without this allele, although
at a later age than those with the autosomal-dominant
forms of AD.
574
The amyloid hypothesis posits that, in AD, the bal-
ance between the production and clearance of Aβ is dis-
rupted, leading to a build-up of excess Aβ in the brain.
The excess Aβ is toxic to neurons, contributes to tau
hyperphosphorylation and tau pathology, and leads to
progressive neurodegeneration, cognitive dysfunction,
and functional impairment (Hardy and Selkoe, 2002;
De Felice et al., 2008). If the hypothesis is correct, poten-
tial therapeutic approaches that lessen the imbalance
between production and clearance and restore Aβ con-
centrations to normal levels may be successful. Toward
this end, a number of therapeutic approaches are cur-
rently being evaluated both preclinically and in clinical
trials. These include beta and gamma secretase inhibi-
tors to reduce Aβ production and anti-Aβ immunother-
apy to facilitate Aβ clearance.
Preclinical studies with anti-Aβ
immunotherapy
Understanding the progression of AD and the potential
role of immunotherapy has been enhanced by transgenic
mouse models of AD that express AD pathology simi-
lar to that of humans (Wilcock and Colton, 2009). Aβ is
derived through cleavage of APP by beta and gamma
secretase. In humans, familial autosomal-dominant AD
is caused by mutations in the APP or presenilin genes,
the latter of which express proteins that form gamma
secretase. These mutations cause overexpression of Aβ.
Transgenic mouse models of AD have been genetically
engineered to overexpress human mutations in APP,
presenilin 1, and/or presenilin 2, in order to generate
amyloid-related pathologies, including amyloid deposi-
tion, synaptic loss, and dystrophic neurites. The PDAPP
mouse, a transgenic mouse model that overexpresses
mutant APP, was the first transgenic mouse reported
to exhibit AD pathology (Games et al., 1995). This same
mouse model was later utilized by Schenk et al. (1999),
who discovered that immunizing PDAPP mice with
full-length Aβ could reduce Aβ plaque burden, gliosis,
and dystrophic neurites. Bard et al. (2000) later showed
that monoclonal antibodies could similarly reduce Aβ
pathology in transgenic mice through passive admin-
istration. Antibodies produced against the N-terminal
regions of Aβ were found to be particularly efficacious
for plaque clearance. It was further demonstrated that

antibody Fc-mediated activation of microglia facilitated
this process.
Transgenic mice often develop age- and Aβ-related
behavioral deficits that resemble the dementia seen in
humans. The behavioral deficits may precede Aβ depo-
sition and formation of plaque (Comery et al., 2005).
The latter suggests that soluble Aβ species may be
important in causing or contributing to these behav-
ioral deficits. The importance of nonplaque Aβ species
is also highlighted by the rapid reversal of behavioral
impairments with administration of some antibodies
that bind only soluble A β and not fibrillar Aβ (Dodart
et al., 2002; Kotilinek et al., 2002). Nevertheless, the
potential importance of removing Aβ plaque cannot
be discounted. Some investigators have found amelio-
ration of dystrophic neurites in regions where plaque
has been removed (Brendza et al., 2005; Serrano-Pozo
et al., 2010). It also seems likely that various species of
Aβ are in equilibrium, so the targeted removal of only
soluble Aβ could lead to replenishment of this pool by
Aβ present in plaques. Transgenic mice that have been
immunized with Aβ or administered anti-Aβ antibod-
ies show cognitive performance that is superior to that
of control transgenic mice (Janus et al., 2000; Morgan
et al., 2000). The effectiveness of anti-Aβ antibodies to
reduce behavioral deficits in non-plaque-bearing trans-
genic mice may vary, depending on the species of Aβ to
which the antibody binds, the Aβ epitope to which the
antibody is directed, and the sequence and structure
of the antibody (Basi et al., 2010). Partly because it is
unclear whether plaque clearance, binding to soluble
Aβ, or other factors may be most relevant for clinical
efficacy, a sizeable number of antibodies that are pur-
ported to interact differentially with different Aβ spe-
cies have been generated and are being studied in the
clinic.
Some transgenic mice treated with anti-Aβ antibodies
developed brain microhemorrhages, particularly at high
doses (Wilcock and Colton, 2009). It is possible that these
microhemorrhages are related to Aβ clearance from amy-
loid-laden blood vessels. Some evidence indicates, how-
ever, that the temporal clearance of vascular amyloid and
appearance of microhemorrhages may be a self-limited
process, ultimately leading to restoration of vessel integ-
rity (Schroeter et al., 2008).
Clinical experience with Aβ
immunotherapy
Several therapeutic approaches are currently being
evaluated in clinical trials. Aβ immunotherapy can be
divided into active and passive forms. Active immu-
notherapy refers to immunization with the Aβ peptide
or fragments derived from it; passive immunotherapy
Immunotherapy for Alzheimer’s Disease 575
refers to the parenteral administration of anti-Aβ
antibodies. The first agent to be used in active
immunization was AN1792.
AN1792
Based on the striking results of Aβ immunotherapy in
transgenic mice, clinical trials of active vaccination with
full-length Aβ (AN1792) were initiated in 2000. In a
phase 1, multiple ascending dose study lasting 84 weeks,
80 subjects were randomized to AN1792. Approximately
60% of subjects developed positive antibody responses.
Clinical benefits were observed on the Disability Assess-
ment for Dementia (DAD), evidenced by a slowing
of decline in the treated group at week 84. One patient
developed meningoencephalitis (ME) (diagnosed at
autopsy after the patient expired 12 months later). This
patient showed findings similar to Aβ immunization in
transgenic mice (Nicoll et al., 2003), including extensive
areas of cortex that had a lower-than-expected density of
amyloid plaques that were devoid of dystrophic neurites
and astrocytosis.
In a subsequent phase 2 trial (Gilman et al., 2005),
300 patients were randomized to AN1792 and 72 patients
to placebo. Dosing in the trial was halted due to the
occurrence of ME in 6% of subjects in the active treatment
group. However, patients continued to be followed for up
to 12 months after dosing was stopped. Most patients in
the trial received one or two doses. Approximately 20%
of patients developed sufficient antibody responses to be
considered antibody responders. No significant treatment
differences were observed on most clinical endpoints at
the end of 12 months. However, an apparent treatment
benefit on the neuropsychological test battery (NTB)
was observed in antibody responders (Figure 23.3a). In
addition, in a subset of study subjects in whom CSF was
obtained before and after treatment, CSF tau was reduced
in antibody responder patients, compared to placebo
patients. Unexpectedly, antibody responders showed
greater reduction in brain volume compared to placebo,
despite demonstrating better performance on the NTB. It
is unclear whether this volume loss was due to amyloid
plaque removal or other mechanisms, leading to fluid
shifts from the brain parenchyma to the CSF spaces (Fox
et al., 2005).
Among those patients in the AN1792 studies who
developed anti-Aβ antibodies, most generated antibod-
ies to the N-terminal, or amino terminus of Aβ (Lee et al.,
2005). By contrast, studies into the etiology of ME sug-
gested that this side effect was likely caused by a proin-
flammatory T-cell response against the carboxy terminus
of Aβ. Also, because ME was not observed in patients
until after the addition of polysorbate 80 to the study drug
formulation (added to enhance the solubility of the Aβ in
solution), it seems possible that this addition may have
altered the conformation of the full-length Aβ antigen, to
576 Therapeutics for the Geriatric Neurology Patient

AN1792 AN1792
(a) Antibody (b) Antibody
Placebo Responders Placebo Responders
0.10 0

Mean change from baseline on DAD

0.05 (N = 36) –10 Figure 23.3 (a) AN1792 phase 2 study
Mean change from baseline on

neuropsychological test battery (NTB)

0.00 –20 results showed an improvement on the
NTB after 1 year

after ~ 4.5 years

nine-component NTB composite after
–0.05 –30 1 year in antibody responders, compared
to the placebo group. Data from Gilman et
–40 al. (2005). (b) AN1792 follow-up study after
–0.10
approximately 4.5 years found that patients
(N = 24) initially classified as antibody responders
–0.15 –50 in the AN1792 phase 2 trial had less decline
in activities of daily living as determined
–0.2 –60 (N = 27)
by the Disability Assessment for Dementia
(N = 48)
p = 0.015 (DAD), compared with placebo-treated
p = 0.020
–0.25 –70 patients. Data from Vellas et al. (2009).

permit induction of this proinflammatory T-cell response with the original AN1792 results, which showed a poten-
(Schenk et al., 2005; Pride et al., 2008). tial treatment effect on the NTB in antibody responders,
less decline was seen on the DAD (Figure 23.3b), the
AN1792 follow-up studies Dependence Scale and Rey Auditory Verbal learning
A long-term follow-up study on the patients included in test, in the antibody responders, compared to the pla-
the AN1792 phase 1 study was reported by Holmes et al. cebo group. The data support the possibility that even
(2008). They found that a number of subjects who had sustained, low levels of anti-Aβ antibodies could have
developed elevated titers during the initial study period long-term cognitive and functional benefits, and support
had a high degree of plaque removal at autopsy, but nev- the contention that earlier treatment for longer periods
ertheless continued to show progressive dementia prior may be the most effective way to avert or lessen decline
to death. This finding suggests that reducing Aβ may not in patients with AD pathology.
be sufficient to halt the progressive neurodegeneration
at the late stage of AD at which treatment was initiated. Second-generation immunotherapies
The authors suggested that although it is possible for Aβ Because most patients developed N-terminal antibod-
to be an initiating factor in the neurodegenerative pro- ies in response to AN1792 and ME is hypothesized to
cess, it may be less critical in fostering neurodegenera- be related to a T-cell response against the carboxy ter-
tion later after other downstream pathologies (such as minus, novel, alternative approaches to immunotherapy
neurofibrillary pathology) are underway. Interestingly, are being tested. One approach is to actively immunize
among the autopsied subjects, the patients with the lon- patients with Aβ immunogens that are comprised of
gest survival had the least amount of brain Aβ depos- small Aβ peptide fragments conjugated to carrier pro-
its. This raises the possibility that reduction in brain teins. This approach utilizes Aβ peptide fragments that
amyloid in patients may be a relatively slow process in are of insufficient size to elicit a T-cell-specific immune
immunized patients and that initiating treatment earlier response to Aβ while still allowing B-cells to gener-
and for a longer period of time when patients are either ate antibodies against the small peptide fragment. The
asymptomatic or have fewer cognitive deficits might be purpose of the carrier protein is to induce a T-helper
more effective. response that promotes the generation of antibodies. A
A follow-up study of the phase 2 AN1792 study was second approach is passive immunotherapy, wherein
reported by Vellas et al. (2009). Subjects initially iden- anti-Aβ antibodies are produced in modern bioreactors
tified as antibody responders were compared with pla- outside the human body and are parenterally adminis-
cebo-treated subjects approximately 4.5 years after the tered. Both of these approaches are designed to capital-
patients were immunized with AN1792. Most of the ize on the possible benefits conferred by anti-Aβ antibod-
antibody responders who were tested (17/19) contin- ies while avoiding the potentially harmful Aβ directed
ued to have detectable antibody responses 4.5 years T-cell responses that appear more likely to occur if the
later, although at much lower levels than during the full-length Aβ peptide were administered (Schenk et al.,
first year after their initial immunization. Consistent 2005; Pride et al., 2008).

Passive versus active immunotherapy
Active and passive immunization each has relative
advantages and disadvantages (Table 23.8). Both meth-
ods should circumvent the activation of T cells and
reduce the likelihood of ME, as observed with AN1792.
With passive immunization, the administered antibod-
ies can be tested and selected for their ability to bind
specific Aβ epitopes to soluble or plaque forms of Aβ
or to specific conformations of peptide. The dose can
be specified or individualized based on patient char-
acteristics. If adverse reactions occur, subsequent infu-
sions can be stopped and the antibody can be cleared
from the patient in accordance with its biologic half-life.
With active immunization, not everyone will necessarily
produce an optimal antibody response or even an ade-
quate antibody response, and the response is polyclonal.
Hence, the quantity and quality of the antibody response
differ from patient to patient. This usually requires an
adjuvant to induce an adequate antibody response, and
the adjuvant itself may be associated with or contribute
to adverse events. If an adverse event occurs, it may be
difficult or impossible to turn off the immune response,
and it may take a long time for antibody titers to drop,
even if subsequent immunizations are not administered.
The principal advantage of active immunization is that
it does not require intravenous infusions (they are typi-
cally injected intramuscularly), it should be possible
to administer the immunizations less frequently at a
lower cost, and, if very safe, it would be more accept-
able for prevention in preclinical AD or in a prodromal
AD population, where the presence of raised antibody
concentrations for 5–15 years or longer might be most
beneficial. Passive immunization through subcutaneous
dosing is yet another option if dosing regimens require
long periods of administration to be effective. Subcuta-
neous dosing has been used in other chronic diseases
that require long-term administration, such as interferon
Table 23.8 Comparison of passive and active immunotherapy
Passive
Drug product Peripherally administered anti-Aβ antibodies that are uniform Aβ antigen induces anti-Aβ titers by the patient’s native
over time, with well-characterized Aβ epitope specificity
Treatment Dependent in part on the half-life of the antibody; may
frequency range from every few days to every few months
Route Typically intravenous or subcutaneous
Control over antibody Antibody concentrations more readily controllable due to
titers strong dose dependence
Ability to reduce Antibody levels decline in relation to antibody half-life when
antibody exposure if antibody administration is stopped; plasma exchange is an
adverse events occur option
Immunotherapy for Alzheimer’s Disease 577
beta-1b (Betaseron); glatiramer acetate (Copaxone), used
for multiple sclerosis; and omalizumab (Xolair), used for
asthma. A number of companies are now studying sub-
cutaneous formulations of anti-Aβ monoclonal antibod-
ies in AD and prodromal AD.
Mechanisms of anti-Aβ immunotherapy
A number of hypotheses have been proposed to explain
how anti-Aβ immunotherapy clears Aβ deposits from
the brain. One possibility is that a small proportion of
the peripherally administered anti-Aβ antibodies crosses
the blood–brain barrier and induces the opsonization
of Aβ aggregates. According to this proposal, activated
microglia bind the anti-Aβ antibodies at their Fc region
and phagocytize the Aβ and anti-Aβ antibody complexes
via Fc receptor-mediated phagocytosis. While microglial
activation may play an important role for some antibod-
ies, microglial-independent mechanisms are also pos-
sible. Anti-Aβ antibody fragments (Fab) that lack the Fc
domain necessary for microglial activation seem effective
at removing plaques (Bacskai et al., 2002), as do anti-Aβ
antibodies that have had their Fc function decreased
through enzymatic deglycosylation (Wilcock et al., 2006).
Active immunization in transgenic mice that lack func-
tional Fc receptors is similarly capable of reducing plaque
burden (Das et al., 2003).
These findings suggest that “catalytic disaggregation” of
Aβ plaques is a potential mechanism of anti-Aβ immuno-
therapy. This mechanism proposes that anti-Aβ antibodies
bind amyloid fibrils and disrupt their tertiary structure.
This then leads to solubilization of Aβ deposits and efflux
of the soluble Aβ from the brain via perivascular pathways
(Weller et al., 2009). According to a recent study, Aβ42 the
form of Aβ that is typically found in plaques in AD patients,
was increased in the cerebral blood vessels of some patients
after immunization with AN1792 (Boche et al., 2008). This
increase may be a transient phenomenon because it was
not apparent in the patients with the longest follow-up
Active
immune system; often includes carrier proteins and added
adjuvants; polyclonal antibody response changes over time
within patients and variable between patients
Relatively few administrations generally required to induce
and maintain anti-Aβ titers
Typically intramuscular or subcutaneous
Antibody concentrations vary, depending on patient’s immune
response
Anti-Aβ antibody immune response more long lasting; titers
may remain elevated for years
578 Therapeutics for the Geriatric Neurology Patient

after treatment with AN1792, suggesting that, over time, A phase 1 study determined a half-life for bapineu-
Aβ was cleared from both the parenchyma and cerebral zumab of 24 days (Black et al., 2010), permitting an
vasculature. The data are consistent with the hypothesis IV infusion schedule every 13 weeks. A bapineuzumab
that anti-Aβ immunization solubilizes plaque Aβ42, which phase 2, multiple ascending dose trial that enrolled
then at least partially exits the brain via the perivascular 234 subjects (124 on bapineuzumab and 110 on pla-
pathway. cebo) did not show statistically significant benefits over
The “peripheral sink” hypothesis is yet another pro- 78 weeks when analyzed by individual dose cohorts,
posed mechanism to explain how anti-Aβ immunother- but a number of exploratory analyses were promising:
apy may clear Aβ deposits from the brain. In this model, When all the dose cohorts were combined, favorable
peripheral anti-Aβ antibodies bind circulating Aβ; this treatment trends were observed on the Alzheimer’s
then leads to a shift in the Aβ concentration gradient Disease Assessment Scale–Cognitive subscale (ADAS-
between brain and blood, with a net increase in Aβ efflux cog) (Figure 23.4) and NTB (Salloway et al., 2009).
from the brain (DeMattos et al., 2001). Favorable treatment differences were also observed on
the ADAS-cog and DAD in study completers (subjects
Clinical experience with passive immunization who received all doses of bapineuzumab during the
Aβ immunotherapy can be divided into active and pas- study). Exploratory analyses in ApoE ε4 noncarriers
sive forms. Passive immunotherapy refers to the paren- also suggested potential treatment benefits on a num-
teral administration of anti-Aβ antibodies in contrast to ber of cognitive and functional endpoints. In contrast
active immunotherapy, which refers to immunization to the results in the AN1792 study, however, bapineu-
with the Aβ peptide or fragments derived from it. The zumab-treated ApoE ε4 noncarriers demonstrated less
largest published data is on bapineuzumab, while a large brain volume loss on MRI compared to placebo-treated
number of other immunotherapies are in clinical trials. patients, paralleling the clinical findings. In a CSF
Tables 23.9 and 23.10 summarize these. substudy among patients in whom CSF was obtained
before and after treatment, there was a trend (p = 0.056)
Bapineuzumab for reduced CSF phosphorylated tau protein (phospho-
Bapineuzumab is a humanized monoclonal antibody tau) in bapineuzumab-treated subjects compared to
directed against the N-terminus of Aβ. N-terminal anti- placebo (Figure 23.5).
bodies have been shown to bind both deposited and A smaller, phase 2 bapineuzumab clinical trial (n = 28)
soluble Aβ to reduce amyloid burden and plaques and was conducted in patients who also received a series
to produce beneficial effects on dystrophic neurites, syn- of carbon-11-labelled Pittsburgh compound B, positron
apses, and behavior in transgenic mice (Bard et al., 2000; emission tomography (PIB PET) scans during their course
Bussiere et al., 2004; Buttini et al., 2005; Games et al., of treatment (Rinne et al., 2010). PIB PET was used as a
2006; Shankar et al., 2008; Basi et al., 2010). It is therefore measure of cortical fibrillar amyloid-β load. Compared
hypothesized that bapineuzumab should similarly bind to placebo, bapineuzumab-treated patients showed an
to Aβ in the brain, facilitate its removal, and result in ben- approximate 25% reduction in amyloid load as mea-
eficial clinical effects. sured by PIB PET over the course of the 78-week study

mITT Population Completers

(a) (b) Figure 23.4 Bapineuzumab
2 Placebo 2 Placebo phase 2 exploratory analyses for
Bapineuzumab Bapineuzumab four combined dose cohorts in (a)
0 0 the modified intent-to-treat (mITT)
Change from baseline

and (b) the completer populations.

Change from baseline

–2 –2 Figure shows estimated mean

change from baseline over time on
–4 –4
Alzheimer’s Disease Assessment
Scale–Cognitive subscale
–6 –6
(ADAS-cog). Error bars represent
–8 –8 one standard error. A positive
change from baseline represents
–10 –10 improvement. The p values are not
Rx difference at week 78 = 2.3 Rx difference at week 78 = 4.3
p = 0.078 adjusted for multiple comparisons.
p = 0.003
–12 –12 Source: Salloway et al. (2009).
0 11 24 37 50 63 78 0 11 24 37 50 63 78 Reproduced with permission of
Weeks Weeks Lippincott Williams & Wilkins.
 Immunotherapy for Alzheimer’s Disease 579

Change in CSF phospho-tau from baseline 2 immunotherapy-treated patients (Boche et al., 2010b;
0
–2
–4
–6
Placebo (n = 15)
–8
–10
–12
–14
–16 Bapineuzumab (n = 20)
Figure 23.5 One-year change from baseline in CSF phospho-tau
(pg/mL) in bapineuzumab- and placebo-treated groups from
bapineuzumab phase 2 clinical trial 201. Graph shows mean
change (+/− SE) and p value from analysis of covariance model.
Source: Salloway et al. (2009). Reproduced with permission of
Lippincott Williams & Wilkins.
(Figure  23.6). The amyloid reduction (Figure 23.7) was
apparent in all six brain regions prespecified for analysis,
and the treatment difference between the bapineuzumab-
treated group and placebo group increased over the
course of the study. Some of the patients in the study
also had CSF collected before and after treatment. Post
hoc analyses combining the CSF phospho-tau and total
tau data from both bapineuzumab phase 2 studies dem-
onstrated a lowering of CSF phospho-tau (p < 0.05) in
the treated group versus placebo group (Blennow et al.,
2010). The lowered phospho-tau would appear to sup-
port potential downstream physiologic effects for bap-
ineuzumab beyond the reduction of amyloid and would
be consistent with downstream effects on tau as posited
by the amyloid cascade hypothesis (Hardy and Selkoe,
2002) and seen in preclinical models (Oddo et al., 2004,
2006; De Felice et al., 2008) and at autopsy in AN1792
Serrano-Pozo et al., 2010).
Collectively, these phase 2 results, including the possi-
ble treatment benefits observed, the slower brain atrophy
on MRI in ApoE ε4 noncarriers, the reduced phospho-tau
in CSF, and reduced brain amyloid load as measured by
PIB PET, argue for further testing of bapineuzumab in
phase 3 pivotal trials.
The current phase 3 bapineuzumab program is designed
to evaluate clinical efficacy, safety, and evidence of disease
modification based on a combination of clinical and bio-
marker (Liu et al., 2010). Bapineuzumab is currently being
tested in four phase 3 trials of 18 months’ duration. More
than 4000 subjects worldwide are participating. ApoE ε4
p = 0.056
carriers and noncarriers are being evaluated in separate
trials. The presumption is that if clinical benefits with bap-
ineuzumab are sustained over 18 months with evidence
of slowed disease progression on cognitive and functional
measures, and if alterations in AD-related biomarkers (such
as CSF phospho-tau and PIB PET) are confirmed, these
findings would provide compelling evidence for disease
modification. [Note: The bapineuzumab phase 3 program
has concluded since the original submission of this chapter.
In the North American phase 3 studies both in ApoE 4 car-
riers and non-E4 carriers, no significant differences were
found on the primary clinical endpoints. In carriers, the
0.5 mg/kg dose was associated with reductions in amyloid
plaque accumulation and CSF p-tau. In non-carriers, the
1.0 mg/kg dose was associated with a reduction in CSF
p-tau. No significant differences in brain volume were
observed in either study. Amyloid-related imaging abnor-
malities (ARIA) increased with bapineuzumab dose and
number of ApoE ε4 alleles. The investigation team con-
cluded that in mild-to-moderate AD, clinical efficacy was
not demonstrated despite evidence of target engagement
and changes in a downstream biomarker. Intervention ear-
lier in the course of AD may be necessary to demonstrate
clinical benefits with antiamyloid immunotherapeutic
agents such as bapineuzumab (Salloway et al., in press).]

0.4 Placebo
Bapineuzumab
Estimated mean change from
baseline in mean 11C-PiB

0.3

0.2

0.1
Figure 23.6 Estimated change from baseline over
time in mean ¹¹C-PIB PET for bapineuzumab-
0
and placebo-treated groups. Data shown are
least squares means and 95% CIs. Difference
–0.1
between patients in the placebo group and
those in the bapineuzumab group at week
–0.2
78 = −0.24 (p = 0.003). PiB = Pittsburgh
compound B. Source: Rinne et al. (2010). Baseline 20 45 78
Reproduced with permission from Elsevier. Week
580 Therapeutics for the Geriatric Neurology Patient

Screen Week 78 Screen Week 78

(a) –0.09 (b) –0.33

treated patients
Bapineuzumab

4.0

(c) 0.06 (d) 0.25

treated patients
Placebo

0.0

Figure 23.711C-PIB PET images in two bapineuzumab-treated (a, b) and two placebo-treated (c, d) patients. Average 11C-PIB PET changes

from baseline to week 78 are shown at the top center of each panel for each patient (a–d). The scale bar shows the PiB uptake ratios relative
to the cerebellum. Source: Rinne et al. (2010). Reproduced with permission from Elsevier. (For a color version, see the color plate section.)

In addition to bapineuzumab IV, a subcutaneous for-
mulation of bapineuzumab, administered monthly, is
being studied in mild-to-moderate AD (NCT01254773).
Vasogenic edema with anti-Aβ immunotherapy
An intriguing side effect was also observed on brain
MRI in some of the study participants of the phase 2
study (Salloway et al., 2009). In about 10% of patients,
cerebral hyperintensities on the FLAIR MRI sequence
appeared after dosing that resolved when dosing was
stopped (Figure 23.8). Some of the patients were even-
tually able to be redosed at lower doses after the MRI
abnormalities resolved without recurrence. Radiographi-
cally, the findings appeared to resemble vasogenic edema
(VE), or excess brain tissue water. In some patients, the
VE was asymptomatic and detectable only by MRI; in
others, transient symptoms such as headache and confu-
sion were noted. VE occurred with greater incidence in
ApoE ε4 carriers and patients exposed to higher doses of
bapineuzumab.
The cause of VE in immunotherapy-treated patients is
unknown, but it is interesting to speculate about the poten-
tial mechanisms. One possibility is that VE is related to rapid
clearance or mobilization of Aβ. The association of VE with
higher doses in the bapineuzumab studies supports this
possibility. Another possibility is that rapid mobilization of
amyloid from the parenchyma into perivascular drainage
pathways may overload the capacity of the drainage system,
with resulting extravasation of fluid (Boche et al., 2010a). Yet
another possibility is that direct removal of Aβ from cerebral

Predose 7 weeks 13 weeks 19 weeks 58 weeks

Figure 23.8 MRI scans from a 69-year-old woman with vasogenic edema (VE) after
treatment with bapineuzumab 1.0 mg/kg IV. She remained asymptomatic despite the
appearance of multiple areas of VE evident on the MRI. The VE was apparent on MRI
by 7 weeks after her first infusion and resolved by 19 weeks. The patient was redosed at
0.5 mg/kg of bapineuzumab IV and followed for more than 2 years without recurrence
of VE. Source: Salloway et al. (2009). Reproduced with permission of Lippincott
Williams & Wilkins.
 Immunotherapy for Alzheimer’s Disease 581

vessel walls results in increased vascular permeability. Such
a mechanism could explain the occurrence of microhemor-
rhages observed on T2* MRI sequences in some VE patients
(Sperling et al., 2009). Presumably, if vascular Aβ removal
was sufficiently robust, the increased permeability of the
vessel wall might permit some red cells to leak out along
with the fluid. ApoE ε4 carriers are known to have more
CAA than noncarriers (Greenberg et al.. 1995). The greater
risk of VE in ApoE ε4 carriers in the bapineuzumab phase
2 trials (Salloway et al., 2009) supports the possibility that
more severe vascular amyloid burden (CAA) at baseline
may be a contributing risk factor to VE. The greater amyloid
burden in the vasculature of ApoE ε4 carriers at baseline
could promote increased vascular permeability in treated
patients when the vascular amyloid is removed. It is also
possible that a focal inflammatory component may contrib-
ute to VE. Reports of spontaneous VE in patients with CAA,
some of whom showed inflammatory changes, support this
possibility (Oh et al., 2004; Kinnecom et al., 2007; Lim et al.,
2008). Lastly, if it is true that vascular Aβ, amyloid plaque,
and soluble Aβ are in equilibrium with each other, VE in
the setting of immunotherapy might be mediated by accel-
erated Aβ clearance relative to Aβ production. In this case,
other amyloid-lowering treatments in addition to immuno-
therapy, such as lowering Aβ production and deposition,
might also induce VE by tipping the balance between Aβ
deposition and clearance in favor of Aβ clearance.
Other passive immunotherapies in
clinical development
Little long-term data from immunotherapy trials other
than bapineuzumab have been published to date, but a
large number of other immunotherapies are in clinical tri-
als. Tables 23.9 and 23.10 summarize these.
Solanezumab is the human analog of the murine anti-
body 266 (Siemers et al., 2010). It is a monoclonal antibody
that binds to the mid-domain of Aβ and is thought to be
selective for soluble Aβ rather than deposited Aβ In contrast
to N-terminal antibodies, which, at least in part, are thought
to clear Aβ through microglial phagocytosis, it is proposed
that solanezumab may promote Aβ clearance from the
brain by altering the equilibrium of soluble Aβ between
the central nervous system and the periphery (see the
peripheral sink hypothesis discussed earlier). Results for a
single-dose phase 2 study in mild-to-moderate AD patients
showed a significant dose-dependent increase in plasma Aβ
and a trend toward increased CSF Aβ with a solanezumab
dose. As expected in a single-dose study, no significant
changes in cognition were observed (Siemers et al., 2010).
Two phase 3 clinical trials are underway to study the effi-
cacy of solanezumab in patients with mild-to-moderate AD
(NCT00905372, NCT00904683). The primary cognitive and
functional outcomes in these trials are the ADAS-cog and
ADCS-ADL. Solanezumab is being infused intravenously
every 4 weeks for 80 weeks. Each trial has approximately
1000 patients enrolled. [Note: The solanezumb phase 3 pro-
gram has concluded since the original submission of this
chapter. Solanezumab did not show a statistically significant
difference between treatment and placebo after 18 months
of treatment in either study on ADAS or ADCS-ADL. In a
prespecified pooled analysis of the studies, solanezumab
showed a significant reduction in the rate of decline com-
pared to placebo in mild subjects (Vellas et al., 2013). Addi-
tional studies are planned.]
Ponezumab (PF-04360365) is a humanized, monoclonal
antibody that binds to amino acids 33–40 at the C termi-
nus of Aβ (Bednar, 2009). It is an IgG2 antibody that has
two site mutations in the Fc region designed to minimize
monocyte activation, complement activation, and Aβ—
dependent cell-mediated cytotoxicity. Preliminary results
from single-dose IV infusion studies found a dose-depen-
dent increase in plasma Aβ and an increase in CSF Aβ at
the 10 mg/kg dose. Ponezumab CSF concentrations were
measurable in only two of eight patients at the highest

Table 23.9 Passive anti-Aβ immunotherapies in clinical trials

Company Product Phase Aβ epitope NCT # on clinicaltrials.gov

Janssen Alzheimer Immunotherapy/Pfizer Bapineuzumab IV (AAB-001) 3 N-terminus NCT00575055; NCT00574132;

Janssen Alzheimer Immunotherapy/Pfizer Bapineuzumab SC
Janssen Alzheimer Immunotherapy/Pfizer AAB-003
Lilly Solanezumab (LY2062430) IV
Pfizer PF-04360365 IV Ponezumab
Roche/Morphosys RG1450 IV gantenerumab
Genentech/AC Immune Anti-Aβ (MABT5102A) IV
Glaxo-SmithKline GSK933776 IV
Baxter Intravenous immunoglobulin
(IVIG); gammaguard)
Octapharma IVIG (Octagam)
2 N-terminus
1 N-terminus
3 Central domain
2 C-terminus
2 N-terminus and central
domain
1 Conformational
1 Not disclosed
3 Mixed
2 Mixed
NCT00667810; NCT00676143
NCT00663026; NCT01254773
NCT01193608
NCT00905372; NCT00904683
NCT00722046
NCT00531804
NCT00736775; NCT00997919
NCT00459550
NCT00299988; NCT00818662
NCT00812565
582 Therapeutics for the Geriatric Neurology Patient

Table 23.10 Active anti-Aβ immunotherapies in clinical trials

Company Product Phase Aβ epitope NCT # on clinicaltrials.gov

Janssen Alzheimer Immunotherapy/Pfizer ACC-001 2 N-terminus NCT00498602;

NCT00479557;
NCT00752232;
NCT01284387; NCT01227564
Novartis/Cytos AG CAD106 2 N-terminus NCT00795418;
Ab 1–6 NCT00956410;
NCT01023685
Glaxo-SmithKline/Affiris Affitope AD1/AD2 1 N-terminus mimetic NCT00495417;
Ab 1–6 NCT00633841;
NCT01117818 (early AD);
NCT01093664; NCT00711321;
NCT00711139
Merck V950 1 Multiepitope NCT00464334
United Biomedical UB 311 1 N-terminus NCT00965588;
1–14 NCT01189084
AC Immune ACI-24 1 N-terminus
1–15

dose tested (10 mg/kg), suggesting limited CNS penetra-
tion (Zhao et al., 2010). Multiple ascending dose studies
of ponezumab with different dosing regimens are ongo-
ing, with the frequency of administration ranging from
monthly to every 90 days (NCT00722046, NCT00945672).
Gantenerumab (R-1450) is a monoclonal antibody that
has completed a multiple ascending dose study in patients
with AD (NCT00531804). Two subcutaneous doses of
gantenerumab are also now being studied in a 2-year
study in patients with prodromal AD (NCT01224106).
Inclusion criteria include a history of memory loss and
MMSE > 24. A substudy is evaluating change in brain
amyloid imaging with PET. Doses are administered every
4 weeks for 104 weeks. The primary outcome of the study
is the change on the CDR sum of boxes. Secondary clini-
cal outcomes include the ADAS-cog and the Functional
Activities Questionnaire.
MABT-5102A, a monoclonal antibody also targeting
Aβ, recently completed a phase 1 study in AD with an IV
formulation (NCT00736775), as well as a phase 1 study
with a subcutaneous formulation in younger healthy vol-
unteers (NCT00997919). GSK-933776 is an anti-Aβ anti-
body that recently completed single- and multiple-dose
phase 1 studies (NCT00459550).
Beyond monoclonal antibodies, passive immuno-
therapy utilizing intravenous immunoglobulin (IVIG) is
being tested (Dodel et al., 2010). The primary hypothesis
behind this polyclonal approach is that IVIG contains
naturally occurring autoantibodies that are specific for
Aβ. IVIG could also have effects in AD by modulating the
immune system independently of Aβ-specific antibody-
mediated activity. Promising results from a small study
with IVIG have been published (Relkin, 2008). A phase 3,
18-month trial with IVIG involving more than 360 AD
patients has recently concluded. In this trial, subjects
were randomly assigned to receive intravenous infusions
with either two doses of IGIV or placebo every 2 weeks
for 70 weeks (36 infusions). The primary outcomes of the
study were cognitive and global function. Like bapineu-
zamab and solanezumab, IVIG failed to reach statistically
significant difference from placebo on cognitive measures
after 18 months of treatment.
Active immunotherapies in
clinical development
ACC-001 is a second-generation active immunotherapy
in which an N-terminal fragment of Aβ is conjugated to
a carrier protein (Pride et al., 2008). The concept behind
this vaccine construct is that it should be capable of gen-
erating anti-Aβ antibodies, while not inducing specific
anti-Aβ T-cell responses, thought to be responsible for
the ME observed with AN1792. The short N-terminal Aβ
fragment is of insufficient length to be bound by MHC
class 1 or class 2 molecules required for an anti-Aβ T-cell
response. Phase 2 studies of ACC-001 in mild-to-moder-
ate AD and in early AD are in progress (NCT00479557,
NCT01284387, NCT01227564). ACC-001 is administered
through IM injections. Inclusion criteria for the early
AD trial, a 2-year study, include a change in cognition, a
global CDR rating of 0.5, a MMSE > 25, and the presence
of amyloid detected on a PET scan. Reducing the amy-
loid burden as determined by PET is the primary outcome
(NCT01227564).
Another active immunization approach is based on
affitopes, in which short peptides that mimic fragments
of native Aβ1-42, but are not identical to it, are used as the
antigenic component. Affitopes AD-01 and AD-02 target
the N-terminal Aβ fragment (Schneeberger et al., 2009).

Affitope AD-02 is currently in phase 2, being studied in a
1-year clinical trial in early AD (MMSE > 20). Entrance cri-
teria include a memory deficit and hippocampal atrophy.
The primary clinical outcomes are change in the modified
ADAS-cog and ADCS-ADL (NCT01117818).
CAD-106 is a vaccine in which the Aβ1–6 peptide is
conjugated to the Qβ virus-like particle. It is currently
in phase 2 in mild-to-moderate AD (NCT01097096). It is
being administered with repeated IM injections over 90
weeks. The study calls for testing two different doses,
with two different adjuvants to evaluate anti-Aβ-specific
antibody responses.
V-950 is a multiepitope anti-Aβ peptide fragment
vaccine (Savage et al., 2010). It is being studied in
a dose-escalating study in which multiple Aβ frag-
ments are conjugated to the outer membrane complex
of Neisseria meningitidis (OMPC) as a protein carrier.
They are administered with an aluminum-containing
adjuvant with or without ISCOMATRIX, an adjuvant
containing saponin, cholesterol, and phospholipids
(NCT00464334).
ACI-24 is a vaccine that contains Aβ1–15 embedded
within a liposomal surface. ACI-24 is designed to stimu-
late the patient’s immune system to produce beta-sheet
conformation-specific antibodies that prevent plaque
deposition or enhance clearance of plaques (Muhs et al.,
2007). ACI-24 entered a phase 1 clinical trial in 2009 (AC
Immune website).
UB-311 is a vaccine in which the immunogen Aβ1–14
is associated with the UBITh peptide (Wang et al.,
2007). A small phase 1 study to evaluate the safety and
immunogenicity of UB-311 is ongoing (NCT01189084;
NCT00965588).
Future directions
Based on the delay between amyloid deposition in AD
in relation to clinical symptoms, it seems possible that
treating earlier in the course of AD for a longer period of
time may provide greater benefits than those seen to date.
Some scientists and clinicians have argued that amyloid
is only an initiating factor in AD, and intervening in mild-
to-moderate patients with advanced neurofibrillary and
synaptic pathology may be too late. There is circumstan-
tial neuropathologic and amyloid imaging evidence that
amyloid may be deposited up to 15 years prior to diag-
nosis (Rowe et al. 2010). Assuming this is correct, starting
immunotherapy treatment earlier in the disease course
may be advantageous. Prior MCI trials were unsuccessful,
in part, due to the clinical heterogeneity of the enrolled
population (Grundman et al., 2006); for example, a sig-
nificant percentage of patients have demonstrated the
absence of amyloid deposition in recent MCI cohorts that
have undergone amyloid imaging (Jack et al., 2009; Rowe
Immunotherapy for Alzheimer’s Disease 583
et al., 2010). The finding that donepezil showed a positive
treatment difference in MCI subjects who were ApoE ε4
carriers suggests that some treatments may be successful
at the stage of MCI if a more definitive subgroup with
AD could be identified (Petersen et al., 2005). The current
availability of PET ligands that can detect brain amy-
loid deposits (Klunk et al. 2004; Clark et al. 2011) and Aβ
assays that can measure reduced CSF Aβ in patients in the
prodromal or preclinical stage of the disease (Shaw et al.,
2009) provide important opportunities for future research.
Immunotherapy may be most efficacious if started earlier
and Aβ is removed during the preclinical and prodromal
phases of the illness when downstream pathology, synap-
tic loss, and clinical symptoms are less advanced.
Despite the apparent theoretical advantages that should
accrue by treating patients earlier, patients at the very early
clinical stage of AD are more difficult to diagnose and
progress more slowly on clinical scales. Trials for prodro-
mal AD will undoubtedly require different inclusion crite-
ria, more follow-up time, and possibly different outcome
measures than those classically used in mild-to-moderate
AD trials (Aisen et al., 2011). Nevertheless, a number of
immunotherapy clinical trials are just now beginning to
evaluate patients with prodromal AD. The convergence of
improved diagnostics and earlier diagnosis with second-
generation immunotherapies suggests cautious optimism
that timely and effective disease-modifying AD treat-
ments may soon be achievable.
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 Chapter 24
Geriatric Psychopharmacology
Sandra A. Jacobson
University of Arizona College of Medicine-Phoenix, Banner Sun Health Research Institute and Cleo Roberts Center for
Clinical Research, Sun City, AZ, USA

Summary
• Treatment effectiveness depends on correct diagnosis, use of an effective drug, and persistence with the therapeutic
trial until achievement of the desired effect.
• Differences among age peers involves both pharmacokinetic and pharmacodynamic differences.
• Pharmacokinetics: the way drugs move through the body. It depends on absorption, distribution, metabolism, and
excretion as well as drug half-life.
• Pharmacodynamics: the effect of the drug at the receptor. Variables include receptor number and affinity, signal
transduction, cellular response, and homeostatic regulation.
• The pharmacodynamics, drug interactions, adverse effects, indications, and clinical uses of antipsychotics,
antidepressants, anxiolytics, sedatives, and mood stabilizers are reviewed.
• Definitions and treatments for anxiety disorders and substance use disorders are reviewed. For both, initial treatments
should be nonpharmacologic.

Introduction: psychopharmacology of diagnostic formulation. The Diagnostic and Statistical

and aging
The practice of geriatric psychopharmacology is signifi-
cantly complicated by the interplay of aging, disease, and
polypharmacy. Partial treatment of syndromes is common
and often results in formes frustes presentations. Although
periodic review of medications is actually the purview of
the patient’s primary care provider, it is not uncommon
to find that the patient suffers from neurologic symptoms
(such as cognitive impairment or ambulation difficulty)
that are actually caused by psychotropic medications. In
these cases, communication between the neurologist and
the primary care provider or psychiatrist is essential.
Optimizing treatment effectiveness
The three primary determinants of treatment effective-
ness are correct diagnosis, use of an effective drug, and
persistence with the therapeutic trial until the desired
effect is achieved. A common reason for psychotropic treat-
ment failure is incorrect diagnosis. Misconceptions about
psychiatric disease are still prevalent among practicing
physicians. Most psychiatrists and behavioral health cli-
nicians in practice today in North America use the Diag-
nostic and Statistical Manual of Mental Disorders as the basis
Manual of Mental Disorders (DSM) has helped consider-
ably in standardizing psychiatric diagnosis over the past
several decades. The current version, DSM-V was released
in 2013. One problem with the DSM for the geriatrician is
that the manual was not written for the geriatric popula-
tion and incompletely captures the characteristics of psy-
chiatric disease in elderly patients. Even more important
is that human psychopathology is highly complex, rooted
as it is in genetics and early development, and tempered
by factors of personality, experience, and comorbid dis-
ease. Although some proportion of psychiatric presen-
tations can be reduced to medication-responsive syn-
dromes (such as depression, anxiety, or psychosis), this
is not true for all presentations. For individual patients, a
more complete diagnostic formulation may be required,
and for this, a psychiatric referral is indicated.
Of the three determinants of treatment effectiveness,
effective drug is arguably the most easily addressed. The
range of treatment options currently available in geriat-
ric psychopharmacology is, in the opinion of this author,
adequate to treat most psychiatric conditions that arise in
the course of primary care and specialty neurologic care
of the geriatric patient. Much depends on the knowledge
and skill of the prescribing physician. The “References”
section at the end of the chapter lists resources available
to assist the clinician (Jacobson et al., 2007; AHFS, 2011).

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

586

Failure to follow through with a therapeutic trial until
the desired effect is seen—ensuring that an adequate trial
has been given—is possibly the most common reason for
psychotropic treatment ineffectiveness. It is a frequent
occurrence in psychiatric consultation practice to see
patients who are said to be “failing” treatment with a drug
such as an serotonin-selective reuptake inhibitor (SSRI)
antidepressant, when, in fact, they are undertreated—that
is, on a low initial dose of the drug over months or years.
Knowledge of target doses, taking into account the indi-
vidual patient’s renal and hepatic functions, is essential.
In addition, medication side effects often develop in the
geriatric patient, so advance discussion about what to
expect can help both the patient and the physician stay
the course of treatment, at least in the face of “nuisance”
side effects.
Screening for psychotropic use
Whether to use a psychotropic drug at all depends first
on whether the symptoms are primary, or are secondary
to a medical condition (for example, as with panic attacks
in a patient with underlying pheochromocytoma) or a
medication (for example, as with apparent depression in
a patient on a statin drug). When the condition is second-
ary, the cause is treated first; only if the symptoms are
persistent is the condition then treated with an appropri-
ate psychotropic or other modality, such as electrocon-
vulsive therapy or repetitive transcranial stimulation.
The choice of a particular psychotropic drug is driven
by the patient’s diagnosis, comorbid medical problems,
current list of medications, past history with that drug
or class, family history with that drug or class, physical
examination findings, and laboratory test results. Major
depression or panic disorder may be particularly drug
responsive, whereas personality disorders or somato-
form disorders may not be. Comorbid medical problems
may direct treatment away from particular drug choices;
for example, tricyclic antidepressants should be avoided
in patients with coronary artery disease or cardiac con-
duction problems. In addition, current medications
may direct treatment; for example, for many patients
treated with olanzapine, mirtazapine should probably
be avoided because of the high risk of significant weight
gain with this combination. If a patient has had a good
response to a particular drug in the past, this predicts
future response. To a lesser extent, the same is true for
a good response in the case of a first-degree relative.
Table 24.1 summarizes specific elements in the screening
evaluation.
Reducing adverse effects and
drug interactions
To reduce the adverse effects of medications used in geri-
atrics in general, it is recommended that certain drugs
be avoided in treating this population (Beers, 1997; Fick
Geriatric Psychopharmacology 587
Table 24.1 Screening for psychotropic use in the geriatric patient
History
Are the symptoms caused by a medical illness?
Are the symptoms caused by a medication?
Is the patient’s condition one that is responsive to psychotropic
treatment?
What medication has been used for the patient in the past for this
condition?
What medication has been used for first-degree relatives?
Examination
Vital signs (including orthostatic blood pressure and pulse)
Evidence of cardiopulmonary disease
Evidence of hepatic disease
Evidence of primary neurologic disease
Laboratory tests
Albumin
Liver function tests
Blood urea nitrogen (BUN), creatinine
Complete blood count (CBC) with platelets
Chemistries (glucose, electrolytes including Ca++)
TSH
Lipid panel
EKG
Source: Adapted from Jacobson et al. (2007) with permission from
American Psychiatric Publishing.
et al., 2003). Particular drugs of interest to neurologists
include those with anticholinergic effects (amitriptyline,
dicyclomine, diphenhydramine, doxepin, hydroxyzine,
oxybutynin, and thioridazine), benzodiazepines (par-
ticularly flurazepam), barbiturates, muscle relaxants and
antispasmodics (methocarbamol, carisoprodol, chlor-
zoxazone, metaxolone, and cyclobenzaprine), certain
opioids (propoxyphene, meperidine), and amphetamines
Table 24.2 Selected list of potentially inappropriate medications
for older adults
Amitriptyline and other tricyclic antidepressants
Amphetamines
Barbiturates
Benzodiazepines
Dicyclomine
Diphenhydramine
Doxepin
Fluoxetine (if used daily)
Flurazepam
Hydroxyzine and other anticholinergic agents
Meperidine
Muscle relaxants and antispasmodics (methocarbamol, carisoprodol,
chlorzoxazone, metaxolone, cyclobenzaprine)
Oxybutynin (especially XL form)
Promethazine
Propoxyphene
Thioridazine
Source: Adapted from Fick et al. (2003) with permission of American
Medical Association.
588 Therapeutics for the Geriatric Neurology Patient
(see Table 24.2). The patient and family members should
also be educated about potential adverse effects, partic-
ularly those representing more serious conditions such
as cardiac dysrhythmias. Drug interactions can be pre-
dicted based on published resources or web-based pro-
grams such as that offered by American Association of
Retired Persons (AARP) (http://healthtools.aarp.org/
drug-interactions).
Initiating treatment
At the time treatment is initiated, the actual treatment
plan should be decided in collaboration with the patient
and involved family. The frequency of follow-up visits
should be determined in advance. At these visits, inter-
val checks should be made to determine partial response
versus no response. In case of a partial response, the
original plan is continued. In case of no response, the
drug should be tapered off so that an alternative can be
introduced.
Improving treatment adherence
Medication nonadherence among community-dwelling
adults 60 years and older ranges from 26% to 59% (van
Eijken et al., 2003). Nonadherence can be expected to
reach 100% when the patient is not able to afford medi-
cation. This has been a frequent problem in recent years,
with many elders in the United States falling into the
“donut hole” of Medicare coverage. The summary
guidelines on the practice of geriatric psychopharma-
cology shown in Table 24.3 offer several suggestions
that are known to be helpful in improving medication
adherence.
Table 24.3 Summary guidelines: the practice of geriatric
psychopharmacology
Obtain consultation, if necessary, to clarify diagnosis.
If possible, perform a psychotropic-free baseline evaluation.
Identify a set of target symptoms.
Use objective ratings of effect.
Avoid drugs not recommended for elderly patients.
Discuss the cost of medication with the patient before selecting the drug.
Use geriatric doses and titration schedules.
Make only one medication change at a time.
Use monotherapy to the extent possible.
Use the simplest regimen possible (e.g., daily dosing rather than bid).
Give medication instructions in writing.
Encourage the patient to use pillboxes and other adherence aids.
At each visit, ask the patient explicitly about relevant side effects.
Regularly assess the patient’s continuing need for the drug.
Obtain drug levels when indicated.
For each drug trial, clearly document adequacy (dose and duration).
Source: Adapted from Jacobson et al. (2007) with permission from
American Psychiatric Publishing.
Pharmacology and aging
It is a well-known fact that individuals age differently
and at different rates. In reference to pharmacology, a
“typical” 80-year-old is much less like her age peers than is
a “typical” 30-year-old. The differences among age peers
involve both pharmacokinetics, the movement of drugs
through the body, and pharmacodynamics, the effect of
drugs at the receptor. Further heterogeneity among elders
is introduced by genetic differences involving genes that
encode drug-metabolizing enzymes, drug transporters,
and target receptors. These genetic differences continue
into old age and assume even greater importance as the
individual’s list of daily medications grows.
Pharmacokinetics and aging
The four steps of drug pharmacokinetics include absorp-
tion, distribution, metabolism, and excretion. Absorption
is the least affected by aging. It is affected by genetics,
which influence not only CYP3A4 metabolism, but also
P-glycoprotein pump (ABCB1 transporter) activity at
the level of the intestinal wall. The P-glycoprotein pump
serves as the gatekeeper in the gut, determining how
much drug gets into the system. It acts as an efflux pump,
transporting molecules that have entered the cells lining
the gut lumen by diffusion or active transport and depos-
iting them back into the lumen. Inhibitors of the pump
increase drug bioavailability by reducing efflux, while
inducers of the pump decrease bioavailability by increas-
ing efflux. Drugs that induce both the P-glycoprotein
pump and CYP3A4 activity, such as St John’s wort, are
known as double inducers. These drugs greatly decrease
bioavailability of substrates because the CYP3A4 enzyme
is found in proximity to the effluxed drug in the lumen
and rapidly metabolizes the drugs for excretion. Table 24.4
lists selected drugs of interest to neurologists that are
substrates, inducers, and inhibitors of the P-glycoprotein
pump.
In the absence of disease, the extent of absorption is
unaffected by aging, although the rate of absorption can
be slowed with reduced gastric motility. In addition, the
use of fiber supplements or antacids containing alumi-
num, magnesium, or calcium can slow absorption. For
many drugs, slow absorption does not detract from the
main effect and may even reduce the incidence of adverse
effects.
A number of psychotropics are available in alterna-
tive formulations, such as orally disintegrating tablets or
long-acting intramuscular (IM) injections. The speed with
which administered drugs enter the circulation is as fol-
lows: intravenous (fastest); short-acting IM; oral liquid,
oral capsule, or oral tablet; and then long-acting IM or
depot (slowest). The time to onset of action for oral liquids
 Geriatric Psychopharmacology 589

Table 24.4 Selected substrates, inhibitors, and inducers of the The extent to which a drug is taken up in peripheral
p-glycoprotein pump storage depends on body composition, which is signifi-
Substrates Inhibitors Inducers cantly affected by aging. Lean body mass decreases with
aging, such that fat stores are relatively increased, even
Amitriptyline Amitriptyline Dexamethasone
in thin individuals. Highly lipophilic drugs such as diaz-
Carbamazepine Atorvastatin Phenobarbital
Ciprofloxacin Bromocriptine St John’s wort
epam are rapidly taken up by adipose tissue (so that the
Corticosteroids Chlorpromazine Trazodone time of initial efficacy is reduced) but then remain in adi-
Erythromycin Cyproheptadine pose storage sites for prolonged periods, with irregular
Estradiol Desipramine release and unpredictable effects. This is one reason drugs
Fexofenadine Diltiazem such as diazepam should be used with caution—if at all—
Levodopa Erythromycin in elders.
Loperamide Fentanyl
Lovastatin Fluphenazine Metabolism
Morphine Garlic, grapefruit juice, green tea Drug metabolism is considered in two phases: Phase I
Ondansetron Haloperidol (oxidation reactions) and Phase II (most importantly, gluc-
Phenytoin Hydroxyzine uronidation reactions). In general, Phase I processes are
Protease inhibitors Imipramine less efficient with aging, whereas UGT processes are little
Quetiapine Ketoconazole affected. Although enzymes for both phases are found
Lovastatin throughout the body, the most important general meta-
Methadone bolic processes occur in the liver. The major drug-metab-
Midazolam
olizing enzymes include the Phase I cytochrome P450
Nefadozone
(CYP450) enzymes and the Phase II UGT enzymes. Both
Orange juice
CYP450 and UGT exist as isoenzymes, each with its own
Phenothiazines
specific substrate drugs, inhibitors, and inducers. In the
Pimozide
presence of inhibitor drugs or foods, metabolism of sub-
Propranolol
Protease inhibitors
strate drugs is reduced. In the presence of inducer drugs,
Simvastatin
metabolism of substrate drugs is facilitated. Because most
Testosterone drugs are metabolized to inactive metabolites, enzyme
Trifluoperazine inhibition results in increased drug activity, while induc-
Vitamin E tion results in reduced drug activity.
Most significant drug interactions involve the
Source: Adapted from Jacobson et al. (2007) with permission from
CYP450 system. Three CYP450 families are of interest
American Psychiatric Publishing.
in psychopharmacology: CYP1, CYP2, and CYP3. Poly-
morphisms exist for CYP isoenzymes, resulting in dif-
is about the same as for short-acting IM formulations. ferences in activity of these enzymes among individuals,
Adverse effects such as hypotension occur as a function and accounting in part for differences in blood levels of
of speed of onset—the faster, the more likely to occur—so drugs among patients administered the same dose. Table
this should be taken into account in selecting a particular 24.5 shows a partial listing of drugs metabolized by CYP
formulation. isoenzymes that may be of interest to neurologists. A
complete and up-to-date listing is available on the web-
Distribution site of Dr. David Flockhart at the Indiana University
Once absorbed, a drug passes from the small bowel School of Medicine Division of Clinical Pharmacology
through the hepatic portal system to the liver, where it at the website (http://medicine.iupui.edu/clinpharm/
undergoes first-pass metabolism. ABCB1 transporter ddis/) Note that drugs such as carbamazepine appear
(p-glycoprotein pump) activity in cells lining the bile on several different lists, as both substrates and inducers
canaliculi influences the extent of first-pass metabolism. or inhibitors of a single isoenzyme, or involving different
Inducers and inhibitors of transporter activity exert effects isoenzymes.
here, as they do at the gut lining and the blood–brain bar- UGT enzymes are involved in the metabolism of
rier. Metabolites that exit the liver enter the general circu- numerous chemicals and carcinogens, as well as phar-
lation. Those that have been rendered water-soluble (for macologic agents. Two UGT subfamilies are of interest in
example, by conjugation) can be excreted directly by the psychopharmacology: UGT1A and UGT2B. Drugs that are
kidneys. metabolized by UGT enzymes include (via UGT1A) acet-
Drugs entering the circulation are distributed to target aminophen, buprenorphine, chlorpromazine, clozapine,
organs such as the brain and heart, but also to the liver, cyproheptadine, diphenhydramine, doxepin, entacapone,
kidneys, and peripheral storage sites in fat and muscle. ibuprofen, lamotrigine, lorazepam, loxapine, meperidine,
590 Therapeutics for the Geriatric Neurology Patient

Table 24.5 Selected CYP450 substrates, inhibitors, and inducers

Substrates
1A2 2B6 2C9 2C19 2D6 3A4,5,7

Amitriptyline Bupropion Amitriptyline Amitriptyline Amitriptyline Alfentanil

Caffeine Efavirenz Celecoxib Carisoprodol Amphetamine Alprazolam
Clomipramine Methadone Diclofenac Citalopram Aripiprazole Aripiprazole
Clozapine Fluoxetine Clomipramine Atomoxetine Atorvastatin
Cyclobenzaprine Fluvastatin Diazepam Carvedilol Buspirone
Estradiol Glipizide Hexobarbital Chlorpheniramine Cafergot
Fluvoxamine Glyburide Imipramine Chlorpromazine Caffeine
Haloperidol Ibuprofen Indomethacin Clomipramine Calcium channel blockers
Imipramine Meloxicam (S) Mephenytoin (S) Codeine Chlorpheniramine
Naproxen Naproxen Mephobarbital (R) Desipramine Clarithromycin
Olanzapine Phenytoin Moclobemide Dextromethorphan Cocaine
Ondansetron Nelfinavir Donepezil Codeine
Propranolol Omeprazole Duloxetine Dexamethasone
Riluzole Pantoprazole Fluoxetine Diazepam
Ramelteon Phenobarbitone Fluvoxamine Erythromycin
Tacrine Phenytoin Halperidol Fentanyl
Theophylline Primidone Imipramine Gonadal steroids
Verapamil Progesterone Metoclopramide Haloperidol
Warfarin (R) Propranolol Metoprolol (S) Indinavir
Zolmitriptan Warfarin (R) Nortriptyline Methadone
Ondansetron Midazolam
Oxycodone Nelfinavir
Paroxetine Ondansetron
Perphenazine Pimozide
Promethazine Propranolol
Propranolol Quetiapine
Propafenone Quinine
Risperidone Risperidone
Tamoxifen Ritonavir
Thioridazine Saquinavir
Timolol Sildenafil
Tramadol Statin drugs
Venlafaxine Trazodone
Triazolam
Zaleplon
Ziprasidone
Zolpidem

Inhibitorsa

1A2 2B6 2C9 2C19 2D6 3A4,5,7

Amiodarone Ticlopidine Amiodarone Chloramphenicol Amiodarone Amiodarone
Cimetidine Fluconazole Cimetidine Bupropion Aprepitant
Ciprofloxacin Fluvastatin Felbamate Celecoxib Chloramphenicol
Fluoroquinolones Fluvoxamine Fluoxetine Chlorpheniramine Cimetidine
Fluvoxamine Isoniazid Fluvoxamine Chlorpromazine Ciprofloxacin
Interferon Lovastatin Indomethacin Cimetidine Clarithromycin
Ticlopidine Ritonavir Ketoconazole Citalopram Delavirdine
Sertraline Lansoprazole and Clemastine Diltiazem
other PPIs
Sulfamethoxazole Modafinil Clomipramine Efavirenz
Zafirlukast Omeprazole Cocaine Erythromycin
Oxcarbazepine Diphenhydramine Fluconazole
Ticlopidine Doxepin Fluvoxamine

(continued)
 Geriatric Psychopharmacology 591

Table 24.5 (Continued)

Inhibitorsa
1A2 2B6 2C9 2C19 2D6 3A4,5,7

Topiramate Duloxetine Grapefruit juice

Escitalopram Indinavir
Fluoxetine Itraconazole
Haloperidol Ketoconazole
H1 receptor antagonists Mifepristone
Hydroxyzine Nefazodone
Methadone Nelfinavir
Metoclopramide Norfluoxetine
Midodrine Saquinavir
Moclobemide Ritonavir
Paroxetine Star fruit
Perphenazine Telithromycin
Quinidine Verapamil
Ranitidine
Ritonavir
Sertraline
Terbinafine
Ticlopidine

Inducers
1A2 2B6 2C9 2C19 2D6 3A4,5,7

Broccoli Phenobarbital Rifampin Carbamazepine Dexamethasone Barbiturates

Brussels sprouts Phenytoin Secobarbital Prednisone Rifampin Carbamazapine
Char-grilled meat Rifampin Rifampin Efavirenz
Insulin Glucocorticoids
Modafinil Modafinil
Nafcillin Oxcarbazepine
Omeprazole Phenobarbital
Tobacco Phenytoin
Rifampin
St John’s wort

Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.
aStrong and moderately strong inhibitors appear in bold type.

morphine, nalorphine, naloxone, olanzapine, oxazepam,
promethazine, propofol, propranolol, tolcapone, and
trifluoperazine; and (via UGT2B) codeine, diclofenac,
hydromorphone, lorazepam, morphine, nalorphine, nal-
oxone, naltrexone, naproxen, oxazepam, oxycodone,
temazepam, valproate, and nicotine. Most benzodiaze-
pines are metabolized first by the CYP450 system and then
by UGT enzymes. The three exceptions to this rule—loraz-
epam, oxazepam, and temazepam—are directly glucuron-
idated. Because glucuronidation is less affected by hepatic
dysfunction, these drugs are the agents of choice in treat-
ing a patient with hepatic disease.
It is a persistent myth that changes in serum pro-
tein levels with aging and/or displacement of protein-
bound drugs by other drugs with higher affinity for
proteins result in increased drug action or increased
risk of drug interactions. Even in elderly patients,
neither reduced protein levels nor drug displacement
from proteins has significant pharmacologic effects.
Although drug displacement from proteins does result
in a transient increase in an unbound drug, that drug
is as available for metabolism and excretion as for tar-
get receptor binding. Changes in protein binding can
affect interpretation of drug levels, however, because
the laboratory reports total drug concentrations rather
than free drug concentrations. If serum albumin lev-
els are low, such that the unbound percentage of the
drug is high, then the drug level may underestimate the
amount of drug available to act on the target organ (or
be excreted).
592 Therapeutics for the Geriatric Neurology Patient
Excretion
Clearance is the rate at which a drug is removed from
the circulation through hepatic metabolism and renal
excretion. Clearance is inversely related to concentra-
tion at steady state. More precisely, drug concentration
= dosing rate/clearance. P-glycoprotein pump activity
in the cells lining the bile canaliculi and luminal edge
of the proximal tubule promotes clearance through
drug efflux. Aging is associated with reduced clearance
of many drugs because of reduced glomerular filtra-
tion rate (GFR) and hepatic blood flow. When clearance
decreases, steady-state concentrations increase unless
the dosing rate is reduced, by either smaller unit doses
or longer dosing intervals. This is why prescribers are
urged to “start low and go slow” when determining
doses for elderly patients.
Drugs cleared entirely by renal excretion (such as lith-
ium) show clearance decrements with aging proportional
to the decline in GFR. The average GFR for a male of 70
years is 70 mL/min. A GFR <60 mL/min defines Stage III
kidney disease. An estimated GFR is often reported along
with serum creatinine. If the laboratory does not provide
this service, an estimated GFR using the Modification of
Diet in Renal Disease (MDRD) study equation can be cal-
culated automatically by entering patient data (age, eth-
nicity, gender, and serum creatinine value) into a calcula-
tor such as that found on the NIH website (www.nkdep
.nih.gov/professionals/gfr_calculators/idms_con.htm).
Reduced hepatic metabolism is mostly a function of
decreased blood flow to the liver with aging, a reduc-
tion that may be on the order of up to 45% in the absence
of disease (Greenblatt et al., 1982). There is currently
no way to calculate the degree of reduction in hepatic
metabolism, and liver function tests used clinically do
not correlate well with the liver’s drug-metabolizing
ability.
Drug half-life
The elimination half-life of a drug is inversely related to
clearance and directly related to the volume of drug distri-
bution, both of which are affected by aging. Drug half-life
helps predict the time to steady state (when the amount of
drug in the body remains constant) and the time to drug
washout. A general rule of thumb is that steady state or
washout is reached in 4–5 times the half-life of a drug. The
half-life of many psychotropic medications is increased in
elders because of reductions in clearance. When a drug
is titrated and the target dose is not known, it is prudent
to wait until steady state is achieved at a given dose, to
avoid overshooting and causing toxicity. This is particu-
larly true for drugs with a narrow therapeutic index, such
as lithium. Drugs with very short half-lives can be associ-
ated with between-dose rebound of symptoms or with-
drawal symptoms if doses are missed. More problematic
in the elderly population is that drugs with very long
half-lives (even longer in elders) can accumulate with
repeated dosing and cause toxicity.
Pharmacodynamics and aging
Pharmacodynamic changes with aging have been much
less studied and, in general, are poorly characterized. Fac-
tors that affect pharmacodynamics include receptor num-
ber and affinity, signal transduction, cellular response,
and homeostatic regulation. Aging is associated with
reduced density of muscarinic, μ opioid, and dopami-
nergic D2 receptors. The facility with which postsynap-
tic receptors are upregulated or downregulated may be
reduced with aging. Enzyme activities are generally also
reduced except for monoamine oxidase-B activity, which
is increased.
Psychotropic drugs
Antipsychotics
Until the FDA issued a warning in 2005 about the use
of atypical antipsychotic medications in elderly patients
(particularly those with dementia), these drugs were
widely prescribed, even for relatively minor conditions,
such as anxiety and insomnia. In the same year as the
FDA warning, the CATIE-AD trial results emerged, show-
ing an increased mortality risk in elders with Alzheimer’s
disease. Other concerns about these medications were
raised, including stroke risk and risk of metabolic syn-
drome (Schneider et al., 2005). Use of these drugs now
requires careful informed consent, and use as first-line
agents to treat nonpsychotic conditions in elders is gen-
erally discouraged. This presents a dilemma for many
prescribers, because these drugs are highly effective in
treating a variety of behavioral conditions, particularly in
patients with dementia.
Pharmacokinetics of antipsychotics
Antipsychotic medications, both conventional and
atypical, are generally well absorbed when taken orally,
although antacids and anticholinergic drugs may slow
the rate of absorption. Among low-potency drugs (such
as chlorpromazine and quetiapine), bioavailability is
highly variable and dose ranges are wide-ranging. For
higher-potency drugs (such as haloperidol and risperi-
done), dose ranges are narrower so that more specific
dosing recommendations can be made. With the possible
exception of clozapine, therapeutic blood level ranges are
not established for antipsychotics in elderly patients.
Antipsychotic medications are highly lipid soluble.
For reasons noted in an earlier section, this results in
a relatively large volume of distribution and slow

elimination. These drugs reach high levels in the brain
relative to plasma. The drugs are released slowly from
lipid storage sites such as adipose tissue, resulting, in
some cases, in protracted toxicity and in persistence of
urine metabolites. Antipsychotics are generally metabo-
lized in the liver, first by oxidation via CYP450 isoen-
zymes and then by glucuronidation. Reduced activ-
ity of CYP1A2 with aging is associated with reduced
metabolism of clozapine and olanzapine. Clozapine
is also metabolized by demethylation, a process also
affected by aging.
Clearance of both conventional and atypical antipsy-
chotic drugs declines with aging. Atypical drugs appear
to be cleared faster in men. Smoking increases clearance
by CYP1A2 and is a factor for drugs cleared primarily by
this isoenzyme, such as clozapine and olanzapine.
Pharmacodynamics and mechanism of antipsychotics
For all antipsychotic drugs, dopamine D2 receptor bind-
ing is a major determinant of both efficacy against posi-
tive symptoms (such as delusions and hallucinations) and
severity of extrapyramidal effects. Effective doses of atyp-
ical agents are associated with more serotonin receptor
occupancy than D2 occupancy. Clozapine and, to a lesser
extent, other second-generation drugs are also effective
against negative symptoms (such as avolition).
Pharmacodynamic changes with aging are associated
with increasing sensitivity of the dopaminergic system
to pharmacologic challenge. In elders, both therapeu-
tic and toxic effects are seen at lower serum drug levels
than for younger patients. This is particularly true for
elderly patients with dementia. Taking haloperidol as
an example, effective serum levels for elderly patients
with dementia (0.32–1.44 ng/mL; (Lacro et al., 1996) are
much lower than for younger patients with schizophrenia
(2–15 ng/mL; Van Putten et al., 1992). The PET study has
confirmed that, for many elders, sufficient D2 occupancy
can occur at very small doses, such as haloperidol 2 mg
daily (Kapur et al., 1996).
Antipsychotics: drug interactions
The most important drug interactions involving antipsy-
chotic medications relate to clozapine. The combination of
clozapine and benzodiazepines is associated with respira-
tory depression and sudden death (Grohmann et al., 1989).
Benzodiazepines should generally be stopped before clo-
zapine is initiated. If absolutely required for effective treat-
ment, benzodiazepines can be added carefully to a stable
clozapine regimen. Clozapine used in combination with
carbamazepine further heightens the risk of bone mar-
row suppression associated with the latter drug. Several
first-generation antipsychotics potently inhibit CYP2D6
enzyme function, including the following: chlorproma-
zine, fluphenazine, haloperidol, perphenazine, pimozide,
Geriatric Psychopharmacology 593
and thioridazine. Atypical antipsychotics generally have
little potential to interfere with the metabolism of other
drugs. All antipsychotics are substrates for CYP enzymes
(mostly CYP2D6 and/or CYP3A4), and some are sub-
strates for UGT enzymes, so other coadministered drugs
can affect their metabolism.
Adverse effects of antipsychotics
Motor side effects of antipsychotic medications relate to
D2 receptor antagonism in the basal ganglia. Sedation
and weight gain are associated with H1 receptor antag-
onism, hypotension to peripheral α1 receptor blockade,
and anticholinergic effects to muscarinic M1 receptor
antagonism. Adverse effects of individual drugs depend
on relative drug affinities for each of these receptors.
Table  24.6 shows receptor binding profiles for various
antipsychotic drugs. Among elderly patients, the most
important adverse effects of antipsychotics generally
include QTc prolongation, orthostasis and hypotension,
sedation, anticholinergic effects, and metabolic effects.
The latter are particularly problematic with chronic treat-
ment and include weight gain, glucose dysregulation,
and dyslipidemia.
Indications for antipsychotics
In the elderly population, antipsychotic medications
are prescribed for schizophrenia, mania with psychotic
symptoms, dementia with delusions and agitation or
aggression, major depression with psychotic features,
delusional disorder, delirium, and psychotic disorders
secondary to medical conditions. Expert consensus guide-
lines have also enumerated conditions for which antipsy-
chotic medications are not indicated in elderly patients,
including the following: generalized anxiety disorder
(GAD), panic disorder, hypochondriasis, nonpsychotic
major depression, insomnia or other sleep disturbances,
primary irritability or hostility, motion sickness, neuro-
pathic pain, or nausea and vomiting due to chemother-
apy (Alexopoulos et al., 2004).
Clinical use of antipsychotics
Pretreatment evaluation for antipsychotic use should
include the following: examination for abnormal invol-
untary movements (preferably using a standardized scale
such as the AIMS), orthostatic blood pressure and pulse,
fasting blood sugar, lipid panel, WBC count with differen-
tial, liver function tests (alanine aminotransferase [ALT],
aspartate aminotransferase [AST], alkaline phosphatase,
and bilirubin), and ECG with QTc calculated. In addition,
laboratory tests listed earlier in Table 24.1 may be needed,
if they were not already performed.
When antipsychotic medications are used to control agi-
tation or aggression, either scheduled or as-needed (prn)
dosing may be used. When antipsychotic medications are
594 Therapeutics for the Geriatric Neurology Patient

Table 24.6 Receptor binding of various antipsychotic drugs

Adrenergic Dopaminergic Serotonergic 5-HT

Drug α1 α2 D1 D2 D3 D4 H1 M1 NRI SRI 1A 1D 2A 2C 3 6 7

Conventional
✗ ✗ ✗ ✗
antipsychotics
Haloperidol ✗ ✗
Aripiprazole ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗
Asenapine ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗
Clozapine ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗
Iloperidone ✗ ✗ ✗ ✗ ✗ ✗ ✗
Olanzapine ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗
Quetiapine ✗ ✗ ✗ ✗ ✗ ✗ ✗
Risperidone ✗ ✗ ✗ ✗ ✗
Ziprasidone ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗ ✗
Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.
NRI, norepinephrine reuptake inhibitor; SRI, serotonin reuptake inhibitor.

used to treat psychosis (including agitation/aggression
driven by psychotic thinking or hallucinations), sched-
uled dosing should be used. A constant level of drug at
the receptor is needed to control symptoms.
Titration of antipsychotic medications in elderly
patients should proceed slowly, at a rate of 1–2 dose
increases per week (and more slowly for frail elders).
Even in treating schizophrenia in elderly patients, the
“start low and go slow” rule applies; there is no evidence
that rapid neuroleptization confers any benefit, and rapid
titration does cause harm to elders.
Selected patient populations should avoid specific anti-
psychotic drugs. Patients with diabetes, dyslipidemia,
or obesity, should avoid clozapine. Patients with hypo-
tension or orthostasis should avoid low-potency agents
(such as thioridazine, quetiapine, and clozapine) and ris-
peridone. Patients with Parkinson’s disease (PD) should
avoid haloperidol and risperidone. Patients with seizures
should avoid clozapine. Those with tardive dyskinesia
should avoid first-generation antipsychotics. Those with
significant xerophthalmia or xerostomia should avoid
thioridazine and clozapine.
For the treatment of delirium, haloperidol remains the
drug of choice in elders, as in younger patients. The dose
of haloperidol used currently is several orders of magni-
tude lower than that used traditionally, which was asso-
ciated with serious adverse effects, including significant
QTc prolongation. The currently recommended dosing
for the treatment of elders with delirium is haloperidol
0.25–0.5 mg IV q8h (and q6h prn) or 0.5–1 mg PO q12h (and
q8h prn) (Liptzin and Jacobson, 2009). The total daily dose
should be kept below 2 mg (Meyer-Massetti et al., 2010).
For indications other than delirium, many psychia-
trists consider atypical antipsychotics to be the treatment
of choice in elders, in spite of significant risk of stroke
and an increased rate of associated mortality in elders
with dementia. With regard to metabolic syndrome and
dyslipidemia, clozapine and olanzapine appear to have
the greatest risk. Clozapine is generally reserved for
treatment-refractory conditions, when alternatives have
been exhausted.
For the treatment of psychosis in PD, first-line therapy
is quetiapine, starting at 12.5–25 mg daily. The mean
effective dosage is 75 mg daily, and the dosage range
is 25–300  mg daily (Weintraub and Hurtig, 2007). Clo-
zapine is actually the only drug that has demonstrated
efficacy for PD with psychosis, but its use is reserved
for those who do not benefit from quetiapine because of
its serious adverse effect profile and the requirement for
blood monitoring during therapy. Ideally, when clozap-
ine is used, the dose is kept low—50 mg daily or less—
with the modal effective dose being 25 mg daily. Dosing
should be initiated at 6.25 mg daily and titrated slowly.
The dosage range for PD with psychosis is 6.25–150 mg
daily.
In treating psychotic symptoms in the patient with
dementia with Lewy bodies (DLB), antipsychotics are
best avoided. Some evidence, and a great deal of anec-
dotal experience, suggests that cholinesterase inhibitors
treat psychotic as well as cognitive and motor symptoms
in DLB (Weintraub and Hurtig, 2007).
For the treatment of psychotic symptoms in dementias
other than DLB or PDD, either first- or second-generation
antipsychotics could be used. These drugs should be
prescribed at low doses on a scheduled basis. For sun-
downing in dementia, the medication should be given
1–2 hours before the time of usual behavioral escalation.
Optimal dosages for this indication are as follows: ris-
peridone 1 mg daily (Katz et al., 1999), haloperidol 2 mg
daily (Devanand et al., 1998), quetiapine 50–200 mg daily
(Alexopoulos et al., 2004), and olanzapine 5–20 mg daily
(Alexopoulos et al., 2004).
 Geriatric Psychopharmacology 595

Table 24.7 Antipsychotic dosage and titration in elders

Drug Initial dosage Titration rate Dosage range

Aripiprazole 5 mg daily (qhs) Increase by 5 mg after 2 weeks. 2.5–15 mg daily (typical dose is 10 mg qhs)
Asenapine 5 mg daily Increase to 5 mg bid as tolerated (watch for 5 mg daily to bid
orthostasis).
Clozapine 6.25–12.5 mg daily (qhs) Increase by 6.25–12.5 mg every 7 days. 6.25–150 mg daily (≤50 mg daily ideal)
Fluphenazine 0.25–0.5 mg daily to bid Increase by 0.25–0.5 mg every 4–7 days. 0.25–4 mg daily (higher doses divided)
Haloperidol 0.25–0.5 mg daily to tid Increase by 0.25–0.5 mg as tolerated. 0.25–4 mg daily (higher doses divided)
Molindone 5 mg bid Increase by 5–10 mg daily every 4–7 days. 10–100 mg daily (typical dose is 20 mg qhs)
Olanzapine 2.5 mg daily (qhs) Increase by 2.5 mg after 3–4 days. 2.5–15 mg daily (typical dose is 5 mg qhs)
Quetiapine 25 mg daily (qhs) Increase by 25 mg daily every 2–4 days. 50–400 mg (divided bid to tid)
Risperidone 0.25–0.5 mg daily (qhs) Double dose (to bid) after 2–3 days; thereafter, 0.25–3 mg daily (typical dose is 0.5 mg bid)
increase by 0.25–0.5 every 7 days.
Ziprasidone 20 mg bid Increase by 20 mg bid every 4–7 days. 20–80 mg bid

Used at effective doses and for sufficient time, all
antipsychotic medications will treat positive symptoms
such as delusions and hallucinations. Second-generation
drugs (atypicals) also treat negative symptoms such as
avolition and social withdrawal. The choice among anti-
psychotic drugs is made on the basis of cost and adverse
effect profiles. First-generation drugs are cheaper but are
associated with a higher rate of extrapyramidal effects.
Second-generation drugs are associated with other sig-
nificant adverse effects, including glucose dysregulation,
hyperlipidemia, metabolic syndrome, and orthostatic
hypotension. Table 24.7 shows suggested geriatric dos-
ages and titration schedules for selected antipsychotic
medications.
Geriatric patients who are prescribed antipsychotic
medications require more frequent follow-up than is
usual in a neurology clinic. The following guidelines have
been suggested (Alexopoulos et al., 2004).
• After the antipsychotic is initiated, the patient should
be seen within 1–2 weeks.
• After a dose change, the patient should be seen in
10 days to 1 month.
• When the patient is stable on a particular dose for
1 month, the patient should be seen every 2–3 months.
• During maintenance treatment, after 6 months on a sta-
ble dose (for example, with an elder with schizophrenia),
the patient should be seen every 3–6 months.
Antidepressants
The conditions for which antidepressants are used in the
treatment of geriatric patients include primary depres-
sion (major depression and dysthymia), depression in
dementia, failure to thrive, bipolar depression, secondary
mood disorders, panic disorder, social phobia, obsessive–
compulsive disorder (OCD), posttraumatic stress disor-
der (PTSD), GAD, pain disorders including fibromyal-
gia, chronic fatigue syndrome, irritable bowel syndrome,
insomnia, and stress urinary incontinence.
Pharmacokinetics of antidepressants
Antidepressants are rapidly and completely absorbed in
the small intestine, and although food can delay absorp-
tion significantly, this has little clinical effect. Over the
usual dosage range, linear kinetics is seen, so any dosage
increase results in a proportional serum level increase.
Antidepressants are highly lipophilic, so the volume of
distribution and half-life are significantly increased in
elders. In general, antidepressants are extensively metab-
olized, primarily via CYP2D6, CYP3A4, and CYP2C9/19
pathways. Fluvoxamine and TCAs are also metabolized
via CYP1A2. Reduced renal function in elders does affect
clearance of water-soluble antidepressant metabolites
such as10-hydroxy-nortriptyline.
Pharmacodynamics and mechanism of antidepressants
In general, antidepressants increase the concentration
of specific neurotransmitters in the synaptic cleft and
enhance pre- and postsynaptic receptor sensitivity to
those neurotransmitters. Antidepressants also affect
REM sleep and neuroendocrine and neuroimmune func-
tions. Specifically, SSRI antidepressants inhibit the sero-
tonin transporter responsible for moving serotonin from
the synaptic cleft into the presynaptic neuron. Relative
potencies of transporter inhibition are as follows: parox-
etine > citalopram > sertraline > fluvoxamine > fluoxetine.
At higher doses (for example, fluoxetine ≥60 mg daily),
some SSRIs also inhibit reuptake of norepinephrine and
dopamine, with sertraline having the greatest dopamine
reuptake effect (Tulloch and Johnson, 1992). Paroxetine
has a small capacity to block muscarinic receptors; the
significance of this is minimal, except possibly in patients
with a cholinergic deficit, such as patients with Alzheim-
er’s disease. Bupropion is a noradrenergic and dopami-
nergic drug with no serotonergic effects. Mirtazapine
has a unique mechanism as a noradrenergic and specific
serotonergic antidepressant (NaSSA), with effects due
to enhanced release of serotonin and norepinephrine,
596 Therapeutics for the Geriatric Neurology Patient

mainly via α2 antagonism. Venlafaxine and duloxetine
are serotonin and norepinephrine reuptake inhibitors.
With venlafaxine, serotonergic effects predominate at
lower doses, and norepinephrine effects at higher doses
(>150 mg daily). Table 24.8 shows receptor binding pro-
files for antidepressants.
Antidepressant drug interactions
With antidepressants, both pharmacokinetic and pharma-
codynamic drug interactions are seen. Pharmacokinetic
interactions are straightforward and reasonably predict-
able, whereas pharmacodynamic interactions are complex
and dependent upon concomitant medications, as well
as comorbid conditions. Clinically significant CYP450
inhibition is seen with fluoxetine, fluvoxamine, parox-
etine, bupropion, and nefazodone. With the exception of
fluvoxamine, inhibition primarily involves CYP2D6, as
shown in Table 24.5. Fluvoxamine is the “great inducer”
among SSRIs, in that it strongly inhibits CYP1A2 and
CYP2C19 and moderately inhibits CYP3A4 and CYP2C9.
Nefazodone is a potent inhibitor of CYP3A4, and several
antidepressants are substrates of this isoenzyme. Parox-
etine is the only SSRI metabolized by a single CYP path-
way (CYP2D6). When CYP2D6 is inhibited, significant
effects on paroxetine metabolism can be seen. Citalopram
and escitalopram generally have low potential for phar-
macokinetic interactions.
As a practical issue, CYP inhibition is usually less prob-
lematic than CYP induction. Caution is advised when
a CYP450 substrate drug is administered along with an
inhibitor of that isoenzyme, particularly when the thera-
peutic index of the substrate is narrow. Potentially more
troublesome is the administration of a substrate with an
inducer. One case in point is the use of St John’s wort,
an inducer of CYP3A4. This drug can be associated with
reduced efficacy of cyclosporine, with consequent heart
transplant rejection or with reduced levels of antiretroviral
drugs.
Pharmacodynamic interactions are probably more
significant than is generally appreciated. Examples of
known dynamic interactions include upper gastrointesti-
nal (GI) bleeding with SSRI drugs used in combination
with NSAIDs, and serotonin syndrome with SSRIs used
in combination with linezolid. As a rule, greater the num-
ber of receptors bound by a drug, greater is the potential
for dynamic interactions. Accordingly, older tricyclic anti-
depressants and MAO inhibitors have significant poten-
tial for these types of interactions.
Adverse effects of antidepressants
Antidepressant adverse effects that are problematic for
elderly patients include orthostasis, cardiac conduction
disturbance, bleeding, constipation, urinary retention,
blurred vision, sedation, dizziness, delirium, cognitive
impairment, hyponatremia, syndrome of inappropriate
ADH secretion (SIADH), sexual dysfunction, and weight
gain. Most adverse effects occur early in treatment, and
for many, tolerance does not develop over time, no mat-
ter how low the starting dose and how slow the titration.
Specifically, tolerance does not develop to orthostasis, car-
diac rhythm disturbances, or delirium (Glassman et al.,
1993). On the other hand, tolerance to sedation, dizziness,
and GI distress often develops. In general, SSRI antide-
pressants have fewer and less serious adverse effects
than other classes of antidepressants, and this is why
these drugs are usually considered first-line agents in

Table 24.8 Receptor binding of various antidepressant drugs

Transporters Receptors
Drug Norepinephrine Serotonin Dopamine H1 M1 α1 Adrenergic

Amitriptyline +++ ++++ – +++++ +++ +++

Clomipramine +++ ++++++ – +++ +++ +++
Desipramine +++++ +++ – ++ ++ ++
Desvenlafaxine ++ +++ – – – –
Doxepin +++ +++ – ++++++ ++ +++
Nortriptyline ++++ +++ – ++ ++ ++
Citalopram and
– +++++ – + – +
escitalopram
Fluoxetine ++ +++++ – – – –
Paroxetine +++ ++++++ + – ++ –
Sertraline + ++++++ +++ – + ++
Bupropion + – + – – –
Duloxetine ++++ ++++++ + – – –
Mirtazapine – – – ++++++ + +
Nefazodone ++ ++ ++ +++ – +++
Venlafaxine + ++++ – – – –

Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.

geriatrics. SSRIs are associated with sexual dysfunction,
weight gain, and sleep disturbance with daytime somno-
lence. Tricyclic antidepressants (TCAs) are well known to
have cardiac, anticholinergic, and neuropsychiatric side
effects. All TCAs affect cardiac conduction and are rela-
tively contraindicated in patients with ischemic heart dis-
ease, preexisting bundle branch block, or intraventricular
conduction delay (Roose and Glassman, 1994). Newer,
dual-acting antidepressants may cause hypertension.
Mirtazapine is associated with sedation and weight gain.
Use of monoamine oxidase inhibitors (MAOIs) is limited
in elders because of associated orthostasis and the need
for dietary restriction.
Indications for antidepressants
Antidepressant medications are used for a range of indi-
cations beyond major depression, the following of par-
ticular interest to neurologists: dementia with behavioral
disturbance, panic disorder, OCD, PTSD, GAD, pain
syndromes, chronic fatigue syndrome, failure to thrive,
and primary insomnia. For mood and anxiety disorders
secondary to general medical conditions, antidepressants
may be used when the condition is prolonged or only
partially treatable. When these disorders are secondary
to substance use, antidepressants can be helpful in facili-
tating abstinence; the only caveat is that these drugs are
metabolized by the liver, so careful dosing and titration
is needed.
Clinical use of antidepressants
Pretreatment evaluation for antidepressant use includes
the following:
• History: Alcohol and drug use, caffeine and nicotine
consumption (for those with anxiety symptoms), hyper-
tension, ischemic heart disease, cardiac conduction dis-
ease, prostate enlargement, glaucoma, seizures, orthostat-
ic hypotension, sexual dysfunction, current medications
(including herbals), and drug allergies.
• Physical examination: Orthostatic vital signs, cardiac
and pulmonary examinations, neurologic and mental sta-
tus examinations. The latter must elicit current suicidal
thinking or plan, psychotic symptoms (delusions or hal-
lucinations), presence of hypomanic or manic symptoms,
and cognitive screening. Depression and anxiety rating
scales are useful in documenting symptoms that can be
followed over time to determine treatment effectiveness.
• Laboratory studies: Complete blood count (CBC), elec-
trolytes (including calcium and magnesium), creatinine,
liver function tests (AST, ALT, alkaline phosphatase, bili-
rubin), B12 level, RBC folate level, TSH (with or without
FT4), and ECG.
Safety monitoring during continuation and mainte-
nance therapy with antidepressant medications should
minimally include the following: for SSRI antidepres-
sants, pulse checks, electrolytes, and liver function tests
Geriatric Psychopharmacology 597
every 6 months, along with periodic weight checks; for
tricyclic antidepressants, orthostatic vital signs, electro-
lytes, creatinine, and liver function tests every 6 months,
along with periodic weight checks. TCA level should
be checked with every dosage change or change in con-
comitant medication that could affect TCA metabolism.
For any patient with significant weight gain, workup for
metabolic syndrome is indicated.
Elderly patients without significant physical illness,
comorbid personality dysfunction, or unremitting life
stress will eventually respond to treatment with antide-
pressant medications, although often they respond more
slowly than younger counterparts. This population is at
high risk of undertreatment, mostly because of the low
expectations of clinicians regarding their potential for
recovery. In general, although the evidence regarding
relative efficacy of antidepressant classes is mixed, expe-
rienced psychopharmacologists consider TCAs, MAOIs,
and newer dual-acting drugs to be more efficacious than
SSRIs. On the other hand, because of a superior adverse
effect profile, SSRI antidepressants are widely viewed
as first-line drugs in the treatment of geriatric patients.
The use of newer dual-acting agents such as venlafaxine
and duloxetine may be limited by hypertensive effects.
Bupropion is useful for elders with anergia. Low-dose
bupropion given in the morning in combination with an
SSRI given at night is often an effective and well-toler-
ated treatment for elders with dementia and depression.
Mirtazapine has a particular niche in the treatment of
elders with poor appetite and insomnia. Cardiovascular
risk associated with older TCAs has relegated this class
to third-line use; these drugs are used either when cost
is a prohibitive issue or because of patient preference.
Nonselective MAOIs are also third-line agents used in
treatment-refractory cases.
All factors considered, antidepressants preferred for
use in elderly patients include citalopram, escitalopram,
and sertraline. For a selected subset of patients (discussed
previously), mirtazapine is the drug of choice. Second-
line drugs include fluoxetine, paroxetine, and venlafax-
ine. As noted previously, low-dose bupropion can be
used in combination with an SSRI, to good effect. When
an SSRI antidepressant is used to treat panic disorder, it
is imperative that the initial dose of the drug be very low
and that the titration proceed very slowly, to avoid acute
exacerbation of panic. Table 24.9 shows suggested dos-
ages and titration schedules for selected antidepressant
medications.
Among elders treated for depression, some symptom
improvement may be seen in as little as 2 weeks, but
remission of symptoms requires 6–12 weeks of treatment
(Flint, 1997). When remission is achieved, the patient
enters the continuation phase, in which improvement is
preserved and treatment must be maintained. The dura-
tion of antidepressant treatment (acute remission plus
598 Therapeutics for the Geriatric Neurology Patient

Table 24.9 Antidepressant dosages and titration schedules in elders

Drug Initial dosage Titration rate Typical dosage and dosage range

Bupropion SR 100 mg daily Increase by 50–100 mg every 3–4 days. 100 mg bid
Range: 100 mg daily to 150 mg bid
Bupropion XL 150 mg qam If needed and tolerated, increase to 300 mg 150 mg qam
qam. Range: 150–300 mg qam
Citalopram 10–20 mg daily Increase by 10 mg after 7 days. Maintain at 20 mg daily
20 mg for 3–4 weeks, with further titration as Range: 10–40 mg daily
needed and tolerated.
Desvenlafaxine 50 mg daily Usually not indicated. 50 mg daily
Range: 50–100 mg daily
Duloxetine 20 mg daily Increase by 20 mg after 7 days. 20 mg bid
Range: 20 mg daily to 30 mg bid
Fluoxetine 10 mg daily (depression or OCD) Depression/OCD: Increase to 20 mg after 20 mg daily for depression
5 mg daily (panic disorder) 1–2 weeks. Maintain at 20 mg for 3–4 weeks Ranges:
before further dose increases, and increase 5–40 mg daily for depression
only if response is partial. 5–30 mg daily for panic
Panic disorder: Increase to 10 mg after 20–60 mg daily for OCD
1–2 weeks, then to 20 mg after 1–2 weeks
if tolerated.
Mirtazapine Sleep aid and appetite stimulant: Depression: Increase by 7.5–15 mg every 30 mg daily (evening)
3.75–7.5 mg qhs 1–2 weeks. Range: 7.5–45 mg daily for depression
Antidepressant:
7.5 mg q evening
Nortriptyline 10–25 mg daily Increase by 10 mg or 25 mg every 7 days. 50 mg daily
Range: 10–100 mg daily
Paroxetine 10 mg daily Increase to 20 mg after 1–2 weeks. Maintain 20 mg
at 20 mg for 3–4 weeks before further dose Range: 5–40 mg daily (up to 60 mg for
increases, and increase only if response is OCD)
partial.
Paroxetine CR 12.5 mg daily Increase to 25 mg after 1–2 weeks. 25 mg daily
Range: 12.5–50 mg daily
Sertraline 12.5–25 mg daily Increase by 12.5–25 mg every 2–3 days, as 100 mg daily
tolerated. Range: 25–200 mg daily (higher for OCD)
Trazodone Hypnotic: Increase by 12.5–25 mg every 3–5 days, as 25–50 mg qhs
12.5–25 mg qhs needed for sleep and as tolerated. Range: 12.5–300 mg qhs
Venlafaxine XR 37.5 mg daily Increase to 75 mg after 4–7 days; may need 75–150 mg daily
to increase to 150 or 225 mg if response is Range: 37.5–225 mg daily
inadequate.

continuation phase) for elders depends on the number of
previous episodes of depression. For the first episode, the
recommended duration of treatment is 1 year; for the sec-
ond episode, 2 years or more; and for the third episode,
more than 3 years (Alexopoulos et al., 2001). Maintenance
(indefinite) treatment should be considered for those with
greater numbers of episodes or more severe episodes. For
continuation and for maintenance treatment, the same
dose of antidepressant is used as in acute treatment. Little
data are available to guide the duration of treatment for
anxiety disorders in elderly patients.
For the treatment of OCD in elders, SSRIs are the drugs
of choice. The equivalent of 60 mg daily of fluoxetine may
be required for control of symptoms. For the treatment of
depression in elders, titration of SSRI doses above those
recommended for this indication (refer to Table 24.9)
usually leads to worsening of adverse effects with-
out improving the antidepressant effect. For depressed
patients who do not improve at standard antidepressant
doses, options include switching drugs or augmentation
with bupropion, lithium, thyroid hormone, and/or cogni-
tive-behavioral therapy. For bipolar depression, lamotrig-
ine can be used as monotherapy or as an adjunct to a
mood stabilizer. Alternatively, an atypical antipsychotic
can be used. Psychotic depression should be treated with
both an antidepressant and an antipsychotic medica-
tion; use of an antidepressant alone can have dangerous
consequences when a patient who remains psychotic is
activated with the use of an antidepressant. Alterna-
tively, electroconvulsive therapy (ECT) can be used for
psychotic depression and is the foremost indication for
this mode of treatment. Elderly patients with dementia

and depression should be started on smaller initial doses
of antidepressants and titrated more slowly than other
elders. Some respond at lower-than-usual doses; others
require titration to full doses for symptom improvement.
For the treatment of vascular depression and poststroke
depression, SSRIs, nortriptyline, venlafaxine, and dulox-
etine may be useful. Among SSRIs, those with relatively
lower risk of bleeding—citalopram and escitalopram—
are preferred in poststroke depression.
Anxiolytic and sedative–hypnotic drugs
Benzodiazepines, nonbenzodiazepine hypnotics, and
related drugs such as buspirone all have some role in
the treatment of geriatric patients, but these drugs are so
often misused in this population that even legitimate use
is questioned. In general, primary or chronic anxiety dis-
orders in elderly patients are often best treated with anti-
depressant drugs, and insomnia is often best treated with
aggressive sleep hygiene measures.
Pharmacokinetics of anxiolytics and sedatives
The pharmacokinetics of benzodiazepines are influenced
by aging, concomitantly administered medications,
comorbid diseases, and smoking. In general, benzodiaz-
epines are well absorbed, although food and coingested
antacids can delay absorption. Drugs such as nonbenzo-
diazepine hypnotics designed for the treatment of initial
insomnia may have such a rapid onset of action that they
are safely taken only when the patient is already in bed
for the night. For IM administration, lorazepam should
be used in preference to diazepam or chlordiazepoxide,
as only lorazepam is rapidly and completely absorbed by
this route.
Table 24.10 Benzodiazepines and non-benzodiazepine hypnotics: pharmacokinetics and metabolic pathways
Drug Onset of effect
Benzodiazepines
Alprazolam Intermediate
Chlordiazepoxide Intermediate
Clonazepam Intermediate
Diazepam Rapid
Lorazepam Intermediate
Midazolam Rapid
Oxazepam Slow
Temazepam Slow
Nonbenzodiazepine hypnotics
Eszopiclone Intermediate
Ramelteon Intermediate
Zaleplon Intermediate
Zolpidem Intermediate
Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.
aBoldtype indicates major pathway.
Geriatric Psychopharmacology 599
The volume of distribution for all benzodiazepines
except alprazolam increases with age. The most lipophilic
of these drugs (including diazepam) have a short dura-
tion of action with single dosing because of rapid distri-
bution to adipose tissue (Greenblatt, 1991). With repeated
dosing, redistribution is reduced and duration of effect is
prolonged. More hydrophilic drugs such as lorazepam
have a longer duration of action with single dosing and
a smaller change in duration of effect with multiple dos-
ing because tissue distribution is limited (Greenblatt et al.,
1977; Greenblatt and Shader, 1978).
An important distinction is made between benzodi-
azepines that are oxidatively metabolized, including
alprazolam, chlordiazepoxide, clorazepate, diazepam, flu-
razepam, halazepam, quazepam, and prazepam; and those
that are metabolized by conjugation (glucuronidation),
including lorazepam, oxazepam, and temazepam. Drugs
metabolized by oxidation generally have active metabolites,
many with very long half-lives. These drugs are not recom-
mended for use in elderly patients. Drugs metabolized by
conjugation generally have no active metabolizes. Loraz-
epam and oxazepam have half-lives of less than 24 hours,
whereas temazepam has a half-life of up to 40 hours. When
a benzodiazepine is indicated for the treatment of an elderly
patient, lorazepam and oxazepam are good choices.
Clearance of conjugated benzodiazepines is little
affected by aging, whereas clearance of oxidatively
metabolized benzodiazepines is reduced with aging.
Reduced clearance results in increased half-life, necessi-
tating dosage and/or schedule adjustments to avoid day-
time sedation and psychomotor impairment. Table 24.10
shows pharmacokinetic data and metabolic pathways for
benzodiazepines and related drugs.
Parent half-life Metabolite half-life
Peak level (hours) (hours) (hours) Metabolic pathwaysa
1–2 12–15 – CYP3A4, glucuronidation
2–4 5–30 24–96 CYP2C19, 3A4
1–2 18–50 – CYP3A4, acetylation
0.5–2 20–80 50–100 CYP2C19, 3A4, 2B6, 2C9,
glucuronidation
1–6 10–20 – UGT2B7
0.4–0.7 (IV only) 2–5 – CYP3A4, glucuronidation
2–4 5–20 – various UGTs
2–3 10–40 – UGT2B7, CYP2C19, 3A4
1 9 – CYP2C8, 3A4
0.5–1.5 1–2.6 – CYP1A2, 3A4, 2C family
1 1–2 – Aldehyde oxidase, CYP3A4
2.2 2–2.6 (longer in – CYP3A4, 1A2, 2C9
elderly)
600 Therapeutics for the Geriatric Neurology Patient
Pharmacodynamics and mechanism of
anxiolytics and sedatives
Benzodiazepines bind to the GABAA-benzodiazepine
receptor complex located on postsynaptic neurons in the
cerebral cortex, cerebellar cortex, and limbic regions. This
receptor complex also contains binding sites for barbi-
turates, neurosteroids, and several nonbenzodiazepine
hypnotics, including zolpidem, zaleplon, zopiclone, and
eszopiclone. These drugs all act at least partly as GABA
agonists, causing an influx of negatively charged chloride
ions into the neuron, leading to hyperpolarization of the
neuron and a reduced rate of firing.
The GABAA receptor consists of five subunits in a
rosette formation, usually comprising two α subunits,
two β subunits, and one γ subunit. The subunits have
variant forms, such as α-1, α-2, and so forth. GABA itself
binds to the β subunit of the GABAA receptor. Benzodiaz-
epines bind to receptors containing α subunits (either 1,
2, or 3). Zolpidem and zaleplon also bind to the benzodi-
azepine site on the GABAA receptor, but these drugs bind
with high affinity only to receptors containing the α-1 sub-
unit. Eszopiclone also interacts with the benzodiazepine
site on the GABAA receptor, probably binding to specific
“microdomains” within the γ subunit. Because different α
subunits are variably expressed in specific brain regions
(cortex, brainstem, and so on), these binding differences
among agents may have clinical implications in terms of
differential amnestic, sedative, and true hypnotic effects
(Davies et al., 2000).
Buspirone acts not by interaction with the benzodiaz-
epine receptor complex, but as a serotonin (5HT) agonist
at the presynaptic 5HT1A receptor and as a partial agonist
at the postsynaptic 5HT1A receptor. Buspirone binding
causes downregulation of 5HT2 receptors, similar to the
action of antidepressants. This medication is anxiolytic at
usual doses and possibly antidepressant at higher doses.
Buspirone also has complex dopaminergic effects that are
not fully understood. The nonbenzodiazepine hypnotic
ramelteon acts by an entirely different mechanism, bind-
ing selectively to melatonin type 1 (MT1) and type 2 (MT2)
receptors, which act on the suprachiasmatic nucleus to
regulate circadian rhythms. Elderly individuals exhibit
greater pharmacodynamic sensitivity to benzodiazepines
than younger counterparts. Conditions such as traumatic
brain injury (TBI), stroke, and dementia further increase
this sensitivity.
Anxiolytics and sedatives: adverse effects
In general, benzodiazepines are effective in the treatment of
anxiety, are well tolerated, and are safe in overdose unless
ingested with alcohol or other sedatives. In the geriatric
population, however, these drugs have dose-dependent
sedative, cognitive, and motor effects that can be limit-
ing. In elders, sedative effects include weakness, inat-
tention, slowed thought processing, ataxia, and balance
problems (Shader and Greenblatt, 1993). Tolerance to
sedative effects may develop within the first few weeks of
treatment but is persistent in some cases. Benzodiazepine-
associated cognitive impairment sufficient to meet criteria
for dementia may be reversible with drug discontinua-
tion. Motor effects include slowed reaction time, reduced
tracking ability and hand–eye coordination, and impaired
judgment. Drugs with a half-life of more than 24 hours are
associated with a 45% increased risk of motor vehicle acci-
dent with injury in the first 7 days of use (Hemmelgarn et
al., 1997). The increased risk of falls and accidents persists
as long as these drugs are taken.
On the other hand, inadequate doses of benzodiaze-
pines are associated with persistent anxiety symptoms or
between-dose withdrawal. This is particularly problem-
atic with alprazolam, as there is a large inter-individual
variation in the half-life of this drug. While some indi-
viduals are well maintained on alprazolam, many experi-
ence between-dose rebound of anxiety because the half-
life is too short for the dosing interval prescribed. On the
other hand, benzodiazepines with long elimination half-
lives such as diazepam accumulate in fatty tissues with
repeated dosing and can lead to toxic effects, as discussed
in an earlier section.
It has been observed clinically that elderly patients with
coarse brain disease or mental retardation may exhibit
“paradoxical reactions” with benzodiazepines that is not
dose dependent, with symptoms of agitation, aggres-
siveness, and hyperactivity. The mechanism underly-
ing this phenomenon remains unexplained (Shader and
Greenblatt, 1993). Hemodynamic and respiratory depres-
sant effects of benzodiazepines are seen in ICU settings,
where large doses of drugs are administered intrave-
nously. These effects are not covered in this chapter. The
only caveat with outpatient use is that benzodiazepines
should be avoided in patients with sleep apnea, whether
obstructive or central in origin.
The most common adverse effects of nonbenzodiaze-
pine hypnotics include headache, somnolence, dizziness,
lightheadedness, amnesia, and GI disturbances (includ-
ing nausea, diarrhea, and constipation). Hallucinations
and confusional states may be seen with zaleplon and
zolpidem, possibly related to high levels resulting
from coadministered drugs that inhibit metabolism via
CYP3A4 (Terzano et al., 2003). These symptoms are more
commonly seen in elderly patients than in the younger
patients prescribed these drugs.
No evidence indicates that tolerance develops to anx-
iolytic effects of benzodiazepines or to hypnotic effects
of the benzodiazepine-like drugs, even with chronic use
(Dubovsky, 1990; Farnsworth, 1990; Hollister et al., 1993;
van Steveninck et al., 1997). On the other hand, toler-
ance does develop to most adverse effects of these drugs,
including daytime sedation, but not to amnesic effects
(Hollister et al., 1993). How long it takes for tolerance to

develop depends on the half-life of the individual benzo-
diazepine, as well as the specific effect in question (Byrnes
et al., 1993).
The potential for benzodiazepine abuse is low among
elders, except for those with a previous history of alcohol
or sedative abuse (Shader and Greenblatt, 1993; Ciraulo
et al., 1997). For patients with this history, benzodiazepine
use is complicated by rekindling of craving, coingestion
of alcohol with the prescribed medication, and increased
risk of motor vehicle accidents; similar problems could
conceivably occur with the nonbenzodiazepine hypnot-
ics (Gericke and Ludolph, 1994). Benzodiazepines with
a faster onset of action—alprazolam, diazepam, and
lorazepam—have higher abuse potential (greater “street
value”) because of the rapid “kick” associated with inges-
tion (Griffiths and Wolf, 1990).
Unlike abuse and addiction, physical dependence is a
universal phenomenon defined by the appearance of an
objective withdrawal syndrome after a drug is discontin-
ued. Physical dependence occurs when a sufficient dose
of drug is taken for a sufficient length of time (Kruse,
1990; Shader and Greenblatt, 1993). For elderly patients,
physical dependence occurs at usual therapeutic doses
(Shader and Greenblatt, 1993) and after as few as 2 weeks
of treatment (Ayd, 1994). All benzodiazepines are equally
likely to produce physical dependence.
Discontinuation of a benzodiazepine can result in
symptom recurrence, symptom rebound (in which symp-
toms are more intense than they were to begin with),
or withdrawal symptoms (in which physical effects of
reduced GABA neurotransmission are seen). It is diffi-
cult at times to distinguish these phenomena. In general,
interruption of a therapeutic dose of a benzodiazepine is
associated with rebound symptoms, while interruption
of a high dose is associated with withdrawal symptoms
(Pourmotabbed et al., 1996). Rebound symptoms include
anxiety, restlessness, dysphoria, anorexia, and insomnia;
in elderly patients, disorientation and confusion can be
prominent. Withdrawal symptoms can include fever,
tachycardia, postural hypotension, headache, sweating,
photosensitivity, sensory distortion, delirium, tremor,
myoclonus, and seizures; catatonia has also been reported
in elderly patients (Rosebush and Mazurek, 1996). Severe
benzodiazepine withdrawal can be as serious as severe
alcohol withdrawal; in medically compromised elders,
severe withdrawal can be life-threatening. The timing
of the appearance of withdrawal symptoms depends on
the half-life of the drug. In patients of unselected age,
withdrawal reactions peak at 2 days for short half-life
(<6 hours) agents and at 4–7 days for longer half-life
agents (Rickels et al., 1990).
Gradual taper of benzodiazepines, particularly shorter-
acting drugs, mitigates withdrawal symptoms. Most
patients tolerate a taper of 10–25% of the total dose each
week, although the last few dose reductions often require
Geriatric Psychopharmacology 601
longer intervals for the patient to be comfortable (Schweizer
et al., 1990; Shader and Greenblatt, 1993). Patients unable to
tolerate dose reductions may benefit from one of the fol-
lowing: carbamazepine 200–800 mg daily, with a plasma
level of approximately 6 μg/ml; gabapentin 300–900 mg
daily; propranolol for autonomic symptoms; or a switch to
a longer-acting agent and subsequent taper of that agent.
Anxiolytics and sedatives: drug interactions
Benzodiazepines that are metabolized primarily via
CYP3A4 include alprazolam, clonazepam, midazolam,
and triazolam. Concomitant use of CYP3A4 inhibitors
such as antifungals, antibiotics, nefazodone, fluvoxamine,
or grapefruit juice can cause elevated levels of these
drugs. Use of CYP3A4 inducers such as St John’s wort,
carbamazepine, chronic alcohol consumption, or smoking
can be associated with reduced levels.
Benzodiazepines that are recommended for elders
(lorazepam and oxazepam) are not CYP3A4 substrates.
In addition to CYP450 effects, benzodiazepines have
important additive sedative effects with other sedative/
hypnotics and alcohol. Benzodiazepines can be associ-
ated with hypotension and slowing of the heart rate, par-
ticularly when combined with other medications such as
opioids. The potentially serious interaction of benzodiaz-
epines with clozapine is discussed earlier in the section
“Anxiolytics and sedatives: adverse effects.”
Indications for anxiolytics and sedatives
Few primary psychiatric disorders exist for which benzo-
diazepines are drugs of choice in elderly patients. These
drugs are most often used in geriatrics for sedation (as in
during procedures or mechanical ventilation), symptom-
atic anxiety that is expected to be short-lived (as in during
ICU admission), or for specific conditions such as rest-
less legs syndrome. These agents can be used as adjuncts
in the treatment of psychiatric conditions such as mania
and psychosis, but in general, their use is time limited.
Nonbenzodiazepine hypnotics and other drugs discussed
shortly may be used to treat insomnia when nonpharma-
cologic measures have proved inadequate.
Clinical use of anxiolytics and sedatives
When benzodiazepines are used in elders, small doses of
short- or intermediate-acting drugs are preferred. Alpra-
zolam, a drug reputed to have a short half-life, is an excep-
tion to this rule because of wide inter-individual vari-
ability in its kinetics, as mentioned earlier in the section
“Pharmacodynamics and mechanism of anxiolytics and
sedatives.” Benzodiazepines that are not recommended
for use in elders because of prolonged sedative and motor
effects include flurazepam, diazepam, chlordiazepoxide,
quazepam, halazepam, and clorazepate (Fick et al., 2003).
In geriatrics, IM administration of drugs should be
avoided because of the discomfort of injection associated
602 Therapeutics for the Geriatric Neurology Patient
with low muscle mass and (for some drugs) erratic
absorption. For oral use, first-line drugs include loraz-
epam and oxazepam. If longer half-life drugs such as
clonazepam are prescribed (t1/2 = 18–50 hours), frequency
should be once daily or every other day. For parenteral
use, lorazepam is recommended. With IV use, much
smaller doses and more careful patient monitoring are
needed for adverse effects such as respiratory depression.
For patients unable to swallow, other routes/means of
benzodiazepine administration include rectal, sublingual,
and orally disintegrating forms.
For elders with insomnia, sleep hygiene measures are
tried before pharmacologic treatment is considered. When
medication is needed, several options exist: trazodone
and gabapentin (both off-label use), melatonin, ramelteon,
and the nonbenzodiazepine hypnotics. The latter drugs—
which include eszopiclone, zaleplon, and zolpidem—
reduce sleep latency but do not reduce slow-wave sleep,
so they reportedly have a profile superior to that of the
benzodiazepines (Hemmeter et al., 2000; Uchimura et al.,
2006). Doxepin has recently been marketed in a 3 mg
dose for insomnia, which may be effective for a subset of
young-old patients in the absence of Alzheimer’s disease,
but is likely to have limiting anticholinergic effects for
others. Drugs that are not recommended for the treatment
of insomnia in elders include diphenhydramine, chloral
hydrate, antipsychotics such as quetiapine, barbiturates,
meprobamate, ethchlorvynol, glutethimide, and methyp-
rylon (The Medical Letter, 2000).
Before starting a benzodiazepine, a corroborated his-
tory of substance use/abuse should be obtained, for rea-
sons previously described. Current use of alcohol should
prompt a discussion of alternatives to benzodiazepine use
because of the dangers of concomitant benzodiazepine
use. The list of current medications should be reviewed
to identify other drugs with sedative properties, which
could result in additive effects causing falls or accidents.
Informed consent should be obtained, detailing the plan
for dosage and duration of use, as well as risks. In par-
ticular, elders who drive need to be informed that driving
while taking these drugs can be hazardous, just as driving
while intoxicated with alcohol can be hazardous; in some
cases, the hazard is prolonged to the day after taking a
benzodiazepine or benzodiazepine-like drug for sleep.
If a benzodiazepine or related drug is to be prescribed for
an elderly patient presenting for the first time with GAD,
panic disorder, insomnia, or severe anxiety as an isolated
symptom, a possible medical cause should be sought. Labo-
ratory studies recommended for routine workup for GAD
include CBC, fasting glucose, calcium, vitamin B12, RBC
folate, TSH, and ECG (Flint, 2005). Laboratory studies rec-
ommended for routine work-up of panic disorder include
CBC, fasting glucose, calcium, thyroid panel, and ECG
(Flint and Gagnon, 2003). Depending on the description of
panic attacks, an EEG may be indicated to evaluate complex
partial seizures. Patients treated with stimulants such as
theophylline should have levels drawn to exclude toxicity.
Monitoring treatment with anxiolytics
and sedatives
Treatment response is gauged clinically, by changes in tar-
get signs and symptoms and/or the appearance of adverse
effects. The only drug for which a meaningful serum level
can be drawn is alprazolam, and only for the treatment
of panic disorder. For this condition, alprazolam levels
between 20 and 40 ng/mL are associated with therapeutic
response in patients of unselected age with spontaneous
panic attacks (Greenblatt et al., 1993). Therapeutic levels
for geriatric patients have not been established.
Elderly patients requiring chronic treatment with ben-
zodiazepines or nonbenzodiazepine hypnotics should be
evaluated at least every 3–6 months, to assess cognitive
and psychomotor function and to adjust dose downward
as indicated. Older patients treated chronically with ben-
zodiazepines may begin to develop signs of toxicity with
aging, probably a function of gradual alteration in drug
clearance. Escalation of benzodiazepine dosage over time
or concurrent excessive alcohol consumption should be
understood as serious evidence of misuse.
The length of time that the drug is continued in the
elderly patient depends on the specific disorder being
treated, whether it is comorbid with depression or sec-
ondary to a treatable medical condition, and which class
of medication is used for treatment. Early-onset GAD
may require lifelong treatment, while late-onset GAD
with comorbid depression may be treated according to
guidelines governing depression (Flint, 2005). For late-
onset GAD without depression, some experts recommend
treatment for 1 year after remission of symptoms (Flint,
2005). For symptomatic anxiety in the context of a medical
disorder such as hyperthyroidism, treatment with a ben-
zodiazepine can be continued until the underlying condi-
tion is treated and then gradually withdrawn.
For panic disorder, initial treatment may consist of both
an SSRI or dual-acting antidepressant and a benzodiaz-
epine, with the latter continued only for 1–2 weeks as the
antidepressant dose is titrated. The SSRI should then be
continued for a period of 6 months to 1 year, with shorter
times possible in cases where cognitive-behavioral ther-
apy or other nondrug treatment has been used in tandem
with medication.
For insomnia, the benzodiazepine or related drug
should be used for 1–2 weeks, and then the need should be
reassessed. If insomnia persists at 2 weeks, a comorbid
psychiatric or medical condition should be considered.
Some patients do benefit from an extension of treatment,
but it is best if the medication is taken only intermittently
(such as fewer than 4 times per week). The efficacy of
intermittent longer-term use of nonbenzodiazepine hyp-
notics has been demonstrated (Perlis et al., 2004).
 Geriatric Psychopharmacology 603

Treatment of specific anxiety disorders
in elderly patients
Anxiety in the context of dementia may manifest as agi-
tation, anxious mood, or generalized anxiety. In many
cases, it is associated with depression. For acute anxiety
in the patient with dementia, behavioral and environ-
mental approaches are tried first. If the anxiety persists
or worsens, pharmacologic options include SSRIs, loraz-
epam, oxazepam, trazodone, buspirone, and gabapentin.
Nonbenzodiazepines are preferred, as benzodiazepines
generally worsen cognitive function. SSRI doses are kept
low for this indication (for example, sertraline 12.5–25 mg
or fluoxetine 5–10 mg suspension or capsule). Buspirone
can be used at doses ranging from 5 mg bid to 20 mg tid.
Gabapentin can be used at doses ranging from 300 mg to
2400 mg daily divided tid. For any of these drugs, a trial
of at least 12 weeks is needed to determine efficacy. When
no response is seen, a switch to another agent is indicated.
Table 24.11 shows dosage and titration of sedative drugs.
In the elderly population, anxiety is often seen in asso-
ciation with depression, particularly major depression.
Antidepressant medication effectively treats anxiety
along with other symptoms. SSRIs and dual-acting agents
are effective anxiolytics. Use of an anxiolytic alone for
treatment of depression with anxiety is associated with
a very poor outcome (Flint, 2005). A subset of patients
with significant anxiety in the context of depression will
require a benzodiazepine for the first 1–2 weeks of treat-
ment. When an antidepressant is initiated for patients
with depression and panic attacks, very slow titration of
the antidepressant is needed, as discussed shortly.
Anxiety can be secondary to medical illness, par-
ticularly conditions that compromise breathing, such as
asthma, COPD, sleep apnea, and head/neck cancer. For
anxiety in patients with COPD or sleep apnea, SSRIs or
buspirone may be useful because these medications do
not depress the respiratory drive or cause sedation or
cognitive impairment. For panic anxiety in this popula-
tion, SSRI antidepressants may be used. For patients with
terminal lung disease, dyspnea is the focus of a treatment
algorithm involving the correction of physical causes of
dyspnea (hypoxia, anemia, bronchospasm), and then
symptomatic management with opioids along with phar-
macotherapy for anxiety using antidepressants (sertra-
line, venlafaxine) and/or benzodiazepines (Periyakoil et
al., 2005).
Among patients with PD, anxiety may be espe-
cially prominent during “off” periods and appears to
be more prevalent among those with left-sided symp-
toms (Walsh and Bennett, 2001). Optimal pharmaco-
logic treatment has not been established. Management
involves lowering PD medications to the lowest effec-
tive dose and adding antidepressant medication such

Table 24.11 Dosage and titration of drugs for anxiety in elders

Indication/drug Initial dose Titrationa Typical daily dosage Dosage range

Isolated symptom of anxiety

Buspirone 5 mg bid Increase by 5 mg every 2–3 days. 10 mg tid 5 mg bid–20 mg tid
Lorazepam 0.5 mg daily to 0.5 mg bid Increase by 0.5 mg every 4–5 days. 0.5–1 mg bid to tid 0.5–3 mg daily
Oxazepam 10 mg bid to tid Increase by 5–15 mg every 4–5 days. 10 mg tid 10 mg daily–15 mg tid
Trazodone 12.5 mg bid to tid Increase by 12.5 mg every 3–5 days. 25 mg tid 25–50 mg tid
Anxiety in dementia
Sertraline 12.5 mg daily Increase by 12.5 mg every 3–7 days. 12.5–25 mg daily 12.5–100 mg daily
Fluoxetine 5–10 mg daily Increase by 5 mg every 7 days. 5–10 mg daily 5–20 mg daily
Buspirone 5 mg bid Increase by 5 mg every 2–3 days. 5–10 mg tid 5 mg bid–20 mg tid
Gabapentin 100 mg bid to tid Increase by 100 mg every 3–5 days. 100 mg tid 100 mg tid–800 mg tid
Generalized anxiety disorder
Citalopram 10 mg daily Increase by 10 mg after 7 days. 20 mg daily 10–40 mg daily
Escitalopram 5–10 mg daily Increase by 5 mg after 7 days. 10 mg daily 5–20 mg daily
Venlafaxine XR 37.5–75 mg daily Increase to 75 mg after 1–2 weeks; 37.5–75 mg daily ≤ 150 mg daily
further increases at same interval.
Buspirone 5 mg bid Increase by 5 mg every 2–3 days. 10 mg tid 5–20 mg tid
Pregabalin 50 mg daily Increase to 100 mg after 3 days, and 150–200 mg daily 150–600 mg daily (doses
to 150 mg 2 days later (doses divided (doses divided bid divided bid to tid)
bid to tid). to tid)
Panic disorder
Citalopram 5–10 mg daily Increase after 7 days. 20 mg daily 5–40 mg daily
Sertraline 12.5–25 mg daily Increase after 7 days. 50–100 mg daily 12.5–200 mg daily
Venlafaxine SR 37.5 mg daily Increase by 37.5 mg after 1–2 weeks. 37.5–75 mg daily ≤150 mg daily
aDose increases should be made as needed and tolerated.
604 Therapeutics for the Geriatric Neurology Patient
as an SSRI. Benzodiazepines can be used but may
exacerbate PD symptoms. The GABA-agonist effect of
benzodiazepines reduces dopaminergic outflow in the
basal ganglia and, theoretically, could interfere with the
effects of levodopa (Yosselson-Superstine and Lipman,
1982).
Catatonia is a syndrome involving motor abnormalities
and mental status changes that occurs in the context of
medical or neurologic disease, or severe psychiatric dis-
ease such as major depression or schizophrenia. In cur-
rent practice, this syndrome is greatly underdiagnosed
and often is mislabeled in the hospital setting as delirium
or depression. The distinction is important because ini-
tial treatment of catatonia differs significantly from treat-
ment of these other syndromes. Like delirium, the diag-
nosis of catatonia requires timely medical workup and
accurate diagnosis. While this is ongoing, however, the
patient requires symptomatic treatment. Cardinal signs of
catatonia include mutism, immobility or excessive motor
activity, negativism, posturing, stereotypy, and echophe-
nomena (echopraxia, echolalia). Optimally, diagnosis
should be made using a standardized instrument such as
the Catatonia Rating Scale (Bush et al., 1996). Catatonia
is classified into retarded, excited, and malignant types,
the latter including neuroleptic malignant syndrome and
serotonin syndrome.
In addition to definitive treatment of the underlying
medical condition, symptomatic treatment of catatonia is
needed to maintain basic bodily functions (hydration and
nourishment) and to decrease morbidity from immobility.
Catatonia can be treated with benzodiazepines and/or ECT.
Catatonia is a primary indication for ECT in the elderly
population; although controlled studies for this indication
are lacking, substantial clinical experience supports its use.
Clinical experience also suggests that the response of elderly
patients to benzodiazepines may not be as robust as that of
younger catatonic patients. The benzodiazepine of choice
for diagnostic challenge and for treatment of catatonia is
lorazepam, based on its availability in IV and IM formula-
tions, rapid onset of action, and other favorable pharmaco-
kinetic properties. The following algorithm for lorazepam
use in catatonia is recommended (Fink and Taylor, 2003).
• Score the Catatonia Rating Scale.
• Administer lorazepam 1–2 mg IV test dose.
• Score the Catatonia Rating Scale.
• At intervals of 20–30 minutes, repeat dose of IV
lorazepam and score the Catatonia Rating Scale, up to
lorazepam 10 mg total dose, administered over several
hours.
• If significant improvement is seen, calculate how much
lorazepam was given.
• Give that amount of lorazepam daily IV in divided
doses until definitive treatment corrects the underlying
problem and/or the syndrome resolves.
• Anticipate the need for ECT.
When GAD occurs as a primary disorder, several treat-
ment options exist. Antidepressants are the first line of
treatment for GAD for most elderly patients, regardless
of whether depression is present. For the treatment of
elderly patients, preferred drugs include escitalopram,
citalopram, and venlafaxine. Benzodiazepines generally
have a limited role in the treatment of GAD in elderly
patients, but if they are used, lorazepam and oxazepam
are recommended. Other options include buspirone
in the benzodiazepine-naive patient and pregabalin
(Montgomery et al., 2006).
Primary OCD in elderly patients usually represents the
persistence of illness that developed earlier in life. Hoard-
ing behaviors are less likely a manifestation of OCD than
of psychotic illness or dementia. Treatment involves both
exposure and response prevention therapy and high-dose
SSRI therapy. Primary OCD in elders is an indication for
psychiatric referral.
Panic attacks and panic disorder in elderly patients
may be idiopathic, or secondary to a medical condi-
tion or medication. For primary panic disorder, the
recommended treatment is an SSRI such as citalopram
or sertraline. Venlafaxine is another option. If an SSRI
is initiated too aggressively, panic is exacerbated.
(Dosage and titration recommendations are shown
earlier in Table  24.11.) When venlafaxine is used, the
optimal dose is usually ≤150 mg daily because nor-
adrenergic effects become more prominent at higher
doses. A benzodiazepine such as lorazepam may be
needed as adjunctive therapy during the initial weeks
of treatment. Buspirone is not effective for the treat-
ment of panic. When symptoms have been controlled
for 6–12 months, an attempt should be made to slowly
taper and discontinue medication. Patients who have
been treated with cognitive behavioral therapy gen-
erally do very well with discontinuation. Others may
require several discontinuation attempts because of
recrudescence of panic. A minority will require lifelong
treatment. In a small subset of elderly patients, benzo-
diazepines may be required for control of panic anxiety,
in spite of dependence issues and adverse effects. The
frequent association of panic with alcohol dependence
complicates this use. Either lorazepam or oxazepam
could be used for this indication.
In adults, agoraphobia is seen as a complication of
panic, but this phenomenon is not as common in elders.
In this population, agoraphobia more often results from
onset of dementia, depression, or apathy, or occurs as
a consequence of serious medical illness or trauma.
There is no evidence that drug therapy is helpful for
agoraphobia.
PTSD with onset in earlier life may again manifest
in later years. The diagnosis of PTSD is complicated
in elders by cognitive deficits and medical comor-
bidities. The recommended treatment for PTSD is

cognitive-behavioral therapy, so psychiatric or psy-
chological referral is indicated for this condition. The
pharmacologic treatment of choice is an SSRI antide-
pressant, with a target dosage equivalent to fluoxetine
60  mg daily. Dual-acting antidepressants, trazodone,
and lamotrigine may also be useful. The required dura-
tion of treatment has not been established. Benzodiaz-
epines have little or no role in the treatment of PTSD
and are particularly problematic for affected patients
with substance abuse issues. For PTSD-associated
nightmares, the adrenergic antagonist prazosin titrated
to a daily dose of 5 mg was found to be helpful in one
case series (Raskind et al., 2000); clonidine, guanfacine,
and cyproheptadine have also been reported to be use-
ful (Horrigan, 1996).
For social phobia (social anxiety disorder), referral for
cognitive-behavioral therapy is indicated. Recommended
medications include SSRI antidepressants, venlafaxine,
pregabalin, and gabapentin. Buspirone is not effective for
this condition.
The treatment of insomnia first involves the use of
sleep hygiene measures. If these interventions are inef-
fective, pharmacotherapy may be tried. The first step is
to discontinue current treatments that have not worked,
including sedating antihistamines (diphenhydramine,
in particular) and prescription hypnotics. If insomnia
persists longer than 2 weeks after this step and there is
no evidence that a treatable medical condition under-
lies the insomnia, another hypnotic should be con-
sidered. For insomnia of less than 3 weeks’ duration
in elderly patients, any of the following drugs could
be used: zolpidem, zaleplon, eszopiclone, gabapentin,
mirtazapine, trazodone, nortriptyline, or temazepam.
Drugs not recommended for insomnia in this popula-
tion include diphenhydramine, chloral hydrate, and
barbiturates and related sedatives (The Medical Letter,
2000). For chronic insomnia, the same drugs can be
used, although nortriptyline and temazepam should be
used chronically with caution. Table 24.12 shows dose
information.
Table 24.12 Hypnotic dosing in elders
Drug Dose (mg h.s.)
Doxepin 3 failure and renal insufficiency further reduce lithium
Eszopiclone 1–2
Gabapentin 100–300
Mirtazapine 3.75–7.5
Nortriptyline 10
Ramelteon 8 form is distinct from the sustained-release form, which
Temazepam 15
Trazodone 25–50
Zaleplon 10
Zolpidem 5
Geriatric Psychopharmacology 605
Mood stabilizers
The population of elders with primary bipolar disor-
der is highly heterogeneous, with individuals differing
in genetic loading for other psychopathologies, age of
disease onset, number and polarity of episodes, access
to treatment, substance abuse history, and comorbid dis-
ease. With a few notable exceptions, the presenting signs
and symptoms of mania, depression, and mixed states
is similar in elders as in younger patients. Response to
treatment is variable, however, and formes frustes pre-
sentations are common (Young, 2005). Hypertension,
diabetes, and cerebrovascular disease are frequent
comorbidities. More than half of bipolar elderly patients
have cognitive deficits on basic screening such as the
MMSE (mini-mental state examination; Gildengers et
al., 2004). Secondary mania should be considered in any
patient presenting as manic for the first time in old age.
Secondary mania can be due to medication, metabolic
disturbance, endocrine disease, or cancer, among many
other conditions.
Treatment of secondary mania requires treatment of
the underlying condition driving the syndrome. For
pharmacologic treatment of bipolar mania, first-line
drugs include lithium and valproate. Carbamazepine is
relegated to second-line treatment because of adverse
effects and drug interaction. For treatment of bipo-
lar depression, lithium and lamotrigine are drugs of
choice. Lamotrigine is also useful in the treatment of
rapid cyclic illness. Atypical antipsychotics also labeled
for use in bipolar illness include aripiprazole, olanzap-
ine, quetiapine, risperidone, and ziprasidone. Although
these drugs are effective, caution is warranted in their
use in elderly patients because of the risk of increased
mortality.
Mood stabilizers: pharmacokinetics
Aging significantly alters lithium pharmacokinetics.
The volume of lithium distribution decreases with aging
because of a relative decrease in total body water that
occurs in tandem with a relative increase in total body
fat. Lithium is not metabolized. Clearance of lithium is
reduced in proportion to reduction in GFR. The half-life of
lithium in elders is 28–36 hours, compared with 24 hours
in nongeriatric patients. Diseases such as congestive heart
clearance.
Valproate is rapidly absorbed when taken orally,
and the enteric-coated formulation is designed to slow
absorption and minimize GI effects. The enteric-coated
is designed for once-daily dosing. Valproate is highly
protein bound, so the free fraction of drug is increased in
elders with low albumin levels. This could result in over-
dosing if total drug levels are used to guide dose changes,
606 Therapeutics for the Geriatric Neurology Patient
as discussed in an earlier section. Once absorbed, distri-
bution of all forms of valproate is rapid; the drug reaches
the central nervous system within minutes. Valproate is
extensively metabolized, primarily through glucuroni-
dation and mitochondrial β-oxidation, but also through
CYP450 enzymes as minor routes. Active metabolites are
produced. Clearance of valproate is reduced by more than
one-third in elders, necessitating lower initial doses and
slower titration.
Lamotrigine is rapidly and completely absorbed when
taken orally, a process unaffected by food. This drug is
metabolized by glucuronidation to an inactive metabo-
lite and is mostly renally excreted. As renal clearance is
reduced with aging, drug exposure is increased in elderly
patients by more than 50%.
Carbamazepine is very slowly absorbed, with peak
levels reached after four to eight hours. This drug is a
substrate for the P-glycoprotein pump. It is hepatically
metabolized via CYP3A4 to an active epoxide metabolite
that can be toxic in high concentrations. Autoinduction
of carbamazepine results in a reduction in half-life with
repeated dosing, which may necessitate upward dosage
adjustment after two to four weeks. In elderly patients,
clearance of carbamazepine is reduced by about one quar-
ter. Carbamazepine significantly induces CYP3A4 and
CYP2C19, and thus is associated with reduced concen-
trations of psychotropic and cardiac drugs, among other
medications.
Mood stabilizers: pharmacodynamics
and mechanism
The mechanism of action of lithium is not known,
although a number of hypotheses have been advanced.
Among other effects, lithium downregulates AMPA
GluR1 synaptic expression, an effect shared by val-
proate. Valproate also increases availability of GABA.
Lamotrigine is believed to act through voltage-gated
sodium channels to inhibit the release of excitatory
amino acids such as glutamate and aspartate. Pharma-
codynamic effects of carbamazepine resemble those of
phenytoin, primarily related to inhibition of synaptic
transmission.
Mood stabilizers: drug interactions
Lithium has the potential for important drug interactions
with ACE inhibitors, calcium channel blockers, thiazide
diuretics, NSAIDs, COX-2 inhibitors, and virtually all
psychotropic drugs. Use of these drugs in combination
with lithium requires closer monitoring of lithium levels.
In addition, any dietary modifications involving a change
in salt intake (especially sodium chloride) can have signif-
icant effects on lithium levels. Carbamazepine affects lev-
els of other drugs metabolized by CYP3A4 and CYP2C19
(as noted earlier) but also is prone to metabolic inhibition
by other drugs because it is metabolized by a single
isoenzyme: CYP3A4. This isoenzyme can be inhibited by
grapefruit juice or antifungal medications, among other
agents. The combination of carbamazepine with valpro-
ate can be hepatotoxic and requires careful monitoring of
liver function. Lamotrigine can be problematic when used
in combination with any other anticonvulsant. Carbam-
azepine interacts with most coadministered drugs and,
for this reason, is, at best, a second-line choice for elderly
patients.
Adverse effects of mood stabilizers
Lithium is associated with numerous adverse effects
in elderly patients, including cognitive impairment,
drowsiness, fatigue, ataxia, tremor, cerebellar dys-
function, dysarthria, fasciculations, polyuria, urinary
frequency, urinary incontinence, constipation, fast-
ing hyperglycemia, weight gain, exacerbation of skin
conditions such as psoriasis, exacerbation of arthritis,
peripheral edema, and hypothyroidism. Episodes of
lithium toxicity, as well as multiple daily doses, may
be risks for structural injury to the kidneys and should
be avoided. Cardiac effects of lithium include ECG
changes, conduction abnormalities, and dysrhythmias.
T-wave depression occurs commonly, in about one-
quarter to one-third of treated patients. Neuropsychi-
atric effects listed earlier may occur even when lithium
levels are in the therapeutic range. Tolerance does not
develop to these neuropsychiatric effects, but the symp-
toms may improve with dose reduction or discontinu-
ation. Half of lithium-treated patients gain substantial
weight with chronic treatment. Laboratory abnormali-
ties associated with lithium treatment include elevated
TSH (with clinical hypothyroidism in about 6% with
chronic treatment) and leukocytosis involving mature
WBCs (no left shift).
Indications for mood stabilizers
Mood stabilizers are used to treat primary bipolar dis-
orders (bipolar I and bipolar II), cyclothymia, certain
secondary mood disorders (such as substance-induced
disorders), schizoaffective disorder, behavioral and psy-
chological symptoms of dementia, pain syndromes,
movement disorders, anxiety disorders, and alcohol/
sedative withdrawal.
Mood stabilizers: clinical use
Primary bipolar disorder is an indication for psychiatric
referral. One issue in the care of elderly patients present-
ing with depression is that it is important to elicit any
history of mania or hypomania before initiating antide-
pressant therapy; for this reason, many nonpsychiatric
physicians also consider depression an indication for
psychiatric referral. In elderly patients presenting for

the first time with mania, the index of suspicion should
be high for secondary mania, and a cause should be
investigated. The diagnostic evaluation for mania or
bipolar illness is usually performed and ordered by the
psychiatrist. It should include vital signs (orthostatic),
physical and neurologic screening examination, cogni-
tive screening, CBC with platelets, comprehensive meta-
bolic panel, thyroid screening, and ECG. Brain MRI may
be indicated.
The treatment of patients with secondary mania
involves discontinuing any offending drug (such as
a steroid) or treating the underlying medical con-
dition. For primary mania or hypomania, antide-
pressant treatment should be stopped, and initial
monotherapy with lithium, valproate, or an atypical
antipsychotic should be initiated. For mixed states
(mania with depressive features), secondary mania,
or rapid cycling, valproate is preferred. The patient
should be observed for several weeks with initial
therapy before any decision is made on whether a
switch in drug or augmentation is needed. For bipo-
lar depression, initial monotherapy with lamotrigine
or lithium should be initiated. If initial treatment
with one of these drugs is ineffective, a switch to the
other should be tried. If neither is effective, an atypi-
cal antipsychotic should be tried as monotherapy or
add-on therapy. If this is ineffective, either an anti-
depressant in combination with a mood stabilizer
or ECT should be considered, in consultation with a
psychiatrist. Rapid remission of symptoms can occur
after four to six ECT treatments, and the course is
followed by treatment with a mood stabilizer to
maintain remission.
Elderly patients treated with mood stabilizers
should be monitored for efficacy and adverse effects
by physical and mental status examination and labo-
ratory testing, including drug levels (Jacobson, 2012).
Psychiatric follow-up is recommended for these
patients. Table  24.13 shows suggested dosages and
titration of mood stabilizers.
Table 24.13 Dosage and titration of selected mood stabilizers in eldersa
Indication/drug Initial dose Titration
Lithium 75–150 mg daily Increase by 75–150 mg every 4–7 days
Valproate 125–250 mg daily to bid Increase by 125–250 mg every 3–5 days
Carbamazepine 100 mg bid Increase by 100–200 mg every 3–5 days
Lamotrigine 12.5 mg daily Increase by 12.5–25 mg every 2 weeks
aAtypical antipsychotics are also labeled for the treatment of bipolar illness. Dosing of these drugs is shown in Table 24.7.
Geriatric Psychopharmacology 607
Treatments for substance-related
disorders
Substance abuse is not common in the current cohort of
elders, but when present, it is associated with significant
morbidity. In this cohort, the substances most likely to
be abused are alcohol and tobacco. Of prescribed drugs,
benzodiazepines are the most commonly abused; opioid
abuse does occur but is much less common. In general,
substance-related disorders are classified as either sub-
stance use disorders (abuse and dependence) or substance-
induced disorders (intoxication, withdrawal, cognitive dis-
orders, mood disorders, and so on).
Substance abuse is a maladaptive pattern of repeated use
of alcohol, a drug, or a medication that results in harm-
ful consequences. An elderly alcohol abuser could meet
this criterion by failing to maintain adequate hygiene,
having repeated falls, failing to seek needed medical care,
or alienating children through constant argument about
the consequences of intoxication. Substance dependence is
a maladaptive pattern involving the development of tol-
erance, withdrawal symptoms on discontinuation, com-
pulsive use, restriction of activities, and/or continued
use despite adverse physical or psychological effects. In
regard to alcohol, substance dependence is more com-
monly known as alcoholism. In general, alcohol abuse is
more prevalent than alcohol dependence, and “problem
drinking” (which is not a DSM term) is more prevalent
than abuse. Different definitions of problem drinking
exist; for older drinkers, this could be defined by daily
intake of more than 2 drinks per day in men or more than
1 drink per day in women, or recurrent binge drinking.
When benzodiazepines are prescribed, physiologic
dependence develops with normal clinical use, and a
withdrawal syndrome would occur upon abrupt discon-
tinuation, so physical dependence is expected. Moreover,
some patients with anxiety disorders increase or reduce
the dose of benzodiazepine on their own, depending on
the severity of symptoms. Patients who do so responsibly
do not warrant a diagnosis of addiction.
Typical daily dosage Dosage range
300–900 mg 150–1800 mg daily
500–1000 mg (divided bid) 250–1500 mg
(divided bid)
300 mg bid 200–800 mg daily
(divided bid)
50 mg bid 100–300 mg daily
(divided bid)
608 Therapeutics for the Geriatric Neurology Patient

Diagnosis of substance-related disorders Table 24.14 Alcoholism: signs, symptoms, and associated
Substance abuse/dependence is usually covert, so conditions
detection requires a high index of suspicion. Diagnosis Abdominal obesity Hostility
requires a careful and corroborated history, physical Aggression Hygiene problems
and mental status examinations, and laboratory testing. Amnesia Hypercortisolemia
In the emergency room, drug screens need to be done Anemia Hyperhomocysteinemia
quickly and, if possible, sent within 1 hour of presenta- Anxiety Hypertension
tion. Alcohol can be detected in the urine for only a brief Apathy Infection
period, up to 7–12 hours (Moeller et al., 2008). Both serum Ataxia Insomnia
and urine specimens should be obtained. Serum drug Bruising Irritability
screening is usually performed for ethanol, acetamino- Cardiomyopathy Legal problems
phen, and salicylates, the latter to exclude overdose. Cerebellar degeneration Malignancy
Urine drug screening is usually performed for opioids, Cirrhosis Malnutrition

heroin, methadone, benzodiazepines, cocaine, amphet- Dehydration Medical noncompliance

Delirium Nausea/vomiting
amines, methamphetamines, and barbiturates. Specific
Delusions Neuropathy
included drugs vary by laboratory. Often laboratories
Dementia Osteoporosis
do not distinguish individual opioids or metabolites, but
Dental caries Pancreatitis
can perform more specific analyses upon request. False-
Depression Panic attacks
positive test results occur with many coadministered
Electrolyte derangements Pneumonia
drugs (Moeller et al., 2008). Esophageal varices Seizures
Falls Sexual dysfunction
Alcohol-related disorders Fractures Social isolation
Gastritis Suicidal ideation
Alcohol dependence Gastrointestinal bleeding Trauma
Although a variety of drinking patterns are seen, most Hallucinations Ulcers
elders who drink do so in small amounts on a daily basis. Hepatitis Wernicke’s encephalopathy
The effects of aging, medications, and comorbid medical Homicidal ideation
conditions on alcohol kinetics and dynamics are such that
Source: Adapted from Jacobson et al. (2007) with permission from
these small amounts can have large effects. Drinking pat-
American Psychiatric Publishing.
terns can be longstanding with persistence into old age
or can be of late onset (after age 60). Those with early-
onset disease are often easily identified because of seri- In males, GGT and CDT together provide a reliable
ous medical comorbidities (such as COPD, cirrhosis, or indicator; in females, GGT alone has better predictive
history of TBI) and legal and family problems. Cases of value. GGT and CDT begin to normalize within days of
more recent onset may be more difficult to detect. Elderly cessation of drinking and return to normal levels within
drinkers often present with a constellation of individual 2 weeks.
signs, symptoms, and conditions, which are listed in Although physician counseling about alcohol overuse
Table 24.14. This list can be used as a “review of systems” has definite short-term effects in decreasing consump-
for alcoholism. Eliciting the patient’s report of quantity tion, continued abstinence depends on participation in
and frequency of drinking is also helpful after completing a multifaceted program involving regular attendance at
a screening such as the Michigan Alcoholism Screening groups such as Alcoholics Anonymous or Rational Recov-
Test-Geriatrics version (MAST-G) because this can miti- ery, an ongoing 1:1 relationship with a supportive family/
gate the tendency to minimize drinking. friend surrogate (usually a sponsor or counselor), regu-
Laboratory abnormalities supporting the diagnosis of larly scheduled medical and psychiatric follow-up visits,
alcoholism include the following (Jacobson, 2012). and repeated reinforcement for abstinence. Some elders
• Elevated gamma glutamyl transerase (GGT) (>47 U/L do well in group therapy directed toward resocialization,
in men or >25 U/L in women) is consistent with four or as long as they are placed with age-peers with the same
more drinks daily for 4 weeks or more. Takes 2–3 weeks history of alcohol dependence. Family therapy is useful to
of abstinence to normalize. reduce enabling, deal with family conflicts, and address
• Elevated carbohydrate-deficient transferring (CDT) poor family dynamics. For homebound elders, identifica-
(≥ 2.6%). tion and education of the “supplier” of alcohol is a critical
• Elevated AST > ALT (ratio >2:1). step. Helping the patient and family to identify appropri-
• Elevated mean corpuscular volume (MCV). ate medical, dental, and home health services can be use-
• Elevated uric acid level. ful, as can the arrangement of Meals on Wheels or partici-
• Elevated total homocysteine level (>15 μmol/L). pation in senior center activities.

Medications currently approved by the FDA for treat-
ment of alcohol dependence include naltrexone (oral and
long-acting injectable forms), acamprosate, and disul-
firam. Although these drugs can be used to treat elders,
none have been extensively studied in this population.
Naltrexone is a nonspecific opioid antagonist that
reduces the reinforcing effects of alcohol, making it less
likely that the patient will continue drinking after a slip.
Limited available data suggest that naltrexone is safe and
effective in older patients (Oslin et al., 1997). The drug
should always be administered in conjunction with the
nonpharmacologic interventions listed earlier. Treatment
should not be initiated until the patient is completely
detoxified from opioids, with abstinence verified by urine
opioid screening and/or a naloxone challenge test. Oral
naltrexone (Revia) should be initiated in elderly patients
at 25 mg daily and either maintained there or increased
to 50 mg daily for the duration of treatment (Oslin et al.,
1997). Pharmacokinetics of the long-acting injectable form
(Vivitrol) have been understudied in the geriatric popula-
tion. The initial dose of Vivitrol for patients of unselected
age is 380 mg IM every 4 weeks.
Acamprosate is a GABA agonist and glutamate antago-
nist that may have a role not only in treatment for alcohol
dependence, but also in neuroprotection during with-
drawal. This drug is understudied in geriatrics; its effi-
cacy and safety have not been demonstrated in this popu-
lation. When the drug is used, it should be started as soon
as possible after abstinence has been achieved and con-
tinued for 12 or more months, even through relapses. The
geriatric starting dose is 333 mg 3 times daily, increased
to 666 mg 3 times daily after 1 week. The drug promotes
continued abstinence and reduces the severity of relapses.
In nongeriatric populations, the drug has been used suc-
cessfully in combination with other drugs such as naltrex-
one or disulfiram.
Disulfiram is little used in geriatrics because of the
seriousness of adverse effects in patients who drink dur-
ing treatment. Disulfiram inhibits the enzyme aldehyde
dehydrogenase, resulting in the buildup of toxic metab-
olites when ethanol is ingested. The effects vary among
individuals and are dose dependent. Symptoms range
from flushing and nausea to marked tachycardia or bra-
dycardia, hypotension, myocardial infarction, cardiovas-
cular collapse, heart failure, and seizures. The more severe
reactions are seen with high doses of disulfiram, with sig-
nificant alcohol ingestion, or in patients with preexisting
cardiovascular disease. There is no specific antidote. The
“antabuse reaction” can occur with any alcohol-contain-
ing substance, including some over-the-counter cough
syrups and mouthwashes, and prescribed medications
such as metronidazole, tolbutamide, and trimethoprim/
sulfamethoxazole (Bactrim).
There are numerous medical contraindications to disul-
firam use. When disulfiram is prescribed to an elderly
Geriatric Psychopharmacology 609
patient, the dose should be maintained at 125–250 mg
daily. Some question centers on whether this dose gener-
ates a blood level sufficient to produce an alcohol–disul-
firam reaction if the patient drinks; the deterrent might
be merely the threat of a reaction. In regular users, disul-
firam compliance can be determined by testing urine for
diethylamine, a metabolite. When disulfiram is prescribed,
liver function tests should be checked at baseline, then
every 2–3 weeks for 2 months, and then every 3 months.
Other drugs used to treat alcohol dependence include
SSRI antidepressants and anticonvulsants. Among non-
geriatric patients, SSRI use is associated with reduced
craving and drinking during the first weeks of treatment,
but these effects may not be sustained in all patients. As
with all other pharmacologic interventions for alcohol
dependence, treatment using SSRIs is best carried out in
a structured abstinence program with close follow-up,
as discussed earlier. Although topiramate up to 300 mg
daily has been found effective in treating alcohol depen-
dence in a nongeriatric cohort, this drug can be associated
with significant adverse effects in elderly patients. Other
anticonvulsants reported to have some effect in treating
alcohol dependence include valproate, carbamazepine,
and lamotrigine, but none of these medications have been
studied systematically in the geriatric population for this
indication.
Alcohol withdrawal
The signs and symptoms of alcohol withdrawal in elderly
patients are like those seen in younger counterparts, but
they may be more severe and longer lasting (Brower et al.,
1994). These include fever, tachycardia, tachypnea, hyper-
tension, unstable blood pressure, diaphoresis, tremor,
hyperreflexia, marked startle response, mydriasis, seizures,
headache, disorientation, anxiety, agitation, insomnia,
delusions (usually persecutory), perceptual disturbances/
hallucinations, and nausea/vomiting. Minor withdrawal
symptoms such as tremor and anxiety are seen early, usu-
ally 6–12 hours after the last drink. Hallucinations occur
after 8–24 hours, seizures after 24  hours, and delirium
tremens (DTs) after 72  hours (Rubino, 1992). An episode
of DTs may begin earlier in patients with a prior history
of delirium tremens. DSM-IV-TR refers to any delirium
that is secondary to alcohol withdrawal as delirium tre-
mens, but this latter term also connotes a severe delirious
state, often with seizures. Elderly patients with delir-
ium tremens have a high mortality rate due to cardiac
arrhythmias, hypovolemic shock, aspiration pneumonia,
hepatic failure, and falls or other accidents (Feuerlein and
Reiser, 1986). Severity of the withdrawal syndrome can be
assessed using a scale such as the revised Clinical Institute
Withdrawal Assessment for Alcohol (CIWA-Ar) (Sullivan
et al., 1989).
Initial supportive measures for the patient in alcohol
withdrawal include hydration, nutrition, and rest in a
610 Therapeutics for the Geriatric Neurology Patient
quiet environment. Parenteral thiamine 100 mg IM or IV
should be given before any glucose-containing IV solu-
tion is started because glucose metabolism utilizes thia-
mine and could precipitate Wernicke’s encephalopathy
in marginally deficient patients. Folate and a multivita-
min should also be given, and electrolyte derangements
should be corrected. Magnesium repletion is particularly
important. Parenteral thiamine 100 mg daily should be
given for at least 3 days (Mayo-Smith et al., 2004)—longer
if the patient has any neurologic or cardiovascular signs
to suggest the presence of Wernicke’s encephalopathy.
Prescription of one IV Rally Pack (“banana bag”) daily
would meet this requirement and also supply folate 1mg,
multivitamins 10 mL, and magnesium sulfate 2 g in 1 L of
5% dextrose/water or normal saline.
Benzodiazepines are used to control the rate of with-
drawal, utilizing either a fixed-dose regimen or symp-
tom-triggered therapy. In general, when medication is
administered only for a CIWA-Ar score above a thresh-
old of 8–10 (symptom-triggered therapy), less medication
is used and the duration of detoxification is shortened
(Daeppen et al., 2002). Compared with the fixed-dose
strategy, however, symptom-triggered therapy is associ-
ated with higher average CIWA-Ar scores for more days
(Daeppen et al., 2002), and this could place the frail elder
at risk for an adverse medical outcome. Thus, although
some clinicians prefer symptom-triggered therapy for use
in nonelderly patients, low fixed doses of medication may
be preferable to prevent symptom progression in elders.
Any benzodiazepine can be used to control with-
drawal, but pharmacokinetic differences make some
agents better choices for elderly patients. Lorazepam
is the first-line drug for elders in alcohol withdrawal
because it can be given PO or IV (as well as IM, although
IM administration is problematic in elderly patients
with reduced muscle mass), has a relatively rapid onset
of action and a moderate duration of effect, is not oxi-
datively metabolized and thus can be used for patients
with hepatic impairment, and is not highly lipophilic
and thus does not accumulate in the body. Except for
IV availability, oxazepam has the same advantages.
Chlordiazepoxide (Librium) can be used in young–old
patients in withdrawal whose hepatic function is intact;
in old–old patients and in those with even moderate
degrees of hepatic dysfunction, this drug should be
avoided. Librium has the advantage of a longer half-life,
which facilitates a smoother withdrawal and possibly
greater effectiveness in preventing withdrawal seizures.
The disadvantage of the longer half-life in elders is the
increased risk of oversedation. Diazepam is not a good
choice because of its tendency to move rapidly into lipid
compartments and out of the general circulation.
For fixed-dose treatment, lorazepam is dosed 2 mg
every 6 hours for 4 doses, then 1 mg every 6 hours
for 8 doses, along with 2–4 mg every 1–2 hours prn
(Mayo-Smith, 1997). For symptom-triggered treatment,
lorazepam is dosed 2–4 mg every 1–2 hours when the
CIWA-Ar score is ≥8. Lorazepam should be dosed IV if
the patient has severe withdrawal symptoms, is vomiting,
or has GI bleeding or pancreatitis. When the IV route is
used, initial doses should be half of those recommended,
with rapid upward titration as needed and tolerated. Hal-
lucinations may respond to benzodiazepine treatment
alone, but an antipsychotic should be added for severe
or persistent psychotic symptoms. Haloperidol is usually
selected for this indication, although any antipsychotic
may be used. It should be noted that all antipsychotics
lower the seizure threshold.
Anticonvulsants such as valproate, carbamazepine,
and gabapentin have been used as adjunctive treat-
ments for alcohol withdrawal, with some benefit in
terms of reducing the burden of withdrawal symptoms
and lowering the total dose of benzodiazepine adminis-
tered. β Blockers such as atenolol have been used to treat
patients in withdrawal with persistent hypertension and/
or tachycardia. Alcohol withdrawal seizures are usually
of the generalized tonic–clonic type, with a brief postic-
tal period. Adequate treatment of alcohol withdrawal
with a benzodiazepine prevents the development of sei-
zures. When an alcohol-withdrawal seizure does occur,
IV lorazepam 2 mg can decrease the likelihood of recur-
rence (D’Onofrio et al., 1999).
Nicotine-related disorders
Nicotine use disorder (tobacco dependence)
Smoking is the most common substance-related disorder
among the current cohort of elders in the United States.
It is associated with significantly increased morbidity
and mortality, particularly among smokers grown old.
Regardless of age, quitting smoking confers health ben-
efits (LaCroix et al., 1991). Elders who stop smoking for
5  years reduce cardiovascular mortality to that of non-
smokers and also reduce their risk of lung cancer.
Medically based smoking cessation programs are a par-
ticularly important intervention in the geriatric population.
Pharmacologic treatments include nicotine-replacement
therapies and bupropion. With a few caveats, these treat-
ments are considered safe in elders when used in accor-
dance with prescribing recommendations.
Nicotine-replacement therapies (gum, lozenges,
patches, sprays, and inhalers) double the rate of quitting
smoking compared with placebo. Effects are maintained
over time in many patients. Patient selection may be nec-
essary, as caution is advised in using nicotine replacement
for those with coronary artery disease, severe or worsen-
ing angina, recent myocardial infarction (MI), uncon-
trolled hypertension, or serious cardiac dysrhythmia. In
addition, the two forms of nicotine replacement available
by prescription only—intranasal spray and oral inhaler—
should be used with caution. When nicotine-replacement
 Geriatric Psychopharmacology 611

Table 24.15 Selected nicotine replacement therapies

Amount of Time to
Form of nicotine Trade name Strength nicotine delivered peak level Instructions for use Initial taper

Chewing gum Nicorette, 2 mg Up to 0.8 mg 20–30 min Alternate chewing and parking gum for 6 weeks
various 4 mg Up to 1.5 mg 20 min. 1 piece q 1–2 h and prn; NTE
generics 24 pieces/day.
Lozenge Commit, 2 mg (geriatric 25% more than 20–30 min Weeks 1–6: 1 lozenge q 1–2 h 6 weeks
various dose) gum Weeks 7–9: 1 lozenge q 2–4 h
generics 4 mg Weeks 10–12: 1 lozenge q 4–8 h
Lozenge should not be chewed or swallowed.
Transdermal Nicoderm CQ, 16-h patch: 5, Variable 8–9 h Apply new patch every 24 h to hairless, 4–6 weeks
patch Habitrol, others 10, 15 mg clean, dry skin on upper body or arm. Rotate
24-h patch: 7, 14, sites.
21 mg For Nicoderm CQ or Habitrol, dose for
“young–old” depends on smoking history:
≥10 cigarettes daily—21 mg for 4–6 weeks,
then 14 mg for 2 weeks, then 7 mg for
2 weeks. For frail or low body weight elders
or those with cardiovascular disease—14 mg
for 4–6 weeks, then 7 mg for 2–4 weeks.

Source: Adapted from Jacobson et al. (2007) with permission from American Psychiatric Publishing.

therapy is initiated, the patient must quit smoking to
avoid toxic levels of nicotine.
Table 24.15 shows nicotine doses delivered by gum,
lozenges, and patches. Although the nicotine content of
one cigarette ranges from 6 to 11 mg, the actual amount
of nicotine delivered by smoking may be only 1–3 mg per
cigarette. The amount of nicotine delivered by a replace-
ment product varies according to the dose used. The par-
ticular product selected depends primarily on patient
preference, although the patch appears to be particularly
well suited to elderly patients because it provides a con-
stant rate of nicotine exposure.
Both 16- and 24-hour patches are available; the 16-hour
patches should be removed at bedtime, and the 24-hour
patches should be removed in the morning before the
next patch is applied. Removal of the 24-hour patch at
bedtime may be indicated if the patient develops insom-
nia. Patches with smaller doses of nicotine (7, 14, or
15 mg) should be used for elderly patients. Higher doses
may be tolerated by young–old patients and are required
for those who smoke more than ten cigarettes daily. It is
important that tobacco use not continue while the patch
is in use, or nicotine levels can become toxic. The recom-
mended treatment period for the patch is 8 weeks. There
is no evidence of significant withdrawal when the patch
is discontinued.
Use of the antidepressant bupropion SR doubles the
quit-smoking rate. When used with behavioral inter-
ventions, the drug also reduces withdrawal-related
dysphoria and weight gain. In acute withdrawal,
bupropion is about as effective as nicotine-replacement
therapies, and the combination of bupropion with
nicotine replacement may be superior to monotherapy,
although the safety of this combination has not been
specifically studied in elders. For smoking cessation,
bupropion is started while the patient is still smok-
ing, and a “quit date” is selected, usually 1–2 weeks in
the future. Bupropion SR should be initiated in most
elderly patients at a dose of 100 mg daily; this should
be increased to 100 mg bid after 4–7 days, as tolerated.
SR doses should be separated by 8 hours. Young-old
patients may tolerate an initial dose of bupropion SR
150 mg (Zyban), with a dose increase to 150  mg bid
after 4–7 days. Bupropion SR should be continued for
7–12 weeks; at 7 weeks, if the patient has made no prog-
ress toward quitting, the medication should be discon-
tinued. The goal of therapy is complete cessation of
smoking. Ideally, when this is achieved by 12 weeks,
the medication is stopped; tapering is not necessary,
although the patient should be monitored for the emer-
gence of depressive symptoms.
Benzodiazepine dependence
Psychological dependence on benzodiazepines (“addic-
tion”) may manifest as escalation of dose over time, dis-
agreements with health-care professionals about use, and
sometimes antisocial behaviors (such as using multiple
providers and/or pharmacies). Addiction to benzodiaz-
epines is more likely to develop in patients with a current
or previous history of substance abuse, usually involving
tobacco or alcohol. Benzodiazepines most likely to induce
psychological dependence are those with fast onset
(high lipophilicity) and short duration of action (such as
alprazolam) (Ciraulo et al., 2005).
612 Therapeutics for the Geriatric Neurology Patient
In contrast, physical dependence is an expected conse-
quence of use of a sufficient amount of a benzodiazepine
for a sufficient length of time. Physical dependence does
not define addiction. Many individuals who take benzo-
diazepines chronically to treat an anxiety disorder do not
require increasing doses over time, as tolerance to their
anxiolytic effects does not develop. On the other hand, even
in the absence of psychological dependence, chronic use
of benzodiazepines in some elderly patients is associated
with depression, residual anxiety, cognitive impairment,
daytime sedation, ataxia, falls, and poor physical health.
Cognitive impairment with benzodiazepines may present
as an amnestic syndrome or as a dementia characterized
by inattention, memory problems, psychomotor slowing,
and incoordination. Cognitive symptoms generally resolve
when these medications are tapered and discontinued.
For older patients treated chronically with therapeutic
doses of benzodiazepines, a trial off-drug may be indi-
cated. For these patients, a slow taper (by 10–25% per
week) is usually tolerated. When very short-acting agents
such as alprazolam are used, a switch to a longer-acting
drug may be necessary; if so, the equivalent dose of the
second drug should be cut by 10–25% to avoid overdosing
(Ciraulo et al., 2005). A subset of patients will do poorly,
even with slow withdrawal. These patients are likely to
have underlying conditions such as GAD, with benefit
from chronic treatment that may or may not outweigh the
risk. The use of flumazenil is not recommended to expe-
dite withdrawal in elderly patients.
Withdrawal for patients treated over the long term with
high doses of a benzodiazepine should be accomplished in
an inpatient medical setting. The patient should be on a car-
diac monitor with frequent checks, and vital signs should
be taken on a schedule (for example, every 4 hours). The
drug should then be tapered at a rate of 10–25% per day. If
the patient develops fever, tremulousness, or diaphoresis,
the dose of drug should be increased again, and the patient
should be hydrated and watched more closely until stable.
The emergence of new symptoms or a new perceptual dis-
turbance (such as tinnitus) can help to identify too-rapid
withdrawal and to distinguish it from anxiety (Ciraulo et
al., 2005). Propranolol (30–60 mg daily divided tid) may
be used to attenuate adrenergic signs and symptoms, and
an anticonvulsant may prevent or treat seizures. After the
period of detoxification, medications that can help pro-
mote abstinence include buspirone, SSRI antidepressants,
and venlafaxine (Ciraulo et al., 2005).
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 Chapter 25
Nonpharmacologic Treatment of
Behavioral Problems in Persons
with Dementia
Gary A. Martin1 and John Ranseen2
1
Integrated Geriatric Behavioral Health Associates, Scottsdale, AZ, USA
2
Department of Psychiatry, University of Kentucky College of Medicine, Lexington, KY, USA

Summary
• Dementia patients commonly exhibit neuropsychiatric and behavioral symptoms such as physical and nonphysical
aggression, anxiety, irritability, dysphoria, aberrant motor behavior, disinhibition, delusions, and hallucinations.
• Behavioral problems are associated with a worse prognosis that can diminish the quality of life for both the patient and
the caregiver and is one of the main reasons for institutionalization.
• Most dementia-related behavioral problems are linked to confusion, delirium, medication-induced delirium, pain,
environmental factors, and the intrusive aspects of caregiving.
• Models of nonpharmacologic treatments include good care/comfort care, unmet needs, environmental intervention,
learning theory, antecedent control, family and caregiving education and training, and psychosocial and individualized
therapies.
• Treatments for specific dementias
• AD: Antecedent control strategies are more effective than consequence-oriented learning, especially in advanced
stages.
• VD: Variability in clinical presentation and severity makes it difficult to prescribe a certain treatment. Those with
higher cognitive ability may benefit from social learning approaches.
• LBD: Environmental and antecedent control techniques may be most effective. Caregiver education and training also
help to manage LBD behaviors. Physical restlessness may be addressed with “on the run” care.
• FTDs: Environmental and behavioral treatments are most recommended, including “on the run” care.
• PD: Environmental, psychoeducational, and counseling-oriented interventions are most recommended. Research
suggests that caregivers speak and act slowly with frequent repetition, avoid multi-tasking, and make use of
compensatory strategies.

Introduction Prevalence

Health-care professionals in the field of geriatrics are
well aware that behavioral and psychiatric symptoms
are extremely common in persons with dementia. When
it comes to treating these problems, a majority of the
energy, funding, and literature has focused on pharma-
cologic options to treatment. However, over the past
decade, there has been a growing interest in the develop-
ment and use of nonpharmacologic treatment approaches
to addressing dementia-related behavioral problems. This
chapter provides an overview of the use of nonpharmaco-
logic interventions in treating behavioral problems asso-
ciated with common types of dementia.
More than 60% of community-dwelling persons with
dementia exhibit some sort of neuropsychiatric or behav-
ioral symptoms. The rate of aggressive behavior for this
population is from 34% to 64% (Lyketsos et al., 2000;
McNeese et al., 2009). In institutional settings, such as
nursing homes and assisted living centers, the percent-
ages are even higher, at more than 80% exhibiting neu-
ropsychiatric or behavioral symptoms. The lifetime risk
of developing such problems approaches 100% (Lyketsos
et al., 2000; Jeste et al., 2008). The prevalence of nonphysi-
cal aggression or agitation in nursing homes is reported
to be between 48% and 82%, with physically aggressive

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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616 Therapeutics for the Geriatric Neurology Patient
behavior ranging from 11% to 44% (Zuidema et al., 2007).
Other overall symptom prevalence rates for persons with
dementia include anxiety (48%), irritability (43%), dys-
phoria (38%), aberrant motor behavior (38%), disinhibi-
tion (36%), delusions (22%), and hallucinations (10%).
Prevalence of psychosis is 25% in cross-sectional studies
and 50–70% in longitudinal studies (Mega et al., 1996).
Common behavioral problems
The list of behavioral problems commonly exhibited
by persons with dementia is lengthy and includes such
behaviors as combative with care, assaultive to peers
and caregivers, sexual acting out, verbal abuse, physical
restlessness, wandering, rummaging, hoarding, elope-
ment, inappropriate urination, sleep disturbances, eating
disorders, repetitive/disruptive vocalizations (crying,
moaning, yelling), disrobing in public, and “sundown-
ing.” Related psychiatric conditions such as depression,
anxiety, and psychotic thinking are also reported, includ-
ing related symptoms of apathy, social withdrawal, obses-
sive–compulsive behaviors, delusions, and hallucinations
(Zuidema et al., 2007).
The literature discusses behavioral problems in broad,
vaguely defined terms like agitated, aggressive, and disrup-
tive. Phrases like behavioral disturbances and neuropsychiat-
ric symptoms are often used interchangeably, without being
more specific or descriptive in their definitions. As such,
problematic behaviors in dementia patients lack accepted
uniform definitions, making it difficult to compare stud-
ies in this area. Agitation, for example, is a widely used
term in the literature, yet it includes a variety of related
but discretely different behaviors such as irritability, rest-
lessness, physical and verbal aggression, resisting caregiv-
ers, pacing, and wandering (Teri et al., 1998). “Aggressive
behavior” is often associated with acts of violence against
others, but it can also include verbally threatening/abu-
sive behaviors or even various forms of property destruc-
tion and disruptive behaviors (Turner, 2005; Pulsford and
Duxbury, 2006). While this inconsistency in nomenclature
poses obvious problems for researchers and academi-
cians, it does not negate the fact that behavioral problems
are not only common, but nearly universal when it comes
to persons with dementia, especially as their dementia
progresses.
Clinical repercussions
The clinical repercussions of these behavioral problems
can be quite serious. Dementia patients who exhibit neu-
ropsychiatric and behavioral symptoms have a worse
prognosis than their peers. They tend to follow a more
rapid course of decline in cognition, exhibit diminished
functional skills, have a higher mortality rate, and expe-
rience a diminished quality of life (Jeste et al., 2008). In
addition, their caregivers experience greater problems
with distress, negative feelings, emotional exhaustion,
and general burnout (Pulsford and Duxbury, 2006). This,
in turn, increases the possibility of caregivers acting
physically or emotionally abusive toward the persons
for whom they provide care (Gates et al., 2003). More-
over, for noninstitutionalized patients who live in the
community, neuropsychiatric and behavioral symptoms
are often the reason for families placing their loved ones
in nursing homes and other institutional settings (Buhr
et al., 2006).
Rationale for nonpharmacologic
approaches
The most common treatment modality for dementia
patients with behavioral problems is pharmacologic.
A 2005 comprehensive review of 2.5 million Medicare
beneficiaries residing in nursing homes found antipsy-
chotic medications being prescribed at the highest lev-
els in more than a decade (Briesacher et al., 2005) with
the greatest number going to persons with dementia
who exhibit behavioral disturbances (Jeste et al., 2008).
A recent study of nursing home admissions found that,
in the first 3 months, 71% of all new admissions received
at least one psychoactive medication, with 15% receiv-
ing four or more such medications. This occurred even
though, 6 months prior to admission, nearly two-thirds
of those patients were receiving no psychoactive medica-
tions. Conversely, only 12% of those same newly admit-
ted patients received some sort of nonpharmacologic
treatment (Molinari et al., 2010).
But psychoactive medications have their challenges
and pitfalls. First, many behavioral problems are the
direct result of environmental stressors and poor care-
giving practices rather than being a function of any
neuropsychiatric condition (Kitwood, 1997; Cohen-
Mansfield and Mintzer, 2005; Pulsford and Duxbury,
2006). For example, patients will become agitated when
physical and emotional needs are not met (Algase et al.,
1996; Cohen-Mansfield, 2000). While medications may
diminish neuropsychiatric and behavioral symptoms,
they do not address the cause of the behavior, which
may go undetected and unresolved. (Cohen-Mansfield
and Mintzer, 2005).
Second, many of the drugs used to treat neuropsychiat-
ric and behavioral symptoms can cause lethargy, cognitive
slowing, and increased confusion and greatly increased
risk for morbidity and complications from falls, failing
mobility, and the development of parkinsonism. These
medications can further incapacitate dementia patients
who already suffer cognitive and functional decline
 Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia
from their dementia, potentially depriving them of what
limited resources are still available to them (Cohen-Man-
sfield and Mintzer, 2005).
Third, studies suggest that the pharmacologic treat-
ment of problems such as psychosis and agitation may
not be as effective as was once believed (Sink et al., 2005).
While some clinical trials have shown modest efficacy in
symptom reduction, others have yielded limited or no
positive results (Schneider et al., 2006). Moreover, the
placebo response rate in clinical trials on the use of anti-
psychotic medications with dementia patients is between
30% and 50%, raising questions about the use and efficacy
of those medications, especially when balanced with their
side effect burden (Jeste et al., 2008).
Fourth, elderly persons with dementia are particu-
larly susceptible to the adverse side effects of psycho-
active medications. Anticholinergic, extrapyramidal,
and parkinsonian side effects are common. To date, the
FDA has not approved any medications for the treat-
ment of behavioral symptoms in patients with demen-
tia, so all such treatment is “off label.” There is also a
growing concern over the potential for cerebrovascular
adverse events and higher mortality rates with the use
of certain antipsychotic medications, prompting the
FDA to issue “black box” warnings in 2003 and 2005
(US FDA, 2005).
As a result, the American Geriatrics Society and the
American Association for Geriatric Psychiatry in a con-
sensus statement ( American Geriatrics Society and the
American Association for Geriatric Psychiatry, 2003)
recommended, “After associated medical conditions are
assessed and treated, the initial treatment of behavioral
symptoms should be nonpharmacologic when there are
no psychotic features and when there is no immediate
danger to the resident or others” (p. 1295). This recom-
mendation was reinforced in a white paper article by
the American College of Neuropsychopharmacology
(Jeste et al., 2008) recommending that “good clinical care,
independently from pharmacotherapy, may be help-
ful for patients with dementia-related psychosis and/or
agitation, and their caregivers, through nonspecific and
specific interventions. Nonspecific interventions such as
empathy and attention to interpersonal and social issues
may be particularly helpful [while] specific interventions
include environmental, psychosocial, behavioral, and
medical interventions” (p. 965). It was further noted that
“not all psychotic symptoms or agitations need pharma-
cotherapy. Only severe symptoms that are persistent or
recurrent and cause clinical significant functional disrup-
tion would generally be considered appropriate for ongo-
ing pharmacologic management” (p. 966). Overall, these
conclusions seem unequivocal. The pharmacologic treat-
ment of behavioral problems exhibited by persons with
dementia should be considered as a last resort rather than
first resort.
617
Types of dementia: the brain, cognition,
and behavior
Although numerous types of dementias arise, the non-
pharmacologic treatment of dementia has focused
on those with the highest prevalence rates, including
Alzheimer’s disease (AD), Lewy body dementia (LBD),
frontotemporal dementia (FTD), Parkinson’s disease with
dementia (PDD), and vascular dementia (VD). Although
AD, LBD, FTD, and PD are considered distinctly different
entities, there is a great deal of overlap in etiology, under-
lying neuropathology, symptom presentation, and course
of illness (Holmes et al., 1999; Barker et al., 2002). All
involve degenerative neuronal changes leading to brain
atrophy. Additionally, it is not unusual for VD to coex-
ist with other dementias, particularly AD (Roman, 2001;
Karlaria, 2002). Thus, all the dementias can display typi-
cal cognitive impairment with decline over time, affecting
attention and memory, language, visuospatial skill, and
executive functions. All dementias can directly impact
areas of the brain implicated in modulating emotional
control such as the amygdala, cingulate gyrus, insula, and
inferior frontal cortex. Thus, patients with dementia often
exhibit increased behavioral volatility, emotional lability,
and impulsivity. Similarly, other problematic behavioral
presentations, including apathy or inactivity, psychosis,
loss of self-awareness, inappropriate social behavior,
and resistance to caregiving, can be evident in any of the
dementia types. However, differences in underlying neu-
ropathology lead to different general patterns of cogni-
tive and behavioral functioning between the dementias
particularly early in the disease course. Understanding
these distinct behavioral problems and cognitive profiles
is critical in differential diagnosis and behavioral treat-
ment strategy.
Alzheimer’s disease
AD, by far the most commonly encountered dementia,
is characterized by loss of neurons in the cerebral cor-
tex, usually starting in the medial temporal lobes and
including the hippocampus, parahippocampal gyri, and
subiculum. A loss of cholinergic neurons in the nucleus
basalis of Meynert and locus ceruleus is found, with the
loss of cortical neurons predominantly affecting large
pyramidal neurons. Cell loss extends fairly rapidly to the
parietal and frontal lobes. Microscopic neuronal changes
include distinct contortions of neurofibrils termed neuro-
fibrillary “tangles,” with structures outside of the neuron
known as neuritic plaques, composed of an amyloid core
surrounded by degenerating dendrites and axons. Early
changes to the cholinergic projection system result in the
typical early clinical presentation involving impairment
in memory and new learning.
Due to the involvement of limbic structures, some change
in emotionality is common, yet relative preservation of
618 Therapeutics for the Geriatric Neurology Patient
social tact and personality is often noted until later in the
disease course. This is attributed to relative preservation of
frontal lobe neurons, which is in notable contrast to FTD.
Progressive cortical atrophy, however, leads to impair-
ment across multiple cognitive domains leading to a full
range of behavioral problems and necessitating increas-
ingly higher levels of care as the disease progresses.
Along with diminishing self-help skills and safety-related
problems (driving, cooking, getting lost), behaviors typi-
cal of early-stage AD are often associated with depres-
sion and anxiety, including social withdrawal, personal
neglect, temper outbursts, and repetitive verbalizations
and actions. Behavioral problems found in the middle/
moderate stages of AD are quite varied and tend to be
associated with confusion and the subjective distress
found in individuals who do not fully understand their
surroundings and the actions of others, especially caregiv-
ers. Thus, their behavioral problems are often classified as
“agitated,” “aggressive,” or “disruptive.” Patients with
advanced AD are most susceptible to issues of comfort
and tend to exhibit behavioral problems in response to
physical, environmental, and psychosocial discomforts.
Vascular dementia
VD is a term used for a heterogeneous group of disorders
in which dementia is due to cerebrovascular insufficiency.
Considered the second most common general dementia,
VD can result from multiple causes, including large or
small vessel disease, thromboembolism, a stroke affect-
ing a critical brain area, small cortical and/or subcortical
strokes, cortical hypoperfusion, hemorrhagic events, or
mixed VD–AD pathology. In fact, half of all dementias
are thought to involve a mixed VD–AD process (Mendez
and Cummings, 2003). VD is determined by a history
of vascular risk factors, focal neurologic signs, and neu-
roimaging. Multiple small vessel lacunar infarcts and
white matter lesions account for a majority of VD cases.
Given its heterogeneous nature, multiple clinical presen-
tations can be seen. Some generalizations regarding VD
with multiple infarcts include a less continuous decline
in function with stepwise deterioration of cognitive and
behavioral functions, reflecting abrupt changes due to
new infarcts. Focal neurologic signs might include weak-
ness, hemiparesis, sensory deficit, dysarthria, inconti-
nence, and gait disturbance. Abrupt neuropsychologi-
cal signs might include transient confusion, language
impairment, memory impairment, or changes in emo-
tions and personality. However, VD patients typically
exhibit less severe memory impairment and retain good
awareness for these changes relative to their AD coun-
terparts. They often have a greater degree of motor and
cognitive slowness. In contrast to the other dementias,
patients with VD can have highly variable clinical course
with progressive decline, lengthy static periods, or even
some degree of remission.
Because of this highly variable clinical course, patients
with VD tend to exhibit an idiosyncratic pattern of behav-
iors that varies greatly from one person to the next. As
with AD and FTD, apathy, irritability, and agitation are
common. Patients with VD tend to exhibit more overt
symptoms of depression and emotional lability than
patients with the other dementias. As with patients with
AD and LBD, VD patients tend to exhibit problems associ-
ated with disinhibition. Nevertheless, some studies have
found no significant difference between VD and AD on
neuropsychiatric symptom profiles (Srikanth et al., 2005).
Lewy body dementia
LBD is a disease characterized by overlapping clinical
characteristics with both AD and PD. Although there is
diffuse cortical involvement, neuropathology finds Lewy
body inclusions but a lesser or absent number of neuro-
fibrillary tangles and senile plaques characteristic of AD.
There is a loss of dopamine-producing neurons in the
substantia nigra similar to PD neuropathology, as well
as a loss of acetylcholine-producing neurons in the basal
nucleus of the Meynert and elsewhere similar to AD. Spe-
cific symptoms and behavioral patterns of patients with
LBD vary; however, the core features include progressive
dementia, but with fluctuating cognition with variations
in attention and alertness, recurrent visual hallucinations,
and motor symptoms similar to PD (McKeith et al., 2005).
These patients may tend to be quite reactive to medica-
tions, particularly antipsychotic medications, but also
including L-dopa. Up to 50% of patients with LBD who
receive antipsychotic medication experience severe neu-
roleptic sensitivity, including worsening cognition, heavy
sedation, increased parkinsonism, or neuroleptic malig-
nant syndrome (Lewy Body Dementia Association, 2010).
Neuropsychiatric symptoms generally include apathy
that is characterized by decreased spontaneity, motiva-
tion, and effortful behavior. Changes in personality and
mood are common and can include symptoms of depres-
sion and anxiety. Visual hallucinations occur in approxi-
mately 80% of LBD patients (Keister, 2006). Symptoms
also often include paranoid delusions and excessive day-
time sleepiness. Delusional thinking may include redupli-
cative paramnesia. REM sleep behavioral disorder may
present years before the onset of dementia, as may symp-
toms of parkinsonism.
Frontotemporal dementias
FTDs include a group of degenerative brain disorders that
share many neuropathologic features with each other and
with AD. However, neural degeneration is seen predomi-
nantly within the frontal and temporal lobes rather than
the temporal and parietal lobes, which is more character-
istic of AD. One defined FTD is that of Pick’s disease (also
known as behavioral variant FTD (bvFTD) or frontal vari-
ant FTD (fvFTD)) that is diagnosed on neuropathologic
 Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia
criteria rather than on clinical presentation. Atrophy
tends to be more circumscribed and asymmetric than seen
in AD. Histology finds that neurons are swollen, with a
characteristic argentophilic or “Pick body” within the
cytoplasm. It is unclear whether other FTDs that do not
show Pick’s bodies are distinct disorders, but the clinical
presentation tends to be quite similar. In contrast to AD,
FTD is more likely to strike at a younger age and to first
present with personality and emotional changes attrib-
utable to executive functioning deficits associated with
frontal lobe changes (Mendez et al., 1993).
Primary progressive aphasia and semantic dementia
are FTD variants that result from atrophy of the tem-
poral lobes. Patients suffer from prominent language
impairment with decreased fluency, word-finding dif-
ficulty, paucity of speech, and eventual loss of language
comprehension and mutism. Patients with these FTD
variants are not prone to exhibiting significant behav-
ioral problems.
Loss of social tact, social disinhibition, poor self-
awareness, and lack of judgment are symptomatic of the
bvFTD/fvFTD and often cause serious social and family
problems. Early on, patients may lose their sense of safety
and demonstrate poor financial judgment, compulsive
buying, and other compulsive behaviors (such as hand
washing). As the FTD progresses, patients often exhibit
increasing problems with apathy and social withdrawal.
They are also prone to exhibiting more overt signs of
disinhibition, including hypersexuality (sexually touch-
ing others, public masturbation, exhibitionism) and/or
an insatiable appetite and food-seeking (Srikanth et al.,
2005; Weiss, 2010). Patients may have relatively preserved
memory, so psychiatric diagnosis and treatment prior to
recognition of dementia are quite common (McKhann et
al., 2001). Active behavioral and family intervention often
is necessary in such cases early in the course of the illness.
Over time, patients with FTD typically become gradually
less involved in routine daily activities and withdraw
emotionally from others. Additional behavioral problems
include impulsivity, repetitive and stereotyped behaviors,
and poor personal hygiene.
Parkinson’s disease
Parkinson’s disease (PD) is a disorder that affects motor
systems due to basal ganglia disease, leading to the core
features of bradykinesia, resting tremor, postural insta-
bility, and rigidity. PD is associated with a loss of pig-
mented cells in the substantia nigra, impacting dopa-
minergic projection systems. Remaining cells contain
eosinophilic cytoplasmic inclusions surrounded by a
halo, known as Lewy bodies. Patients may display very
subtle motor problems, typically asymmetric at first, pre-
dating formal diagnosis, such as mildly reduced move-
ment, stiffness, and reduced eye blinking. With disease
progression, patients may develop slowed voluntary
619
movement, an expressionless face (sometimes referred
to as “mask-like”), tremor of fluctuating severity, a gait
that may become shuffling with small steps to avoid
falling (“festinating”), and significant muscular rigid-
ity. Although a majority of patients exhibit difficulties
largely confined to motor changes, a significant number
(approximately 30%) also exhibit a progressive dementia
with changes similar to AD (Aarsland et al., 2005). Such
cases sometimes involve multisystem atrophy and are
referred to as one of the “Parkinson’s plus” disorders (as
is LBD). Subtle cognitive changes in patients with PDD
include significantly slowed mentation, impairment in
memory recall (less than typical of AD), difficulty with
effortful memory tasks, visuospatial impairment, and
diminished executive functioning. With disease progres-
sion, deterioration in problem solving, cognitive flexibil-
ity, and decreased initiative may reflect relative atrophy
of frontal executive control systems.
Depression, apathy, anxiety, and other neuropsychi-
atric problems are common in PDD, although slowed
movement and facial rigidity can also be misdiagnosed
as indicative of mood disturbance. Dopaminergic medi-
cations used to treat PD can result in additional neuro-
psychiatric symptoms, including visual hallucinations,
delusions, and sleep disturbances; as well as problems
with impulse control and repetitive behavioral disor-
ders, such as compulsive buying, gambling, engaging in
sexual behavior, and punding (Lee et al., 2010; Sohtao lu
et al., 2010).
Aggravating factors
Researchers and clinicians have posited a number of
models to explain the underlying causes of neuropsychi-
atric and behavioral symptoms in persons with demen-
tia. The medical model focuses on biologic and genetic
causes, with behaviors characterized as psychiatric or
neurologic syndromes. This model emphasizes a phar-
macologic approach to treatment and strives to develop
psychoactive agents that are more effective in modifying
and alleviating neuropsychiatric symptoms and behav-
iors. In contrast, various psychosocial models emphasize
the impact of social and environmental factors on demen-
tia patients. These models are not mutually exclusive, and
most experts acknowledge that biomedical, genetic, envi-
ronmental, and social factors all come into play when con-
sidering the reasons people with dementia exhibit behav-
ioral problems. Regardless of the origins of a person’s
dementia and associated symptoms and behaviors, it is
clear that exigent factors, including confusion, delirium,
pain, medication interactions, and environmental stress-
ors, aggravate these symptoms and must be considered
when assessing and treating patients with dementia who
exhibit behavioral problems.
620 Therapeutics for the Geriatric Neurology Patient
Confusion
While the issue of confusion seems all too obvious when dis-
cussing problems associated with dementia, it is nonethe-
less a subject worth addressing. A clear relationship exists
among a patient’s severity of dementia, level of confusion,
and severity of neuropsychiatric and behavioral symptoms.
Thus, the more confused a person becomes, the greater the
likelihood of behavioral problems (Teri et al., 1988).
Confusion is at the heart of most dementia-related
behavioral problems. People with early-stage dementia
become confused with handling money, driving their
cars, and managing their lives, resulting in misunder-
standings, missteps, accidents, and increased frustration
and depression. People with moderate-stage dementia
have difficulty understanding their surroundings and
the actions of others, including and especially caregivers,
to the point of acting on their confusion in highly prob-
lematic ways (wandering, intrusions, defensive/reactive
aggression, elopement, paranoid actions). With advanced
dementia, the confusion is so profound that virtually any
type of stimulation, including well-intentioned hands-
on caregiving, can be emotionally distressing, and sim-
ple sensory stimuli can be startling and overwhelming
(Martin and McCarthy, 2011).
When confused dementia patients do not understand
what is going on around them or do not understand the
actions of others, they are more likely to become upset,
scared, and reactive. They are prone to seek familiar sur-
roundings when none exist, and they are more likely to
retaliate against caregivers who are perceived as strangers
violating them. In addition, they are more likely to have
problems identifying, understanding, and controlling
such basic feelings as pain, discomfort, loneliness, and
boredom, so the expression of subjective discomfort and
distress is often reduced to basic and reflexive emotional
and behavioral responses (fight-or-flight reactions, physi-
cal restlessness, distressed vocalization). Although psy-
choactive medications might be helpful in alleviating a
sense of distress, those same medications may result in an
overlay of additional confusion that could actually exac-
erbate behavioral symptoms. Conversely, efforts to make
the environment and social interactions clearer and less
confusing can diminish situational confusion and help
alleviate behavioral symptoms, with no such side effects.
Delirium
Older adults, including those with dementia, are at
increased risk of experiencing delirium. Persons with
dementia are especially prone to delirium, even from such
seemingly minor stressors as urinary tract infections, mild
injuries, or low levels of pain. It is significant to note that
the superimposition of delirium on dementia has been
estimated to be high, ranging from 22% in patients liv-
ing in the community, to 89% in hospital patients (Fick et
al., 2002). Statistically, delirium in persons with dementia
is associated with significant morbidity, mortality, and
resource utilization (Fick et al., 2002). Because of their
impaired cognition and diminished functional abilities,
it can be difficult to distinguish delirium from demen-
tia, or to recognize delirium superimposed on dementia.
As a result, delirium can go unrecognized, and underly-
ing acute medical disorders such as infection, electrolyte
imbalance, dehydration, metabolic disturbances, and
adverse drug reactions then may go undiagnosed and
untreated (Fick and Foreman, 2002).
In persons with dementia, sudden changes in behavior
are often symptomatic of delirium. These behaviors are
usually accompanied by changes in levels of conscious-
ness and attention. In nearly all persons with moderate or
greater dementia, delirium causes a significant decline in
cognitive, behavioral, and functional abilities. Associated
behaviors may include agitation, restlessness, extreme
lethargy, crying/moaning, repetitive vocalizations
(including yelling), changes in appetite, and/or changes
in sleep pattern. In addition, patients with delirium may
also exhibit neuropsychiatric symptoms, including hal-
lucinations, paranoia, and delusions. Because delirium is
such a grave prognostic sign, health-care professionals,
caregivers, and family members must be suspicious of
its occurrence whenever they observe abrupt behavioral
changes in persons with dementia.
Medications
Virtually any medication or medication interaction can
have adverse effects on the behaviors of persons with
dementia, much in the same way that many acute medi-
cal conditions trigger delirium. Because the aging process
changes the pharmacokinetics and pharmacodynamics of
medications in elderly patients, they are more prone to
adverse reactions than other age groups. Moreover, most
drugs in the market do not have clear dosing recommen-
dations for the elderly, and polypharmacy prescribing
is high. As a result, iatrogenic drug-related delirium is
common in the elderly, and even more so in persons with
dementia, due to their relatively high rate of psychotropic
drug use and the potential for adverse affects from those
medications (Whitehouse and George, 2008).
As with delirium, adverse effects from medications
often cause neuropsychiatric and behavioral symptoms
in dementia patients, including agitation, restlessness,
extreme lethargy, changes in appetite, changes in sleep
pattern, and psychosis. A sudden onset of behavioral
symptoms or rapid changes and unusual presentations
of current behaviors are the behavioral hallmark of med-
ication-induced delirium, especially when symptoms
coincide with a change in medication regimen. In cases of
medication-induced delirium, sometimes the only symp-
toms present are changes in behavior, so it is important
for hands-on caregivers to observe and report to their
health-care providers any such changes noted.
 Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia
Pain
Pain of any sort potentially alters and aggravates the
behaviors of persons with dementia. Dementia patients
who are in pain tend to express their pain through their
behaviors. Common behavioral problems associated with
dementia can be very basic and reflexive responses to pain
and, as such, are diagnostic indicators of pain. Examples
include moaning, crying, yelling, repetitive vocalizations,
verbal abuse, fidgeting, pacing, rocking, motor restless-
ness, resisting care, physical aggression, and irritability
(Buffman, Hutt, Chang, Craine and Snow, 2007). Unfor-
tunately, these patients often cannot identify, describe,
locate, or otherwise verbalize their pain; as a result, they
are less likely to be assessed or treated for pain (Fries et
al., 2001). Instead, caregivers and medical providers are
likely to interpret the behavioral symptoms as “agitation”
and prescribe psychoactive agents rather than pain medi-
cations. Consequently, pain may go unrecognized and
untreated while psychotropics are given that can mask
the pain, making it even more difficult to recognize and
treat (Dougherty, Sgrillo, and Swan, 2011).
Of the more than two million elders living in nursing
homes today, as many as 65% suffer from some form of
persistent pain (Brown, 2001). Yet less than half of the
nursing home patients who experience pain are pre-
scribed routine pain medications (Hutt et al., 2006). More-
over, while persons with cognitive impairment experi-
ence pain at a higher rate than those who are cognitively
clear, they are less likely to be assessed and treated for
their pain (Fries et al., 2001). In effect, as their dementia
progresses, patients are more likely to experience pain but
are less likely to be treated for it. This is one of the several
reasons, there is a significant correlation between severity
of dementia and the severity of neuropsychiatric symp-
toms (Cohen-Mansfield and Libin, 2005).
Environmental stressors
The behaviors of persons with dementia often reflect their
environment. If the environment is either over-stimulat-
ing or under-stimulating, or has noxious, disturbing, or
sterile (in other words, institutional) qualities, the person
with dementia will often behave in a distressed or agi-
tated fashion. The list of environmental stressors in long-
term care settings is lengthy and includes such things as
high volumes on televisions or stereos, darkness or bright
lights, heavy foot traffic and intrusions by peers and care-
givers, loud and busy meals, high-energy activity pro-
grams, and loud talking and laughing between caregiv-
ers. Additionally, each person is unique and has his or her
own idiosyncratic environmental stressors. Yet the patient
is often unable to articulate what is bothersome. Conse-
quently, unsuspecting caregivers may never realize the
cause-and-effect of the situation and are likely to ignore
the behavior or seek further pharmacologic treatment,
rather than remedy the problem in the environment.
621
As a general rule, the environment must be made as
warm, personable, comfortable, and homelike as pos-
sible. A large body of literature addresses environmental
design for persons with dementia (Fazio, 1999; Brawley,
2001; Calkins, 2001; Werezak and Morgan, 2003; Chalfont,
2007; Cutler, 2007; Rabig et al., 2007; Dewing, 2009; Geboy,
2009; Martin et al., 2011). Recommendations tend to cover
issues including the use of space, furniture placement,
seating arrangements, personalizing space, accessibility
of activity props, and dining arrangements. They also
make recommendations about decorations, colors, floor-
ing materials, window treatments, and other aspects of
the physical environment that can impact subjective com-
fort and behavior.
Nursing homes and other care facilities can be unpleas-
ant places for any person to live. The nursing home resi-
dent must contend with bright lights, hard surfaces, cold
hallways, loud noises, and unpleasant odors. There is
often a constant commotion as caregivers perform their
jobs, residents engage in activities, visitors come and
go, housekeepers clean, and maintenance workers make
repairs. The sounds of televisions, call bells, overhead
intercoms, telephones, alarms, and cleaning equipment
combine with loud activity programs, staff conversations,
and disruptive residents. The onerous smells of disinfec-
tants, detergents, and urine are common, while mealtimes
and shift-change times can be chaotic. In this type of envi-
ronment, it is easy to understand why confused persons
with dementia exhibit agitated and aggressive behaviors.
Caregiving
As patients with dementia decline, they require an ever-
increasing hands-on care. They become increasingly
dependent on others for assistance in all aspects of their
lives, including basic issues of grooming and hygiene.
Eventually, they come to need total care, relying on others
to handle all activities of daily living, including ambula-
tion, continence care, and feeding.
Caregiving for persons with dementia involves highly
personal, intimate, and intrusive actions on the part of
caregivers. These actions can be, and often are, physi-
cally and emotionally uncomfortable and distressing to
persons with dementia, especially because their increas-
ing confusion renders them unable to comprehend their
own need for care or the actions of their caregivers. The
intrusiveness and physicality of caregiving can trigger
reflexive emotional and behavioral responses in confused
patients, including resisting, fighting, yelling, crying, and
other symptoms of emotional distress. Aggressive behav-
ior exhibited by persons with dementia occurs most fre-
quently when they are receiving the most intimate types
of care, such as incontinence care and bathing (Keene et
al., 1999). Moreover, aggressive behavior increases when
a caregiver’s approach is characterized by negative com-
munication or disrespect, or by rushing and not giving
622 Therapeutics for the Geriatric Neurology Patient
verbal prompts (Skovdahl et al., 2003; Somboontanont
et al., 2004). The common practice of focusing on getting
the task done quickly instead of on the process of inter-
acting with the person receiving the care significantly
increases the likelihood of aggression.
Nonpharmacologic treatment
The fairly large body of nonpharmacologic treatment
research shows results that, overall, are positive and
impressive. Experts agree that nonpharmacologic treat-
ment approaches are often effective in diminishing
dementia-related behavioral problems (Cohen-Mansfield,
2001; Livingston et al., 2005; Spira and Edelstein, 2006;
O’Connor et al., 2009). The accepted protocol for treat-
ing behavioral problems in patients with dementia is to
first assess for possible delirium, including issues relating
to medication reactions and possible undiagnosed pain.
Nonpharmacologic interventions should be attempted
before proceeding to psychopharmacologic treatment,
especially if there are no psychotic features and there is no
immediate danger to patients or their caregivers (Ameri-
can Geriatrics Society and the American Association for
Geriatric Psychiatry, 2003; Cohen-Mansfield and Mintzer,
2005; Pulsford and Duxbury, 2006; Salzman et al., 2008;
Kalapatapu and Neugroschl, 2009).
However, the current nonpharmacologic treatment
research has drawbacks. Most of the studies are based
on single-case designs or include relatively few partici-
pants. Additionally, most of the research is conducted
in residential care settings, where standardization and
strict adherence to research protocols are challenging.
As a result, caution is advised when drawing conclu-
sions from a number of these studies (Ayalon et al.,
2006; Pulsford and Duxbury, 2006; Jeste et al., 2008).
Moreover, most of the research does not meet the strict
requirements necessary to be considered evidence-
based treatments. The reasons for this include the
following:
• Poor funding (Cohen-Mansfield, 2001; Cohen-
Mansfield, 2003; O’Connor et al., 2009)
• General frailty, cognitive deterioration, and high
attrition (illness, death) in research subjects (Cohen-
Mansfield, 2001; Logsdon et al., 2007)
• Poorly controlled research settings (Cohen-Mansfield
2001)
• Variability and inconsistencies in caregivers (Logsdon
et al., 2007)
• A culture of care that resists change (O’Connor et al.,
2009)
• Simultaneous and confounding use of psychoactive
medications (Cohen-Mansfield, 2001)
• A lack of methodological rigor in research designs
(Spira and Edelstein, 2006; Logsdon et al., 2007)
Nonpharmacologic treatment models
Good care/comfort care
Treating behavioral problems begins with the concept and
practice of good patient care. People with dementia who
do not receive good care are much more likely to experi-
ence the pains and discomforts that lead to exacerbated
behavioral problems. Cohen-Mansfield and Mintzer (2005)
reported that a substantial portion of dementia-related
behavioral problems occur when the needs of persons with
dementia either go unrecognized or are not adequately
addressed by their caregivers. Such needs include hunger
and thirst, cleanliness and hygiene, and the appropriate
treatment of pain. But this also includes more complex
social and emotional needs, such as treatment for bore-
dom and loneliness. The practice of good care assumes that
quality time will be spent with patients so that caregivers
will more likely be able to identify and resolve the causes
of problematic behavior without the need for psychophar-
macology. Health-care professionals should never assume
that this type of good patient care is the norm or that it is
being provided to their individual patients.
In a similar vein, Martin and McCarthy (2011) discuss the
importance of subjective comfort, labeling dementia care
as “comfort care.” In this regard, making the person with
dementia comfortable, both physically and emotionally, is
one of the primary considerations in the care of all persons
with dementia, including those with behavioral problems.
Persons with dementia, who are truly comfortable, are
likely to be less confused, are more functional, and exhibit
fewer behavioral problems than those who are physically or
emotionally uncomfortable. Patients who are comfortable
rarely hit, scream, moan, or cry, and are much less likely to
be agitated or restless (Pelletier and Landreville, 2007).
Unmet needs
The unmet needs model for the care of persons with
dementia considers behaviors as indicators of unmet
needs. In this model, problematic behaviors stem from
normal human needs—physical, emotional, and social—
that caregivers fail to recognize, understand, or address.
Effective interventions require that caregivers gain a deep
understanding of the persons for whom they care so that
they can anticipate, prevent, and/or resolve needs, thus
diminishing or eliminating the behaviors associated with
those needs. This includes basic care issues associated with
hunger and thirst, hygiene and grooming, and toileting
procedures, as well as sufficient lighting, better commu-
nication, and proper treatment of pain. Just as important,
less tangible needs must be addressed, including qual-
ity social interactions, adequate and appropriate sensory
stimulation, and engagement in meaningful activities.
The unmet needs model covers a wide range of
approaches and greatly overlaps general health-care prac-
tices and virtually all other nonpharmacologic treatment
 Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia
models. The literature from this model includes studies
involving environmental approaches, antecedent con-
trol, sensory stimulation, and psychosocial interventions.
Additionally, all caregiver training should include ways
to identify, anticipate, and address the many needs of
dementia patients. The evidence-based treatment (EBT)
research strongly supports the efficacy of these treatment
efforts (Cohen-Mansfield and Mintzer, 2005; Kovach et al.,
2005; Turner, 2005).
Environmental interventions
The literature includes a plethora of information con-
cerning the importance of environmental interventions
on minimizing dementia-related behavioral problems.
Environmental interventions are often inexpensive, are
easy to administer, and appear to intuitively make sense
to caregivers. For example, simply removing objects
or other stimuli that cause patients to become agitated
or to act inappropriately can reduce many problematic
behaviors. This can be as simple as locking or unlocking
doors, improving lighting, eliminating noxious sounds,
or changing flooring patterns at exit doors. This can also
include interventions such as changing paint colors and
other furnishings, using environmental prompts to aid
with orientation, and strategically using light, music, or
even television to help comfort or stimulate a person.
Virtually all reviews of the research have found well-
constructed environmental interventions effective in
reducing problematic behavior, including wandering,
physical aggression, and verbal aggression, as well as vari-
ous forms of agitation (Spira and Edelstein, 2006). In addi-
tion, aroma therapy and individualized music have been
effective in calming agitated dementia patients (O’Connor
et al., 2009) as has bright light therapy (Lovell et al., 1995).
Learning theory model
Learning theory involves identifying the antecedent con-
ditions and the consequences that trigger, reinforce, and
control problematic behavior so that learning situations
can be modified to improve the behavior. Consequences
can either encourage or discourage new behaviors and
are given strategically to increase positive behaviors and
decrease problematic behaviors.
The most commonly cited use of the learning theory
with dementia patients is the A-B-C approach to behav-
ioral analysis. In this approach, A stands for antecedents, B
is behavior, and C is consequences, with an emphasis on the
relationship between B and C and how the consequences
of behaviors impact those behaviors. Interventions typi-
cally involve the immediate delivery of reinforcing posi-
tive consequences to patients after they exhibit posi-
tive behaviors, as a means of promoting repetition and
encouraging them to learn those positive behaviors.
Results in studies using the learning theory model
are inconsistent, with some studies reporting significant
623
reductions in behavioral problems (Ayalon et al., 2006;
Logsdon et al., 2007) and others reporting inconsistent
results or no effects (Cohen-Mansfield, 2001; Spira and
Edelstein, 2006). Some authors note that consequence-
oriented approaches should be viewed with caution
because persons with dementia exhibit deficits in learn-
ing new skills (Weiner and Teri, 2003). Others argue that
dementia patients can potentially learn new behaviors
and that interventions based on learning theory should
be further explored (Spira and Edelstein, 2006).
Antecedent control
Antecedent control focuses on the relationship between
antecedents and behaviors (the A-B connection in the “A-B-
C” triad) and how the antecedents to behaviors can alter
and control those behaviors. Unlike learning theory, ante-
cedent control does not require the individual to remem-
ber or learn anything new for behaviors to change. This
form of behavioral treatment first identifies the aspects of
the situation that trigger a behavioral problem (character-
istics of the environment, caregivers’ approaches, and so
on) and then changes the antecedents to something more
likely to trigger more appropriate behaviors.
Researchers note that interventions using antecedent
control are particularly useful with dementia patients
because they capitalize on already-established aspects of
an individual’s behavioral repertoire and do not require
new learning to take place. Many of the reviews of the
research report positive results from interventions based
on this model, especially for problems with wandering,
physical aggression, verbal aggression, and a broad spec-
trum of “agitated” behaviors (Spira and Edelstein, 2006).
Family/caregiver education and training
Another approach to managing dementia-related behav-
iors is to educate and train families and professionals on
how to effectively deal with such behaviors. To date, a
large body of literature addresses the importance and effi-
cacy of educating and training families and care staffs in
recognizing, assessing, treating, and monitoring behav-
ioral problems. Models and approaches used in training
vary greatly, from simple and practical (for example, the
“3 Rs” of repeat, reassure, and redirect) to more involved
behavioral approaches, such as the A-B-C approach. A
number of more structured and standardized training
programs also are available, including Savvy Caregiver,
Staff Training in Assisted-Living Residences-Caregivers,
Resources for Enhancing Alzheimer’s Caregiver Health,
Activity-Based Alzheimer’s Care, and CarePro (Salzman et
al., 2008; Alzheimer’s Association, n.d. Coon et al., 2010).
Research results strongly support the use of caregiver
education and training as an effective treatment approach
to dementia-related behavioral problems. Trials have
shown that caregivers can acquire behavioral techniques
that decrease problematic behaviors, reduce the use of
624 Therapeutics for the Geriatric Neurology Patient
antipsychotic medications, and delay institutionalization
for those who live at home (Ray et al., 1993; Doody et al.,
2001; Burgio et al., 2002; Teri et al., 2005; Livingston et al.,
2005; Logsdon et al., 2007).
Psychosocial
Psychosocial interventions include those that emphasize
social contact as the intended treatment effect. Such dis-
parate treatment strategies as music therapy, pet therapy,
sensory stimulation, enhanced therapeutic activities,
social interaction, one-to-one interaction, and simulated
interaction fit into this general model.
Research in this area finds that whenever family mem-
bers and caregivers spend extra time with patients,
especially when they offer attention and affection, it
has a positive impact on behaviors. This occurs dur-
ing many different types of treatment interventions,
even when attention is incidental to the actual research
design (Doody et al., 2001; Pulsford and Duxbury, 2006;
O’Connor et al., 2009).
Individualized approaches to treatment
Many researchers contend that perhaps the most criti-
cal factor in the use of nonpharmacologic treatment
approaches is how the intervention is individualized and
customized to best fit the person, the person’s unique
behaviors and living situation, and the resources avail-
able for treatment (Maslow, 1996; Cohen-Mansfield et al.,
2007). Moreover, it is important to match the treatment
intervention with the function of the behavior being
treated, which requires the inclusion of functional assess-
ments in intervention protocols (Spira and Edelstein,
2006; Zec and Burkett, 2008). When treatment interven-
tions and behaviors are well matched, most treatment
strategies have been found to be highly effective.
Evidence-based treatment research
A small but significant number of studies on nonpharma-
cologic treatment interventions meet the stringent crite-
ria set forth by the American Psychological Association
(APA Presidential Task Force on Evidence-Based Practice,
2006; Yon and Scogin, 2007) so that they achieve EBT sta-
tus. These studies provide greater insight into the effec-
tiveness and potential of nonpharmacologic treatment
approaches in dementia and lend considerable support to
the legions of professionals and caregivers who currently
practice such approaches and believe in their efficacy.
A number of review articles critique the nonpharma-
cologic treatment research relative to these stringent
EBT standards. In one of the more recent review articles,
O’Connor et al. (2009) found that only 25 of 118 studies
of psychosocial treatment approaches met methodologi-
cal criteria for inclusion. In reviewing those 25 studies,
they concluded that aromatherapy (Ballard et al., 2002;
Holmes et al., 2002), use of preferred music (Burgio et al.,
1996; Ragneskog et al., 1996), person-centered bathing
techniques (Sloane et al., 2004), simulated family pres-
ence (Garland et al., 2007), and muscle relaxation therapy
(Suhr et al., 1999) all reduced behavioral symptoms, com-
pared with controlled conditions.
In a similar review, Logsdon et al. (2007) examined
57 randomized clinical trials and found that only 14 of
those studies met EBT methodological criteria. Of those
14 studies, they were able to identify two general psy-
chological interventions that were effective in treating
dementia-based behavioral problems: (1) structured
behavioral approaches based on behavioral and social
learning theory (Teri et al., 1997, 2003, 2005) and (2) indi-
vidualized counseling or consultation interventions that
focus on decreasing behavioral problems by modifying
the caregiving environment (Gerdner et al., 2002).
Other reviews of the research found similar results.
In a more ambitious review process, Livingston et al.
(2005) examined 1632 studies and found that 162 (or 10%)
of those studies met methodological inclusion criteria.
Positive treatment effects were found for interventions
involving caregiver education, individualized behavior-
management techniques, cognitive stimulation (Teri et al.,
1997), and, to a lesser extent, music therapy (Remington,
2002), Snoezelen therapy (Baker et al., 1997), and sensory
stimulation (Burgio et al., 1996). In their examination of
the research on behavioral interventions with agitation
behaviors, Spira and Edelstein (2006) identified 23 articles
that met strict methodological criteria. They found that
wandering behavior and physical aggression improved
with antecedent control interventions and that physical
aggression also improved with the differential reinforce-
ment of other behaviors and with cognitive behavioral
interventions. Caregiver training was also effective in
reducing agitation in nursing home residents.
In each of these review articles, the authors concluded
that the research shows great promise for the efficacy of
environmental, behavioral, and psychosocial treatment
of neuropsychiatric and behavioral symptoms in persons
with dementia. However, they also noted that, other than
the EBT-qualified studies, much of the research in this
area is too limited, loosely designed, and inadequately
reported to warrant definitive conclusions about what
aspects of the treatment have been found to be effective.
Treatment of specific types of dementia
Alzheimer’s disease
More has been written on AD than any other type of
dementia, and the literature is rich with material that
deals with behavioral problems associated with AD.
Moreover, research conducted on persons with unspeci-
fied “dementia” draws primarily from an AD population.
As a result, much of the treatment issues discussed in this
chapter are relevant and applicable to persons with AD.
 Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia
When considering nonpharmacologic treatment
approaches with AD patients, it is important to consider
the patient’s degree of cognitive impairment. The social
learning model emphasizes the effects of consequences
on behaviors, yet AD causes deterioration in memory and
learning to the point that consequences to behaviors may
no longer achieve desired learned behavioral change. It
is not uncommon for this treatment approach to cause
patients to become frustrated and exhibit an exacerba-
tion of their behaviors. Therefore, consequence-oriented
behavioral approaches are often not recommended when
treating persons with moderate or advanced dementia.
On the other hand, behavioral approaches that focus on
antecedent control strategies can continue to be effective
in managing behaviors well into the advanced stages of
AD (Martin and McCarthy, 2011).
Vascular dementia
In contrast to AD, VD is not well represented in the demen-
tia literature. A search of the literature found no studies
on the use of nonpharmacologic treatment approaches
specifically with VD patients. This may be because VD
patients exhibit higher variability in their clinical course,
with behavioral problems differing greatly in type and
severity from one person to the next. Consequently,
behavioral trends and consistencies are difficult to iden-
tify across patients, making treatment highly variable and
quite individualized.
It is fair to say that many of the nonpharmacologic
treatments found to be effective with AD patients may
also be effective with VD patients, as long as their levels
of confusion and behavioral presentations are compara-
ble to those of AD patients. However, such assumptions
should be made with caution because persons with VD
often exhibit different cognitive and emotional patterns,
as compared with AD patients. In residential settings,
VD patients are generally found to be more cognitively
capable than their AD counterparts, exhibiting greater
learning and memory skills and with a more fluctuating
cognitive presentation. As such, social learning-based
treatment approaches may be much more applicable and
effective than with AD patients. Conversely, distraction
techniques may be less effective with VD patients.
VD patients tend to present with more obvious signs
and symptoms of depression and anxiety, and to be more
emotionally labile than AD patients. Persons with VD
are more likely to exhibit persistent problems with cry-
ing, moaning, and disruptive vocalizations that can be
quite challenging to treat. These problems may dissipate
when caregivers distract and engage VD patients in some
personally meaningful fashion (such as 1:1 attention,
personal grooming, preferred snacks, and multisensory
effects) while not directly attending to the behavior. Per-
sons with VD are also more likely to exhibit persevera-
tion of thoughts and behaviors and to act repetitious and
625
disruptive in demanding food/drink or cigarettes or ask-
ing to be taken to the toilet or bed. Putting the individual
on a reasonable, responsive, and highly personalized
care/attention schedule (for example, assisted to the toilet
every hour) can help alleviate these problems.
Lewy body dementia
Although there is a rapidly expanding body of literature
on LBD, it is lacking in studies that specifically exam-
ine nonpharmacologic treatment approaches with LBD
patients. One reason may be that LBD-based behaviors
are not seen as severe or as problematic as the behaviors
associated with AD and FTDs. However, because up to
50% of patients with LBD experience neuroleptic sensi-
tivity, especially to antipsychotic medications, the devel-
opment of nonpharmacologic alternatives in treating the
neuropsychiatric and behavioral symptoms of LBD is
clearly needed.
Caregivers often describe LBD patients as being “in
their own world,” responding more to internal stimuli
than the physical and social environment around them.
Thus, effective nonpharmacologic treatment strategies
might include environmental considerations (such as
making the living environment safe, comfortable, and
clear), antecedent control involving the environment and
caregiving, and the education and training of caregivers
on best-care practices for dealing with LBD-based behav-
iors. Psychotic symptoms, including visual/auditory hal-
lucinations and delusional thinking, are best managed by
providing comforting support, distracting and engaging
patients’ attention with more reality-based activities, and
avoiding discussing with patients or confronting patients
about their thinking and behavior. Physical restlessness
and akathisia can be challenging and may include care-
giving strategies associated with providing care “on the
run” (allowing patients to move and walk freely while
providing care) and allowing them to eat “on the run,”
often with finger foods.
Frontotemporal dementia
FTD has a more substantial literature base than VD and
LBD, including a small number of studies that specifi-
cally address the nonpharmacologic treatment of behav-
ioral problem (Merrilees, 2007; Wittenberg et al., 2008;
Arvanitakis, 2010; Lough and Hodges, 2002). The focus of
this research is mostly on the bvFTD.
The two most commonly recommended nonpharmaco-
logic treatment approaches are environmental and behav-
ioral. Environmental approaches focus on modifying the
environment to ensure safety and comfort, and also to
more directly diminish behavioral problems. Environmen-
tal changes include locking exit doors, securing food stor-
age areas, and ritualizing set daily schedules and routines.
As with LBD, physical restlessness and akathisia may
require caregivers to provide care and meals “on the run.”
626 Therapeutics for the Geriatric Neurology Patient
Behavioral strategies tend to focus on antecedent con-
trol and, to a lesser degree, interventions based on the
social learning model. Consequence-oriented interven-
tions are worth considering because memory functions
remain more intact with FTD patients, as compared to AD
patients (McKhann et al., 2001). This can be done by con-
sistently rewarding positive behaviors such as self-help
skills, cooperation with caregiving, and desirable thera-
peutic activities. Preferred snack items are often effective
rewards, especially for patients who exhibit aggressive
food-seeking behavior.
Parkinson’s dementia
Although there is a large body of literature on PD, most
of the research on treatment of PDD problems focuses on
medication management, with only an occasional mention
of nonpharmacologic treatment strategies (Rongve and
Aarsland, 2006). The actual study of such strategies is rare
(Rongve and Aarsland, 2006; Rosner and Henchcliffe, 2010).
Effective nonpharmacologic treatment approaches
tend to focus on environmental, psychoeducational, and
counseling-oriented interventions. The Parkinson’s Dis-
ease Foundation (Marsh, 2010) recommends many such
interventions on its website. For example, caregivers are
instructed to avoid multitasking, keep activities and tasks
simple, and focus on one goal or concept at a time. They
also recommend that caregivers act and talk slowly, use
frequent repetition, and assist with developing compen-
satory strategies (for example, using clocks, timers, plan-
ners, notes, and voice recorders). Special mention is made
of ways to help PD patients with impulse-control prob-
lems (such as pathologic gambling, hypersexuality, medi-
cation abuse, and excessive shopping), with environmen-
tal strategies being most recommended for dealing with
such problems.
Conclusion
Patients with dementia constitute a rapidly expanding
population of adults who suffer from diminished cogni-
tive capacity, functional skills, and ability to live inde-
pendently. Behavioral disorders are the inevitable result
of these conditions as persons with dementia struggle
to understand their condition, accept a need for care,
and communicate underlying problems such as pain,
discomfort, or emotional distress. Humane caretaking,
including medical care, requires a range of treatments
to lessen behavioral disorders. Such approaches extend
to environmental design to promote safety and comfort,
psychosocial planning to better meet emotional needs,
and individualized behavior-management techniques
to directly target such problems as agitation and aggres-
sion. Admittedly, a gap exists between the relative lack of
well-designed, evidence-based, nonpharmacologic treat-
ment studies and the general acceptance that nonphar-
macologic approaches should be the primary treatment
approach. Nevertheless, research to date supports the use
of these techniques. Future research will need to further
address their efficacy in specific populations of persons
with different types of dementia at different stages of the
illness.
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 Chapter 26
Expressive Art Therapies in Geriatric
Neurology
Daniel C. Potts1, Bruce L. Miller2, Carol A. Prickett3, Andrea M. Cevasco3, and
Angel C. Duncan1
1
Cognitive Dynamics Foundation, Veterans Affairs Medical Center, The University of Alabama, Tuscaloosa, Alabama
2
Memory and Aging Center, University of California, San Francisco, CA, USA
3
School of Music, College of Arts and Sciences, University of Alabama, Tuscaloosa, AL, USA

Summary
• Expressive art therapies work to improve quality of life, enhance self-worth, and promote human dignity; all of which
contributes to better health.
• Music and art therapies have been shown to significantly improve social participation, communication, and mood while
reducing symptoms of depression, anxiety, and agitation.
• Dance and movement therapies combine movement with counseling and rehabilitation to reduce stress and improve
ambulation.
• Drama, poetry, and bibliotherapy have been shown to improve both physical and psychological symptoms through
self-expression and reflection.
• Reminiscence and story-telling therapies promote communication and interaction using memorabilia, photographs,
and narration of the patients’ life history.

Introduction Depersonalization of care threatens our modern health-

The present is an age of unrivaled scientific advance-
ment in health care. Molecular geneticists, biotechnolo-
gists, physician scientists, and others are elucidating the
pathophysiology of disease at its most fundamental level.
Such burgeoning information will make possible targeted
therapies to both prevent and effectively treat (and per-
haps cure) many of the chronic illnesses of our time. This
scientific progress parallels an increasing life expectancy
in most developed countries, bringing neurologic dis-
eases of aging to the forefront of interest—diseases such
as Alzheimer’s and other dementias, Parkinson’s disease
(PD), and stroke.
Though advances may lead to more effective treatments
and potential cures, the burden of geriatric neurologic
disease will remain high. There will be nonresponders to
treatment, not all will have access to therapies, and there
will always be struggling caregivers. The need to nurture
and preserve the psychological, emotional, and spiritual
well-being of patients will still exist, helping them main-
tain their dignity and sense of self-worth. Furthermore,
caregiver respite will always be a crucial need.
care system as much as rising costs and lack of access.
Most current models fail to incentivize actually caring for
the “core” of a human being, for tuning all senses toward
expressions of need, for validating each person in the con-
dition of loss or ill health, for providing therapies to pro-
mote restoration of wholeness, and for supporting care-
givers. Instead, providers are rewarded for spending as
little time as possible with patients so that schedules may
be filled and for meeting as many “quality indicators” as
possible. Geriatric patients who are more likely to have
experienced loss (loss of productivity, independence, cog-
nitive and physical capabilities, and so on), are the ones
who stand to suffer the most from such a system. And
this population is the fastest growing segment of society.
An emerging body of evidence supports expressive art
therapies as a means of improving quality of life, enhanc-
ing a sense of self-worth, and promoting human dignity.
Such therapies include music, art, drama and dance,
poetry, and bibliotherapy, and often incorporate remi-
niscence therapy, storytelling, and cognitive/behavioral
therapy in the treatment plan. Creativity is an essential
human characteristic. Philosopher Erich Fromm once

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

630

wrote, “Being creative means considering the whole
process of life as a process of birth and not interpreting
each phase of life as a final phase” (Hannemann, 2006).
According to Gene Cohen, founder of the National Cen-
ter for Creative Aging, creativity reinforces neuronal con-
nections, improves emotional resiliency, enhances a sense
of well-being, and improves memory. Aesthetic forms of
expression, including music, painting, and literature, help
to confront a negative view of aging by offering individu-
als a new way of looking at themselves and the world.
Such forms of expression provide a channel for communi-
cation and lessen feelings of isolation, thereby generating
a sense of community.
“Art in all its forms is the purest medium of human con-
nection, the one which most truly promotes holistic com-
munion between individuals. The innate power of art lies in
its ability to meld the heart and mind of the artist with that
of the observer, to call to consciousness in another the depth
of emotion, experience, spirituality, and intellect behind the
creation of the artistic work” (Potts, personal communica-
tion, 2010). Creativity is a necessity for healthy and fruitful
living and is a casualty of cognitive impairment. Expression
through artistic creation helps bypass roadblocks to creativ-
ity, again promoting self-worth and dignity (Hannemann,
2006). Assimilation of life elements into a story of which
one is cognizant is also an innately human trait. Many neu-
rologic diseases of the elderly inhibit one’s ability to for-
mulate and share this life story and to have it heard and
appreciated. Conditions such as Alzheimer’s disease (AD),
for example, rob one’s ability to express oneself through
language, producing isolation and the inability to be
understood. This contributes in no small way to the mor-
bidity of the dementing illnesses. Expressive art therapies
can improve an individual’s ability to communicate his or
her story and can stimulate memories, foster community,
promote positive relationships with caregivers, diminish
adverse behaviors, enhance cognitive abilities, and elevate
and stabilize mood. The end result is an enlivened sense of
self-worth and fostering of dignity, which should be impor-
tant outcomes of any health-care intervention.
The World Health Organization defines health as “a
state of complete physical, mental, and social well-being
and not merely the absence of disease or infirmity”
(Cohen, 2009). In the Creativity and Aging Study, prin-
cipal investigator Cohen concluded from statistically sig-
nificant findings that elderly participants in health inter-
ventions utilizing the expressive arts had better health,
fewer doctor visits, less medication usage, and increased
activities and social engagement (Cohen, 2007). Obvious
secondary benefits include substantial cost savings to
the health-care system. The use of art and music in the
inpatient setting reduces the length of hospitalization
and is associated with a decreased need for pain medi-
cation in critical care patients (Stuckey and Nobel, 2010).
Scientific evidence also indicates that exposure to a rich,
Expressive Art Therapies in Geriatric Neurology 631
stimulating environment in older age (including partici-
pation in artistic creativity) increases the length and num-
ber of neuronal dendrites and their connections (Hanna
and Perlstein, 2008). Research has shown brain activity to
be less lateralized in older adults than in younger adults,
enabling better integration of left- and right-hemispheric
function (Cohen, 2009). It has been hypothesized that
activities that facilitate integrated right/left function are
appealing to the brain. Virtually every form of art pro-
vides optimal utilization of the benefits of synchronized
hemispheric involvement. Furthermore, gerontologic
research has shown positive health benefits in elderly
individuals who can experience a sense of control (mas-
tery) over their environment. The act of creating fosters
such a sense of control (Cohen, 2009).
The field of creative aging—comprising the arts, aging,
education, health, and humanities—has developed a
variety of categories of arts programs that address the
needs of older people. Educational programs include
lifelong learning through arts in conjunction with higher
education extension services and community schools of
the arts. Community-building programs offer social and
civic engagement through participation in arts initiatives.
Health-care programs provide professional arts and arts-
therapy opportunities for frail older people who are in the
care of others at home, in long-term care facilities, or in
health-care institutions. The Global Alliance for Arts and
Health is a leading national organization that supports
developing and sustaining arts programs within medi-
cal settings, including long-term care facilities (Hanna
and Perlstein, 2008). Furthermore, as medical profession-
als are beginning to recognize the role the expressive arts
play in the healing process, arts in medicine programs,
such as the Arts in Medicine Program at the University of
Florida, are beginning to emerge worldwide (Stuckey and
Nobel, 2010). Research at Florida has shown that partici-
pation in such a program is related to improved quality-
of-life measures, as well as trends toward improvement
in depression and certain laboratory and hemodialysis
measures (Stuckey and Nobel, 2010).
The following discussion outlines the benefits of expres-
sive art therapies, reviews pertinent literature, and makes
a call to embrace such therapies as a focus for research,
reimbursement, and implementation in practice.
Music therapy
The intuition that music may facilitate physical and emo-
tional well-being appears to be as old as humankind. As
anthropology and ethnomusicology developed during
the twentieth century, major figures in these fields noted
that, in every civilization studied, even preliterate societ-
ies, music and rhythm not only were a part of the cultural
climate, but were assumed to have a unique role in healing
632 Therapeutics for the Geriatric Neurology Patient
rituals, spiritual rites, and expressions of the essence of
human nature (Nettl, 1956; Merriam, 1964; Sachs, 1965).
Whether reading the biblical story of David playing his
harp to dispel King Saul’s tormenting spirit, reading Wil-
liam Congreve’s seventeenth-century poetry stating that
“Musick has Charms to sooth a savage Breast,” or inves-
tigating the strict music censorship by totalitarian gov-
ernments in current times, a strong connection between
music and states of mind to promote maximum function-
ing has been a continuing theme in human development.
Only within the past 60–75 years has an accountable pro-
fessional discipline been developed that uses music in
therapeutic ways.
The field of music therapy has been made possible by
the development of two aspects of modern behavioral
sciences: (1) standardized formats for social/behavioral
research, which generate reliable and comparable quan-
titative and qualitative findings, and (2) development of
technologies that monitor subtle behavioral and physi-
ologic changes associated with emotional phenomena.
The information that neuroimaging will reveal in com-
ing years will assist in determining why brains and bod-
ies react to music in certain ways. However, almost five
decades of behavioral research in musical responses
already have yielded sufficient information for effective
clinical use of music by Board Certified Music Therapists
(MT-BC) (Solomon, 1993; Heller, 2000).
“Best practice” in music therapy, across all populations,
rests on three foundational principles. Music therapy
combines standard therapeutic strategies with a musi-
cal (or rhythmic) format to address clients’ specific non-
musical therapeutic needs. Music therapy is interactive,
involving participation at whatever musical level a client
may be. Music therapy incorporates recipients’ favorite
music, with no genre being innately therapeutic. MT-BC
engage in assessment, treatment planning, and delivery
in line with clients’ individualized needs and documenta-
tion of the efficacy of treatment.
Music therapy’s unique contributions to the aged were
brought to public attention in 1991 when the United States
Senate Committee on Aging held a hearing supporting
the inclusion of music therapy in the list of services to be
provided for elderly people (Special Committee on Aging,
United States Senate 1991). Subsequently, the reauthoriza-
tion of the Older Americans Act cited music therapy as an
appropriate service for the geriatric population.
Although testimonials concerning music therapy’s
effectiveness in the special issues associated with demen-
tias began to accumulate since the beginning of the pro-
fession, as recently as 1988, there were no data-based
research articles to support treatment decisions. By the
turn of the century, however, a review of the research lit-
erature yielded 60 studies with enough data and experi-
mental control to be useful in designing effective treat-
ment sessions for people with Alzheimer’s and related
dementias (Prickett, 2000). As national interest in dealing
with dementias has increased, the number of investiga-
tions has continued to keep pace. The rigor of the studies,
the number of people included in each project, and the
replicability of the results has improved dramatically in
the past decade.
Brotons et al. (1997, 1999) reviewed the empirical lit-
erature available at the end of the 1990s; overall, the fol-
lowing seminal conclusions were well established and
provide context for more recent investigations (example
studies are cited):
1 People diagnosed with Alzheimer’s and related de-
mentias can continue participating in structured music
activities late into the disease (Clair, 1996).
2 Playing instruments and dancing/moving can be very
effective even into later stages and are well liked by par-
ticipants (Brotons and Pickett-Cooper, 1996).
3 The therapist’s or caregiver’s skill in modeling a de-
sired response increases participation (Clair and Ebberts,
1997).
4 Individual and small group settings are far more use-
ful than larger groups in facilitating participation (Clair
et al., 1995).
5 Social/emotional skills, including interaction and
communication, can be improved during music ses-
sions and for a period of time after the sessions conclude
(Sambandham and Schirm, 1995).
6 Cognitive recall may be enhanced, particularly for per-
sonal memories, when music associated with those mem-
ories is sung or played (Prickett and Moore, 1991).
7 Music interventions may be an alternative to pharma-
ceutical or physical restraints in controlling agitation or
wandering (Brotons and Pickett-Cooper, 1996; Thomas et
al., 1997; Clark et al., 1998).
8 Additional studies during the 1990s laid the ground-
work for later clinical work by establishing protocols
for singing, rhythmic, and musical activities (Clair and
Bernstein, 1990).
Building on this groundwork, twenty-first-century
music therapy researchers have worked to define situa-
tions and refine techniques in two basic areas: increase in
desired behaviors such as communication or participa-
tion with others, and decrease in undesirable behaviors
such as agitation, anxiety, and depression. Additionally,
although live music presented by a professional therapist
has been shown to be most effective, the potential to gain
some degree of improvement through ambient or back-
ground music has been explored.
Increasing participation in sociable group activi-
ties and with caregivers has been a focus of research in
this century. Cevasco and Grant (2003) assessed clients’
involvement in exercise to music sessions when vocal
or instrumental music was used and found that more
people joined in during the instrumental music; in a sec-
ond portion of this study, more people were able to be

successful when simply exercising to music rather than
when moving while playing instruments. In both cases,
the investigators deduced that eliminating competing
stimuli (vocal music conflicted with verbal cues; actions
required to hold or play an instrument conflicted with
simply moving the limbs) increased the likelihood of
successfully completing the task. In a later study, the
same authors (Cevasco and Grant, 2006) explored the
efficacy of various commonly used musical instruments,
as well as a cappella singing, during a variety of sing-
ing, instrument playing, and movement activities. The
details of their findings offer guidance to clinical music
therapists for structuring sessions that will elicit a high
participation rate.
Initial findings exploring verbal communication, espe-
cially with caregivers, revealed significantly improved
scores for speech content and fluency in spontaneous
speech during and following music therapy sessions
(Brotons and Koger, 2000; Brotons and Marti, 2003). Non-
verbally, clinicians working with patients with demen-
tia employ touch to increase alertness. Belgrave (2009)
explored differential effects of expressive touch (such as
nurturing and caring) versus instrumental touch (assist-
ing in completing a task such as stroking wind chimes)
during musical activities, as well as a no touch condi-
tion. Both touch conditions increased ratings of client/
therapist rapport, with expressive touch being signifi-
cantly more effective in initial sessions for increasing alert
behavior in individuals who have late-stage dementia.
The use of small group music therapy interventions,
particularly those structured to engage reminiscence, has
proved effective in reducing symptoms of depression
and anxiety (Ashida, 2000; Guétin et al., 2009; Sung et
al., 2010) and behavior problems associated with irritabil-
ity, anxiety, and depression at mealtime (Liao et al., 2004).
It is particularly important that, in each of these studies,
the reduction of symptoms continued to be evident for a
notable period of time after the last session.
It is extremely difficult to verify whether any person is
actually listening to music in the environment. If the musi-
cal task is singing and the person sings along with a music
source, measures such as counting the number of words
sung (judged by lip movements) may indicate that, to
some degree, the singer is also listening; with people who
have dementia, differential response rates for musical ver-
sus spoken stimuli have been demonstrated (Prickett and
Moore, 1991). A later study (Groene, 2001) demonstrated
that when a leader is singing, whether accompanied by
live or recorded music with simple or complex structure,
seniors with a dementia diagnosis participated equally
well in all conditions. However, behaviors such as leav-
ing after the song decreased when accompaniments were
complex (more harmonies and more rhythmic enhance-
ment). Patients’ differential response to the accompani-
ments indicates that they were listening to the music.
Expressive Art Therapies in Geriatric Neurology 633
Gregory (2002) attempted to measure listening attention
by asking older adults in an Alzheimer’s care group to
respond in real time to music versus silence conditions,
indicating their perception using a Continuous Response
Digital Interface dial. Compared with college students or
older peers with no diagnosis, people with mild cognitive
impairments performed somewhat less accurately, but
with the same basic pattern of distinguishing different
music excerpts or silence as the older adults and college
students. Establishing that people with dementia diagno-
ses can respond in ways that indicate the ability to make
aural discriminations, even when the ability for meaning-
ful verbal communication has been compromised, is an
important distinction for differences in processing music
versus speech communication.
Two studies have explored the effect of ambient music
in the environment (background music), especially music
that can be documented as being preferred by the clients
(Park and Specht, 2009; Ziv et al., 2007). Both articles
report significant reductions in agitated behaviors and
an increase in positive social behaviors, even though
the patients were not engaged in any structured activity
while the music was playing.
Music therapy researchers never claim to “cure” or
reverse symptoms of dementia. The aim of music ther-
apy with this population is to maximize quality of life
and facilitate interactions with caregivers. The useful-
ness of music-based assessments of cognition, especially
compared with the MMSE, has been demonstrated with
a “uniqueness to the melodic, singing, and rhythmic
aspects of music cognition” (Lipe et al., 2007). Improved
MMSE scores immediately after a music therapy session
and, even more, the next day have been demonstrated,
although after a week had passed, the improvement
had faded, indicating that frequent sessions may main-
tain cognitive function across time (Bruer et al., 2007). A
two-year follow-up of patients receiving weekly music
therapy sessions found a significantly lower increase in
systolic blood pressure, compared to control subjects, as
well as better maintenance of other indicators of physi-
cal and mental states (Takahashi and Matsushita, 2006). In
short, clinical and research evidence continues to support
hypotheses that music elicits different—and beneficial—
responses from people with Alzheimer’s disease and
related dementias, even though the neurologic mecha-
nisms responsible for this have yet to be established.
The uses of music therapy in poststroke rehabilitation
draw on both the physical attributes of musical stimuli
(such as the emphasis of a beat or pulse, and regular pre-
dictability of a steady beat in time), the physical require-
ments inherent in singing (control of all aspects associated
with producing an oral sound), and the reinforcing effects
of musical participation. The research examples that fol-
low explore various useful clinical techniques of music
therapy.
634 Therapeutics for the Geriatric Neurology Patient
Establishing a steady gait is one of the primary
focuses of therapy for many stroke patients. An early
study (Staum, 1983) employed music and percussive
rhythm as a template for persons in therapy for gait
disorders; footfalls increasingly matched the rhyth-
mic stimulus and, over time, the stimulus was effec-
tively faded so that rhythmic walking and consistency
of speed could be maintained outside the clinic. Later
work (Thaut et al., 2007) has replicated and expanded
this idea, putting to use more advanced technology
for documenting results and extremely fine variations
in responses. Based on research, Thaut has developed
a systematic training program (Rhythmic Auditory
Stimulation [RAS]) for this and other aspects of neu-
rorehabilitation (Schauer and Mauritz, 2003; Jeong and
Kim, 2007); training is offered to MT-BC, and gradu-
ates of this training may be identified by the letters
MT-BC, NMT after their names. After publishing in
numerous peer-reviewed journals, Thaut compiled the
major points of RAS into one book, Rhythm, Music, and
the Brain: Scientific Foundations and Clinical Applications
(2007). The following are examples of peer-reviewed
research projects that have demonstrated the efficacy
of music therapy in commonly encountered poststroke
rehabilitation challenges:
1 Nonfluent aphasia: Speech therapists have employed
versions of Melodic intonation therapy for decades, but
recent advances in imaging and consistencies in clinical
observations have allowed the development of a protocol
that uses music therapy to increase speech fluency (Kim
and Tomaino, 2008).
2 Grasp strength: Using common orchestral percus-
sion instruments (such as tambourine, cymbal, drum, or
claves), patients can measurably increase grasp strength
while playing the instruments in a musical setting (Co-
francesco, 1985).
3 Swallowing: Preliminary results for a protocol that al-
ternates singing, breathing training, and laryngeal eleva-
tion exercises across a 30-minute period of time were sta-
tistically significant after only six sessions, with increasing
effectiveness demonstrated after 12 sessions (Kim, 2010).
4 Mood and social interaction: When music therapy
sessions were paired with standard rehabilitation tech-
niques, participants’ families and treatment staff rated
them significantly higher with regard to posttreatment
social interaction, active involvement in therapy, and co-
operation with therapeutic regimens (Nayak et al., 2000).
Besides the formal training in RAS mentioned already,
research-based clinical applications of music therapy for
all categories of stroke populations have been made avail-
able to the entire music therapy profession by Elizabeth
Wong, MT-BC. Her book Clinical Guide to Music Therapy
in Physical Rehabilitation Settings (Wong, 2004) has become
a standard textbook in university music therapy degree
programs.
Art therapy
The Merriam-Webster dictionary defines art as a “skill
acquired by experience, study, or observation; the con-
scious use of skill and creative imagination, implying a
personal creative power which cannot be analyzed: the
creation of beautiful or significant things.” Perhaps art
may be thought of as a form of self-expression, a means
of communicating with the self, a process by which shape
and meaning may be given to something that otherwise
may have remained unformulated. Aesthetically, creating
art may give one the satisfaction of bringing something
into being that enriches life. Artistic expression may thus
allow the person to function with a greater degree of per-
sonal contentment (Allan and Killick, 2000). Historically,
art has been used as a means to communicate ideas with
religious and cultural significance to the masses when
the ability to read was not widespread (Allan and Killick,
2000). The ability to communicate is one of the most defin-
ing of human traits. Unfortunately, many people suffering
from degenerative brain diseases progressively lose their
ability to communicate through verbal, linguistic methods.
Conditions such as AD take away the full mosaic of a per-
son’s past (Sandrick, 1995). However, where words are lost,
images can remain. Visual art provides a means of commu-
nication that bypasses roadblocks to traditional expression.
Furthermore, for those who are nearing life’s end, artistic
expression gives the opportunity to shape inner experi-
ence before that capability is lost. Neurologist Oliver Sacks
describes the “undiminished possibility of reintegration by
art, communion, and touching the human spirit.”
Grounded in human developmental theory and psy-
chological theory formulated initially by Carl Jung and
Sigmund Freud, the field of art therapy arose in the 1930s
(Pratt, 2004). The American Art Therapy Association
defines art therapy as “a mental health profession that uses
the creative process of art making to improve and enhance
the physical, mental, and emotional well-being of individ-
uals of all ages. It is based on the belief that the creative
process involved in artistic self-expression helps people
to resolve conflicts and problems, develop interpersonal
skills, manage behavior, reduce stress, increase self-esteem
and self-awareness, and achieve insight” (American Art
Therapy Association, 2010). Medical art therapy may help
the patient synthesize and integrate issues such as pain,
loss, and death (Pratt, 2004). It also offers a unique opportu-
nity to help elderly clients engage in the creative process to
facilitate communication, manage emotions, exert control
over their environment, and engage in the process of life
review. Furthermore, art therapy provides a means of non-
verbally assessing cognitive and developmental deficits,
and analysis of a client’s artwork may be useful in deter-
mining diagnosis or response to treatment. The American
Art Therapy Association was formed in 1969 and provides
certification to qualified therapists.
 Expressive Art Therapies in Geriatric Neurology 635

Art therapists typically work in either group settings

or individual sessions engaging participants to create
expressive images. Trained professionals use high-quality
materials to foster a mature, dignified activity for this self-
expression. Where necessary or helpful, guided directives
are provided to advance the process. Evaluation of the
work can provide diagnostic insight to the therapist as
well as positive, validating effect to the individual par-
ticipant.
Evaluation of the artwork and stories told by images
often reveals persistent communication abilities in
patients thought to lack self-awareness. The artwork
becomes a compelling way for an individual to say to
the world, “I’m still here,” and lends support for person-
centered, validating care even in patients with end-stage
impairment. It also serves as a means of organization to a
ravaged mind and raises questions about preserved capa-
bilities even in those with advanced cognitive disorders.
For example, Potts describes abstract representations of
family members in the late-stage Alzheimer’s watercol-
ors of his father after verbal expression was essentially
Figure 26.1 Blue jay.
lost (Potts, personal communication, 2011). Art therapy
is an essential component of person–environment sys-
tems of care that are supportive and safe, heightening evaluating a patient’s use of space, line, and shape, art
an individual’s sense of normalcy, competency and well- therapists are able to help in this differentiation as well
being despite cognitive impairment, whether that be for as aid in staging the disease process. Numerous small
a moment or an hour (Rentz, 2002). Such systems will be anecdotal and observational studies have shown ben-
increasingly common with the aging of the population eficial effects of art therapy in patients with traumatic
and rising prevalence of AD and other dementias. brain injury, stroke, depression, bereavement, cancer,
For the artist, participation can also be a valuable tool for pain management, sexual abuse, and HIV disease (Pratt,
improving quality of life and enhancing self-worth, bring- 2004). Case studies in cancer patients have shown that art
ing a sense of pride and satisfaction from completing a therapy helps individuals explore the meanings of past,
work (Duncan and Potts, personal communication, 2010).
Art therapy brings respect and dignity to people who are
often isolated and infantilized, yet whose lives were previ-
ously full of accomplishment and adventure. Figures 26.1
and 26.2 show some examples of Lester Potts’s artwork
created after the diagnosis of Alzheimer’s disease.
For those with cognitive disorders, creating visual art
becomes a means of enlivenment and communication in
a world otherwise laden with confusion, isolation, and
stigma from society. As Gibson observes, “Dementia
strips people down to the essence of their being and frees
them to be in more direct touch with their emotions. They
communicate with greater authenticity than our custom-
ary conventional reliance on controlled emotional expres-
sion” (Gibson, 1998).
In the medical arena, art therapy interventions are com-
monly used as a tool to distinguish between symptomati-
cally similar clinical presentations and have been shown
to offer benefits in many different conditions. For example,
major depressive disorders with psychotic features may
present similarly to dementia of the Alzheimer’s type,
and an apparent bipolar disorder presentation could,
in fact, represent frontotemporal dementia (FTD). By Figure 26.2 Three birds.
636 Therapeutics for the Geriatric Neurology Patient
present, and future, thereby integrating cancer into their
life story and giving it meaning. Artistic self-expression
is thought to contribute to maintaining or reconstructing
a positive identity (Stuckey and Nobel, 2010). Art can be
a refuge from the intense emotions associated with ill-
ness (Stuckey and Nobel, 2010). It has been suggested
that, when incorporated into treatment programs for the
elderly, art therapy can help clients cope with the chal-
lenges aging brings (Johnson and Sullivan-Marx, 2006).
Though research involving art therapy interventions in
the geriatric population is relatively sparse, a few key
studies have demonstrated benefits, primarily in those
with cognitive disorders. Some of its documented posi-
tive effects include promotion of well-being, enhanced
communication and socialization, facilitated decision
making, improved mood, maintenance of function, and
improved expression of emotions.
In 2003, a collaborative study was conducted by the
Alzheimer’s Association of Northern California, North-
ern NV, the VA Palo Alto Health Care System, and the
Department of Psychiatry and Behavioral Sciences, Stan-
ford University School of Medicine. Researchers evalu-
ated patients with AD to compare benefits derived from
participating in an art therapy group versus a current
events group, the latter being a more commonly employed
group activity in dementia care facilities. Thirty-five male
and female dementia patients between the ages of 65
and 100 years participated in the study. Due to cognitive
and communication deficits and inability to respond to
traditional psychometric assessments, researchers used
the Apparent Affect Rating Scale (AARS; Lawton et al.,
1996) as a measuring assessment for direct observation.
Trained raters used the scale to indicate how long a sub-
ject displayed each of five emotions (anger, anxiety/fear,
sadness, pleasure, and alertness) over 5–10 minutes. Par-
ticipants in the art therapy group were shown to be more
alert, more aware of their environment, and more socially
interactive, and had levels of positive affect seldom seen
outside this group. Family members reported that these
effects persisted past group activities, with some partici-
pants remembering their experience and talking about
how much they enjoyed it.
Memories in the Making, originating from California’s
Orange County Alzheimer’s Association program model,
is an art program for those in the early and middle stages
of dementia (Rentz, 2002). Despite diminished verbal and
organizational skills, participants in this program (guided
by trained facilitators) use watercolors and acrylics to
express themselves by creating visual images on paper or
canvas. In an outcome-based evaluation of this program’s
effect on well-being conducted by researchers affiliated
with the Greater Cincinnati Chapter of the Alzheimer’s
Association, results indicated that participants more often
worked with sustained attention, had a pleasurable sensory
experience, derived pleasure from the activity as evidenced
by laughter and relaxed body language, and verbalized
feeling good about themselves and their accomplishments.
More than two-thirds of the clients always smiled, and more
than 80% of the artists never displayed agitation or discom-
fort during the sessions. Comments such as “This gives my
hand such pleasure” and “In here I feel like a person again”
lend support for the intervention’s beneficial effects (Rentz,
2002). Those with mild cognitive impairment and early
stage AD need an outlet to express their thoughts and emo-
tions in a safe and trusting environment, especially follow-
ing initial diagnosis, when emotions are raw. Art therapy
groups provide this “safe place” where emotions can be
distributed on paper and processed accordingly (Duncan,
personal communication, 2010).
Viewing products of the creative effort has been shown
to have benefits as well and may often inspire the writ-
ing of poetry or the telling of stories, which have added
therapeutic effects (Johnson and Sullivan-Marx, 2006). In
the “MoMA Alzheimer’s Project: Making Art Accessible to
People with Dementia” program (Metropolitan Museum of
Modern Art in New York), specially trained museum edu-
cators engage participants with mild-to-moderate demen-
tia and their caregivers in lively discussions by focusing on
iconic art from MoMA’s collection. Results from an evalu-
ation of the program by researchers at New York Univer-
sity showed that the warm and interactive approach of the
educators rekindled feelings of self-worth. The participants
felt that having the opportunity to learn, to be intellectu-
ally stimulated, and to experience great art together was
of significant benefit. Family members expressed gratitude
that the participant with dementia could have such an
experience and, just as important, that they could share it
together with the caregiver. The sense of safety and feelings
of regard for the participants created by the educators and
staff at least temporarily removed the stigma of AD so that
participants could enjoy the experience. Both the persons
with dementia and their caregivers felt positive changes
to mood both directly after the program and in the days
following the museum visit. Caregivers reported fewer
emotional problems, and all but one person with demen-
tia reported elevated mood. The program also served as a
catalyst for new conversation in the days to follow (Meet
Me at MoMA, 2009).
Miller has written extensively about creativity in the
context of neurologic illness, including the neurology of
art production and the phenomenon of the discovery of
artistic talent in the dementias (Cummings et al., 2008;
Miller et al., 1998; Miller and Hou, 2004;). The emergence
and evolution of visual creativity in dementia offers a
window into the artistic process while hinting at the
extraordinary cognitive flexibility of individuals expe-
riencing progressive loss of cortical neurons (Miller and
Hou, 2004), particularly when the injury is localized to
the language hemisphere. Two visual streams, a dorsal
stream that localizes where an item has been perceived

Figure 26.3 Sunset in Kauai.
and a ventral stream involved in the recognition of what
is seen, are essential for visual art production (Miller and
Hou, 2004). Internally represented visual scenes absorbed
over one’s lifetime are perceived through components of
the ventral stream that localize to the occipital and tempo-
ral cortices. Such internal imagery provides the creative
soil for the production of visual art. Precision is added
through the dorsal stream, which frames scenes per-
ceived in the ventral stream and helps to place them on
canvas (Miller and Hou, 2004), as shown in the artwork in
Figures 26.3 and 26.4.
The “nondominant” hemisphere is dominant for visual
art, and right parietal injury, with its attendant neglect and
loss of visuoconstructive skills, is devastating for artistic cre-
ation (Miller and Hou, 2004). Many other brain regions are
likely also involved in the production of visual art, including
dorsolateral prefrontal cortex (artistic planning and organi-
zation), cingulate cortex (drive and emotion), motor and
premotor frontal regions, basal ganglia, and cerebellum (pre-
cise motor control). Furthermore, the language hemisphere
Figure 26.4 Yoshida palm.
Expressive Art Therapies in Geriatric Neurology 637
contributes symbolic and linguistic concepts drawn upon in
much visual art (Miller and Hou, 2004).
AD is characterized by progressive loss of visuospatial
skills caused by the degeneration of posterior parietal
and temporal brain regions. One might speculate that this
would make creation of visual art difficult, if not impossi-
ble. This is not always the case. However, art generated by
Alzheimer’s patients does tend to lose realistic precision,
albeit retaining appealing color and form (Miller and Hou,
2004). This phenomenon is apparent in the art of Dutch–
American abstract expressionist Willem de Kooning, who
is believed to have developed AD complicated by other
conditions that adversely affected cognition (alcoholism,
atherosclerosis, depression, and so on; Espinel, 1996). In
the case of de Kooning, not only was his later art intrigu-
ing and aesthetically appealing, but also it apparently
provided therapeutic benefits to the artist (Espinel, 1996).
Potts describes the previously unknown artistic talents
of his father, an Alabama saw miller, which emerged in
early to midstage AD (Potts, 2006). Characteristic loss of
accurate spatial representation was followed by vibrant
use of color (especially blues and greens) and production
of imagery from childhood (saws, fences, trees, and so
on). In late-stage disease, after the loss of linguistic ability,
the elder Potts painted abstractions of his father and his
childhood home, easily recognizable by family members
(Figure 26.5) (Potts, personal communication, 2011).
FTD is associated with a different pattern of visual
artistic expression. In some cases, especially in the sub-
type semantic dementia, spontaneous bursts of creativ-
ity seem to have been triggered by the illness, most often
in the presence of aphasia. In this entity, focal degenera-
tion of the left anterior temporal lobe is seen. Remarkably,
some patients develop a new interest in art and produce
progressively more successful paintings (Miller and Hou,
2004). These works are generally approached compulsively
and are characterized by realistic or surrealistic content
Figure 26.5 Blue collage, a late-stage Alzheimer’s watercolor of
Lester Potts, depicting his father’s hat, shoes and saw.
638 Therapeutics for the Geriatric Neurology Patient
with lack of symbolic or abstract themes (Miller and Hou,
2004). Explanatory theories regarding this visual creativity
include sparing of nondominant posterior parietotemporal
function, compulsivity regarding the creative act, and dis-
inhibition of the nondominant hemisphere through hypo-
metabolism and the dominant left anterior temporal region
(Miller and Hou, 2004). In both AD and FTD, the study of
art in dementia is a model for recognizing strengths, not
just weaknesses of patients. As such, the use of art therapy
in dementia helps to conquer disability and degeneration
(Cummings et al., 2008) and plays an important role in vali-
dating, person-centered dementia care.
One of the premises held in art therapy is that art can serve
as a unifying language, even across cultural and socioeco-
nomic divisions. In art therapy settings, artists from different
backgrounds and cultures sit together, paint, and share their
life stories. Art becomes the common thread. The goal of art
therapy in each participant is not the production of beauti-
ful art; it is the fostering of dignity in a life that is isolated,
demeaned, and sometimes noncoherent. Self-expression
through art making gives the satisfaction of making oneself
known to the world as seen in the Figures 26.6, 26.7, and
26.8. (Potts and Duncan, personal communication, 2010).
Figure 26.6 Cabin by the lake.
Figure 26.7 Dad’s barn.
Figure 26.8 Yoshida beach sunset.
Dance/movement and drama therapies
Although dance has been a mode of emotional expres-
sion for millennia, dance therapy originated in the
realm of inpatient psychiatry in the 1940s (Pratt, 2004).
Marian Chace, a dancer and choreographer influenced
by psychiatrist Carl Jung, conducted dance classes at
St. Elizabeth’s Hospital in Washington, D.C., among
patients who had been traumatized by World War II.
As an alternative to verbal therapies (Westbrook and
McKibben, 1989), this early dance therapy resulted
in improvement in many patients. Over the next few
decades, dance therapy continued to be developed
under the influence of psychodynamic psychotherapy
(Pratt, 2004). The American Dance Therapy Association,
founded in 1966, defines dance/movement therapy as
“the psychotherapeutic use of movement to promote
emotional, cognitive, physical, and social integration of
individuals” (Pratt, 2004). This organization has more
than 1200 professional and nonprofessional members.
According to its published materials, it maintains high
standards for education, training, and professional
practice for dance/movement therapists (American
Dance Therapy Association, 2010).
A growing interest in dance and movement therapy
has accompanied recognition of mind and body ben-
efits of motor activity (Stuckey and Nobel, 2010). Such
therapy combines body movement with the skills of psy-
chotherapy, counseling, and rehabilitation (Pratt, 2004) to
produce improvements in perceived stress and anxiety,
physical symptoms and ambulation, range of motion and
body image, quality of life and concept of self, and other
cognitive and psychological measures. Movement-based
creative expression focuses on nonverbal, primarily phys-
ical forms of expression as psychotherapeutic or healing
tools (Killick and Allan, 1999).

Though much of the research on the benefits of dance
and movement therapy has been conducted in the psychi-
atric inpatient population, a growing body of literature is
showing its benefits in patients with cancer (Killick and
Allan, 1999), PD (Westbrook and McKibben, 1989), stroke
(Pratt, 2004), and dementia (O’Maille and Kasayka, 2005),
as well as in the cognitively normal elderly population
(Stuckey and Nobel, 2010). Involvement in leisure activi-
ties has been shown to delay the onset of AD for those
at risk of the disorder. Dance was at the top of the list of
activities that were shown to have this effect (Cohen, 2009).
Among breast cancer survivors in Connecticut, statistically
significant improvement was seen in quality of life mea-
sures, body image and shoulder range of motion after 12
weeks of dance/movement therapy in a small, random-
ized controlled trial (Stuckey and Nobel, 2010). When stan-
dard outpatient therapy with exercise was compared to
dance/movement therapy in patients with PD, the latter
produced statistically significant relative improvements in
walking times, including improvement in movement initia-
tion (Westbrook and McKibben, 1989). Subjective improve-
ments in mood were also observed. Patients who had suf-
fered stroke and participated in 45-minute dance/move-
ment therapy sessions twice weekly for 5 months gained
improvements on measures of physical, psychological,
and cognitive function. A meta-analysis published in 1996
suggests that dance/movement therapy may help elderly
persons with anxiety (Ritter and Low, 1996). Inactivity is
one of the leading causes of morbidity and mortality in the
elderly. Occupational therapy programs for older people
often include dance /movement therapy interventions.
Improvements in range of motion have been documented
in persons treated in this way (Ritter and Low, 1996). Fur-
thermore, dance/movement therapy has been touted to
reestablish connections with others in persons who have
withdrawn inwardly due to dementia (Zeisel, 2009).
Tai chi, a form of semi-meditative movement therapy
derived from the martial arts, has been used to help
reduce falls on older adults and to improve health sta-
tus. In a 48-week randomized controlled trial, tai chi was
compared with wellness education in a cohort of elderly
women. The tai chi group exhibited significant improve-
ments in physical functioning and ambulation, as well
as borderline significant improvements in the Sick-
ness Impact Profile body care and movement category
(Stuckey and Nobel, 2010).
Mindful Affective Timalation Dance/Movement Ther-
apy is a holistic group psychotherapy process for persons
with end-stage dementia, developed by O’Maille and
centered in Kitwood’s philosophy of person-centered care
(O’Maille and Kasayka, 2005). It combines the techniques
of traditional dance/movement therapy with engage-
ment of the senses, incorporating elements of spiritual-
ity, bodywork, and dance/movement theory in a process
that can be likened to Lamaze (O’Maille and Kasayka,
Expressive Art Therapies in Geriatric Neurology 639
2005). Touted to help end-stage dementia patients tran-
sitioning into death, this technique has similarities to
validation therapy, developed by Naomi Feil, MSW,
ACSW (Feil, 1993). Validation is a method of communi-
cating with and helping disoriented very old dementia
patients, which has been shown to reduce stress, enhance
dignity, and increase happiness. The theory suggests that
elderly dementia patients struggle to resolve unfinished
life issues before death and are inhibited from doing so
due to cognitive and physical impairment. In the so-
called “phase of repetitive motion,” movements replace
words and are used to work through unresolved conflicts.
Therapists trained in the techniques and theory of valida-
tion can assist patients during this stage through dance/
movement therapy (Feil, 1993).
Psychodrama is closely related to dance/movement
therapy. Also known as psychodramatic psychotherapy in
the psychiatric disciplines, psychodrama holds that pro-
fessionally supervised “role playing” can lead patients to
perceive new solutions to psychological conflicts (Stuckey
and Nobel, 2010).
The National Association for Drama Therapy, established
in 1979, defines drama therapy as “the intentional use of
drama and/or theater processes to achieve therapeutic
goals” (North American Drama Therapy, 2012). The benefit
of short-term drama therapy and theater to enhance cogni-
tive and affective functioning in adults aged 60–86 years
was described by Noice and Noice (2006). In this study,
participants were given exercises designed to enable them
to experience the essence of acting (to become engrossed in
the drama). After 4 weeks of instruction, statistically signif-
icant gains were made by the treatment group on both cog-
nitive and psychological well-being measures; specifically,
word and listening recall, problem solving, self-esteem,
and psychological well-being improved (Noice and Noice,
2006). Similarly, cinema, or movie, therapy employs the
judicious use of film-viewing as part of a broader thera-
peutic process to promote psychological growth and heal-
ing (Stuckey and Nobel, 2010). Drama is often employed
in combination with dance/movement therapy for greater
therapeutic impact (Zeisel, 2009).
Poetry/bibliotherapy, storytelling, and
reminiscence
Poet Yu Xuanji (A.D. 843–868) alluded to what could later
be described as the therapeutic effects of poetry in the
following passage: “Reciting poems in the moonlight/
riding a painted boat (el)/Every place the wind carries
me is home.” The following was used as a guideline for
this text change: http://libguides.pstcc.edu/content.
php?pid=24540&sid=1751623
The term therapy encompasses bibliotherapy (the inter-
active use of literature) and journal therapy (the use of
640 Therapeutics for the Geriatric Neurology Patient
life-based reflective writing), as well as therapeutic sto-
rytelling, the use of film in therapy, and other language-
based healing modalities. The National Association for
Poetry Therapy was formed approximately 30 years ago,
as standards were set for the discipline. Certifications in
Poetry Therapy may now be obtained (National Associa-
tion for Poetry Therapy, 2011).
Poetry has been used for healing and personal growth
since ancient times. Shamans were believed to have
chanted poetry for the well-being of the tribe or indi-
vidual. In ancient Egypt, words were written on papyrus
and then dissolved into a solution that the patient could
ingest, to take effect quickly. Soranus, the first recorded
“poetry therapist,” was a first-century A.D. Roman physi-
cian who prescribed tragedy for his manic patients and
comedy for the depressed. It is not surprising that Apollo
is the god of poetry and of medicine, since medicine and
the arts have been historically entwined (National Asso-
ciation for Poetry Therapy, 2011).
Remaining obscure for centuries, the link between
poetry and the healing arts became somewhat more
developed in colonial America. Pennsylvania Hospital,
founded by Benjamin Franklin in 1751 and the first hos-
pital in the United States, employed reading, writing, and
publishing of results as ancillary treatments for mental
patients. Dr. Benjamin Rush, called the Father of Ameri-
can Psychiatry, introduced music and literature as effec-
tive treatments, and his patients published poetry in a
newspaper.
Bibliotherapy was coined as a term in 1916 and refers
to the use of literature in medical therapeutics. It was
first adopted by librarians who favored having a special
designation for the practice of selecting and using books
helpful to psychiatric patients. Only with the popular-
ity of group therapy in the 1960s did the term begin to
encompass organized discussion of the reader’s personal
reactions to the presented materials. Touted by such pio-
neering physicians as Freud, who said “Not I, but the poet
discovered the unconscious,” poetry therapy became an
accepted component of group therapy sessions con-
ducted by mental health professionals. Eli Greifer, a poet,
pharmacist, and lawyer, began a campaign to show that a
poem’s didactic message has healing power. He played a
key role in the development of modern poetry therapy in
association with psychiatrists Jack J. Leedy and Sam Spec-
tor at Cumberland Hospital in New York City in the 1950s
and 1960s (Lenkowsky, 1987).
Though controlled studies are difficult to find in poetry
therapy literature, there is growing interest in its role
in palliative care, with regard to treating both patients
and their caregivers. (Coulehan and Clary, 2005). How-
ever, some literature supports the benefits of writing on
health. Studies have shown that expressive writing or
journaling about traumatic experiences results in statis-
tically significant improvements in various measures of
physical health, reductions in physician visits, and better
immune system functioning (Stuckey and Nobel, 2010).
Writing about upsetting experiences produces long-term
improvements in mood and health (Stuckey and Nobel,
2010). Dozens of studies have shown that emotional
writing can influence frequency of physician visits,
immune function, stress hormones, blood pressure, and
a number of social, academic, and cognitive variables.
These efforts have been shown to hold across cultures,
age groups, and diverse samples (Stuckey and Nobel,
2010). Expressive writing can also improve control over
pain, depressed mood, and pain severity (Stuckey and
Nobel, 2010). Several authors have described the use of
poetry to help people find their voice and gain access
to the wisdom they already have but cannot experience
because they cannot find the words in ordinary lan-
guage (Stuckey and Nobel, 2010). Finding one’s voice
via poetry can be a healing process because it opens up
the opportunity for self-expression not otherwise felt
through everyday words. Journal writing has also been
linked to creativity, spiritual awareness, and expansion
of the self (Stuckey and Nobel, 2010). Living Words, a
creative writing program for persons with dementia
developed by psychologists at Wofford College in South
Carolina in collaboration with the Alzheimer’s Asso-
ciation, encourages participants to explore emotions,
insights, and memories in a workshop setting (Bopp,
personal communication, 2010). Touted benefits include
cognitive stimulation, reminiscence and reflection upon
one’s life, and release of stress (Bopp, personal commu-
nication, 2010).
As previously noted, a person’s ability to formulate
and relate his or her life story may be adversely affected
by disorders of cognition such as AD. This can promote
a sense of isolation, as family and friends become less
able to interact, grow uncomfortable with the situation,
and visit less frequently. As a result, the patient’s life and
very existence may be indirectly invalidated, or at least
self-perceived this way. Storytelling and reminiscence,
alone or in combination with other expressive art thera-
pies, can be an effective means of eliciting the patient’s
life story, thereby enhancing communication and pro-
moting validation. In 1975, Robert Butler, MD, published
Why Survive?: Being Old in America, which linked psy-
choanalyst Erik Erikson’s theory of the life cycle to the
process of aging. Erikson theorized that in the final stage
of aging, which he called “Integrity vs. Despair,” the key
developmental task was to examine one’s past, come to
terms with one’s losses, and celebrate one’s successes,
thereby achieving a sense of integrity. Butler saw remi-
niscence as central to integrating one’s life—working out
unresolved issues from one’s past, present, and future
(Hanna and Perlstein, 2008). In this vein, video biogra-
phies (Therapeutic/Restorative Biographies) have been
developed as a means of making patients’ life histories

accessible to others and to encourage communication
and interaction between patients and caregivers, fami-
lies, and friends (Cohen, 2002). These biographies are
created using videotaped snapshots of old photographs
and other memorabilia, with narration provided by fam-
ily members and friends (Cohen, 2002). Such interven-
tions have been found to enhance memory temporarily
in dementia patients and to positively alter the experi-
ence for the patient and visitor (Cohen, 2001). Moreover,
an important intergenerational dimension is added
to the intervention when young family members par-
ticipate in the creation of the video biography (Cohen,
2002). In addition to benefits as a therapeutic interven-
tion for the patient, video biographies provide families
with a biography of their loved one they otherwise may
not have had (Cohen, 2002).
TimeSlips is a nationwide arts in health-care pro-
gram developed by Anne Basting, PhD, at the Center
on Age and Community at the University of Wisconsin
Milwaukee. It is an innovative, effective storytelling
method in which groups of people in the middle stages
of dementia tell stories (Hanna and Perlstein 2008).
The facilitator plays down the importance of memory,
using an image to prompt creative responses. She or he
asks open-ended questions and weaves together all the
answers, from the poetic to the nonsensical, into a story.
Other expressive art therapies are often combined as
well. The program celebrates the creativity of people
struggling with AD and other dementias, and rekindles
their hope for human connection (Hanna and Perlstein,
2008). This chapter’s lead author is currently direct-
ing a similarly structured collaborative Alzheimer’s
life story project in rural Alabama, in which expressive
art therapies are utilized to elicit life stories that will
be recorded digitally. (Art to Life, sponsored by Cog-
nitive Dynamics Foundation in collaboration with the
University of Alabama Honors College; Potts, personal
communication, 2011).
Summary
The expressive art therapies (music, art, drama and dance,
poetry and bibliotherapy, reminiscence therapy, and sto-
rytelling) have numerous beneficial effects in geriatric
neurology patients and their caregivers. The end result
is fostering dignity, preserving a sense of self-worth, and
improved quality of life. Though cure is not possible for
many neurologic diseases of the elderly, the expressive
art therapies are important components of rehabilitative
treatment protocols and should be increasingly utilized
in the current and future health-care environment. Fur-
ther research is needed to rigorously document their ben-
efits and to elucidate the scientific basis of the restorative
potential of human creativity.
Expressive Art Therapies in Geriatric Neurology 641
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Part 5
Important Management Issues
Beyond Therapeutics in the Geriatric
Neurology Patient
 Chapter 27
Dietary Factors in Geriatric Neurology
Yian Gu and Nikolaos Scarmeas
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center,
New York, NY, USA

Summary
• Certain dietary factors may influence the risk or progression of Alzheimer’s disease (AD), Parkinson’s disease (PD), and
stroke. Conclusions from relevant research can be limiting since there are conflicting results.
• High intake of vitamin E, vegetables, B vitamins, n-3 PUFA, and fish may reduce risk of AD.
• High intake of vitamin E and caffeine, a moderate intake of CoQ, and low intake of dairy may reduce risk of PD.
• High intake of vitamin C, folate, tea, whole grains, and a low intake of sodium may reduce risk of stroke.
• Moderate consumption of alcohol and adherence to a healthy diet may reduce risk for AD, PD, and stroke.

Introduction The primary objective of this chapter is to review the

Within the next 50 years, approximately 30% of the pop-
ulation will be aged 65 years or older. Neurologic disor-
ders commonly increase in incidence with age. The major
geriatric neurologic disorders include Alzheimer’s disease
(AD), Parkinson’s disease (PD), and stroke. AD is the most
common cause of dementia in elderly people (Alzheimer’s
Association, 2010). An estimated 5.1 million Americans
aged 65 and older currently suffer from AD; nearly 1 in
8 people aged 65 and older (13%) have AD. PD is the sec-
ond most common neurodegenerative disorder after AD,
with a prevalence of 2% among persons of 65 years and
older (de Lau and Breteler, 2006). Stroke is the third lead-
ing cause of death among US adults age 65 or older (CDC,
2005); nearly three-quarters of all strokes occur in people
over the age of 65 (Weir and Dennis, 1997). All together,
these conditions lead to disability, cognitive and physical
function decline, and loss of independence of the elderly.
Although various vascular risk factors have been identi-
fied for stroke, including high blood pressure, high choles-
terol, cigarette smoking, and diabetes, the etiology for AD
and PD remains elusive. Furthermore, no known treat-
ment stops, decelerates, or reverses the progression of AD
or PD. Current medications for PD can help patients man-
age symptoms, but eventually the drugs lose their effec-
tiveness. Therefore, it is important to explore and develop
primary preventive strategies that can potentially help
prolong healthy life free of aging-related neurologic dis-
eases. Such strategies may target lifestyle factors, with diet
being one of the most investigated and promising.
evidence for dietary factors as potential modifiable life-
style factors to prevent cognitive decline, AD, PD, and
stroke. Hypotheses and supporting evidence relating
dietary factors to these disorders can be obtained from
a variety of sources, including in vitro studies; animal
experiments; epidemiologic studies, including cross-
sectional, retrospective, and prospective studies; and
randomized clinical trials. Although in vitro and animal
studies may provide critical direction for research and
aid in the interpretation of epidemiologic studies, species
differences may preclude direct extrapolation of findings
from animal experiments to humans. Cross-sectional and
retrospective case-control studies (in which information
about previous diet is obtained from diseased patients
and compared to that of subjects without the disease)
generally provide information efficiently and rapidly and
are useful in generating a hypothesis (Willett, 1998). How-
ever, because disease outcome cannot be established as a
result of dietary exposure or a cause for dietary changes,
cross-sectional and retrospective case-control studies can-
not be counted on for a causal inference.
Therefore, to identify methodologically sound causa-
tion studies (Haynes et al., 2005), this chapter focuses on
reviewing data from prospective studies and randomized
clinical trials in humans. In prospective studies, informa-
tion on diet is obtained from disease-free subjects who are
followed to determine disease rates according to levels
of dietary factors (Willett, 1998). Randomized clinical tri-
als usually randomly assign participants to a treatment
group (diet intervention) or placebo group and compare

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

647
648 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
them for outcome, which is either a successful treatment
of the disease, control of disease progression, or reduction
in disease occurrence. For the purpose of dietary preven-
tion of geriatric neurologic conditions, both of these types
of studies may provide valuable information on whether
a certain diet can prevent disease or control disease pro-
gression and, if so, which diet is best.
Dietary factors in relation to cognitive
function and Alzheimer’s disease
There is conflicting data about dietary interventions in
improving cognitive function in AD. While case series
and cohort studies point to a protective effect on cognition
with several dietary interventions, confirmatory testing
with randomized controlled clinical trials using individ-
ual agents have not shown a significant treatment effect
on cognition in early AD (See also Chapter 36). Designing
clinical trials to accurately test for a combined treatment
effect of multiple dietary agents (used concurrently) is
prohibitively expensive. This is because the sample size
and cost increase exponentially with each agent added
into the combination trial design. Designing clinical tri-
als with more than eight treatment arms is significantly
limited by the cost factor.
Antioxidants
It has been hypothesized that antioxidants from food
may reduce the risk of AD because antioxidants may
reduce neuronal loss due to oxidative damage. A range
of antioxidants from foods—namely, vitamin E (tocoph-
erol), vitamin C (ascorbic acid), other carotenoids (includ-
ing α-carotene, β-carotene, γ-carotene, lycopene, lutein,
β-cryptoxanthin, zeaxanthin, and astaxanthin), and fla-
vonoids (including isoflavone and catechin)—have been
investigated regarding their associations with the risk of
AD. Important sources of vitamin E are grain, nuts, milk,
and egg yolk. Vitamin C is mainly found in citrus fruits,
kiwi, sprouts, broccoli, and cabbage. Important sources of
β-carotene are kale, carrots, broccoli, and spinach. Flavo-
noids are found in cranberries, green and black tea, soy
foods, and legumes.
Several studies have found an inverse association
between dietary intake (Engelhart et al., 2002a; Morris et al.,
2002; Devore et al., 2010) and total intake (intake from diet
plus supplements) (Corrada et al., 2005) of vitamin E and
risk of AD. In addition, the French Personnes Agees QUID
(PAQUID ) cohort found that subjects with low plasma
vitamin E concentrations (Helmer et al., 2003; Larrieu et
al., 2004) are at a higher risk of developing a dementia in
subsequent years. In contrast, other longitudinal studies
(Luchsinger et al., 2003; Laurin et al., 2004; Dai et al., 2006;
Vercambre et al., 2009) did not find a significant association
between dietary intake of vitamin E and risk of AD.
Among the seven studies that examined the association
of vitamin C intake and risk of AD, only an earlier report
from the Rotterdam study found that high intake of vita-
min C was significantly associated with reduced risk of
AD (Engelhart et al., 2002a); other studies (Morris et al.,
2002; Luchsinger et al., 2003; Laurin et al., 2004; Corrada
et al., 2005; Dai et al., 2006; Vercambre et al., 2009) did
not find a significant association. Recently, an updated
report from the Rotterdam study again failed to confirm
the inverse association between dietary vitamin C intake
and risk of AD with a longer (nearly 10 years) follow-up
(Devore et al., 2010).
Use of vitamin E and vitamin C supplements have
also been investigated in a few studies, but the results
are inconsistent. Combined use of vitamin E and vita-
min C was associated with reduced prevalence and
incidence of AD in the Cache County Study (Zandi et
al., 2004), with reduced risk of vascular dementia and
better cognitive function but not AD in the Honolulu-
Asia Aging Study (HAAS) (Masaki et al., 2000). Nev-
ertheless, these two studies found no evidence of a
protective effect on AD prevention with use of vitamin
E or vitamin C supplements alone (Masaki et al., 2000;
Zandi et al., 2004). Furthermore, vitamin E and vitamin
C supplements were not associated with risk of AD in
two other studies (Morris et al., 1998, 2002; Luchsinger
et al., 2003). Finally, several clinical trials conducted to
date also found conflicting results on the association
between antioxidants and cognitive decline or AD pro-
gression. In a randomized trial of patients with moder-
ately severe impairment from AD, treatment with vita-
min E (alpha-tocopherol, 2000 IU a day) delayed onset of
death, institutionalization, loss of the ability to perform
basic activities of daily living, and severe dementia but
did not slow rates of cognitive deterioration (Sano et
al., 1997). However, beneficial effects of vitamin E were
lacking in later clinical trials with lower dosage com-
bined with other antioxidants, in either healthy older
adults (Yaffe et al., 2004; Kang et al., 2006) or subjects
with preexisting cardiovascular disease (CVD) or CVD
risk factors (Kang et al., 2009).
In the PAQUID cohort, higher intake of antioxidant fla-
vonoids was found to be associated with a reduced risk of
incident dementia (Commenges et al., 2000), with better
cognitive performance at baseline (Letenneur et al., 2007)
and with a better evolution of the performance over time
(Letenneur et al., 2007). Another large prospective study,
the Rotterdam study, found that flavonoids intake, with
or without subjects with supplement flavonoids use, was
not associated with a risk of AD (Engelhart et al., 2002a).
A short-term (6 month) double-blind, randomized, pla-
cebo-controlled clinical trial in postmenopausal women
found that isoflavone supplementation had a favorable
effect on cognitive function, particularly verbal memory
(Kritz-Silverstein et al., 2003).

β-carotene has been hypothesized to be associated with
reduced risk of AD due to its potent antioxidative func-
tion. However, none of the six well-established prospec-
tive studies found a signification association (Engelhart
et al., 2002a; Morris et al., 2002; Luchsinger et al., 2003;
Laurin et al., 2004; Dai et al., 2006; Vercambre et al., 2009).
The Physicians’ Health Study II (PHS-II), a randomized
trial of β-carotene and other vitamin supplements for
chronic disease prevention, found that mean global cog-
nitive z-score and verbal memory score were both signifi-
cantly better in the β-carotene treatment group than in the
placebo group after long-term (mean treatment duration
18 years) but not short-term (1 year) treatment (Grodstein
et al., 2007). Therefore, it seems there is a threshold, in
terms of either amount or duration, for carotene to have
beneficial effect for AD.
Fruits, vegetables, and fiber
Three observational studies found no association between
fruits intake and rates of cognitive decline (Kang et al.,
2005; Morris et al., 2006b; Vercambre et al., 2009). Higher
consumption of vegetables, on the other hand, has been
associated with slower decline of cognitive function
(Kang et al., 2005; Morris et al., 2006b) or less functional
impairment (Vercambre et al., 2009). With regard to inci-
dence of AD, the Three-City Study in France found that
the risk of all-cause dementia or AD was about 30% lower
in participants who regularly consumed fruits and veg-
etables (Barberger-Gateau et al., 2007). Finally, the Kame
Project found that fruit and vegetable juice consumption
was associated with lower risk of AD; this inverse associ-
ation tended to be more pronounced among those with an
Apolipoprotein E (ApoE) e-4 allele and those who were
not physically active (Dai et al., 2006).
B vitamins
Studies have shown that elevated circulating homocys-
teine temporally precedes the development of dementia
and that there is an inverse linear relationship between
plasma homocysteine concentrations and cognitive func-
tion in older persons (Seshadri, 2006). Homocysteine is
an amino acid that is involved in methionine metabolism
and is associated with dietary intake of folate and vita-
min B12. The Framingham Study found that deficiencies
in folate, vitamin B12, and pyridoxal-5′-phosphate were
primary determinants of homocysteinemia in the study
cohort (Selhub et al., 1993). Thus, it is conceivable that B
vitamins might also be associated with AD risk or cog-
nition. Several longitudinal studies have examined the
association between the dietary intake levels of B vita-
mins (vitamin B2, B6, vitamin B12, folate) and cognitive
function or the risk of AD.
In the Veterans Affairs Normative Aging (VANA) study,
declines in constructional praxis were significantly associ-
ated with plasma homocysteine, folate, and vitamins B6
Dietary Factors in Geriatric Neurology 649
and B12, as well as with the dietary intake of each vita-
min; dietary folate was also protective against a decline
in verbal fluency (Tucker et al., 2005). In the prospective
Chicago Health and Aging Project (CHAP) study, unex-
pectedly, high folate intake from food sources and/or
supplements was associated with a faster rate of cogni-
tive decline (Morris et al., 2005a), while intake of vitamin
B12, with or without vitamin supplementation, was not
significantly associated with cognitive change (Morris
et al., 2005a). Finally, the E3N study in France found that
the odds of functional impairment increased significantly
with decreasing intakes of vitamins B2, B6, and B12, but not
with intake of folate; none of the B vitamins was associ-
ated with cognitive decline (Vercambre et al., 2009).
Four well-established cohorts have examined the associ-
ation between dietary intake of B vitamins and risk of inci-
dent AD (Corrada et al., 2005; Morris et al., 2006a; Luchs-
inger et al., 2007; Nelson et al., 2009). Significant inverse
associations between folate intake (total or dietary) and
risk of AD were found in two studies (Corrada et al., 2005;
Luchsinger et al., 2007), and between vitamin B6 and risk
of AD in two studies (Corrada et al., 2005; Morris et al.,
2006a); none of the four studies found significant associa-
tion between vitamin B12 intake and risk of AD.
At least six randomized clinical trials have examined
the effect of vitamin B6 or B12 or folic acid supplementa-
tion, alone or in combination, on cognitive function in
subjects with either normal or impaired cognitive func-
tion. The Folic Acid and Carotid Intima-media Thick-
ness (FACIT) trial found that folic acid supplementation
(800 μg/day) for 3 years significantly improved memory,
information processing speed, and sensorimotor speed
in healthy elderly people in the Netherlands (Durga et
al., 2007). In contrast, none of the other studies found a
significant effect of vitamin B6 or B12 or folic acid supple-
mentation, alone or in combination, on cognitive decline
(Eussen et al., 2006; McMahon et al., 2006; Sun et al., 2007;
Aisen et al., 2008; Kang et al., 2008).
Fish and unsaturated fatty acids
Unsaturated fatty acids (UFAs) include polyunsaturated
fatty acids (PUFAs) and monounsaturated fatty acids
(MUFAs). Fish is a major dietary source of long-chain ω-3
(n-3) PUFAs, specifically eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA), which are critical for brain
structure and function (Salem et al., 2001). Foods that con-
tain the highest level of MUFA are nuts, olive oil, and oil
made from seeds and vegetables. Existing epidemiologic
data relating fish or UFAs to cognition or dementia risk
are somewhat mixed, however.
Only a few studies have investigated the relationship
between fish consumption and the intake of n-3 PUFA
and cognitive decline. Results of an early analysis of the
Zutphen Elderly Study found no clear inverse association
between fish, linoleic acid (an n-6 PUFA), EPA, or DHA
650 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
consumption and 3 year cognitive decline (Kalmijn et
al., 1997a), but with longer follow-up (5 years), a strong
inverse association between fish, EPA, or DHA consump-
tion and cognitive decline was observed (van Gelder et
al., 2007a). The CHAP showed that fish consumption but
not dietary intake of n-3 PUFA was associated with less
cognitive decline (Morris et al., 2005b). No significant
associations between fatty fish or n-3 PUFA intake and 6
year cognitive change was observed in the VANA study
(van de Rest et al., 2009). In the E3N study, higher fish
and total n-3 PUFA consumption were both associated
with lower odds of recent (over the past year) cognitive
decline measured 13 years later (Vercambre et al., 2009).
In the European Prospective Investigation into Cancer
and Nutrition (EPIC)–Greece cohort, intake of PUFA was
inversely associated with cognitive function. This asso-
ciation was largely accounted for by a similar association
with seed oils. Intake of olive oil, MUFA, and saturated
fatty acid (SFA) showed weak positive but not signifi-
cant associations with cognitive function (Psaltopoulou
et al., 2008). In the Italian Longitudinal Study on Aging
(ILSA), high MUFA, PUFA, and total energy intakes were
significantly associated with a better cognitive perfor-
mance after a median follow-up of 8.5 years (Solfrizzi et
al., 2006a). Additional findings from ILSA demonstrated
that although dietary fatty acids intakes were not associ-
ated with incident mild cognitive impairment (MCI), high
PUFA intake appeared to have borderline nonsignificant
trend for a protective effect against the development of
MCI (Solfrizzi et al., 2006b). The Three-City Study found
participants with intensive use of olive oil (used for both
cooking and dressing), a major source of MUFA, com-
pared to those who never used olive oil, showed lower
risk of cognitive decline for visual memory during the 4
year follow-up (Berr et al., 2009).
Some (Kalmijn et al., 1997b; Morris et al., 2003; Larrieu
et al., 2004; Huang et al., 2005; Barberger-Gateau et al.,
2007) but not all (Engelhart et al., 2002b; Schaefer et al.,
2006; Devore et al., 2009) large prospective studies found
that higher intakes of fish and DHA from dietary sources
were associated with a lower risk of dementia or AD. In
the Rotterdam study, fish intake was inversely associ-
ated with dementia over a 2 year follow-up (Kalmijn et
al., 1997b), but n-3 or n-6 PUFA intake (Engelhart et al.,
2002b) was not associated with dementia risk over a 6
year follow-up. Furthermore, a longer follow-up (9.6
years, on average) of the same cohort found that neither
total fish intake nor n-3 PUFAs (EPA and DHA) was asso-
ciated with dementia risk or AD risk (Devore et al., 2009).
In the Framingham Heart Study, fish intake was nonsig-
nificantly associated with reduced risk of incident demen-
tia, but plasma DHA levels were significantly associated
with reduced risk of all-cause dementia (Schaefer et al.,
2006). In the CHAP study, although EPA intake was not
associated with AD risk, weekly consumption of fish,
consumption of DHA, or consumption of total n-3 PUFA
was each associated with reduced risk of AD, and alpha-
linoleic acid (ALA, an n-6 PUFA) was associated with
reduced risk only in ApoE e4 noncarriers (Morris et al.,
2003). Participants of the PAQUID cohort who ate fish or
seafood at least once a week had a significantly reduced
risk of incident dementia (Larrieu et al., 2004). In the Car-
diovascular Health Cognition Study (CHCS) in the United
States, consumption of fatty fish more than two times per
week was significantly associated with reduced risk of
AD in comparison to those who ate fish less than once per
month—and the effect was selective for noncarriers of the
ApoE e4 allele (Huang et al., 2005)—while lean fried fish
or total fish intake was not associated with AD risk. In
the Three-City cohort study, weekly consumption of fish
was associated with a reduced risk of AD and all-cause
dementia, but again, only among ApoE e4 noncarriers.
Regular use of oils rich in n-3 was marginally associated
with a decreased risk of all-cause dementia, while regu-
lar consumption of oils rich in n-6 was associated with
an increased risk of dementia among ApoE e4 noncarri-
ers (Barberger-Gateau et al., 2007). In the Zutphen Elderly
Study, fish, EPA, or DHA consumption was not associ-
ated with risk of incident cognitive impairment, but an
increased risk was found for linoleic acid (an n-6 PUFA)
(Kalmijn et al., 1997a).
Current evidence from clinical trials does not support
a beneficial effect of n-3 PUFA (especially EPA+DHA)
supplementation on cognitive function. In a random-
ized clinical trial with 302 Dutch cognitively healthy sub-
jects age ≥65  years, there were no significant differential
changes in any of the cognitive domains for either low-dose
(400 mg/d) or high-dose (1800 mg/d) EPA+DHA supple-
mentation, compared with placebo (van de Rest et al., 2008).
In addition, intake of 1500 mg/day EPA+DHA for 3 months
was found not to have beneficial effect on cognitive func-
tion in another study with 218 mildly-to-moderately
depressed individuals (Rogers et al., 2008). Similarly, no
beneficial effect of 2 year 200 mg/day EPA + 500 mg/day
DHA supplementation on cognition was found in a recent
study of 867 cognitively healthy adults (Dangour et al.,
2010). In another study, however, compared to subjects
in the control arm, subjects receiving 800 mg/day DHA,
12  mg/day lutein, or combined supplementation of both
had improved cognitive function, including verbal fluency,
memory, and rate of learning (Johnson et al., 2008). How-
ever, these findings need to be confirmed because the study
was small (49 subjects) and follow-up was short (4 months)
(Johnson et al., 2008). In the OmegAD study, another ran-
domized, double-blind clinical trial, 6 months’ administra-
tion of 1.7 g/day of DHA and 0.6 g/day of EPA in patients
with mild-to-moderate AD did not delay the rate of cogni-
tive decline (Freund-Levi et al., 2006). However, beneficial
effects were observed in a small group of patients with very
mild AD (Freund-Levi et al., 2006).

Alcohol
To date, alcohol drinking is one of the mostly investi-
gated dietary factors with regard to their associations
with dementia. While a few studies did not find any asso-
ciation between alcohol intake and AD risk or cognitive
change (Broe et al., 1998; Yip et al., 2006; Peters et al., 2009;
Vercambre et al., 2009), the vast majority of observational
investigations have reported a protective association.
In the Hisayama Study in Japan, researchers found
alcohol intake was associated with increased risk of over-
all dementia and vascular dementia, but not with risk of
AD (Yoshitake et al., 1995). However, in this study, alcohol
consumption was dichotomized into “yes” and “no,” and
no detailed information was collected for further analy-
sis of dose–response relationship (Yoshitake et al., 1995).
Later, the PAQUID study found that moderate drinkers
(three or four glasses of wine daily) had a decreased risk
of developing dementia or AD compared to nondrinkers,
while subjects with alcohol intake more than moderate
did not seem to have reduced risk compared to nondrink-
ers (Orgogozo et al., 1997). Furthermore, in the Kungshol-
men Project, light to moderate alcohol consumption
(1–21 drinks per week in men, 1–14 drinks per week in
women) was associated with a 50% decrease in incidence
of dementia or AD (Huang et al., 2002). In general, moder-
ate alcohol consumption (compared to nondrinking), has
been repeatedly confirmed to be associated with reduced
risk of dementia or AD in many cohorts, including the
Copenhagen City Heart Study (monthly and weekly
consumption of wine) (Truelsen et al., 2002), the CHCS
(one–six drinks weekly of alcohol) (Mukamal et al., 2003),
the Washington/Hamilton Heights–Inwood Columbia
Aging Project (WHICAP) (>0 and ≤4 servings per day of
wine) (Luchsinger et al., 2004), and a Chinese cohort (1–21
drinks per week in men, 1–14 drinks per week in women
of total alcohol or wine) (Deng et al., 2006).
In addition, the Cardiovascular Risk Factors Aging and
Dementia (CAIDE) study found that participants who
drank no alcohol and those who drank alcohol frequently
(several times a month) at midlife were both twice as likely
to have MCI in old age as participants who drank alco-
hol infrequently (less than once a month) (Anttila et al.,
2004). The Rotterdam study did not find a significant asso-
ciation between alcohol drinking and AD, but the study
found mild-to-moderate alcohol drinking (one to three
drinks a day) was associated with a decreased risk of any
dementia or vascular dementia (Ruitenberg et al., 2002). In
these studies, more than moderate alcohol consumption
in general was found to be either not associated or posi-
tively associated with increased risk of AD, suggesting a
U-shape relationship between alcohol intake and AD risk.
Interestingly, several studies found that the potential
beneficial effect of alcohol consumption may be mostly
due to wine consumption. For example, both the PAQUID
study (Orgogozo et al., 1997) and the Three-City cohort
Dietary Factors in Geriatric Neurology 651
study (Barberger-Gateau et al., 2007) found a reduced risk
of AD associated with moderate intake of wine, while beer
and liquor were not investigated. The Copenhagen City
Heart Study (Truelsen et al., 2002) and the Chinese study
(Deng et al., 2006) found moderate intake of wine asso-
ciated with decreased risk of AD, while monthly intake
beer or spirits increased AD risk. The Canadian Study of
Health and Aging (CSHA) study (Lindsay et al., 2002) and
the WHICAP study (Luchsinger et al., 2004) found mod-
erate intake of wine protective, while beer, spirits, and
other types of alcohol were not associated with AD risk.
The Rotterdam study was the only study that did not sug-
gest a different effect of specific types of alcoholic bever-
ages beyond the effect of alcohol itself (Ruitenberg et al.,
2002). In the Kame project, wine intake (at least once per
week) was associated with a nonsignificant reduced risk
of AD (Dai et al., 2006).
Coffee, tea, and caffeine
Five longitudinal studies have investigated the relation-
ship between coffee, tea, or caffeine consumption and
dementia/AD or cognitive decline (Lindsay et al., 2002;
Laurin et al., 2004; van Gelder et al., 2007b; Ritchie et al.,
2007; Eskelinen et al., 2009). In the CSHA study, daily
coffee drinking decreased the risk of AD by 31% during
a 5 year follow-up (Lindsay et al., 2002). The Finland,
Italy, and Netherlands Elderly (FINE) study also found
that drinking more than three cups of coffee per day was
associated with the least 10-year cognitive decline among
elderly men (van Gelder et al., 2007b). Furthermore,
results from the Three-City Study indicated that ≥3 cups/
day of caffeine (from coffee and tea) were associated with
less decline in verbal cognitive functioning and, to a lesser
extent, in visuospatial memory among women, but not
among men (Ritchie et al., 2007). Caffeine consumption
did not reduce dementia risk over a 4 year period in the
same study (Ritchie et al., 2007). Recently, the CAIDE
study reported that coffee drinkers at midlife had the
lower risk of dementia and AD later in life, compared
with those who drank no coffee or only little coffee; the
lowest risk (65% decreased) was observed in people who
drank three to five cups per day (Eskelinen et al., 2009). In
contrast, tea drinking (Lindsay et al., 2002; Dai et al., 2006;
Eskelinen et al., 2009), or flavonoid intake from tea (Lau-
rin et al., 2004), has not been associated with a reduced
risk of dementia/AD in longitudinal studies.
Dietary patterns
In addition to the studies on single nutrients and foods
reviewed earlier, there has been growing interest in
assessing the relationship of diseases with dietary pat-
terns, because people eat combinations of foods/nutri-
ents that are likely to be synergistic (or antagonistic).
One dietary pattern that has attracted increasing interest
is the Mediterranean diet (MeDi). The MeDi is characterized
652 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
by high intake of vegetables, fruits, nuts, legumes, cere-
als, and fish; high intake of UFAs (mostly in the form of
olive oil in salad dressing and cooking) and low intake of
SFA; low to moderate intake of wine; and low intake of red
meat and poultry (Roman et al., 2008). The MeDi seems to
encapsulate many of the components reported in literature
as potentially beneficial for various diseases (Sofi et al.,
2008; Babio et al., 2009). Therefore, it is conceivable that a
MeDi may also be associated with reduced risk for neuro-
logic disorders. Based on analyses among more than 2000
participants of WHICAP (Scarmeas et al., 2006), subjects
with higher adherence to MeDi at baseline had a lower risk
of incident AD over an average follow-up period of 4 years,
even after adjustment for potential confounders (Scarmeas
et al., 2006). The association between MeDi and risk of inci-
dent AD was independent of physical activity (Scarmeas
et al., 2009a). In the same cohort, higher adherence to the
MeDi was also associated with a trend for reduced risk of
developing incident MCI and reduced risk of MCI conver-
sion to AD (Scarmeas et al., 2009b). The role of MeDi was
further investigated in the Three-City cohort study, which
demonstrated that better adherence to the MeDi was asso-
ciated with slower rates of cognitive decline (Feart et al.,
2009). No associations with incident dementia or AD were
noted in this study (Feart et al., 2009), but power to detect
such associations was extremely limited. In addition, no
association between MeDi adherence and risk of MCI was
found in the Mayo Clinic Study of Aging study after a short
(median of 2.2 years) follow-up (Roberts et al., 2010), and
baseline adherence to a MeDi was not associated with cog-
nitive function 6–13 years later in the EPIC–Greece cohort
(Psaltopoulou et al., 2008).
A recent report from the WHICAP further supports
the beneficial role of a MeDi-like dietary pattern (Gu et
al.,2010). In this study, 33 food groups were combined in
search for the existence of dietary patterns that can explain
variation in seven AD-related (based on previous litera-
ture) nutrients using reduced rank regression analysis.
The study identified a dietary pattern that was positively
correlated with n-3 PUFA, n-6 PUFA, folate, and vitamin
E, and negatively correlated with SFA and vitamin B12
intakes. The dietary pattern was characterized by higher
intakes of oil and vinegar-based salad dressing, nuts, fish,
tomatoes, poultry, cruciferous vegetables, fruits, and dark
and green leafy vegetables; and a lower intake of high-
fat dairy products, meat, and butter, thus resembling the
MeDi, to some extent. This dietary pattern was strongly
associated with lower incident AD risk (Gu et al., 2010).
Other dietary patterns have also been explored. The
Recommended Food Score (RFS) (Kant et al., 2000) is a
measure of dietary diversity by summing the number
of foods recommended by current Dietary Guidelines
for Americans (Ritchie et al., 2007). In the Cache County
Study on Memory and Aging in Utah (Wengreen et al.,
2009), compared with participants who had lower RFS
score, participants who had a higher RFS score (indicat-
ing consumption of more recommended foods, including
fruits, vegetables, whole grains, nuts, fish, and low-fat
dairy products) had higher cognitive function at baseline
and experienced less cognitive decline over 11 years of
follow-up (Wengreen et al., 2009).
In another report from the Three-City cohort, partici-
pants consuming diets high in fruits, vegetables, fish,
and n-3 fatty acids had decreased incidence of all-cause
dementia and AD compared with those with diets low in
these foods and nutrients (Barberger-Gateau et al., 2007).
Only one clinical trial investigated dietary patterns in
relation to cognition or AD risk. The Dietary Approaches
to Stop Hypertension (DASH) diet is characterized as rich
in fruits, vegetables, and low-fat dairy foods and having
reduced amounts of saturated fat, total fat, and cholesterol
(Appel et al., 1997). In a recent randomized clinical trial of
124 participants with elevated blood pressure who were
sedentary and overweight or obese, subjects on either the
DASH diet plus weight management arm or the DASH diet
alone arm exhibited greater neurocognitive improvements,
compared with subjects on the usual diet (Smith et al., 2010).
Summary
Overall, some evidence from observational studies shows
an inverse association between higher fish or n-3 PUFA
consumption and slower cognitive decline or reduced
risk of AD. Higher intake of folate, vitamin B6, or vita-
min B12 has been associated with a slower cognitive
decline or a reduced risk of AD in some but not all obser-
vational studies. In addition, consistent observational
epidemiologic evidence indicates that moderate alcohol
consumption (particularly wine consumption) and cof-
fee or caffeine consumption (but not tea consumption)
are inversely associated with the incidence of AD or with
cognitive decline. Finally, as for antioxidants (vitamin E
or C, carotenes, or flavonoids) either from dietary or sup-
plement sources, there is little or conflicting evidence that
they play an important role in preventing or treating AD
and cognitive decline.
Observational studies also found several beneficial
dietary patterns (including the MeDi, RFS score, and oth-
ers) that might be related to lower risk of cognition decline
or AD. Of interest, fruits, vegetables, fish, nuts, and n-3
PUFA have been consistently included in these dietary
patterns as beneficial components, while meat and SFA
have been considered detrimental components in some of
the examined dietary patterns.
The current evidence from intervention studies does not
suggest a protective role of n-3 PUFA or B vitamins sup-
plementation. Clinical trials conducted to date also found
conflicting results on the association between antioxidants
and cognitive decline or AD progression. No randomized
trials have studied the effects of alcohol or coffee con-
sumption on cognitive function or dementia risk. The only

intervention trial of dietary pattern suggests some benefits
on preventing cognitive decline among subjects assigned
to the DASH diet, alone or with weight management.
Dietary factors in relation to
Parkinson’s Disease
Similar to AD, case series and cohort studies suggest a
protective effect of dietary intervention on PD symptoms,
but confirmatory testing with randomized controlled
clinical trials failed to show a robust treatment effect.
Antioxidants
Several antioxidants, including vitamin E (tocopherol),
vitamin C (ascorbic acid), vitamin A, provitamins of vita-
min A (α-carotene, β-carotene, β-cryptoxanthin), lyco-
pene, lutein, and zeaxanthin, have been studied regard-
ing their association with PD risk.
In a case-control study nested within HAAS, midlife
consumption of legumes, which had high vitamin E con-
tent, was associated with reduced risk of PD (Morens et
al., 1996). Other preselected foods high in vitamin E (veg-
etable oils and animal fats) and total vitamin E consump-
tion were not associated with risk of PD (Morens et al.,
1996). In another nested case-control study based on the
Leisure World Laguna Hills (LWLH) cohort in California,
a borderline increased risk for PD was reported among
individuals in the highest tertile of dietary vitamin C
intake and total vitamin A intake, but the association was
no longer significant after controlling for other factors
(Paganini-Hill, 2001). In the Health Professionals Follow-
Up Study (HPFS) and the Nurses’ Health Study (NHS)
cohorts, the association between various antioxidants and
risk of incident PD was evaluated (Zhang et al., 2002).
Compared to individuals in the lowest intake, those in
the highest dietary intake of vitamin E had a significantly
reduced risk of PD (particularly for women) (Zhang et al.,
2002). Those in the highest quintile of dietary vitamin C
intake (compared to the lowest quintile) had marginally
decreased risk of PD (Zhang et al., 2002). Intakes of dietary
α-carotene, β-carotene, β-cryptoxanthin, lycopene, and
lutein/zeaxanthin; total vitamin E; total vitamin C; or use
of vitamin E or vitamin C supplements or multivitamins
was not significantly associated with risk of PD (Zhang et
al., 2002). In the Singapore Chinese Health Study (SCHS),
higher dietary vitamin E intake was found to be associ-
ated with reduced risk of PD, while dietary carotenoids,
vitamin A, or vitamin C was not associated with PD risk
(Tan et al., 2008).
This landmark Deprenyl and Tocopherol Antioxidative
Therapy of Parkinsonism (DATATOP) study, a large, pro-
spective, randomized, double-blind, placebo-controlled
trial (The Parkinson Study Group, 1993), examined the
effects of deprenyl (a monoamine oxidase inhibitor)
Dietary Factors in Geriatric Neurology 653
10  mg/day and α-tocopherol (vitamin E) 2000 IU/day
alone and in combination on 800 untreated patients in
early stages of PD, for an average standard deviation
(SD) of 14 (6) months. The primary endpoint was pro-
gression to initiation of levodopa therapy. Tocopherol
supplementation was not found to reduce the probability
of requiring levodopa therapy, alone or in combination
with deprenyl, compared with placebo (The Parkinson
Study Group, 1993).
Fruits and vegetables
The only prospective study that investigated the associa-
tion between dietary intake of fruits or vegetables and PD
risk, using data from the NHS and HPFS cohorts, sug-
gested that fruits or vegetables were not associated with
risk of PD in either men or women (Chen et al., 2002).
B vitamins
In the Rotterdam Study, higher dietary intake of vita-
min B6 was found to be associated with a significantly
decreased risk of PD, which might be restricted to smok-
ers as found in stratified analyses (de Lau et al., 2006). No
association with PD was observed for dietary folate and
vitamin B12 in this study (de Lau et al., 2006). The study
including both the HPFS and the NHS populations found
that neither folate, vitamin B6, nor vitamin B12 intakes
were associated with risk for PD (Chen et al., 2004).
Dietary fat
At least four prospective studies have investigated the
associations between fat intakes (measured as total, ani-
mal fat, vegetable oil, dairy fat, SFA, MUFA, PUFA, and
trans-fat) and PD risk. In a case-control study nested in
Honolulu Heart Program (HHP) cohort, PD occurrence
was not associated with the intake of either vegetable oil
or animal fat (Morens et al., 1996). In the pooled analy-
sis of the HPFS and the NHS cohorts, total fat intake was
not associated with PD risk. No associations were found
for any major types of fat, including vegetable oil, MUFA,
PUFA, trans-unsaturated fat or cholesterol. Among indi-
vidual fatty acids of the PUFA, only arachidonic acid,
an n-6 PUFA, tended to be inversely associated with PD
risk, while none of the other specific fatty acids (linoleic
acid, α-linolenic acid, fish n-3 fatty acid, EPA, and DHA)
was significantly associated with risk of PD (Chen et al.,
2003). In the Rotterdam Study (de Lau et al., 2005), intakes
of total fat, MUFA, and PUFA were significantly associ-
ated with a lower risk of PD, while no associations were
found for dietary SFA, cholesterol, or trans-fat (de Lau et
al., 2005). In the SCHS, only MUFA was found to be mar-
ginally associated with reduced risk of PD; there was no
association between PD risk and total fat, SFA, PUFA, n-3
PUFA, or n-6 PUFA (Tan et al., 2008).
Finally, in a randomized, double-blind, placebo-
controlled clinical trial among PD patients, participants
654 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
taking fish oil (containing n-3 PUFA), with or without
antidepressants, had improvements in their depressive
symptoms, suggesting a possible role of n-3 PUFA in
treatment of mood symptoms in PD (da Silva et al., 2008).
Dairy
The first investigation of the associations between dairy
intakes and PD risk was carried out in a combined analy-
sis of the HPFS and the NHS cohorts (Chen et al., 2002).
In this study, a positive association was found between
dairy intake and PD risk in men, but not in women. Fur-
ther analyses among men showed significant positive
associations with PD risk for intakes of several dairy
foods, including cheese and sour cream, as well as dairy
nutrients, including dairy source of calcium, vitamin D,
protein, and lactose, but not dairy fat (Chen et al., 2002).
In a second prospective study of Japanese American
participants in the HAAS cohort, men who consumed >16
oz/day of milk at midlife had a 2.3-fold excess of PD than
men who did not drink milk, after adjusting for dietary
and other factors. The effect of milk consumption on PD
was also independent of the intake of calcium. Calcium
from dairy and nondairy sources was not associated with
PD risk in this study (Park et al., 2005).
The most recent study of the American Cancer Soci-
ety’s Cancer Prevention Study II Nutrition Cohort (CPS-II)
found that, among men and women combined, dairy prod-
uct consumption was positively associated with risk of PD.
A higher risk among dairy product consumers was found
for both men and women, although the association in
women appeared nonlinear (Chen et al., 2007). In nutrient
analyses, dairy source of calcium, vitamin D, protein, and
fat was not associated with a higher risk of PD, although
total intake from all sources of calcium and protein was
associated with increased risk of PD (Chen et al., 2007).
Alcohol
To date, there have been at least two prospective inves-
tigations (Paganini-Hill, 2001; Hernan et al., 2003) of the
association between alcohol consumption and risk of PD.
A nested case-control study based on the LWLH cohort
found that consuming two or more drinks per day reduced
risk for PD (Paganini-Hill, 2001). However, in a pooled
analysis of HPFS and NHS (Hernan et al., 2003), the risk of
PD was similar in individuals who usually consume mod-
erate amounts of alcohol and in nondrinkers/abstainers.
Among three common types of alcoholic beverage (beer,
wine, and liquor), beer seems to be more consistently asso-
ciated with decreased risk of PD than wine and liquor. In
the California study (Paganini-Hill, 2001), the odds ratio
(OR) of PD comparing drinkers (≥2 drinks/day) with non-
drinkers was much lower for beer drinkers than for wine
or hard liquor drinkers, although none of the associations
was significant. In the pooled analysis of HPFS and NHS
cohorts (Hernan et al., 2003), beer drinkers (≥1 drink/
week) had a 30% lower incidence of PD than those who
consumed beer <1 drink/month; consumption of wine or
liquor was not associated with the incidence of PD. There-
fore, it is possible that some components of beer, other
than the common ethanol among all alcoholic beverages,
may be associated with reduced risk of PD. For example,
serum antioxidative and neuroprotective uric acid, which
has been seen to increase more after beer consumption
than after wine or liquor consumption, may contribute to
the association between beer and PD (Collins, 2002).
Coffee, tea, and caffeine
The associations between frequency of coffee intake, fre-
quency of tea intake, or amount of total dietary caffeine
intake and risk of PD have been evaluated in several pro-
spective studies.
In the HHP, age-adjusted incidence of PD declined con-
sistently with increased amounts of coffee intake, from
10.4 per 10,000 person-years in men who drank no coffee
to 1.9 per 10,000 person-years in men who drank at least
28 oz/day. Similar relationships were observed for total
caffeine intake and for caffeine from noncoffee sources.
Other nutrients in coffee, including niacin, were unre-
lated to PD incidence (Ross et al., 2000).
In a case-control study nested within the LWLH cohort,
intake of ≥2 cups/day of regular coffee was associated
with reduced risk of PD compared with nondrinkers,
while decaffeinated coffee or tea drink was not associated
with PD risk (Paganini-Hill, 2001).
Similarly, in the HPFS cohort, an inverse association was
observed for consumption of coffee, total caffeine, caffeine
from noncoffee sources, and tea, but not decaffeinated
coffee (Ascherio et al., 2001). Among women participants
of NHS, the relationship between caffeine or coffee intake
and risk of PD was U-shaped, with the lowest risk observed
at moderate intakes (1–3 cups of coffee per day, or the third
quintile of caffeine consumption) (Ascherio et al., 2001).
The protective effect of coffee and tea is further sup-
ported in two large prospective studies in Finland, which
found reduced risk of PD for subjects with more coffee
drinking (Hu et al., 2007; Saaksjarvi et al., 2008) or more
tea drinking (Hu et al., 2007), compared to nondrinkers.
In SCHS, total caffeine intake was inversely related to
PD risk. After adjusting for total caffeine intake, smoking,
and other covariates, black tea, but not coffee or green tea,
was found to be associated with reduced PD risk, sug-
gesting that ingredients of black tea other than caffeine
might be responsible for this beverage’s protective effect
against PD (Tan et al., 2008).
Coenzyme Q10
Coenzyme Q10 (CoQ10) is an intrinsic component of the
mitochondrial respiratory chain. In a double-blind, pla-
cebo-controlled pilot study, 80 patients with early stage
PD were randomized to receive placebo or 300, 600, or

1200 mg/day of oral CoQ10 (Shults et al., 2002, 2004). The
study found that high doses of oral CoQ10 (1200 mg/
day) were associated with a reduced rate of deterioration
in motor function and an improved daily living activ-
ity scores from baseline over the 16-month course of the
trial. In another smaller, placebo-controlled, randomized,
double-blind trial of oral CoQ10 360 mg/day for 4 weeks,
28 treated and stable PD patients showed a statistically sig-
nificant mild symptomatic benefit in their PD symptoms
(Muller et al., 2003), but motor symptoms did not improve.
In a recent clinical trial of 131 midstage PD patients, intake
of CoQ10 (300 mg/day for 3 months) did not improve PD
symptoms (Storch et al., 2007). Nevertheless, the Hoehn
and Yahr scale scores, one of the six secondary clinical out-
come variables, improved significantly in the CoQ10 group
but not in the placebo group, with a significant difference
between groups. Analysis according to the stratification
revealed significant changes only in the levodopa stratum
of the CoQ10 group (Storch et al., 2007). Despite these con-
flicting data, a recent futility study, a Phase II clinical trial
designed to determine whether it is worthwhile to evaluate
the possible disease-modifying effects of an agent in future
Phase III trials, suggested that CoQ10 could not be rejected
as futile and, therefore, met the criteria for possible further
clinical testing (NINDS NET-PD Investigators, 2007).
Other foods
The only prospective study that investigated the associa-
tion between meat products and PD risk, the NHS and
HPFS cohorts, reported that there was no statistically sig-
nificant association between meat, fish, or poultry intake
and risk of PD (Chen et al., 2002).
The combined analysis of HPFS and NHS cohorts
reported that consumption of nuts was significantly asso-
ciated with a reduced risk of PD (Zhang et al., 2002).
Dietary patterns
Several dietary patterns have been evaluated in rela-
tion to the risk of PD in the HPFS and NHS cohorts. A
principal components analysis (PCA)-derived “pru-
dent” dietary pattern (characterized by high intakes of
fruit, vegetables, and fish) was inversely associated with
PD risk, and a PCA-derived “Western” dietary pattern
(characterized by high intakes of red meats, processed
meats, refined grains, French fries, desserts and sweets,
and high-fat dairy products) was not significantly asso-
ciated with PD risk. Two additional dietary scores were
calculated. The Alternate Healthy Eating Index (AHEI)
included nine components, including vegetables, fruit,
nuts and soy, ratio of white to red meat, cereal fiber, lower
trans-fats, ratio of polyunsaturated to saturated fat, long-
term multivitamin use, and alcohol (0.5–1.5 servings/
day contributes most to the total score), with a higher
score suggesting a higher dietary quality. The second
one, the alternate Mediterranean Diet Score (aMed), was
Dietary Factors in Geriatric Neurology 655
based on intake of nine items: vegetables (without potato
products), legumes, fruit, nuts, whole grains, fish, ratio
of MUFA to SFA, alcohol, and red and processed meat. A
higher aMed score suggested a higher dietary quality. The
study found a significantly reduced risk of PD associated
with AHEI and a borderline reduced risk of PD associated
with aMed. No interventional studies of dietary patterns
have been performed.
Summary
Overall, some evidence from observational studies indi-
cates an inverse association between alcohol (particularly
beer), caffeine or caffeinated beverages consumption, and
PD risk, and a positive association between dairy con-
sumption and risk of PD. However, data from clinical tri-
als are lacking.
Observational evidence in general suggests that dietary
vitamin E intake might be associated with reduced risk
of PD, while findings of the association between dietary
vitamin C intake and risk of PD are conflicting. However,
vitamin E has been found to be ineffective regarding PD
progression in a clinical trial.
The current research on B vitamins is largely inad-
equate to confidently support the hypothesis that higher
dietary intake of B vitamins could reduce the risk of
developing PD.
Observational studies suggest limited evidence to sup-
port an association between fats intake and PD risk, with
some exceptions that have reported possible beneficial
associations with UFA. A pilot intervention study showed
some benefits of n-3 PUFA for improvements in depres-
sive symptoms among PD patients.
Overall, minor benefits of uncertain clinical significance
for patients with PD have been observed with high doses of
CoQ10 in clinical trials. Whether CoQ10 is associated with
risk for developing PD has not been adequately explored.
The NHS and HPFS cohorts are the only studies to
investigate meat products, fruits, vegetables, and various
dietary patterns in relation to PD risk. PD risk was not asso-
ciated with meat products, fruits, or vegetables consump-
tion. Dietary patterns, including a PCA-derived “prudent”
dietary pattern (high intakes of fruit, vegetables, and fish),
AHEI, and aMeD, are associated with reduced PD risk. No
clinical trials in relation to PD on these foods or dietary
patterns have been conducted to date.
Stroke
Dietary interventions in stroke patients reported ben-
efit in case series and cohort studies, but confirmatory
testing with randomized controlled clinical trials using
individual agents failed to show benefit. Secondary and
subgroup analyses suggest combining multiple dietary
factors may augment their effect.
656 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
Antioxidants
Vitamin C (ascorbic acid)
Most of the earlier studies worldwide reported that vita-
min C intake was not related to the risk for stroke or
mortality for stroke, including a study in Gothenburg,
Sweden (Lapidus et al., 1986); the Zutphen Study in the
Netherlands (Keli et al., 1996); the Chicago Western Elec-
tric Study (Daviglus et al., 1997); a prospective study of
middle-aged men in Shanghai, China (Ross et al., 1997);
and the HPFS (Ascherio et al., 1999).
The first hint of a potential protective role of dietary
vitamin C came from a small (99 cases) Norwegian study,
which showed that intake of vitamin C was inversely
related to the risk for hemorrhagic stroke but not ischemic
stroke (Vollset and Bjelke, 1983). A much larger British
study of 730 elderly (aged ≥65 years), community-dwelling
subjects reported that both vitamin C dietary intake and
plasma concentrations of vitamin C had a strong inverse
correlation with the 20 year risk of death from stroke (Gale
et al., 1995). The Alpha-Tocopherol, Beta-Carotene Cancer
Prevention (ATBC) study in Finland showed that vitamin
C intake was inversely associated with risk for intracere-
bral hemorrhage, but not cerebral infarction or subarach-
noid hemorrhage (Hirvonen et al., 2000). In the Iowa
Women’s Health Study (IWHS), overall vitamin C intake
was associated with reduced risk for death from stroke,
although the association appeared somewhat U-shaped
(Yochum et al., 2000). More recently, the Rotterdam Study
found that higher intake of vitamin C was associated
with a lower risk of first-ever ischemic stroke (Voko et al.,
2003). This study also found that the beneficiary effect was
mainly confined to smokers (Voko et al., 2003).
Results are much more consistent for studies examin-
ing the association between circulating (plasma or serum)
vitamin C and risk of stroke. Strong inverse associations
have been observed between serum/plasma vitamin
C concentration and risk for stroke or mortality of total
stroke (Gey et al., 1993; Hensrud et al., 1994; Gale et al.,
1995; Yokoyama et al., 2000; Kurl et al., 2002; Myint et al.,
2008), ischemic stroke (Yokoyama et al., 2000; Kurl et al.,
2002), and hemorrhagic stroke (Yokoyama et al., 2000;
Kurl et al., 2002).
These studies have led to some clinical trials of vitamin
C supplementation in the prevention of stroke. The data
from the PHS-II (Sesso et al., 2008), however, showed no
significant effect of vitamin C (500 mg of vitamin C daily)
on the prevention of total stroke in middle-aged and older
men (Sesso et al., 2008).
Vitamin E
The IWHS found an inverse association between dietary
vitamin E intake and death from stroke, but not the
risk of incident stroke (Yochum et al., 2000). The Rotter-
dam Study found that higher intake of vitamin E was
associated with a lower risk of first-ever ischemic stroke,
but the reduced risk was limited to smokers only (Voko
et al., 2003). Four other studies, including the Zutphen
Study in the Netherlands (Keli et al., 1996); a prospective
study of middle-aged men in Shanghai, China (Ross et
al., 1997); the HPFS study (Ascherio et al., 1999); and the
ATBC study (Hirvonen et al., 2000), did not find an asso-
ciation between dietary intake of vitamin E and risk of
either stroke or stroke mortality.
The ATBC study (Leppala et al., 1999b) found that
baseline high serum α-tocopherol (the most active form
of vitamin E) was associated with decreased risk of intra-
cerebral hemorrhage by half and of cerebral infarction by
one third. No significant association was found between
plasma α-tocopherol and stroke incidence in a case-con-
trol study nested within the Physician Health Study (Hak
et al., 2004).
Several randomized clinical trials of vitamin E supple-
mentation have been conducted with regard to its effect
on stroke. In the ATBC study, vitamin E supplementa-
tion increased the risk of subarachnoid hemorrhage and
decreased risk of cerebral infarction in hypertensive men,
but had no effect among normotensive men (Leppala
et al., 2000a, 2000b). The PHS-II randomized controlled
trial found that 400 IU of vitamin E every other day was
not associated with total stroke, but was associated with
an increased risk of hemorrhagic stroke (consistent with
the ATBC study) (Sesso et al., 2008). A daily dose of nat-
ural-source vitamin E in the Heart Outcomes Prevention
Evaluation (HOPE) trial showed no protective effect for
stroke prevention (Yusuf et al., 2000; Lonn et al., 2005). The
Heart Protection Study Collaborative Group reported that
vitamin E supplementation did not produce any signifi-
cant reductions in the 5 year mortality from, or incidence
of, any strokes of any particular type or severity (Heart
Protection Study Collaborative Group, 2002). Similarly,
the Women’s Health Study did not find 600 IU of natural-
source vitamin E on alternate days effective for preventing
stroke (Lee et al., 2005). Results from the Women’s Antioxi-
dant Cardiovascular Study showed there were no overall
effects of ascorbic acid, vitamin E, or β-carotene on cardio-
vascular events among women at high risk for CVD, but
those randomized to both active ascorbic acid and vitamin
E experienced fewer strokes (Cook et al., 2007).
Other antioxidants: β-carotene (Pro-Vitamin A),
flavonoid, and catechins
Observational studies on the association between various
antioxidants and stroke have produced mixed findings.
The Zutphen Study found that dietary flavonoids (mainly
quercetin) and β-carotene were inversely associated with
stroke incidence (Keli et al., 1996). The ATBC study found
that dietary intake of β-carotene was associated with
reduced risk for cerebral infarction, lutein plus zeaxan-
thin with reduced risk for subarachnoid hemorrhage, and

lycopene with reduced risks of cerebral infarction and
intracerebral hemorrhage (Hirvonen et al., 2000). Find-
ings from the Kuopio Ischaemic Heart Disease Risk Fac-
tor Study (Mursu et al., 2008) suggest that high intakes of
flavonoids may be associated with decreased risk of isch-
emic stroke. In the HPFS, an inverse relationship between
lutein intake and risk for ischemic stroke was seen but
was not independent of other dietary factors (Ascherio
et al., 1999). Other studies did not find significant asso-
ciations between these antioxidants (carotenes, flavonoid,
and catechins) and stroke risk (Yochum et al., 1999, 2000;
Hirvonen et al., 2000; Knekt et al., 2000; Arts et al., 2001;
Sesso et al., 2003; Voko et al., 2003; Marniemi et al., 2005;
Mink et al., 2007).
Fruits and vegetables
Many observational studies (Gillman et al., 1995; Joshi-
pura et al., 1999; Liu et al., 2000a; Bazzano et al., 2002b;
Johnsen et al., 2003; Sauvaget et al., 2003a; Hak et al., 2004;
Larsson et al., 2009; Mizrahi et al., 2009), with the excep-
tion of the Atherosclerosis Risk in Communities (ARIC)
study (Steffen et al., 2003), showed that subjects with the
highest intake of fruit and vegetable had a lower inci-
dence of stroke and a reduced mortality from stroke. All
categories of fruit and vegetables may play a protective
role on ischemic stroke risk, particularly cruciferous green
leafy vegetables and citrus fruit and juice (Gillman et al.,
1995; Mizrahi et al., 2009).
Fish and unsaturated fatty acids
Cumulative data suggest that a high intake of n-3 fatty
acids may be cardioprotective. Thus, fish and seafood, as
the main sources of n-3 fatty acids, and their relationship
with stroke risk have been evaluated in a number of pro-
spective studies.
An early meta-analysis of nine independent cohorts
(from eight studies) (Keli et al., 1994; Morris et al., 1995;
Gillum et al., 1996; Orencia et al., 1996; Iso et al., 2001;
Yuan et al., 2001; He et al., 2002; Sauvaget et al., 2003b)
concluded that fish consumption might be inversely asso-
ciated with risk of stroke, particularly ischemic stroke (He
et al., 2004b). The Large-scale Census-based Cohort Study
in Japan, which was not included in the meta-analysis,
also found an inverse association between fish intake and
risk of mortality from hemorrhagic stroke (Kinjo et al.,
1999). Conflicting results, however, have been shown in
later studies. Some studies confirmed that fish or UFAs
intake was associated with reduced risk of stroke (Laak-
sonen et al., 2005; Mozaffarian et al., 2005), while a few
other studies did not show a beneficial effect of fish (Keli
et al., 1994; Morris et al., 1995; Orencia et al., 1996; Yuan
et al., 2001; Folsom and Demissie, 2004; Nakamura et al.,
2005; Myint et al., 2006; Yamagishi et al., 2008; Montonen
et al., 2009; Bravata et al., 2007) or UFAs (Seino et al., 1997;
He, 2003; Wennberg et al., 2007; Yamagishi et al., 2008)
Dietary Factors in Geriatric Neurology 657
on stroke. Moreover, a nested case-control study found
increased risk of stroke among men with increasing
fish intake (Wennberg et al., 2007), and a Finnish study
reported that consumption of salted fish was associ-
ated with an increased risk of intracerebral hemorrhage
(Montonen et al., 2009).
A few studies examined the specific type of fish con-
sumed. Consumption of tuna or other (boiled or baked)
fish was associated with lower risk of ischemic but not
hemorrhagic stroke, while intake of fried fish or fish sand-
wiches was associated with a higher ischemic stroke, sug-
gesting that how fish is prepared could be an important
factor (Mozaffarian et al., 2005). Similarly, in the Cardio-
vascular Health Study, tuna/other fish consumption was
associated with trends toward lower incidence of subclin-
ical infarcts on MRI examinations, while no significant
associations were found between fried fish consumption
and subclinical infarcts (Virtanen et al., 2008).
Tea
A recent pooled meta-analyses (Arab et al., 2009) of eight
cohort studies (Sato et al., 1989; Klatsky et al., 1993; Keli et
al., 1996; Yochum et al., 1999; Hirvonen et al., 2000; Sesso
et al., 2003; Kuriyama et al., 2006; Kuriyama, 2008; Lars-
son et al., 2008a) showed that tea consumption was asso-
ciated with reduced risk of stroke and reduced mortality
from stroke. Subjects drinking more than or equal to three
cups of tea daily appear to reduce risk of a fatal or non-
fatal stroke by approximately 21%, compared with non-
drinkers of tea (Arab et al., 2009). In addition, both black
tea and green tea may have a similar effect, and the effect
did not appear to be specific to Asian or non-Asian popu-
lations. However, no associations between tea and stroke
incidence or stroke mortality were found in a recent study
(de Koning Gans et al., 2010). The mechanism of action by
which tea may protect against stroke is not entirely clear,
but speculations surround the antioxidant functions and
anti-inflammatory actions.
Coffee
For many years, studies have suggested that coffee con-
sumption may increase the risk of coronary heart disease
(CHD) (LaCroix et al., 1986). Thus, a similar association
between coffee consumption and stroke was also suspected.
The HPFS, however, found for the first time that total coffee
consumption was not associated with an increased risk of
stroke (Grobbee et al., 1990). Studies continued to support
that coffee consumption was not associated with increased
risk of or mortality from stroke (Bidel et al., 2006; Zhang et
al., 2009; Leurs et al., 2010; Sugiyama et al., 2010).
Additionally, several studies showed that coffee drink-
ing could be associated with reduced risk of stroke or
stroke mortality. For example, there is a significant reduc-
tion in mortality from stroke among those drinking —five
to six cups daily as compared to those drinking —zero to
658 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
two cups daily (Bidel et al., 2006). The NHS found long-
term coffee drinking (either caffeinated or decaffeinated)
associated with reduced risk of stroke in women (Lopez-
Garcia et al., 2009). The ATBC study suggested that high
consumption of coffee might reduce the risk of cerebral
infarction (but not intracerebral or subarachnoid hemor-
rhage) among male smokers (Larsson et al., 2008a). Finally,
the Japan Collaborative Cohort (JACC) showed coffee con-
sumption was associated with a linear risk reduction for
mortality from stroke in men but not in women; a U-shaped
association was also observed between caffeine intake and
stroke in both men and women (Mineharu et al., 2009).
Nevertheless, the HHP found that the risk of thrombo-
embolic stroke (but not of hemorrhagic stroke) was more
than double for men who consumed three cups of coffee
per day, compared to nondrinkers of coffee (Hakim et al.,
1998). A recent EPIC–Netherlands cohort also suggested a
modestly increased risk of stroke among coffee consumers,
although the linear trend of increasing risk with increasing
cups of coffee drink was no longer significant after multi-
variate adjustment (de Koning Gans et al., 2010).
B vitamins
Findings from the National Health and Nutrition Exami-
nation Survey I Epidemiologic Follow-up Study (NHEFS)
indicated an inverse relationship between dietary intake
of folate and subsequent risk of overall stroke (Bazzano
et al., 2002a). In the HPFS, intake of folate was associated
with a significantly lower risk of ischemic but not hemor-
rhagic stroke (He et al., 2004a). Similarly, the Finnish ATBC
study (Larsson et al., 2008b) found a high folate intake
associated with a statistically significant lower risk of
cerebral infarction but not intracerebral or subarachnoid
hemorrhages. In the CardioVascular Disease risk FACtor
Two-township Study (de Koning Gans et al., 2010), low
folate intake was significantly and independently associ-
ated with an increased ischemic stroke risk, whereas no
association was observed for plasma folate concentration.
On the contrary, a nested case-control study based on the
Northern Sweden Health and Disease Cohort (NSHDC)
found a significant inverse linear association of dietary or
plasma folate with hemorrhagic stroke, but not with isch-
emic stroke risk (Van Guelpen et al., 2005).
In a population-based cohort study, stroke mortality rates
were reduced after the U.S. Food and Drug Administration
in the United States and Canada mandated a folic acid forti-
fication of enriched grain products (Yang et al., 2006).
The ATBC and NSHDC studies have reported that vita-
min B6 and vitamin B12 intakes were not significantly asso-
ciated with any subtype of stroke (Van Guelpen et al., 2005;
Larsson et al., 2008b). The HPFS was an exception: Intake
of vitamin B12 (but not B6) was marginally inversely associ-
ated with risk of ischemic stroke (He et al., 2004a).
A meta-analysis of eight randomized trials of folic
acid supplementation suggested that folic acid supple-
mentation with or without a combination with other B
vitamins could effectively reduce the risk of stroke by
18% (Wang et al., 2007). Stratification analysis showed a
greater benefit with a treatment duration of more than
36 months, achieving a decrease in the concentration of
homocysteine of more than 20%, including populations
not consuming fortified grain, and enrolling subjects with
absent stroke history (Wang et al., 2007). However, a large
placebo-controlled trial of US high-risk women did not
show any effect of the combination of folic acid, vitamin
B6 and B12 on stroke or total cardiovascular events after
7.3 years (Albert et al., 2008). Similarly, recent updates
from two large trials did not support combined folic acid
and B vitamin supplementation for secondary prevention
of stroke. The VITAmins TO Prevent Stroke (VITATOPS)
trial showed that daily administration of folic acid, vita-
min B6, and vitamin B12 to patients with recent stroke or
transient ischemic attack was safe but did not seem to be
more effective than placebo in reducing the incidence of
major vascular events (composite of stroke, myocardial
infarction, or vascular death) (VITATOPS Trial Study
Group, 2010). The Study of the Effectiveness of Additional
Reductions in Cholesterol and Homocysteine (SEARCH),
a double-blind, randomized controlled trial of 12,064 sur-
vivors of myocardial infarction, found substantial long-
term reductions in blood homocysteine levels with folic
acid and vitamin B12 supplementation, but no beneficial
effects on stroke risk (Armitage et al., 2010).
Grains
Intake of cereal fiber was first found to be inversely asso-
ciated with risk of total stroke in the HPFS (Ascherio et al.,
1998). The Finnish ATBC study found cereal consumption
to be marginally associated with reduced risk of intrace-
rebral hemorrhage in male smokers (Larsson et al., 2009).
In the IWHS, there was a nonsignificant trend of reduced
mortality from stroke associated with higher intake of
whole grains (Jacobs et al., 1999). The PHS reported that
whole-grain breakfast cereal intake was significantly
inversely associated with mortality from stroke (Liu
et al., 2003). The NHS observed an inverse association
between whole grain intake and ischemic stroke risk (Liu
et al., 2000b). Whole-grain intake was inversely associated
with incident ischemic stroke among participants of the
ARIC study, but the association was attenuated and no
longer significant after multivariate adjustment (Steffen
et al., 2003). Interestingly, all of these four studies found
no association between refined grain (Liu et al., 2000b,
2003; Steffen et al., 2003) or total grain (Liu et al., 2000b)
and mortality from or risk of stroke, suggesting that the
beneficial effect might be specifically associated with
whole grain. This might be the result of refined grains
containing mostly starch, providing fewer nutrients and
phytochemicals (contained in bran and germ in the whole
grain) (Steffen et al., 2003). Indeed, one study found bran

(added to food) to be significantly associated with risk
of stroke even after multivariate adjustment (Mink et al.,
2007). Nevertheless, in the Finnish Mobile Clinic Health
Examination Survey, whole grain, refined grain, or total
grain was not associated with ischemic stroke or intrace-
rebral hemorrhage (Mizrahi et al., 2009).
Alcohol
Over the last several decades, more than 30 prospective
studies have examined the association between alcohol
drinking and risk of stroke (Donahue et al., 1986; Kono et
al., 1986; Gordon and Doyle, 1987; Stampfer et al., 1988;
Klatsky et al., 1989; Shaper et al., 1991; Goldberg et al.,
1994; Iso et al., 1995, 2004; Kiyohara et al., 1995; Palmer
et al., 1995; Yuan et al., 1997; Maskarinec et al., 1998;
Truelsen et al., 1998; Berger et al., 1999; Leppala et al.,
1999a; Gaziano et al., 2000; Jousilahti et al., 2000; Sankai et
al., 2000; Mukamal et al., 2001, 2005a, 2005b; Djousse et al.,
2002, 2009; Klatsky, 2002; Jackson et al., 2003; Emberson et
al., 2005; Nielsen et al., 2005; Elkind et al., 2006; Bazzano
et al., 2007; Peng et al., 2007; Ikehara et al., 2008, 2009; Lu
et al., 2008; Sundell et al., 2008; Bos et al., 2010; Beulens et
al., 2007). Overall, as suggested by many investigators and
supported by a recent meta-analysis (Patra et al., 2010) of
17 cohort studies, the cumulative results indicate the fol-
lowing. There seems to exist a positive association between
heavy alcohol consumption (>30 g/day) and hemorrhagic
stroke mortality in both men and women and risk of hem-
orrhagic stroke in men. Moderate consumption of up to
three drinks might be associated with reduced risk of hem-
orrhagic stroke in women. For ischemic stroke, the asso-
ciation between alcohol consumption and ischemic stroke
mortality or risk seems to be more consistent across gen-
ders, with an overall J-shaped association—that is, moder-
ate drinking (one to two drinks, or 10–30 g alcohol, per
day) is protective, whereas heavy drinking is harmful—
compared to the nondrinkers or lowest drinkers.
Some studies also explored the association of stroke
with different types of alcohol. One study found red wine
but not other types of alcoholic beverages was associ-
ated with reduced risk of stroke (Bos et al., 2010); another
study observed the strongest risk reduction for liquor
(Beulens et al., 2007). Thus, although red wine has been
postulated to contain additional elements (polyphenols)
that provide even greater cardiovascular benefit than
alcohol alone, it remains unclear whether red wine has
any advantage over other forms of alcoholic beverages
(Saremi and Arora, 2008).
Dairy
The health effects of milk and dairy food consumption on
stroke has been evaluated in several prospective cohort
studies. Several studies reported a reduced risk of stroke
(Abbott et al., 1996; Iso et al., 1999; Kinjo et al., 1999; Ume-
sawa et al., 2006, 2008b; Warensjo et al., 2009) associated
Dietary Factors in Geriatric Neurology 659
with higher consumption of dairy or dairy components.
The HHP study found a decreased risk of stroke associ-
ated with increasing milk intake, and this association could
not be explained by intake of dietary calcium (Abbott et
al., 1996). In the Large-scale Census-based Cohort Study
in Japan, dairy milk, by itself or with meat and fish, was
associated with the risk of mortality from total, ischemic,
and hemorrhagic strokes (Kinjo et al., 1999). Other studies
mainly focused on the effect of dairy components intake
(calcium and milk fat) rather than dairy intake itself on
risk of stroke incidence or mortality. Analysis of NHS data
found an inverse association between calcium intake and
with mortality from total stroke, and the association was
stronger for dairy than for nondairy calcium intake (Iso et
al., 1999). In the JACC study, dairy calcium intake was asso-
ciated with decreased risks of mortality from total and isch-
emic stroke, but not for hemorrhage stroke (Umesawa et
al., 2006). Another Japanese study, the Japan Public Health
Center (JPHC) study, found dairy calcium intake associ-
ated with a reduced incidence of total and ischemic strokes
(Umesawa et al., 2008b). A nested case-control study in Swe-
den found biomarkers of milk fat intake, the proportions of
fatty acids 15:0+17:0 and 17:0 among plasma lipids, were
significantly and inversely related to stroke risk (Warensjo
et al., 2009). Recently, the Boyd Orr cohort in England and
Scotland found childhood calcium intake inversely associ-
ated with stroke mortality in adulthood, but a family diet in
childhood high in dairy products was not associated with
stroke mortality (van der Pols et al., 2009).
A few studies found no association between dairy
intake (He et al., 2003; Elwood et al., 2004; van der Pols et
al., 2009) and stroke risk, though. Furthermore, the ATBC
study even observed positive associations between whole
milk intake and risk of intracerebral hemorrhage and
between yogurt intake and subarachnoid hemorrhage.
However, inverse associations were also found between
cream intake with both cerebral infarction and intracere-
bral hemorrhage in men, and no associations were found
between intakes of total dairy, low-fat milk, sour milk,
cheese, ice cream, or butter and risk of any stroke subtype
(Warensjo et al., 2009).
Various nutrients
The relationship between certain electrolytes and risk of
stroke has been explored in several studies. In general, the
current findings from observational studies suggest that
higher intake of magnesium (Larsson et al., 2008c), cal-
cium (Iso et al., 1999; Umesawa et al., 2006, 2008b; Weng
et al., 2008; van der Pols et al., 2009), potassium (Iso et al.,
1999; Weng et al., 2008), iron (Marniemi et al., 2005; Weng
et al., 2008), or lower intake of sodium (salt) (Umesawa
et al., 2008a; Strazzullo et al., 2009) is associated with
reduced risk of stroke.
The NHS reported that intake of calcium was signifi-
cantly inversely associated with risk of ischemic stroke,
660 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
and potassium intake showed marginally significant
inverse association with ischemic stroke, while no associ-
ation with any stroke subtypes was found for magnesium
(Iso et al., 1999). In a population-based health survey, low
intake of vitamin D, low serum levels of 1,25-dihydroxy-
vitamin D, and low serum levels of iron predicted were
significantly predictive of stroke (Marniemi et al., 2005).
In a Finnish cohort of male smokers, a high magnesium
intake was associated with a statistically significant lower
risk of cerebral infarction, but no association was found
with intracerebral or subarachnoid hemorrhages. Cal-
cium, potassium, and sodium intakes were also exam-
ined in this Finnish cohort, but they were not significantly
associated with risk of any subtype of stroke (Larsson et
al., 2008c). The JACC study found dairy calcium intake
associated with decreased risks of mortality from total
and ischemic stroke (Umesawa et al., 2006), and the JPHC
study found dairy calcium intake associated with reduced
incidences of total and ischemic strokes (Umesawa et al.,
2008b). The JACC study also found that potassium intake
was not associated with stroke risk, but was inversely
associated with mortality from total CVD (Umesawa et
al., 2008a). In addition, this study found sodium intake
positively associated with mortality from total stroke,
ischemic stroke, and total CVD (Umesawa et al., 2008a).
The CardioVascular Disease risk FACtor Two-township
Study found that potassium, iron, and calcium were all
associated with ischemic stroke (Weng et al., 2008).
Dietary patterns
Two large prospective studies, the Healthy Ageing: A
Longitudinal study in Europe (HALE) (Knoops et al.,
2004) and the American Association of Retired Persons
(AARP) Diet and Health Study (Mitrou et al., 2007), both
found that better adhering to a MeDi was associated with
a lower risk of mortality from CVD (including stroke
events). Recently, in the NHS, women with a higher aMed
score, indicating a greater adherence to the MeDi, were
associated with a lower risk of incident stroke, as well as
lower risk of CVD deaths (fatal CHD and strokes com-
bined) (Fung et al., 2009).
In the Women’s Health Study, a large prospective
cohort of apparently healthy women, a healthy lifestyle,
consisting of healthy diet (high in cereal fiber, folate, and
n-3 PUFA, with a high ratio of PUFA to SFA, and low in
trans-fat and glycemic load), as well as abstinence from
smoking, low body mass index, moderate alcohol con-
sumption, and regular exercise, was associated with a sig-
nificantly reduced risk of total and ischemic stroke but not
of hemorrhagic stroke (Kurth et al., 2006).
In the NHS, two major dietary patterns were identified
using factor analysis: a “Western” pattern, typified by
higher intakes of red and processed meats, refined grains,
and sweets and desserts; and a “prudent” pattern, higher
in fruits and vegetables, fish, and whole grains. The
Western dietary pattern was significantly associated with
increased risk of total strokes, whereas the prudent diet
pattern was significantly associated with lower stroke
risk (Fung et al., 2004).
In the same NHS cohort, the DASH-style diet, which is
high in fruits and vegetables, moderate in low-fat dairy
products and low in animal proteins, was also examined
in relation to incidence of stroke (Umesawa et al., 2008a).
The DASH score was found to be significantly associated
with lower risk of stroke (Fung et al., 2008).
In the Women’s Health Initiative Dietary Modification
Trial, 48,835 postmenopausal women aged 50–79 were
randomly assigned to a dietary intervention (reduced
total fat intake and increased intakes of vegetables, fruits,
and grains) versus a free-living setting for more than
8  years. The dietary intervention did not significantly
reduce the risk of stroke (Howard et al., 2006).
Summary
Some, but not all, epidemiologic studies suggest an
inverse association between dietary intake of and blood
levels of vitamin C and risk for stroke or stroke mortality,
but interventional studies have not confirmed this asso-
ciation or a treatment effect.
Observational studies on the association between vita-
min E and stroke have produced conflicting results. Many
clinical trials have failed to demonstrate a beneficial role of
vitamin E in the prevention of stroke. Furthermore, some
studies have demonstrated a potentially detrimental effect
for vitamin E (increased risk for hemorrhagic stroke).
Some, but not universal, evidence from observational
studies indicates that intake of folic acid might be associ-
ated with reduced risk of stroke. The association between
vitamins B6 and B12 and stroke is even more controversial.
Findings from randomized clinical trials do not support
use of folic acid, vitamin B6, or B12 for primary or second-
ary prevention of stroke.
Some evidence suggests that dietary fibers (especially
whole grains), fruits and vegetables, tea, fish, and mod-
erate alcohol consumption might be inversely associated
with both reduced risk of stroke and mortality from stroke.
The association between coffee or dairy consumption and
stroke remains controversial in observational studies.
Limited data from observational studies suggest that
higher intake of magnesium, calcium, potassium, or iron,
or lower intake of sodium (salt) might be associated with
reduced risk of stroke.
Among the dietary patterns, observational studies have
consistently reported MeDi to be associated with a lower
risk of mortality from CVD (including stroke events).
Other beneficial dietary patterns, including DASH (high
in fruits and vegetables, moderate in low-fat dairy prod-
ucts and low in animal proteins), a PCA-derived “pru-
dent” dietary pattern (higher in fruits and vegetables,
fish, and whole grains), and a predefined healthy diet

(high in cereal fiber, folate, and n-3 PUFA, with a high
ratio of PUFA to SFA, and low in trans- fat and glycemic
load) were all associated with reduced risk of stroke. On
the other hand, a PCA-derived “Western” diet (high in
red and processed meats, refined grains, sweets, and des-
serts) was associated with increased risk of stroke. How-
ever, the only dietary intervention study did not find
significant reduction in stroke events among participants
assigned to a healthy diet (reduced total fat intake and
increased intakes of vegetables, fruits, and grains).
Overall, consistent with the previously mentioned find-
ings, according to the current Guideline from the Ameri-
can Heart Association/American Stroke Association
Stroke Council, a reduced intake of sodium (≤2.3 g/day)
and increased intake of potassium (≥4.7 g/day) are rec-
ommended to lower blood pressure, which may thereby
reduce the risk of stroke. A diet containing five or more
servings of fruits and vegetables per day, moderate alco-
hol drink, and components of the DASH diet is also rec-
ommended (Goldstein et al., 2006).
Conclusions
Due to the increasing proportion of older adults in the
US population and the absence of an effective cure for
major geriatric neurologic disorders, including AD, PD,
and stroke, there is an urgent need for effective preven-
tive measures to prolong the period of healthy life and
ease the disease burden for society. As we reviewed here,
cumulative evidence indicates that regular consumption
of certain dietary factors may be associated with risk of
AD, PD, and stroke. For example, high consumption of
vitamin E, vegetables, B vitamins, n-3 PUFA, and fish;
moderate consumption of alcohol; and adherence to
healthy dietary patterns (such as MeDI, RFS, and DASH)
might be associated with lower AD risk. High consump-
tion of vitamin E and caffeine; moderate consumption
of alcohol and CoQ10; low consumption of dairy; and
adherence to healthy dietary patterns (such as AHEI)
might be associated with lower PD risk. High consump-
tion of vitamin C, folate, tea, and whole grains; moderate
consumption of alcohol; low consumption of sodium, and
adherence to healthy dietary patterns (such as MeDi and
DASH) might be associated with lower stroke risk.
However, most evidence derives from observational
studies. Given the practical and financial limitations
of interventional studies, very few foods and nutrients
(mostly vitamin supplementations) have been evaluated
in large multicenter, randomized clinical trials in older
persons. Furthermore, many controlled trials do not con-
firm findings from observational studies. As a result, sci-
entific confidence on truly effective dietary habits regard-
ing AD, PD, and stroke is currently quite limited, preclud-
ing population recommendations.
Dietary Factors in Geriatric Neurology 661
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 Chapter 28
Exercising the Brain: Nonpharmacologic
Interventions for Cognitive Decline
Associated with Aging and Dementia
Brenna A. Cholerton1, Jeannine Skinner2, and Laura D. Baker3
1
Department of Psychiatry and Behavioral Science, University of Washington School of Medicine and Geriatric Research,
Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
2
Department of Neurology, Vanderbilt School of Medicine, Nashville, TN
3
Department of Medicine - Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC, USA

The idea is to die young, as late as possible.

Ashley Montagu

Summary
• Physical activity improves cardiovascular health, increases neurogenesis and neurotrophic factors, reduces
inflammation, and maintains insulin-signaling pathways.
• Exercise is used as a method of prevention and intervention for cognitive decline in preclinical populations. After
diagnosis, the efficacy of exercise therapies is unclear.
• Potential moderating factors include the age at intervention, genotype, gender, the intensity and type of exercise,
stress, and depression.
• Mental activity and exercise are associated with a reduced risk of cognitive decline. After diagnosis, cognitive
rehabilitation may improve several areas of cognitive function.
• Social activity and support has been linked to higher cognitive function and reduced risk of global cognitive decline and
dementia.

Alzheimer’s disease (AD) and other dementias are rapidly
increasing in prevalence in the United States and are thus
a major source of concern for the aging population and
its health-care providers. Neurochemical and structural
changes associated with AD likely begin years before the
development of even mild cognitive symptoms (Smith et al.,
2007); as a result, health-care providers must explore pos-
sible interventions before the onset of serious cognitive dis-
ability. Established risk factors for cognitive impairment and
dementia that are amenable to intervention include medi-
cal complications such as cardiovascular disease (Waldstein
and Wendell, 2010) and diabetes (Akter et al., 2011), as well
as sociologic factors such as an inactive cognitive lifestyle
(Fratiglioni and Wang, 2007) and a lack of positive social
support (Seidler et al., 2003). In this chapter, we present
three potential nonpharmacologic approaches for prevent-
ing cognitive decline: physical exercise, mental stimulation,
and social support. Whether these interventions prevent or
merely slow the progression of cognitive decline, widespread
implementation could vastly reduce the socioeconomic and
financial burdens associated with dementia. Each treat-
ment approach is examined with respect to multiple levels
of intervention: (1) primary prevention, intended to reduce
dementia risk in the entire population; (2) secondary preven-
tion, aimed at individuals at risk for dementia due to either
age or the onset of mild cognitive symptoms; and (3) tertiary
prevention, meant to mitigate the effects of dementia after it
has been clinically diagnosed.
Physical exercise
Aerobic exercise has potent remedial effects on multiple
body systems, and growing evidence indicates that exercise
may benefit cognitive function not only for healthy older
adults (Kramer et al., 1999, 2006), but also for adults with
cognitive impairments (Lautenschlager et al., 2008; Baker
et al., 2010a). The results of numerous human and animal
studies support a relationship between increased physi-
cal activity and improvements in learning and memory

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

669
670 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
(Archer, 2011). Several interrelated mechanisms underly-
ing the protective effects of exercise in the brain have been
proposed, including improved cardiovascular and cerebro-
vascular functions (Ainslie et al., 2008; Black et al., 2009),
anti-inflammatory processes (Colbert et al., 2004; Kampus
et al., 2008), neurogenesis (Kannangara et al., 2011), and
enhanced insulin-dependent energy metabolism (Gomez-
Pinilla et al., 2008). When compromised, any of these con-
fer an increased risk of cognitive decline and dementia.
Cardiovascular health and cerebral perfusion. Cardio-
vascular risk factors, including hypertension, hyperlipid-
emia, obesity, and impaired glucose regulation, are among
the most well-established of the potentially modifiable risk
factors associated with both AD and vascular dementia
(Altman and Rutledge, 2010; de Toledo Ferraz Alves et al.,
2010; Waldstein and Wendell, 2010). Even before the onset
of dementia, a steeper downward cognitive trajectory is
noted for individuals with one or more cardiovascular risk
factors (Waldstein and Wendell, 2010). Cardiorespiratory
fitness is also closely linked with cerebral perfusion and
brain vascularization; age-related reductions in cerebral
perfusion are exacerbated in AD and may represent an
early marker of disease pathogenesis (Johnson et al., 2005).
The numerous documented benefits of physical activity on
cardiovascular and cerebrovascular health, which are likely
mediated by improved blood flow (Brown et al., 2010),
neurotrophic factors (van Praag et al., 2005), inflammatory
influences (Kasapis and Thompson, 2005), and insulin sig-
naling (Teixeira-Lemos et al., 2011), provide a rationale for
exercise-based interventions aimed at improving cognitive
function and/or preventing cognitive decline.
Neurogenesis and neurotrophic growth factors. The link
between physical activity and neurogenesis in the dentate
region of the hippocampus has been well characterized
in animal models. In rodents, physical exercise leads to
augmentation of long-term potentiation, hippocampal
cell proliferation, increased dendritic arborization, and
greater density of dendritic spines for both aged animals
and animals exposed to stressful environments and inter-
ventions (Archer, 2011). A reversal of age-related decline
in new neuron generation in the hippocampus and corre-
sponding improvements on tasks of learning and memory
are apparent when rodents are permitted to exercise freely
(van Praag et al., 2005). Recent evidence, obtained by mea-
suring regional cerebral blood volume on MRI, suggests
that exercise-induced angiogenesis (and likely neurogen-
esis) occurs in the dentate region of the hippocampus in
humans as well (Pereira et al., 2007). These effects are most
likely mediated by multiple neurotrophic factors, includ-
ing brain-derived neurotrophic factor (BDNF) (Gomez-
Pinilla et al., 2011), insulin-like growth factor (Trejo et al.,
2001), and vascular endothelial growth factor (Yasuhara
et al., 2007). Indeed, aerobic exercise is associated with
increased hippocampal size in older adults (as com-
pared with nonexercising controls), which coincides with
augmentation of BDNF levels in serum and improved
spatial memory (Erickson et al., 2011).
Inflammation. Pro-inflammatory markers increase with
age and are likely involved in the corresponding age-related
decrease in hippocampal neurogenesis (Viviani and Boraso,
2011). AD is associated with even greater cerebral inflam-
mation and oxidative stress (Rogers and Shen, 2000; Lue
et al., 2001), and anti-inflammatory drugs have been noted
to suppress both inflammation and neurotoxicity in labo-
ratory models (Lim et al., 2000). High levels of inflamma-
tory cytokines, including interleukin-1 (IL-1), interleukin-6
(IL-6), and tumor necrosis factor-α (TNF-α) are found in
brains of AD patients, as compared with normal controls
(Bauer et al., 1992; Dickson et al., 1993). Exercise has long
been lauded for its role in creating an “anti-inflammatory
environment” and is associated with lower levels of inflam-
matory biomarkers (Kasapis and Thompson, 2005).
Insulin-signaling pathways. An important established
risk factor for cognitive decline and dementia relates to dis-
ruptions in insulin sensitivity characterizing type 2 diabe-
tes and even subclinical impaired glucose tolerance (Akter
et al., 2011). Disturbed insulin signaling in the brain likely
contributes to age- and disease-related changes in cerebral
blood flow through its effects on hemodynamic functions
such as capillary recruitment and vasoreactivity (Cersosimo
and DeFronzo, 2006). Altered insulin signaling in the brain
also influences regulation of amyloid-β (Aβ) (Craft, 2007)
and other AD biomarkers, such as BDNF (Gomez-Pinilla et
al., 2008) and cortisol (Mastorakos and Pavlatou, 2005). Cog-
nitive impairments affecting executive control have been
linked to reduced vasodilation, with pronounced effects on
frontal–subcortical circuits that are particularly susceptible
to insulin-dependent microvascular changes in vulnerable
areas with watershed arteriole architecture (Campbell and
Coffey, 2001). Aerobic exercise is an effective treatment for
impaired glucose tolerance and diabetes, and thus may help
to attenuate the negative influence of impaired insulin action
on cognition (Baker et al., 2010a; Teixeira-Lemos et al., 2011).
Given the multitude of known and suspected beneficial
effects of physical activity, aerobic exercise may serve as
a cost-effective therapeutic approach with the potential
to amend numerous physiologic and cognitive processes
compromised by age and AD pathology. The following
sections discuss the implications of exercise interventions
at all levels of prevention.
Primary prevention: lifetime exercise and
dementia risk
The beneficial effects of exercise on later cognitive func-
tion may begin at an early age, during the course of neural
development. This theory is supported by animal models,
which suggest that physical exercise may have the most
pronounced beneficial effects on neural network reserves at
younger ages (Black et al., 1991; Maniam and Morris, 2010).
In humans, this connection is less clear; however, the level of

physical activity during the teens and early 20s (by retrospec-
tive self-report) is associated with higher scores on global
cognitive function in women aged 65 and over (Middleton
et al., 2010) and with improved processing speed in older
men (Dik et al., 2003). Lifelong moderate physical activity
is linked with improved performance on tasks of working
memory, processing speed, and global intelligence in post-
menopausal women (Tierney et al., 2010). Regular exercise
during midlife is also related to subsequent reduced risk
for dementia and milder impairments in memory at older
ages (Andel et al., 2008; Geda et al., 2010). In one study, older
adults who met the American Heart Association recommen-
dations for exercise (30 min per day, 5 days per week) during
the 10 years prior to evaluation had lower levels of amyloid
burden in several brain regions (measured using Pittsburgh
compound B, PiB, on PET scan), including the prefrontal
cortex and lateral temporal areas (Liang et al., 2010). These
results support an early and consistent lifelong exercise rou-
tine as an important primary method in the prevention of
later cognitive decline.
Secondary prevention: the impact of exercise
in older age
Normal aging. Normal aging is associated with declines
in processing speed, executive functioning, and memory
(Charlton et al., 2010; Silver et al., 2011; Smith, 2011). Physical
activity in older age appears to attenuate cognitive decline,
particularly in domains most susceptible to age-related
losses (Colcombe et al., 2004; van Uffelen et al., 2008; Baker
et al., 2010a, 2010b). Multiple large-scale epidemiologic
studies, including the Canadian Study of Health and Aging
(Middleton et al., 2008), the Honolulu-Asia Aging Study
(Abbott et al., 2004), the Adult Changes in Thought Study
(Larson et al., 2006), and others (Yaffe et al., 2001), provide
supportive evidence linking increased physical activity in
older adults to a reduced risk of cognitive decline. There is
even some suggestion that older adults may benefit more
from exercise than younger adults in terms of specific physi-
ologic functions, such as cerebral vascular tone (Ogoh et al.,
2011), and reduced risk for cognitive decline (Colcombe and
Kramer, 2003).
Large-scale exercise intervention trials in older adults
with and without cognitive impairment are underway to
corroborate findings from epidemiologic studies; however,
results from smaller-scale studies provide compelling sup-
port for the use of aerobic exercise as an intervention to
improve cognitive function. To date, the most pronounced
salutary cognitive effects are for executive control processes
such as selective attention and multitasking (Kramer et al.,
2006; Baker et al., 2010a), observed in both physically healthy
and glucose-intolerant older adults who are at increased
risk of cognitive decline. In addition, aerobic exercise has
favorable effects on brain regions that support executive
function, with reports of reductions in age-related volume
loss (Colcombe et al., 2003, 2006) and improved efficiency
Exercising the Brain 671
of brain activity in associated networks (Voss et al., 2010).
Recently, Erickson et al. (2011) reported that 12 months of
aerobic exercise training increased hippocampal volume by
2%, which effectively reversed age-related volume loss by
about 2 years (Figure 28.1).
Mild cognitive impairment. Although it appears that
exercise may be an effective intervention for those who are
at risk for AD by virtue of their age, a more targeted popula-
tion for intervention includes older adults who are already
experiencing mild declines in cognitive function. Mild cog-
nitive impairment (MCI) characterizes a cognitive state that
falls on the continuum between normal cognitive aging and
dementia (Petersen, 2004; Winblad et al., 2004), and it is a rec-
ognized risk factor for dementia (Petersen, 2004; de Rotrou
et al., 2005; Petersen, 2006; Schmidtke and Hermeneit, 2008).
For this reason, intervention at the MCI stage may be of criti-
cal importance for prevention. As with cognitively normal
adults, physical activity may represent an effective nonphar-
macologic strategy to prevent or delay further cognitive
decline in older at-risk adults (Teixeira et al., 2012).
Although epidemiologic studies have consistently
shown that exercise reduces the risk of developing cogni-
tive impairment, only a limited number of experimental
studies have been designed to examine the impact of aero-
bic exercise on cognition in people diagnosed with MCI.
Initial findings from randomized trials that employ moder-
ate- to high-intensity exercise interventions provide prom-
ising results. In a small but well-publicized, randomized
controlled 6-month trial of aerobic exercise versus a stretch-
ing control condition for sedentary adults with amnestic
MCI and in the earliest stage of AD pathology (Morris and
Cummings, 2005), Baker et al. (2010b) reported exercise-
induced improvements in cardiorespiratory fitness, insulin
sensitivity, and performance on four tasks of executive func-
tion (Figure 28.2). Consistent with other reports in normal
older adults (Colcombe et al., 2003), the cognitive effects
in this study were more pronounced for women than for
men. For all subjects, plasma levels of Aβ tended to decline,
with aerobic exercise signifying a possible disease-modify-
ing effect of this intervention. In another, larger 6-month
randomized controlled trial (n = 170) (Lautenschlager et
al., 2008), subjects in the active group who exercised at a
moderate intensity for 150 min per week over and above
what they were completing at the outset of the study (that
is, not necessarily sedentary at study entry) showed small
but significant improvements on the Alzheimer Disease
Assessment Scale (ADAS-Cog) scores. In contrast, a recent
study examining the effects of a multimodal exercise pro-
gram on older adults with MCI residing in a structured liv-
ing environment demonstrated improved cardiovascular
fitness in the absence of improvement in cognitive function
(Miller et al., 2011). These results may indicate that, as cog-
nitive impairment progresses and a greater level of struc-
ture is required to ensure compliance, individuals may
benefit less from a prescribed exercise intervention. This
672 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient

Left hippocampus Right hippocampus

(a) Hippocampus 5.2 5.2
5.1 5.1

Volume (mm3)

Volume (mm3)
5 5
4.9 4.9
4.8 4.8
4.7 4.7
4.6 4.6
Baseline 6 months 1 year Baseline 6 months 1 year

(b) Caudate nucleus

Left caudate nucleus Right caudate nucleus
4.9 5.3

4.8 5.2
Volume (mm3)

Volume (mm3)
4.7 5.1

4.6 5

4.5 4.9

4.4 4.8
Baseline 6 months 1 year Baseline 6 months 1 year

(c) Thalamus Thalamus

15.00
Exercise
Volume (mm3)

14.50 Stretching

14.00

13.50

13.00
Baseline 6 months 1 year
Figure 28.1 Brain region examined using MRI, and graphs demonstrating 1-year effects of aerobic exercise versus a stretching control in
cognitively healthy older adults (n = 120). (a) Example of hippocampus segmentation and graphs demonstrating an increase in hippocampus
volume for the aerobic exercise group and a decrease in volume for the stretching control group. The Time by Group interaction was
significant (p < 0.001) for both left and right regions. (b) Example of caudate nucleus segmentation and graphs demonstrating the changes in
volume for both groups. Although the exercise group showed an attenuation of decline, this did not reach significance (both p > 0.10).
(c) Example of thalamus segmentation and graph demonstrating the change in volume for both groups. None of the changes were
significant for the thalamus. Error bars represent SEM. Source: Erickson et al. (2011). Reproduced with permission of National Academy of
Sciences. (For a color version, see the color plate section.)

final point raises some concern on the potential of exercise
as an effective intervention for AD.
Tertiary prevention: exercise and dementia
Once the clinical symptoms of dementia become evident, is
it possible to reverse or at least slow the progression of the
disease? This question, of course, is the crux of numerous
ongoing pharmacologic and nonpharmacologic investiga-
tions. To date, the search for a disease-modifying interven-
tion has proven elusive; it seems apparent that once the
disease process produces significant clinical symptomatol-
ogy, substantial and permanent reversal of symptoms is
unlikely. However, a number of interventions are aimed at
slowing the progression of symptoms and improving qual-
ity of life for patients with dementia. Given the beneficial
effects of an active lifestyle on health conditions associated
with dementia, the demonstrated neuroprotective effects
of exercise on brain functioning and morphology, and the
initially positive findings of exercise on cognition in nonde-
mented and mildly impaired older adults, it is surmised that
increased physical activity may be a relatively cost-effective
and efficacious strategy to decelerate disease progression.
Unfortunately, the small number of trials completed to
date do not support substantial improvements in cognitive
function for adults once AD symptoms become apparent
(Eggermont et al., 2009). Of note, however, there appears to
 Exercising the Brain 673

(a) Symbol-digit modalities (b) Verbal fluency Letter

Stretching Stretching
Aerobic *p < 0.05
6 *p < 0.05 6 Aerobic
Category
Correct answers (No.)

Correct answers (No.)

4 Stretching
2 Aerobic
2
0
–2 0
–4
–2
–6
–4
–8
–10 –6
Women Men Women Men

(c) Stroop (d) Trails B

*p < 0.05
150 4
interference stimuli (ms)
Voice onset latency to

100 3

(Log-transformed s)
Time to complete
2
50
1
0
0
–50 –1

–100 –2
Women Men Women Men
Figure 28.2 Means (SEM) representing improvements over baseline for adults with mild cognitive impairment completing 6 months of
aerobic exercise versus stretching (n = 29) on tests of executive function, expressed as residual scores, including (a) Symbol–digit modalities
test (number correct in 120 s), (b) Verbal fluency by letter and by category, (c) Stroop color word interference test (computer administered),
voice onset latencies (ms) to interference stimuli, and (d) Trails B, time to complete the task (s, log transformed). Source: Baker et al. (2010b).
Reproduced with permission of American Medical Association.

be a significant positive correlation between cardiorespira-
tory fitness and parietal and medial temporal lobe volume
(specifically, white matter in the bilateral inferior parietal
cortex) in patients with AD (Honea et al., 2009). Increased
frailty in this population and related safety concerns typi-
cally restrict interventions to include only low-intensity
exercise, which may not be sufficient to induce changes in
cognitive function. In contrast, even low-intensity exercise
programs may improve some aspects of activities of daily
living, increase social and cognitive stimulation, and boost
mood—factors that could remediate some of the deleterious
consequences of dementia (Logsdon et al., 2005).
Non-Alzheimer’s disease dementia syndromes
Few studies have investigated the potential benefits of
physical activity for non-AD dementia syndromes. Vascu-
lar dementia shares many of the same risk factors with AD,
and the two often co-occur. As with AD, the risk of vascu-
lar dementia may be ameliorated by midlife exercise, with
up to a 70% reduction in risk associated with moderate
exercise (Ravaglia et al., 2008). Again, less is known about
what happens when the disease process significantly
impacts activities of daily living. Presumably, however,
an exercise-related reduction in stroke risk alone (Ainslie,
2009) may prevent additional decline in some patients
with vascular dementia. Potential problems associated
with the implementation of moderate-intensity exercise
programs, similar to those for AD groups, include safety
concerns linked to high medical comorbidity.
Less still is known about the effects of exercise on
Parkinson’s-related dementia and on dementia with Lewy
bodies. Exercise programs may lead to some improvements
in executive function, motor control, and mood for people
with Parkinson’s disease (PD) (Tanaka et al., 2009; Dereli
and Yaliman, 2010; Combs et al., 2011; Cruise et al., 2011).
A number of ongoing trials are exploring the potential
PD-modifying effects of aerobic exercise, as indicated
by intervention-related changes in brain chemistry (via
lumbar puncture), structure (via MRI), and function (via
functional connectivity MRI, PET). Again, the efficacy of
exercise interventions on cognitive functions after a clini-
cal diagnosis of dementia is made remains unclear.
Potential moderating factors
Earlier, we illustrated the potential effects of exercise on a
number of neurobiologic risk factors related to cognitive
decline, described the association between exercise
and dementia risk, and provided initial evidence that
exercise may help improve cognitive functions in older
adults before the onset of dementia. A number of factors,
674 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
however, may moderate those most likely to benefit from
exercise-based interventions.
1 Age at intervention: For health of the body, it is never too
late to start. For health of the mind, lifelong exercise likely
has the greatest risk benefit. A reduction in dementia risk
may be related to the cumulative effects of exercise through-
out life. With this in mind, however, a number of reports
indicate that older adults show an enhanced cognitive re-
sponse to exercise compared with young adults, although
this trend may reflect limitations of the assessment tools
rather than age-related differences in cognitive response.
2 Genotype: Preliminary evidence suggests that the
beneficial effects of exercise in older adults may be par-
ticularly evident for those without an APoE ε4 allele
(Lautenschlager et al., 2008); however, even those with an
ε4 allele may derive some cognitive benefit potentially via
reparative effects of exercise on the vascular system. Ad-
ditional studies are needed to more definitively charac-
terize the interaction between exercise and genotype as it
relates to cognitive response and risk of dementia.
3 Gender: Some reports indicate greater cognitive response
for women (Middleton et al., 2008; Baker et al., 2010b); others
do not discriminate by gender (Lautenschlager et al., 2008).
To date, no study has compared cognitive response with
exercise in men and women in a head-to-head, randomized
trial. Further research is needed to elucidate what role, if
any, gender plays in predicting response to exercise and to
identify potential responder variables that might account for
gender differences if they do exist (for example, severity of
comorbidities, such as coronary artery disease, with poten-
tial consequences for cognitive response to exercise).
4 Intensity of exercise: To date, consensus from a number
of studies points to moderate- or high-intensity exercise to
improve cognitive function and reduce dementia risk (Etgen
et al., 2010; Geda et al., 2010; Tierney et al., 2010). The ques-
tions “How much is enough?” and “Is there too much?”
have not yet been answered, although a number of trials are
now underway to address these issues. As mentioned previ-
ously, the low-intensity exercises employed in AD trials may
not be sufficient to induce changes in cognition.
5 Type of exercise: The intervention most commonly as-
sociated with cognitive benefit to date involves aerobic
exercise using stationary equipment such as a treadmill or
elliptical trainer, or walking programs. Fewer but promis-
ing trials with respect to their cognition-enhancing effects
have used multimodal exercise interventions with some
combination of aerobic, strength resistance, and flexibility
(Marmeleira et al., 2009; Williamson et al., 2009). Other
studies have examined the effects of resistance training
alone and report a positive effect on executive function
in cognitively healthy older adults (Liu-Ambrose and
Donaldson, 2009; Anderson-Hanley et al., 2010; Davis
et al., 2010; Liu-Ambrose et al., 2010). It is possible that
resistance training and/or multimodal exercise regimes
may lead to increased mental activity, thereby promoting
improved cognitive function beyond the benefits of aero-
bic exercise.
6 Role of stress/depression: Depression is often a promi-
nent feature in patients with MCI and dementia, and
those with depression are at a higher risk for multiple
health conditions that can impact cognition. Physical ex-
ercise has been shown to be an effective intervention for
depression in older adults (Hill et al., 1993). However,
depression may also moderate the likelihood that a per-
son will engage in physical activity. Further evaluation of
the complex interplay among depression, exercise, and
cognitive impairment is warranted; however, the overall
improvement in mood and reduction in stress associated
with physical activity provides additional compelling
support for exercise as an intervention technique in aging.
Conclusions: physical exercise
Despite the uncertainty surrounding the ability of exer-
cise-based interventions to significantly modulate cogni-
tion in people already diagnosed with clinical dementia,
general consensus supports the role of such interven-
tions in preventing cognitive decline and even enhanc-
ing certain cognitive abilities in healthy aging and MCI.
Particularly when combined with a multimodal interven-
tion approach that includes mental stimulation and social
engagement, physical exercise is a compelling nonphar-
macologic approach to prevent cognitive impairment.
Mental exercise
An enriched cognitive environment may have a place in
the prevention of both age-related cognitive decline and the
development of dementia. The results of animal and human
studies indicate favorable effects of cognitive training on the
aging brain for both structure and function, suggesting that
brain plasticity persists late into the lifespan (Costa et al.,
2007; Harburger et al., 2007; Engvig et al., 2010; Lovden et al.,
2010). The following sections review several potential points
of intervention, from early life cognitive enrichment to the
treatment of cognitive decline associated with dementia.
Primary prevention: education and lifetime
cognitive experiences
Lower levels of education are consistently associated with
a significantly higher risk of later cognitive impairment
(Mortimer et al., 2003; Gatz et al., 2007; Tyas et al., 2007);
conversely, highly educated individuals show a lower risk
(Lindsay et al., 2002). Although education is the most com-
monly used marker for lifetime cognitive capacity, occupa-
tional complexity and choice of leisure activities throughout
the adult lifespan have also been linked with a reduced
dementia risk in observational studies (Valenzuela and
Sachdev, 2006). Valenzuela, et al. (2008) estimated lifetime
cognitive experiences using the Lifetime of Experiences

Questionnaire, a retrospective self-report measure that pro-
duces a score based on education, occupation, social engage-
ment, physical activity, and daily activities and hobbies.
They found that higher scores correlated negatively with
hippocampal atrophy over time in later life. Despite a gen-
eral consensus that education and other life experiences are
in some way related to later dementia risk, several impor-
tant questions concern the nature of this association.
• Is dementia risk associated with education, per se, or do
factors underlie the ability to attain higher levels of educa-
tion? Level of education is often seemingly inextricable from
other factors. Socioeconomic status, in particular, can impact
access to nutrition, health care, social support, and educa-
tion, all of which may be associated with later-life health and
dementia risk (Borenstein et al., 2006). In addition, individu-
als with lower levels of education may be more likely to tran-
sition into high-risk occupations that increase the likelihood
of injury and exposure to toxins, and may provide a less rich
cognitive environment. However, the general consensus is
that the relationship between education and dementia risk
persists even when other factors, including health, socioeco-
nomic status, and other measures of lifelong cognitive ac-
tivity, are considered (McDowell et al., 2007). Furthermore,
although lower socioeconomic status during childhood is
associated with lower lifelong cognitive capacity, it does not
necessarily appear to be related to cognitive decline in late
life (Wilson et al., 2005a).
• Chicken or the egg: what is the direction of the as-
sociation between education and dementia risk? Neuro-
pathologic processes linked to AD begin decades before
the clinical expression of the disease. The question thus
arises whether individuals predisposed to develop AD
may be more likely to choose less stimulating occupations
and leisure activities, and even complete fewer years of
education. Conversely, a lack of early and ongoing cogni-
tive stimulation may promote a greater degree of neuro-
pathology and earlier clinical expression of the disease.
Although the precise nature of the association is yet un-
known, improving access to and quality of education and
other mentally stimulating activities during the younger
ages may be an important point of early intervention.
• Does enhanced cognitive stimulation lead to a true
reduction in neurodegenerative pathology, or merely in
the expression of the clinical symptoms of the disease?
Results from the Nun Study (Riley et al., 2005) show that
linguistic complexity in early adulthood is associated with
later cognitive function and brain neuropathology. Those
with more sparsely written autobiographies (at an aver-
age age of 22) were more likely to show clinical symptoms
of MCI and dementia. Interestingly, lower levels of lin-
guistic complexity were also associated with greater neu-
ropathology on autopsy, including lower brain weight,
higher levels of atrophy, and greater plaque and tangle
burden. The same study, however, found that although a
low level of education was associated with more frequent
Exercising the Brain 675
clinical expression of dementia, it was not associated with
greater neuropathology (Mortimer et al., 2003).
The final point has relevance for the cognitive reserve
hypothesis (Whalley et al., 2004; Fratiglioni and Wang, 2007),
which posits that older adults present with extremely varied
clinical symptomatology as a function of the overall intel-
lectual capacity, or “reserve,” of the individual. The reserve
theoretically comprised all the components that impact cog-
nitive function throughout the lifespan, including genetic
factors, education, and lifetime experiences. It is not clear
whether this reserve results in specific structural and func-
tional differences in the brain or merely affects the thresh-
old at which neuropathologic changes impact behavior and,
thus, clinical expression of the disease. A more intellectually
stimulating adult life is associated with larger hippocampal
size and reduced AD pathology in later life (Valenzuela et al.,
2008). In contrast, cognitive reserve may be associated with a
latent onset of dementia, but not necessarily with protection
against the AD neuropathology. In support of this hypothe-
sis, individuals with higher levels of education often exhibit
faster decline once clinical symptoms manifest (Scarmeas et
al., 2006; Bruandet et al., 2008). This phenomenon is consis-
tent with the idea that, for adults with increased cognitive
reserve, performance deficits occur at a higher threshold of
neuropathologic disease. However, there is one important
caveat: those with higher premorbid intelligence may be
overlooked by clinicians in the earlier stages of a neurode-
generative condition, while those with lower than average
premorbid abilities are less likely to go unnoticed and thus
contribute disproportionately to the demographic profile.
In the clinical setting, it is particularly important to rely on
a thorough history to determine whether current cognitive
abilities represent a change from previous functioning.
Secondary prevention: later-life cognitive
experiences and cognitive training
Normal aging. The observation that brain plasticity and
hippocampal neurogenesis persists into old age provides a
foundation for the use of cognitive stimulation as a health-
promoting intervention for older adults. Indeed, despite
the strong association between earlier-life cognitive experi-
ences and later cognitive function, current mental activity
may actually be more predictive of cognitive abilities, even
after controlling for lifelong mental stimulation (Wilson et
al., 2005b; Boron et al., 2007). Neurobiologic correlates show
that memory training is associated with increased cortical
thickness (Engvig et al., 2010) and that white matter plas-
ticity may be enhanced by training working memory, epi-
sodic memory, and perceptual speed (Lovden et al., 2010),
with the greatest effects in areas likely to support prefrontal
regions (Figure 28.3). These findings provide the foundation
for a number of commercial and noncommercial cognitive
training programs aimed at reducing cognitive decline asso-
ciated with aging and dementia, efforts that have demon-
strated at least some level of success.
676 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient

domain-specific improvements, effects that persisted at 2-

(a)
and 5-year follow-up intervals. These benefits are somewhat
enhanced with cognitive “booster” training sessions follow-
ing the initial intervention. Interestingly, initial and 2-year
2 3 follow-up data did not show any relation to independent
4
functional abilities; however, those randomized to the rea-
1 5
soning group did report less difficulty in independent activi-
ties of daily living 5 years following the initial intervention.
A number of smaller studies have also shown benefits from
(b) Change in segment 1 (genu) cognitive training, despite utilizing widely disparate meth-
ods of intervention (Rebok et al., 2007). In general, interven-
Younger Older
tions that focus primarily on the areas of cognition most
0.01 strongly associated with decline in normal aging (fluid intel-
ligence) seem to produce the greatest improvement in cogni-
tion and may be more likely to generalize to other areas of
0
Δ Mean diffusivity*

function (Tranter and Koutstaal, 2009). For example, older

adults trained on a verbal working memory task showed not
–0.01 only task-specific improvements, but also enhanced perfor-
mance on visual working memory, processing speed, verbal
memory, and general fluid intelligence (Borella et al., 2010).
–0.02 Cognitive training on processing speed alone may be the
most strongly associated with simultaneous gains in activi-
–0.03 ties of daily living, with direct consequences for other areas
of cognitive function (Edwards et al., 2002; Ball et al., 2010).
Importantly, many studies report promising longitudinal
(c) Younger Older
effects of cognitive training (Valenzuela and Sachdev, 2009;
0.02
Borella et al., 2010). Multimodal approaches—those that
not only target specific skills, but also incorporate complex
Δ Fractional anisotropy

0.01 goal management, problem solving for everyday skills, cre-

0 Taken together, there is compelling evidence to indicate
–0.01
–0.02
Intervention Control
*10–9m2/s
Figure 28.3 Midsagittal slice showing corpus callosum subsegmented
(a) and 6-month cognitive training-induced improvements over
baseline in genu (likely connecting prefrontal regions) in white
matter microstructure, as measured by mean free diffusion of
water (b) and directional rate (anisotropy) of water diffusion (c) for
younger and older adults (n = 32). *units of measurement for Mean
Diffusivity. Source: Lovden et al. (2010). Reproduced with permission
of Elsevier. (For a color version, see the color plate section.)
Programs that target training of specific cognitive func-
tions have generally produced enhanced ability in the area
trained, but often these improvements do not generalize to
other cognitive domains. The Advanced Cognitive Training
for Independent and Vital Elderly (ACTIVE) study (Willis
et al., 2006), a large-scale, randomized trial that examined
the effects of cognitive training in three target areas (pro-
cessing speed, reasoning, and memory), demonstrated
ativity, and psychosocial engagement—have also achieved
some success (Carlson et al., 2008; Stine-Morrow et al., 2008).
that mental stimulation can help maintain and potentially
enhance cognitive function in healthy older adults.
MCI. Although the previous strategies may be an effective
intervention for individuals who exhibit changes associated
with normal aging, less is known about the effectiveness for
individuals with MCI. However, it does appear that teach-
ing specific mnemonic strategies may be of particular benefit
to this group (Belleville et al., 2006; Hampstead et al., 2011).
Subgroup analyses of the ACTIVE study showed that indi-
viduals with MCI displayed improvement similar to a cogni-
tively healthy sample when trained in the areas of reasoning
and processing speed, but not in memory, indicating that the
beneficial effects of cognitive training may be attenuated for
this group (Unverzagt et al., 2009). Alternatively, this finding
suggests that cognitive training may help to optimize exist-
ing capacities but cannot overcome marked impairment that
results from disease-related changes in neuronal structure
or function. Another study comparing treatment with cho-
linesterase inhibitors alone and in combination with com-
puterized cognitive training found that those who received
only the medication intervention showed improvements in
mood, while both interventions together produced better
performance on tasks of memory and abstract reasoning,
in addition to improved behavior (Rozzini et al., 2007). In

addition, some reports indicate that adults with MCI may
benefit to some degree from any type of cognitive training
when conducted in a small group session; however, these
results may be more a function of positive social influences
(Jean et al., 2010). Despite the discrepant findings related to
the amount and type of benefit achieved through cognitive
training techniques, these interventions appear to offer some
promise for improving cognitive function in patients with
MCI (Li et al., 2011).
Tertiary prevention: cognitive rehabilitation
The extent to which some form of cognitive intervention is
of benefit after dementia is diagnosed remains unclear. Cog-
nitive training trials, although generally small and with vari-
able methodology, indicate that cognitive stimulation may
provide some benefit for individuals with AD across several
domains, including attention, executive function, verbal flu-
ency, learning, and daily functional abilities, effects that may
persist initially for up to 1 year (Requena et al., 2006; Sitzer et
al., 2006). A wide range of cognitive interventions have been
employed with AD patients; those that may be most effec-
tive use strategies that involve general mental stimulation
(problem solving, reading, and general engagement) and
mental repetition (or memory “drills”) techniques (Sitzer
et al., 2006). Patients who received individualized atten-
tion may benefit more than those trained in larger groups;
indeed, although the use of “memory notebooks” (in which
daily activities, goals, general information, and procedural
notes are recorded) appears to improve the ability of patients
with AD to utilize memory strategies, the extra attention and
interaction from caregivers that helped implement interven-
tion may be at least partly responsible for the improvements
(Schmitter-Edgecombe et al., 2008).
Conclusion: mental activity
Mental activity throughout the lifespan and into old
age is associated with improved cognitive function and
decreased risk of cognitive decline, effects that may con-
tinue even with the onset of neurodegenerative disease.
The mechanisms that underlie the relationship between
cognitive stimulation and dementia are likely multifacto-
rial and may involve increased brain plasticity and neu-
rogenesis. In addition, the benefits of mental activity may
relate not only to cognitive stimulation, but also to social
interaction and engagement (Moniz-Cook, 2006).
Social activity
In recent years, it has been postulated that social engagement
and quality social support may be an important aspect in the
prevention of cognitive decline and dementia (Seidler et al.,
2003). Hypothesized mechanisms by which social engage-
ment may positively impact cognitive function include
increased cognitive stimulation associated with social activi-
ties, a reduction in stress and depression, and neurobiologic
Exercising the Brain 677
changes that may accompany these influences (Pillai and
Verghese, 2009). The level of social activity may be closely
related to overall cognitive reserve—that is, people who
engage in more social behaviors are likely to participate in
more physical and mental activities as well, thereby boost-
ing brain reserve (Scarmeas and Stern, 2003). In addition,
social engagement often requires a number of complex
cognitive processes, including attention, executive skills,
and memory. Individuals who lack positive social stimula-
tion are at higher risk for stress, depression, and loneliness
(Cacioppo et al., 2010), which correlates with an increased
risk for cognitive decline (Conroy et al., 2010; Panza et al.,
2010). Although primates are hardwired for social interac-
tion to ensure survival, areas of the brain that play a key role
in social behavior, including temporal and frontal cortices
and the amygdala, are often affected even in the early stages
of a neurodegenerative process (Adolphs, 1999). Research
that examines the link between social support and cognition
is in the early stages, yet initial observational studies point
to social support as a potentially important constituent of a
multidisciplinary approach to intervention.
Primary prevention: lifetime social support
and dementia risk
A retrospective comparison between people with demen-
tia and case controls showed that, even decades before the
onset of dementia, people who subsequently developed
the disease were historically less likely to be involved in
cultural and sports activities, and had less extensive psy-
chosocial networks (Seidler et al., 2003). Middle-aged
adults who live alone are twice as likely to develop demen-
tia, a risk that increases when people are divorced or wid-
owed (Hakansson et al., 2009). Conversely, prospective
results from the Honolulu-Asia Aging Study (Saczynski
et al., 2006) suggest that midlife social engagement is not
predictive of later-life dementia risk. Rather, a decline from
a previously high level of social support from middle to
older age, paired with reduced social support in old age,
was associated with a greater risk of incident dementia.
Secondary prevention: social activity in
older age
Social inactivity in older age may be more closely associ-
ated with incident dementia than midlife social isolation;
however, this relationship is difficult to interpret and may
be primarily an effect of the disease process on sociability.
Social engagement in later years is associated with bet-
ter global function and several other cognitive domains,
even after controlling for cognitive and physical activity
(Krueger et al., 2009). Older adults with larger social net-
works and a high degree of social activity have a reduced
risk of global cognitive decline and dementia (Crooks
et al., 2008). Unfortunately, in the absence of experimen-
tal trials, the question of whether social interventions in
older age may be protective against dementia remains
unclear.
678 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
Tertiary prevention: increasing social
interaction in patients with dementia
Again, to date, no controlled trials have examined the effec-
tiveness of social interventions on cognition in patients with
dementia. However, it is possible that increasing pleasant
activities and social interaction can lead to improved mood,
as well as reduce wandering and other problematic behav-
iors associated with advancing AD (Cohen-Mansfield and
Werner, 1997; Arai et al., 2007). At this level of intervention,
a great deal of focus has been on reducing caregiver burden
and stress via increased social support. Intervening in this
manner leads to stress reduction, improved mood, and bet-
ter health profiles for the caregivers, benefits that also have
consequent indirect but favorable effects for the care of the
dementia patient (Sierpina et al., 2005).
Conclusion: social interaction
Social interaction is the least well studied of the nonphar-
macologic interventions discussed in this chapter. However,
cognitive reserve theory and initial observational findings
support that social activity may have a positive influence on
cognitive function. These effects may occur either directly by
influencing the neuropathologic processes associated with
cognitive decline or indirectly through increased mental
stimulation and feeling of well-being.
Conclusion
Cognitive decline and dementia represent an increasing
source of concern for health-care professionals and soci-
ety at large. The anticipated rapid growth in the number
of dementia cases over the next few decades and corre-
sponding lack of available pharmacologic interventions
fuel concerns that the financial and socioeconomic burden
associated with dementia could reach crisis proportions.
Fortunately, with appropriate intervention, several modi-
fiable risk factors could lead to a substantial reduction in
future dementia cases. Among others, increased physi-
cal activity, mental stimulation, and social engagement
are promising tools that may help attenuate the cogni-
tive decline associated with aging and dementia. These
interventions are associated with positive effects across a
range of functions, including cognition, mood, and health
status. Used alone or in conjunction with pharmaco-
logic interventions, these strategies may be cost-effective
approaches for treating and preventing cognitive decline.
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 Chapter 29
Driving Impairment in Older Adults
Anne D. Halli-Tierney and Brian R. Ott
Warren Alpert Medical School of Brown University and The Alzheimer’s Disease and Memory Disorders Center, Rhode
Island Hospital, Providence, RI, USA

Summary
• Aging is associated with changes in sensory systems, mobility, and cognition, which affect driving ability.
• Drivers with dementia are at high risk for hazardous driving.
• Other medical conditions are also associated with impaired driving ability and medical assessments of vision, motor
function, and cognition should be done to determine driving competence.
• Performance-based evaluations, simulators, and road tests are used as methods to assess and monitor older drivers.
• Social networks are heavily relied upon for transportation after cessation of driving. Depression, economic burden, and
social withdrawal may develop if such networks are unavailable.
• Physicians face uncertainty regarding their responsibility to report unsafe drivers. Older individuals may also resist the
revocation of their driving privileges.

Introduction
The US population is aging at a rate unseen in the his-
tory of the country. From 1998 to 2008, the percentage
of the population aged 65 or older has grown by 13% to
34 million; by 2030, this number is expected to increase to
72 million (NHTSA, 2008). This cohort has been largely
independent and healthy, and an increasing number of
people are remaining active in the workforce and in their
communities. It is thought that 38 million of these elderly
will be driving as of the year 2020 (Freund, 2006), and as
of the year 2007, 31 million licensed drivers (or 15% of all
licensed drivers) were over the age of 65 (NHTSA, 2008).
Driving is seen as a marker of independence and “adult-
hood,” and the aging baby boomer cohort is known for
its fierce independence; thus, it can be inferred that the
number of elderly drivers will continue to increase. The
expansion of elderly motorists can give rise to complica-
tions, especially when, given physical and mental deterio-
ration, some drivers are no longer fit to operate a motor
vehicle. With this impending increase of elderly drivers,
it is important to consider their safety and the safety of
those with whom they share the road.
Elderly drivers cause a great deal of concern because,
as a population, they are seen to be a danger on the road.
Indeed, drivers over the age of 65 are expected to account
for 16% of motor vehicle accidents and 25% of fatal acci-
dents (Eberhard, 2008). The usual cliché is that of the
petite elderly lady with the big car who cannot see over
the steering wheel, drives very slowly, runs a red light,
and crashes into oncoming traffic. This image is pervasive
in the media, and the idea of the “senior Sunday driver”
is prevalent in American society; this can lead to negative
bias about the safety habits of older drivers. However,
elderly persons are actually some of the safest drivers,
with the lowest number of crashes per 100 licensed driv-
ers per year (Eberhard, 2008; Centers for Disease Control
and Prevention, 2010). Older drivers generally tend to
be a self-monitoring population and limit risky driving
behaviors (such as rush hour and evening driving), driv-
ing duration, and driving time as self-perceived deficits
increase. They also are more likely to wear seat belts: 77%
of victims aged 65+ in fatal motor vehicle crashes in 2007
were wearing seat belts, as opposed to 63% for younger
populations (Office of Statistics and Programming,
Centers for Disease Control and Prevention, 2010). And,
they are less likely to be driving under the influence of
alcohol than are younger drivers. Despite these positive
attributes of the older driver, many see them as a general
threat on the road, and they are at greater risk of sustain-
ing injury from a motor vehicle accident.
Given physiologic changes and increases in frailty,
traffic accidents and traffic-related injuries are of par-
ticular concern to this age group. Accidental injury is the
seventh leading cause of death in the elderly, and motor
vehicle accidents are the leading cause of such deaths
in persons aged 65–74 and the second leading cause in
persons aged  75–84 (Staats, 2008). Because older male

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

682

drivers tend to drive more than women through the age
spectrum, they are more likely to suffer a traffic fatality
than their female counterparts (Office of Statistics and
Programming, Centers for Disease Control and Preven-
tion, 2010). As mentioned later, older drivers have a
higher rate of fatality than any other age group except
for drivers under the age of 25, with a disproportion-
ately higher number of chest and head injuries (AMA,
2003; Bauza et al., 2008). These injuries are thought to
be due to increased fragility and chronic medical con-
ditions present in older patients (AMA, 2003; Li et al.,
2003). Assessing the ability to drive in the elderly is
made further complex by the fact that each driver is
unique: Although physiologic aging changes occur uni-
versally and can have an impact on driving ability, it is
important to ascertain which limitations are allowable
with caution and which deficits require restricted driv-
ing privileges. Because of increasing risk of injury to the
older population in the event of a crash, assessing for
motor vehicle safety is of utmost importance to elderly
drivers themselves, as well as the population as a whole.
Any chapter on driving in the elderly, much like any
geriatric topic, must be multifactorial and must take into
account both normal changes associated with aging and
pathologic states that could impact driving ability. We
discuss means of assessing the older driver for suitability
on the road and explore the ramifications of recommend-
ing that someone stop driving, both legally and socially.
Also in this chapter, we hope to assist the concerned fam-
ily member and physician by providing resources to aid
in assessment of the older driver and in education about
safe driving practices.
The aging driver
When determining a particular person’s safety and abil-
ity to drive, it is important to consider functional status
and comorbid conditions. Elderly drivers do have to con-
tend with an increasing number of medical conditions
and diagnoses, as well as reduced physiologic reserve
and increasing medication burden. However, many
elders continue to be functionally intact, so the decision
to limit driving should not be made on chronologic age
alone. A thorough medical history, including a geriatric
assessment that focuses on particular medical condi-
tions, medications, and functional status, should be per-
formed, along with a physical examination that focuses
on strength and coordination. As mentioned, the elderly
driver sees and interacts with the world differently than
does his younger peer, and some of the changes inherent
in aging can impact the ability to drive safely.
Even when at optimum health, the elderly patient has
less physiologic reserve. Although a person continues to
age at the same rate, the differences may be more profound
Driving Impairment in Older Adults 683
in an older subject because, in this person, age-related
changes have already taken place and are continuing to
accumulate. Every organ system is affected by aging and
could potentially be such a detriment to the patient that it
impacts driving. However, in regard to the elderly driver,
one needs to specifically focus on the physiologic changes
that impact the driver’s ability to interact with the world.
Namely, one should be most interested in the changes that
occur in sensory systems, cognition, and mobility, as these
contribute most heavily to awareness of the driving envi-
ronment, integration of sensory input with the motions
of driving, and ability to physically steer a vehicle. The
subject’s general health functioning can also contribute to
problems with all these systems in several different ways
(Boss and Seegmiller, 1981).
Sensory changes
As a person ages, it is normal to experience changes in
the sensory systems. These changes can greatly impact
the way the driver perceives the road and the environ-
ment around him. One of the most common changes
with aging is decreased visual function, which actually
begins as early as aged 40. The elderly eye experiences
a number of changes leading to impaired vision. First
and most common, the eye has a decrease in the abil-
ity to accommodate, or to clearly focus on, close objects:
This decrease stems from thickening and opacification
of the lens, as well as weakening of the ciliary muscles
and flattening of the cornea (Larsen et al., 1997). Elderly
people also have a smaller pupil diameter, which leads
to difficulty with dark–light adaptation. An elderly per-
son needs three times as much light to see as clearly as
a 20-year-old (Gallman, 1995). Compared with younger
people, elderly people have a greater problem discrimi-
nating between shades of “cool” colors due to age-related
yellowish discoloration of the lens, and this change can
also affect depth perception. They experience increased
sensitivity to glare due to the increased opacity of the cor-
nea, and they experience a decreased visual field due to
the combined impairments that occur with age (Gallman,
1995; Larsen et al., 1997).
These changes in vision are seen as functions of normal
aging, but some pathologic conditions are common in the
elderly and need to be taken into account when assess-
ing the older driver. Conditions such as macular degen-
eration, cataracts, glaucoma, and changes due to systemic
illness such as hypertensive or diabetic retinpoathy need
to be considered. All these illnesses can lead to blurred
or decreased vision, decreased visual fields, and eventual
blindness (Matteson, 1988). Thus, it is important to assess
patients for such problems and to discriminate between
normal aging changes and pathologic changes so that
treatments can be implemented early.
Although vision is arguably the most important sense
needed for successful driving, elderly people experience
684 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
changes in several other sensory realms that can have
implications for their safety behind the wheel. Hearing
loss is a problem that increases in the elderly: 10% of per-
sons aged 65–75 and up to 25% of persons aged 75 and
up have some degree of hearing loss (Gallman, 1995). For
the most part, older people have difficulty distinguishing
higher-frequency sounds, due to the neurosensory condi-
tion of presbycusis, caused by atrophy of the cochlea and
degeneration of auditory neurons. The vestibulo-cochlear
function of the ear declines with aging, as otoconia, or
granules of the otoliths accumulate and the vestibular
portion of the eighth cranial nerve degenerates, often due
to chronic diseases or some medications. As presbycusis
progresses, patients have difficulty distinguishing pro-
gressively lower-frequency sounds. This neurosensory
condition is often coupled in the elderly with an increase
of cerumen, which can build up and cause an effective
(albeit manageable) conductive hearing loss (Bade, 2010).
These changes have implications for drivers in the set-
ting of emergency vehicles and sirens, which tend to use
higher-pitched sounds for warning and also drive in a
somewhat unconventional manner to provide the most
rapid assistance. Not being able to hear the siren of an
approaching vehicle is dangerous for an elderly driver,
especially when the situation involves a crossing where
the emergency vehicle may be intending to cross against
a light or against traffic.
Elderly people also experience age-related changes in
the sensations of smell and taste, but these are not as
germane to the driving experience. Changes in the sense
of touch, however, can have an impact on driving. In
general, patients’ tactile losses are a combination of age-
related changes (due to neuron atrophy and decreased
nerve conduction) and longstanding systemic diseases
that may have deleterious effects on the sensation of
touch. Elderly people have an overall decrease in tactile
sensation, which leads to impairments in response time,
proprioception, coordination of fine motor tasks, vibra-
tory sensation, and balance (Blair, 1990; Saleh, 1993).
Neurologic changes such as a loss of mass in the cere-
bellum with particular attention to the anterior vermis
and large Purkinje neurons cause mild decrements in
balance, gait, and tone. Also, proprioception is impaired
because of age-related decline in muscle spindle and
mechanoreceptor functioning. As the nervous system
ages, myelin is lost selectively from sensory nerves,
leading to slower conduction times and neuropathy,
which affects vibratory sensation in the extremities.
Coupled with a decreased ability to receive visual and
auditory input and a deficit in balance caused by altera-
tions in the hearing system, the elderly driver needs a
longer response time and may have difficulty carrying
out tasks that depend on proprioception (such as chang-
ing from accelerator to brake quickly using the feet) in a
crisis situation (Blair, 1990).
Cognitive changes
One of the most important changes that can affect elderly
driving—and, indeed, a change that has garnered a fair
amount of public attention—is that of cognitive decline.
Pathologic cognitive changes and their implications
for driving safety are discussed at length in our clinical
assessment section; here we focus on changes associ-
ated with normal aging that can have an impact on the
driving ability and safety of the elderly driver. Routine
anatomic changes can illustrate the alterations in cogni-
tion seen in the elderly person, and such changes are not
considered pathologic up to a point. As one ages, brain
weight decreases up to 15% starting after the age of 20.
Gray matter exhibits a linear decrease, while white mat-
ter increases until the fifth decade and then decreases at a
faster rate. Neuronal dropout and loss is not global but is
more concentrated in such areas as the hippocampus and
the nucleus basalis of Meynert, with the brainstem and
other areas largely spared. Lipofuscin accumulates, as do
plaques and tangles, which are present to a much lesser
degree even in non-Alzheimer’s disease (AD) brains.
White matter gradually loses myelin and dendritic mass,
and this loss, along with vessel sclerosis, leads to an over-
all loss in brain mass. A smaller brain size can be seen
on imaging in healthy older individuals, with narrower
gyri, wider sulci, and enlarged ventricles and subdural
space. These anatomic changes predispose the healthy
elder individual to definite declines in certain cognitive
domains, while leaving other cognitive abilities intact.
Although the focus is often on the cognitive tasks that
show deterioration in aging, we must also note abilities
that remain unchanged in the elder individual. In the
healthy older adult, sustained attention continues to be
good, but increases in distractibility can be seen, espe-
cially if other information is presented simultaneously.
As a function of this increased distractibility, multitask-
ing becomes less efficient in the older individual. Thus,
the older driver is more easily distracted, which can have
dangerous consequences on the road.
Also, processing speed slows and reaction times, infor-
mation retrieval time, and timed tasks all increase with
age. Overall accuracy in recall declines mildly starting
after the age of 50, but in a healthy individual, this is a
slowly progressing decline. Immediate, or sensory input,
which is information based purely on the senses and does
not often get encoded as a discrete memory, shows no
changes in processing with age, although one could argue
that the information being processed may be altered by
virtue of the changes in the sensory systems described
earlier. Short-term memory, or working memory, where
information is stored for a few minutes, likewise does not
show any deficits. Longer-term memory, which is on the
order of hours to years, can show some declines in some
domains, but in a healthy individual, it remains fairly con-
stant in others. In procedural memory, where the person

remembers how to perform tasks strongly rehearsed in
the past, and semantic memory, where the person remem-
bers meanings of situations, there is little decline. How-
ever, some decline is seen in episodic memory, which
involves recall of discrete events, times, and places. This
may impact the healthy older individual’s ability to navi-
gate to new or previously unvisited locations, but it does
not have an effect on destinations that were visited sev-
eral times in the past.
Mobility/strength changes
Another system that affects the aging driver is the mus-
culoskeletal system. Aging changes can lead to reduced
mobility. Such changes are clearly relevant to risk for falls.
Moreover, the same musculoskeletal changes can impair
the older driver’s ability to maneuver a vehicle and could
increase the risk for serious injury following a motor vehi-
cle accident. Changes in the musculature occur with the
normal aging process, with the most marked deterioration
due to muscle disuse over time. Muscle mass decreases
with age, with a predilection for the dominant side. In
addition, lean muscle mass is replaced by fat in the older
individual; this replacement further decreases muscle
stores and helps perpetuate a cycle of muscle decrement,
followed by lack of exercise and further muscle atrophy.
Tendons and ligaments stiffen, which further limits exer-
cise and also predisposes to injury and increased stiffness
of joints, leading to limited mobility (Boss and Seegmiller,
1981). Muscle fibers experience slowed contraction
time, which can decrease agility and cause a slowing in
response time.
These changes in the musculoskeletal system can
impair the driver’s reaction to sudden stimuli and abil-
ity to physically manipulate the controls of a vehicle.
Changes in the skeletal system can also increase the
elderly driver’s chances of being seriously injured in an
accident. Over the years, older patients are more likely
to have suffered an orthopedic or muscle injury, such as
a fracture or rotator cuff tear, simply because they have
more time to accumulate such injuries. Decrease in bone
mass occurring in older age predisposes to osteopenia
and osteoporosis, which increases the risk for fracture in
a traumatic situation (Bauza et al., 2008). The elderly hip
and knee also have increased flexion capabilities, which
can cause joint subluxation in the event of a crash (Bauza
et al., 2008; Staats, 2008). Finally, increased bony forma-
tion can cause degenerative changes or arthritis, which
can limit mobility in several different ways. The hip and
knee can be affected by arthritic stiffness and pain, which
can increase time needed to move the leg. This increased
reaction time combined with decreased muscle strength
and changes in the sensory system can compromise the
ability of an older driver to react appropriately in an
emergent situation. Also, arthritis can limit mobility in the
neck, which would decrease the driver’s ability to turn
Driving Impairment in Older Adults 685
the head and assess for “blind spot” vehicles and other
obstacles that may cause an accident. Decreased mobility
in the neck can further lead to neck/back injury and pain
if an accident occurred (Bauza et al., 2008; Staats, 2008;
Fedarko, 2010).
The aging driver’s ability to safely operate a motor
vehicle can be further compromised by the combination
of chronic illnesses and treatments and decreased physio-
logic reserve. As a group, older patients carry more medi-
cal diagnoses than do their younger counterparts. These
predispose the elderly to what are called the “geriatrics
syndromes,” some of which can negatively impact driv-
ing. These include impairments in vision and hearing,
as mentioned, as well as dizziness, syncope, gait impair-
ment, falls, dementia, and delirium. A host of medical
problems are associated with these syndromes: these
are discussed in the next section. The additive effects of
chronic medical problems cause a decrease in the older
person’s ability to adapt in a rapid manner. For example,
dizziness may be caused by orthostatic hypotension and
may pass after equilibration of the blood pressure, but in
an older person, that orthostasis may be accompanied by
vision problems, proprioception disturbances, and gait
impairment, and is much harder to treat (Nanda, 2010).
Thus, it is important to keep in mind which changes result
from the normal aging process and which changes result
from pathologic processes or iatrogenic effects (such as
medications) when assessing an older patient for driving
suitability. Also remember that although many older per-
sons are able to remain safe behind the wheel, all people
experience aging changes that must be monitored over
time and treated whenever possible to maximize their
safety and the safety of those around them.
Clinical assessment of the older driver
Driving is a complex task requiring visual, motor, and
cognitive demands impacted by aging as well as age-
related medical conditions. Furthermore, interactions
among the driver, the vehicle, and the environment put
the older driver at varying risk for involvement in auto-
mobile crashes (see Figure 29.1).
Cognitive impairment is arguably the most important
risk factor for impaired driving in the elderly. In a sur-
vey of medical reports to the State of Missouri licensing
agency, dementia/cognitive impairment was the most
common reason for reporting older drivers, accounting
for 45% of reports (Meuser et al., 2009). The literature on
older adults with dementia indicates that some drivers
with a dementing illness continue to drive, many well
into the disease process (Carr et al., 1991; Odenheimer,
1993; Ott et al., 2008). An estimated 4% of current drivers
over 75 years have a dementing illness (Foley et al., 2000).
Results from one study that performed a cognitive screen
686 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
Primary visual
function
Cognition:
Disease AD
- Executive
- Attention
Aging
- Visual perception
Motor skills
Time
Figure 29.1 Multifactorial model of driving impairment in older drivers. AD, Alzheimer’s disease. Source: Ott & Daiello (2010).
Reproduced with permission of Future Medicine Ltd.
on older adults during driver license renewal found that
almost 20% of those over 80 years were impaired (Stutts
et al., 1998). Taken together, these studies probably under-
estimate the actual number of demented drivers on the
road because some older adults with memory loss may
not renew their license and continue driving and/or are
inaccurately reported as having stopped driving.
A number of editorials and review articles have
addressed the issue of driving in older people and those
with dementia (AMA, 2003; Brown and Ott, 2004; Breen et
al., 2007; Man-Son-Hing et al., 2007; Adler and Silverstein,
2008; Marshall, 2008; Uc and Rizzo, 2008; Martin et al.,
2009). Based on overall crash occurrences per year, older
drivers have fewer crashes than younger drivers, largely
due to reduction in driving miles. When gauged on a per-
mile basis, however, older drivers are a significant risk
group, with crash rates approaching those seen in teenage
drivers (Mayhew et al., 2006). Moreover, as previously
discussed, due to frailty, they are more likely to die in a
motor vehicle accident than younger drivers (Kent et al.,
2005; Mayhew et al., 2006). Advanced age by itself, how-
ever, should be regarded not as the problem, but rather as
a proxy for physical or cognitive impairments that lead to
unsafe driving.
With age, right-of-way and traffic sign violations
increase, and the frequency of intersection and left-turn
crashes increases (Mayhew et al., 2006; Braitman et al.,
2007; Abou-Raya and El Meguid, 2009). Older adults
have been noted to take more hazardous actions (such
as speeding, improper turning, and failure to yield)
Driving ability: Motor vehicle
- Road test crashes and
performance traffic violations
External factors:
- Environment
- Other drivers
in multivehicle crashes, compared to younger drivers
(Kostyniuk et al., 2003). Older adults are also more likely
to be involved in overtaking, merging, and lane change
collisions (Clarke et al., 1998; McGwin and Brown, 1999).
Older adults are more often found to cause or contrib-
ute to a crash (Hakamies-Blomqvist, 1993), and they
are overrepresented in angle broadside/crashes (Ryan
et al., 1998). These errors are generally felt to be related to
changes in reaction time, visual perception, and attention.
Aging effects on motor function and other disease-related
factors such as eye disorders (Thiyagesh et al., 2009) add
to decrements in driving ability.
Mild cognitive impairment (MCI) is a syndrome that
is generally regarded as a prodromal stage to AD, and all
AD patients initially pass through an MCI stage. There is
limited data on MCI and driving. One simulator study of
drivers with mild AD and MCI found that MCI drivers
were similar to controls except for a test of time to contact
by rear-end collision (Frittelli et al., 2009). Another study
reported that those with MCI performed less well on a
road test than cognitively normal controls (Wadley et al.,
2009).
Due to similar but more severe deficits, drivers with
dementia are at a particularly high risk for unsafe driv-
ing. Some studies suggest that drivers with dementia
have decreased yearly mileage in comparison to controls.
For example, Trobe and colleagues found that individuals
with AD drove an average of about 5000 km annually in
the 2 years before they stopped driving, compared to an
average of 8000 km driven for controls (Trobe et al., 1996).

Other studies confirm that, as a group, older demented
drivers limit their driving exposure (Dubinsky et al., 1992;
Carr et al., 2000; Freund, 2006). Despite data indicating
that they drive fewer miles and thus have reduced expo-
sure, various studies have demonstrated that drivers with
dementia have a 1.5–8 times greater risk of involvement
in a crash, compared to age-matched controls (Retchin
and Hillner, 1994; Marshall, 2008). The crash risk for a
driver with AD rises above that of the highest-risk group
(teenage males) beyond the third year of disease (Drach-
man and Swearer, 1993).
Other degenerative dementias are not uncommon, and
they, too, negatively impact driving fitness. In a prospec-
tive road test study of controls and mixed medical disor-
der patients with AD, vascular dementia, and diabetes,
driving performance errors were comparable between AD
and vascular dementia patients, suggesting that degree
of  cognitive impairment rather than dementia diagnosis
is the more important determinant of risk (Fitten et al.,
1995). Disinhibited and agitated behaviors in patients with
frontotemporal dementia have been shown to cause haz-
ardous driving (de Simone et al., 2007) and may be even
more dangerous than seen in drivers with AD (Tanikatsu
et al., 2009). The prominent visuoperceptual and attention
deficits, as well as common occurrence of visual halluci-
nations and fluctuating levels of alertness, should raise
significant concerns about driving safety for patients with
dementia with Lewy bodies. To date, driving in this group
has not been studied. While advanced **Parkinson’s dis-
ease (PD) may limit driving due to reduced motor func-
tion, earlier-stage problems are more clearly related to
cognitive deficits (Grace et al., 2005; Amick et al., 2007).
PD patients are particularly prone to distraction (Uc et al.,
2006). In one study, navigational errors and lower driver
safety were associated more with impairments in cogni-
tive and visual function than the motor severity of their
disease in drivers with PD (Uc et al., 2007).
Medical assessment
Older adults with cognitive impairment should be exam-
ined to rule out other diagnoses or comorbidities that
can impair driving ability, many of which may be par-
tially or totally remediable. Medical conditions that have
been associated with impaired driving ability include
alcohol abuse and dependence, cardiovascular disease,
cerebrovascular disease, traumatic brain injury, depres-
sion, dementia, diabetes mellitus, epilepsy, use of certain
medications, musculoskeletal disorders, schizophrenia,
obstructive sleep apnea, and vision disorders (Marshall,
2008). In addition to dementia and cerebrovascular dis-
ease, other neurologic disorders that may significantly
impact driving include brain tumor, migraine, multiple
sclerosis, parkinsonian and other movement disorders,
seizure disorder, sleep disorder, vertigo, and peripheral
neuropathy (AMA, 2003). Classes of drugs that have been
Driving Impairment in Older Adults 687
associated with impaired driving and should be avoided
or minimized when operating a motor vehicle include
sedating antihistamines, antipsychotics, tricyclic antide-
pressants, bowel/bladder antispasmodics, benzodiaz-
epines, muscle relaxants, and barbiturates (AMA, 2003;
Rapoport and Banina, 2007; Rapoport et al., 2008; Rapo-
port et al., 2009). Additional indictors of potential driv-
ing risk include history of fainting, complaints of muscle
weakness, history of recent crashes or near misses, con-
cerns of the family about driving safety, reduced driving
mileage, self-reported situational avoidance, and aggres-
sive or impulsive behavior (Iverson et al., 2010).
Cognitively intact drivers may be able to assess their
own driving competence. To assist them, the American
Automobile Association markets a home self-assessment
program called Roadwise Review. This program is per-
formed though use of a CD-ROM and personal computer.
Domains assessed include leg strength and flexibility,
head and neck flexibility, visual acuity, working mem-
ory, and visual processing. Cognitively impaired drivers
lack sufficient insight to judge their own driving abili-
ties. Caregiver ratings of marginal or unsafe driving by
patients with dementia should be strongly considered,
but they may not recognize driving risks or may have a
biased interest in preserving driving privileges if the per-
son in question is the sole or primary provider of trans-
portation (Brown et al., 2005; Iverson et al., 2010).
Given the limitations of self-report and caregiver rat-
ings, the physician is often called upon to help determine
driving competence or the need for more detailed assess-
ment by a driving rehabilitation specialist. Figure 29.2
summarizes recommendations for office evaluation of the
older driver. The American Medical Association and the
US Department of Transportation have developed a use-
ful guide to the physician in assessing the older driver
(AMA, 2003). After reviewing for the presence of the “red
flag” medical conditions and medications just described,
office assessments of vision, motor function, and cogni-
tion are recommended.
Sensory assessment
Visual acuity requirements vary from state to state, with
many requiring far visual acuity of 20/40 for licensure.
Visual acuity should be measured with both eyes open
or with the best eye open. Subjects should wear any cor-
rective lenses that they normally use when driving and
should stand 20 feet from a Snellen chart. For best cor-
rected distance vision less than 20/70, referral to a driving
rehabilitation specialist for a formal on-road assessment
should be done. For distance vision less than 20/100, the
physician should generally recommend not driving. If the
state allows driving with this acuity, passage of a formal
on-road test is highly recommended (AMA, 2003).
Similarly, state regulations have no uniformity regard-
ing visual field function, although many require a visual
688 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient

Evaluate for mild cognitive impairment or dementia

Screen for dementia using validated tool (e.g., MMSE, short blessed test).
Use standard criteria to diagnose MCI or dementia.
Evaluate for reversible causes of cognitive impairment.
Rate dementia severity.

Is the patient driving now? (dictates urgency of evaluation)

Evaluate for impairment of traffic skills, IADLs, and specific
cognitive domains.
Review history with caretaker.

No Impaired traffic skills, Yes

IADLs, or cognitive
or questionable
domains present?
dementia

Questionable Moderate or
or mild severe
Dementia present?

Consider referral
Subspecialist
Patient refuses
Neuropsychologist
Driving Clinic
DMV

Yes Driving No
recommended?

Stop driving
Discuss transportation
alternatives. Figure 29.2 Approach to evaluating older
Continue driving Steps for resistant
Monitor for progression or adults with cognitive impairment or
drivers. dementia. Source: Carr and Ott (2010).
changes every 6 months.
Reproduced with permission of American
Medical Association.

field of 100 degrees or more along the horizontal plane.
A general estimate of visual field defect can be obtained
at the bedside by confrontation testing, but if there are
any questions, referral to an eye specialist for perimetry
is recommended. Deficits in color vision do not constitute
a significant crash risk. Impaired night vision requires
evaluation and may necessitate night driving restriction
(AMA, 2003).
Mobility assessment
Musculoskeletal disorders and neuromuscular disorders
may also limit driving ability. Musculoskeletal disorders
of particular interest and common occurrence in older
drivers include arthritis with limited cervical spine and
limb mobility and orthopedic problems such as fractures
and rotator cuff injury. Position sensibility may be lim-
ited by peripheral neuropathies. Muscle power may be
limited by both neuropathic and myopathic dysfunction.
Therefore, office examination of the older driver should
include testing of muscle strength and endurance (such
as a rapid-pace walk or manual test of muscle strength),
range of motion (particularly neck), and proprioception
in hands and feet (AMA, 2003).
Cognitive assessment
A wide variety of global and specific cognitive tests have
been studied as potential screening tests to predict the
likelihood of hazardous driving as measured by road test

performance, driving simulator performance, or motor
vehicle accidents (Reger et al., 2004; Brown et al., 2005;
Mathias and Lucas 2009). The ideal test or group of tests
remains unclear because studies employ different subjects
and different outcome measures, making comparisons
difficult. Furthermore, odds ratios and correlation coef-
ficients are provided, generally without defining specific
model formulas or test cutoff values that could be used in
practice (Molnar et al., 2006a).
Stratifying dementia severity using the Clinical Demen-
tia Rating (Morris, 1997) has been shown to be a useful
and valid way to assess risk. This scale has been shown
to be highly correlated with driving performance on road
tests (Duchek et al., 2003; Ott et al., 2008) and is currently
recommended by the American Academy of Neurology
in its Practice Parameter (Iverson et al., 2010). Drivers
with moderate dementia by this scale should be advised
not to drive, while those with lesser severity of dementia
warrant closer scrutiny.
Global screening tests like the Mini–Mental Status
Examination (cutoff 24 or less) may assist the physician
in identifying dementia as a red flag condition, although
this test itself cannot be used as the sole basis for decision
making, due to low accuracy in predicting driving perfor-
mance (Carr and Ott, 2010; Iverson et al., 2010). Formal
neuropsychological testing may provide additional infor-
mation regarding more specific cognitive deficits that can
impact driving ability. Among the tests most commonly
cited as being useful are useful field of view, visual repro-
duction tasks, clock drawing, trail making, and maze per-
formance (AMA, 2003; Mathias and Lucas 2009; Carr and
Ott, 2010).
In one study comparing AD and Parkinson’s driv-
ers, Parkinson’s patients distinguished themselves from
other drivers with a head-turning deficiency. Drivers
with neuropsychological impairment were more likely
to be unsafe drivers in both disease groups, compared
to controls. Driving performance in Parkinson’s patients
was related to disease severity (Hoehn and Yaar stage),
neuropsychological measures (Rey Osterreith Complex
Figure (ROCF), Trails B, Hopkins Verbal List Learning
Test (HVLT)-delay), and specific motor symptoms (axial
rigidity, postural instability), but was not related to the
Unified Parkinson Disease Rating Scale motor score. The
ROCF and Trails B tests were useful in distinguishing safe
from unsafe drivers in both patient groups (Grace et al.,
2005). Neuropsychological tests, which are multifactorial
in nature and require visual perception and visual-spatial
judgments, are the most useful screening measures for
hazardous driving in PD patients (Grace et al., 2005; Uc et
al., 2005; Uc et al., 2006; Amick et al., 2007).
Daily living activities
Driving may be regarded as the ultimate activity of
daily living (Sherman, 2006). Given its complexity as an
Driving Impairment in Older Adults 689
instrumental activity of daily living (IADL) and the pivotal
role driving plays in the mobility and autonomy of older
people, driving ranks high in importance among daily
functions to assess in the office. To date, little research has
been done to integrate driving into the assessment of IADL
instruments. In one study of 79 drivers with dementia, total
IADL scores were highly correlated with driving and had
dropped by 46% in persons no longer able to drive, by 23%
in persons driving only if accompanied, by 22% in persons
driving alone but with difficulty, and by 17% in persons
driving alone without difficulty (Ott et al., 2000).
Performance-based evaluations
In obvious cases of gross neurologic impairment, such as
homonymous hemianopia, hemiplegia, and moderate-to-
severe dementia, or when the patient has already demon-
strated serious safety problems such as at-fault crashes,
the clinician can make a confident recommendation
regarding driving cessation. More often, though, red flag
issues raise concerns about driving safety that may war-
rant a performance-based evaluation to directly observe
how the cognitive or other neurologic deficits directly
impact driving abilities.
Simulators
Little data in the literature addresses specific crash charac-
teristics of demented drivers and how their types of crash
characteristics differ from matched controls or middle-
aged drivers (Carr, 1997). Data on driving simulation have
consistently found that drivers with AD perform worse on
tasks than controls (Rizzo et al., 1997; Cox et al., 1998; Rizzo
et al., 2001; Freund et al., 2002; Uc et al., 2006). Based on
simulator studies, drivers with AD are more likely to drive
off the road, drive slower than the speed limit, apply less
brake pressure when trying to stop, and take more time
while attempting to make left turns (Cox et al., 1998). On
the Iowa simulator, complex analysis of vehicle maneuvers
related to crashes demonstrated that inattention and either
slow or inappropriate responses were key factors leading
to the accidents (Iverson et al., 2010).
The use of driving simulators has been largely con-
fined to research centers; however, they may see more
widespread use in years to come if properly validated
against real-world driving outcomes such as motor vehi-
cle crashes and road test performance. In one study, par-
ticipants (healthy controls and those with dementia) were
tested on both on-road and driving simulator protocols.
A strong correlation was found between the two types
of driving assessment, suggesting that lower driving
simulator scores (with fewer errors) are strongly related
to better on-road driving abilities. Moreover, committing
hazardous or lethal errors on the driving simulator was
strongly related to failing the on-road test (Freund et al.,
2002). Motion sickness may limit evaluations performed
using driving simulators.
690 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
Road tests
Performance-based road tests are another measure of
driving competency. The majority of road test studies
report on qualitative outcomes (such as pass/fail rates) in
comparison to controls, and some studies use point sys-
tems or quantitative outcomes. As expected, demented
drivers have higher failure rates on these evaluations than
controls (Kapust and Weintraub, 1992; Hunt et al., 1993;
Odenheimer et al., 1994; Fitten et al., 1995; Hunt et al.,
1997; Duchek et al., 2003; Uc et al., 2004; Grace et al., 2005;
Whelihan et al., 2005; Ott et al., 2008; Dawson et al., 2009);
however, pooled data from two longitudinal studies,
involving 134 drivers with dementia (Duchek et al., 2003;
Ott et al., 2008), show that 88% of drivers with very mild
dementia (Clinical Dementia Rating 0.5) and 69% of driv-
ers with mild dementia (Clinical Dementia Rating 1.0) are
still able to pass a formal road test. Few studies report on
the actual in-traffic skills that are impaired in demented
individuals. Those that do have noted frequent difficul-
ties with lane checking and changing (Grace et al., 2005;
Dawson et al., 2009), merging, making left turns, signal-
ing to park (Grace et al., 2005), and following routes (Uc
et al., 2004). A recent study suggests that the differences
in serious errors on road tests between older drivers and
demented drivers are more quantitative than qualitative
(Dawson et al., 2009). Data from the Brown Longitudinal
Study showed that the median time to discontinuance of
driving for those with very mild dementia was 2 years; for
those with mild dementia, it was 1 year (Ott et al., 2008).
It should be noted that such studies were performed in
a car and environment/route that was likely novel to the
driver, typically measured only a “snapshot” or less than
1 hour of driving ability, and did not consistently assess
the ability to respond in urgent/emergent traffic situa-
tions. Furthermore, test-taking anxiety may influence out-
comes (Bhalla et al., 2007). It is unknown how the results
of these types of performance-based road tests correlate to
driving in the naturalistic setting and whether they accu-
rately identify driving behaviors that are associated with
an unacceptable safety risk.
Road testing is the traditionally accepted method for
states to determine driving competence, but the cost and
need for repeated follow-up testing and monitoring may
be prohibitive. Typically, such an evaluation costs between
$350 and $500 and is not covered by insurance (Carr and
Ott, 2010). Thus, other methods are being sought to reli-
ably assess and monitor older drivers.
Social implications of driving
restriction and driving retirement
At the heart of the topic of driving in the elderly is the
discussion about the appropriate time to restrict or elimi-
nate driving rights altogether for a particular impaired
elderly patient. This topic is loaded with social, ethical,
legal, and emotional implications and is made even more
challenging by the relative lack of consensus about the
right course of action. As has been examined previously
in this chapter, in the absence of pathologic change, the
aging driver still undergoes changes in body systems
crucial to driving as the effect of pure aging. However,
these changes can sometimes be corrected with assistive
devices and, for a large group of elder individuals, these
aging changes do not critically affect their ability to safely
operate a motor vehicle. This large number of elderly driv-
ers may continue to be safe on the road, but worsening
sensory impairments and pathologic changes may render
other older adults unsafe to drive. Whether the decision
to restrict driving is made by the patient, the patient’s
family members, or the patient’s physician, it can have
far-reaching consequences with regard to the physical,
social, and emotional well-being of the patient and the
patient’s support system, as well as the patient–physician
relationship. In this section, we consider the social impact
of driving restriction, along with ethical concerns and bar-
riers that physicians experiencing in addressing the topic
of driving limitation.
Social implications
The right to drive is typically seen as a sign of one’s inde-
pendence, and gaining that right in adolescence is seen as
a sign of responsibility and maturity. As one is deemed
unable to drive for whatever reason, the removal of that
privilege may be seen as an affront to one’s way of being
and a negative commentary on one’s ability to care for
him or herself. This can cause a fair amount of social strife
for a patient and can lead to feelings of isolation and
depression. In addition, it can lead to physical problems
regarding neglect and inability for self-care. Of course,
many older individuals make the decision to restrict driv-
ing themselves; a survey of older drivers showed that
of those who made the decision to stop driving on their
own, those who stopped driving independently tended to
be older and female, with fewer reported health problems
than respondents who continued to drive. However, those
who reported self-discontinuation of driving tended in
general to view their overall health as poorer than those
who continued to drive, even though the nondrivers had
fewer listed medical diagnoses. This discrepancy may
speak to the difficulty in deciding who is fit or not fit to
drive: those who have better insight may be more easily
persuaded to give up the keys; those more impaired med-
ically or cognitively may also have impaired insight into
their condition, so reasoning with them may be difficult,
if not futile (Dellinger et al., 2001).
Reasons given for cessation of driving tend to involve
medical conditions and problems in vision, but one rea-
son of interest that appeared in a survey study of older
drivers was that “there is always someone available

to drive me where I need to go” (Dellinger et al., 2001).
This response raises an important point about the effect
of restricting driving in the elderly. For many older indi-
viduals, driving may be their only means of maintaining
contact with their surrounding world; they may not have
an intact social support group to which they can reach for
transportation assistance. Some studies have shown that
older patients who no longer drive tend to rely on infor-
mal support systems for transportation, such as family
and friends. Although this arrangement was not a major
problem for many households, some caregivers noted
that their work schedule was significantly disrupted or
that they had to stop work altogether to provide transpor-
tation for the nondriving elder. Nondriving individuals
who did not live with a driver and who were younger
tended to report higher difficulty accessing social and
recreational activities due to their mobility limitations
(Taylor and Tripodes, 2001). Furthermore, elderly indi-
viduals who no longer drive may not use communal
or public methods of transportation or walk to achieve
their travel goals. Whether this is due to a reluctance to
use public transportation or an inability to navigate the
steps needed to procure such transportation (due to finan-
cial constraints or cognitive impairments, for example),
it appears as though, when driving privileges are taken
away, the burden falls on the elder person’s social net-
work to provide transportation.
If such a social network does not exist, the conse-
quences of driving restriction could be profound. An
elder person may become socially withdrawn because
he or she cannot interact with the world as before. If
the elder was continuing to work, the loss of driving
privileges may have a serious economic consequence
because it would interfere with the ability to work.
Along with social isolation and possible economic bur-
den, elderly individuals who have lost the ability to
drive may see such a loss as a blow to their self-esteem
and a comment on their ability to care for themselves
independently. This, combined with the lack of social-
ization and decreased independence caused by lack of
mobility, may precipitate depression in this population,
which can further complicate a medical picture that is
probably already complex. This can make treating the
elderly individual more challenging, as another diagno-
sis has been added to the medical conditions list, and the
logistics of getting the patient to the doctor’s office may
become more difficult if the patient cannot drive.
Caregiver burden and concerns
The patient who can no longer drive may suffer from a
change of self-image, a lack of independence, and possi-
ble depression from the change in situation. Likewise, the
patient’s caregivers, whether informal (as in family mem-
bers and friends) or formal (as in physicians), are also
affected by the issue of whether to have someone give up
Driving Impairment in Older Adults 691
driving. As mentioned earlier, family caregivers are the
ones most likely to be called upon to provide transporta-
tion services if driving is restricted, and this may cause
significant burden on time and effort, as well as lost time
at work and, thus, economic burden. A study analyzing
perceived burden among caregivers of dementia patients
showed that fulfilling transportation needs was a leading
burden in terms of time spent caring for the patient and
was the leading cause of caregivers feeling “out of sync”
or unable to participate fully in life because of their obli-
gation to the patient (Razani et al., 2007). This can cause
impairments in the caregiver’s quality of life and can fos-
ter feelings of hostility toward the nondriving patient.
Furthermore, the impaired elderly driver who does
not believe he or she is unsafe and refuses to stop driving
can be a source of significant stress for family members
and other caregivers. The elder may perceive conversa-
tions regarding driving restrictions as offensive and may
get angry or hostile, especially if the elder does not have
insight into the impairment and thinks that family mem-
bers are being oppressive. In situations such as these, the
family often consults the physician for help in convincing
the patient that he or she is not safe to drive. This can
cause a significant amount of stress for the healthcare pro-
vider as well because it raises a conflict between patient
autonomy and confidentiality and the physician’s obliga-
tion to warn of potential harm; the conversation itself can
put a strain on the physician–patient relationship. The
discussion of whether someone is fit to drive is muddied
by the fact that so many elderly are fit to drive, and no
battery of tests can perfectly identify which elder indi-
vidual will be unsafe. Furthermore, an evaluation must
be ongoing, as geriatric syndromes and aging changes are
progressive: a physician must take this into account when
determining driving ability at a particular point in time
(Fitten, 2003; Razani et al., 2007).
Physicians often have conflicting feelings about the best
way to go about counseling a patient on driving and are
unsure of their role in this matter with regard to patient
confidentiality and public safety. When surveyed, they
are reluctant to bring it up before the patient or family
does, and they worry about being liable if their assess-
ment of someone as either fit or unfit to drive is found to
be erroneous. They are unsure about their obligation to
report an unsafe driver to motor authorities, and they feel
that assessment of the driver would be better conducted
through driving tests, which are not in their purview. In
addition, they feel as though the tests currently used and
available to clinicians do not have adequate predictive
power to identify those most at risk. Finally, they name
the possible damage to the physician–patient relation-
ship as a barrier to effective driving counseling (Bogner
et al., 2004). Patients often see the evaluation for driving
fitness, which includes cognitive testing, as an insult to
their intelligence and an affront to their independence.
692 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
Furthermore, the physician’s need to preserve patient
confidentiality and public duty to report a dangerous
driver are often in conflict, and finding an acceptable res-
olution is difficult, given the lack of consensus about driv-
ing assessment. Thus, driving restriction in the elderly is
a delicate topic made worse by a lack of consensus about
assessment, a social stigma regarding elderly drivers in
general, and the loss of independence and detriment to
quality of life not only for those who lose their licenses,
but also those who provide care for them.
Legal ramifications
The majority of the research and public policy directives
addressing dementia and driving issues have focused on
defining methods to detect unsafe drivers and remove
them from the active driving pool. A number of pro-
fessional societies and consensus meetings have pub-
lished practice guidelines for the clinician in this regard
(American Psychiatric Association, 1997; Johansson
and Lundberg 1997; Small et al., 1997; Patterson et al.,
1999; Dobbs et al., 2000; Alzheimers Association, 2001;
AMA, 2003; Canadian Medical Association, 2006; Lyket-
sos et al., 2006; Iverson et al., 2010). Uniformity of opin-
ion holds that moderately severe dementia precludes safe
driving, but there is still no consensus on how to deal
with seniors with questionable or mild dementia who are
minimally or only mildly dependent on others for assis-
tance with their other daily living activities.
Requirements of physicians to report
elders at risk
Current research indicates that many, but not all,
demented individuals have difficulty in actual driving
situations. The crash data taken as a whole indicate that
the overall risk of this group is not elevated to the point
that clinicians should work toward removing all driv-
ers with a diagnosis of dementia from the road. That is,
some demented drivers may be competent to drive in
the early stages of their illness (Duchek et al., 2003; Ott
et al., 2008). Licensing decisions based only on the diag-
nosis of dementia may unfairly penalize patients and
prematurely limit independence and mobility. Thus, a
diagnosis of dementia should not be the sole justifica-
tion for revoking a driver’s license (Alzheimers Asso-
ciation, 2001). If the patient has a progressive dementia
such as AD, the conversation about future driving retire-
ment being inevitable should take place early in the
discussion. If the clinician determines that the patient
is currently competent to drive, monitoring over time is
imperative. Review of driving risk by the clinician every
6 months has been recommended (Dubinsky et al., 2000;
Duchek et al., 2003; Molnar et al., 2006b; Ott et al., 2008;
Carr and Ott, 2010).
Court decisions have been divided regarding physician
liability for “failure to warn” a patient not to drive when
medical risk is identified. In some cases, physicians have
been held liable for failure to advise patients about medica-
tions side effects, medical apparati, and medical conditions
that may impair driving (AMA, 2003; Anon, 1998).
Many physicians are uncertain of their legal responsibil-
ity to report unsafe drivers to the state (Miller and Morley
1993; Kelly et al., 1999). State regulations vary regarding
the requirement and methods to report medically at-risk
drivers. The reader is advised to review policies provided
in the AMA Physician’s Guide to Assessing and Counseling
Older Drivers (AMA, 2003), as well as contact local licens-
ing authorities about specific laws and policies. At least
nine states call for mandatory reporting of medically at-
risk drivers. These include California, which specifically
requires reporting of drivers with AD and related disor-
ders (Reuben and St George, 1996). Only two states man-
date road testing of older drivers. Seventeen states require
a road test if recommended by examiner or physician or
eye specialist. Seven states mandate and 16 encourage phy-
sicians to report unsafe drivers. Physicians are not required
to report unsafe drivers in 21 states (Aung et al., 2004).
The responsibility to the public safety to report potentially
risky drivers must be balanced against the physician’s ethi-
cal responsibility to maintain patient confidentiality. Con-
sequently, many physicians choose not to report, for fear of
jeopardizing the therapeutic relationship with their patient
or breaking privacy regulations under Health Insurance
Portability and Accountability Act (HIPAA). Many states
recommend voluntary reporting, and some (half) provide
immunity from prosecution by the reported, which offers
some protection to the physician. In states where no such
protection exists, the physician must obtain permission
for the patient to report. Thorough documentation of any
discussions and recommendations in the medical record,
and open discussion with the patient explaining a plan to
report, are recommended, along with strict adherence to
local state laws (AMA, 2003).
How to determine whom to report
Using a decision tree such as the one suggested in Fig-
ure 29.2 may help the clinician make a recommendation
to stop driving. Quite often, though, the safety risk for the
driver is not clear, and in such cases, referral for an on-
road test from a driving instructor or other driving reha-
bilitation specialist is particularly helpful. Another option
for referral, which may include a performance-based road
test, is to contact the state Department of Motor Vehicles.
Most states require the physician to fill out forms that
require medical information and vision testing results,
and provide an opinion on whether the driver should
undergo visual or on-road testing. The road test utilized
is often the same test that is used for the novice or teenage
driver.

Sometimes the physician is faced with a patient who
is deemed unsafe to drive after careful assessment yet
who refuses to retire from driving or get a performance-
based assessment to provide assurance that the safety
risk is acceptable at the time. This is particularly common
among drivers with dementia who lack insight. Sufficient
time to discuss the recommendation should be provided
in the office visit, to allow the patient to vent anger and
frustration, as well as maximize communication. The rec-
ommendation to stop driving should include counseling
on alternative transportation sources. A listing of web-
based resources is provided later in this chapter and may
be helpful. The support and involvement of family mem-
bers in both communicating this recommendation and
enforcing it are key.
Steps that family members can take to ensure compli-
ance include the following:
1 Ask the physician to write a “prescription” for driving
cessation.
2 Ask the physician to refer to other medical conditions
as reasons to cease driving, such as vision problems, ar-
thritis, or limited reaction time.
3 File or otherwise disable the keys.
4 Do not repair the car, or send it out for an indefinite
period of time for “repairs” and arrange for its removal.
5 Remove the car by selling or donating it.
6 Disable the vehicle by removing the distributor cap or
other means.
7 Involve the family lawyer in counseling.
8 Where permitted under state law, sending a referral to
the Department of Motor Vehicles by formal letter may be
necessary (Carr and Ott, 2010).
Currently, 44 states allow a family member to report an
impaired driver. The ethical guidelines of the American
Medical Association address the issue of physician report-
ing and patient confidentiality: “[W]here clear evidence
of substantial driving impairment implies a strong threat
to patient and public safety, and where the physician’s
advice to discontinue driving privileges is ignored, it is
desirable and ethical to notify the Department of Motor
Vehicles.” (AMA Policy Finder, 2000)
Conclusion
Specialized training in age-related disorders that can
affect safe driving allows the geriatric neurologist to be
ideally positioned to provide expert consultation and
counseling to patients and their families on driving inter-
ventions to promote safety and mobility.
Driving interventions to promote safety
and mobility
Given the evidence that many cognitively impaired driv-
ers may still be able to drive safely for several years,
Driving Impairment in Older Adults 693
future efforts should be made to maximize the safety and
driving competence of those still actively driving with
cognitive impairment due to degenerative dementia. This
issue will become more compelling as the baby boom
generation ages yet aims to retain a vigorous and mobile
lifestyle.
Early intervention via forced or voluntary driving
retirement can avoid serious accidents, yet one does not
want to limit driving arbitrarily based on diagnosis alone
because autonomy for the elderly is an extremely impor-
tant goal both socially and economically. A major question
arises: when should a cognitively impaired older person
stop driving? To address these questions, a large number
of epidemiologic risk factor studies and neuropsycho-
logical test studies have been performed using various
outcome measures of driving competence, such as motor
vehicle accidents, performance on driving simulators,
and on-road driving tests. However, relatively little atten-
tion has been paid to the exploration of possible interven-
tions to prolong the time that cognitively impaired older
drivers can drive safely and maintain their transportation
independence.
The development of uniform standards for road test-
ing may improve outcomes. For example, in the Brown
Longitudinal Study, crash rates for drivers with dementia
declined to the levels of healthy controls during a period
of 18 months when evaluated with road tests every
6 months (Ott et al., 2008). The costs of such detailed sur-
veillance may be prohibitive, however, and it is unknown
whether community-based road testing programs would
reproduce these results.
It is generally recognized that memory loss alone does
not impair the critical cognitive processes needed for safe
driving, but it could impact the ability of a driver to navi-
gate without getting lost, as well as increase safety risk
of crashing in challenging circumstances (Anderson et al.,
2007). Family members often try to compensate by hav-
ing a nonimpaired driver serve as “co-pilot.” Assistive
technologies, such as user-friendly GPS devices, need to
be developed to maximize independent living for people
with MCI.
Early studies examining the effectiveness of classroom-
based or on-road training programs for older drivers
failed to show clear benefits. In 2007, however, Marottoli
and colleagues conducted a randomized controlled trial
of 126 drivers age 70 years and older assigned to safety
education versus a combined classroom and on-road
driving training sessions. They were able to demonstrate
improved performance on a road test following the inter-
vention for the active treatment group (Marottoli et al.,
2007). In another study by this group, 178 drivers age
70 years and older were randomized to intervention with
graduated exercises versus controls who received home
and environment safety modules. The active treatment
group maintained driving performance as assessed by a
694 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
road test, while controls significantly declined during the
study period; however, the changes in the intervention
group were modest, at best, and it is unknown whether
the changes would be lost over time and whether the
improvement of several points on a quantitative road
test evaluation would translate to a reduction in crashes
(Marottoli et al., 2007). More recently, studies involving
cognitive speed of processing training in normal elderly
drivers have shown promising short- and long-term
results in improving driving performance on road test
examinations (Roenker et al., 2003; Edwards et al., 2009a;
Edwards et al., 2009b.
Although these studies are encouraging in terms of
prospects for enhancing driver safety among older driv-
ers, brief educational and cognitive training programs
would be challenging for the cognitively impaired and
unlikely to have a lasting benefit for drivers with degen-
erative brain disease such as AD, due to its progressive
nature. Recently, a pilot study of cholinesterase inhibitor
therapy in AD drivers demonstrated that cholinesterase
inhibitor treatment was associated with improvements in
tests of executive function and visual attention, as well
as simulated driving (Daiello et al., 2010). These findings
could have important implications for patients who con-
tinue to drive in the early stages of AD.
The development of more effective therapies for cogni-
tive impairment and methods to slow functional incline
would have an important impact on driving and mobility
in the elderly. Also needed are better road designs that
accommodate the challenges to the older driver, as well
as improved safety warning systems for the vehicles they
drive (Ott and Daiello, 2010).
Role of the geriatric neurologist
Given his or her training in the diagnosis and treatment
of many of the age-related disorders that can affect safe
driving, the geriatric neurologist is ideally positioned to
provide expert consultation and counseling to patients and
their families on this often thorny issue. The ability of the
physician to predict on-road driving performance is, at best,
modest and probably should not be relied upon as the sole
determinant of driving privilege, except in obvious cases.
In one study of drivers with dementia, accuracy of clini-
cian ratings ranged from 62% to 78% for the instructor’s
global rating of safe versus marginal or unsafe. In general,
there was moderate accuracy and inter-rater reliability.
Accuracy could have been improved in the least-accurate
raters with greater attention to dementia duration and
severity ratings, as well as less reliance on the history and
physical examination. The most accurate predictors were
clinicians specially trained in dementia assessment, who
were not necessarily the most experienced in their years of
clinical experience (Ott et al., 2005). Utilizing appropriate
resources such as neuropsychologists and driving rehabili-
tation specialists may result in referrals for more detailed
assessment, to improve accuracy and validity of the driv-
ing assessment process.
Recognizing the problem driver is only the start of
the process. A treatment plan must be developed that
includes medication adjustments, treatment of ocular
disease, sleep disorders, and metabolic problems such as
diabetes. Collaboration with primary care physicians and
specialist in other fields, such as ophthalmology, sleep
medicine, orthopedics, and rheumatology, is important.
Education on driving alternatives and community
resources should be provided, particularly when driving
retirement is advised. Listed next are a number of impor-
tant organizations and resources that can be incorporated
into the overall care plan and mobility counseling.
Support from organizations and internet
educational resources (Carr and Ott (2010)):
caregiver and patient resources
Association for Driver Rehabilitation Specialists
(ADED)
The ADED web page, which describes warning signs of
driving and provides a link to the directory for locating a
driving specialist.
www.driver-ed.org/i4a/pages/index.cfm?pageid=104
American Occupational Therapy Association (AOTA)
Information on occupational therapists and their role in
driving assessment and rehabilitation.
www1.aota.org/olderdriver/
Alzheimer’s Association
The national association’s website on driving and demen-
tia, with links to educational information. Local chapter
websites often list available driving clinics in the area.
www.alz.org/safetycenter/we_can_help_safety_driving
.asp
Family Caregiver Alliance
(1) Fact sheet on dementia and driving.
http://www.caregiver.org/caregiver/jsp/content_node
.jsp?nodeid=432
(2) A review of the myriad caregiver issues related to this
topic.
www.caregiver.org/caregiver/jsp/content_node
.jsp?nodeid=432
(3) Information on dementia and driving and the Califor-
nia state law.
www.caregiver.org/caregiver/jsp/content_node
.jsp?nodeid=433
Lennox and Addington Dementia Network
Dementia and Driving—Family and Caregiver Informa-
tion.
www.providencecare.ca/objects/rte/File/Health_Pro-
fessionals/drivinganddementia_patient.pdf
MayoClinic.com
Caregiver site on when to stop driving.
www.mayoclinic.com/health/alzheimers/HO00046

National Association of Social Workers
Tool for locating a social worker near you.
www.socialworkers.org/
The Caregiver Project
Links to other websites on this topic.
www.quickbrochures.net/alzheimers/alzheimers-
driving.htm
The Hartford
Insurance company website, with links to the brochures
At the Crossroads and We Need to Talk.
www.thehartford.com/alzheimers/
www.thehartford.com/talkwitholderdrivers/
WebMD
Dementia and driving video for caregivers.
www.webmd.com/video/driving-and-dementia
Physician resources
Alzheimer’s Knowledge Exchange website, with selected
links on dementia and driving.
www.candrive.ca/en/resources/physician-resources/
43-driving-and-dementia.html
American Family Physician
Dementia and Driving handout for the office.
www.aafp.org/afp/20060315/1035ph.html
American Medical Association (AMA)
Physician’s Guide to Assessing and Counseling Older
Drivers (see “Dementia and Driving,” page 47).
http://www.ama-assn.org/resources/doc/public-
health/older-drivers-chapter4.pdf
Information on state licensing and reporting laws (last
updated 2004).
http://www.ama-assn.org/resources/doc/public-
health/older-drivers-chapter8.pdf
California Department of Motor Vehicles
Discussion of the California law and dementia severity.
www.dmv.ca.gov/dl/driversafety/dementia.htm
Dementia and Driving Toolkit: The Dementia Network
of Ottawa
A toolkit for clinicians who evaluate and counsel older
drivers.
http://docs.google.com/gview?a=v&q=cache:sU_
gDWuJOa0J:www.cma.ca/multimedia/CMA/Content_
Images/Inside_cma/WhatWePublish/Drivers_Guide/
AppendixD_e.pdf+dementia+and+driving+tookit&hl=en
&gl=us
Insurance Institute for Highway Safety (IIHS)
Website on older driver laws for driver licensing, updated
every six months.
www.iihs.org/laws/olderdrivers.aspx
Neurology
Factors that affect when patients with Alzheimer’s should
stop driving, by Deniz Erten-Lyons
Driving Impairment in Older Adults 695
www.neurology.org/cgi/reprint/70/14/e45?maxtoshow
=&HITS=10&hits=10&RESULTFORMAT=&fulltext=driv
ing+and+dementia&searchid=1&FIRSTINDEX=10&sorts
pec=relevance&resourcetype=HWCIT
Neuropsychiatry
“Driving with Dementia: What is the Physician’s Role?” A
discussion of the physician’s role in this process.
www.neuropsychiatryreviews.com/may02/npr_may02_
demdrivers.html
Psychiatry Weekly
“Psychogeriatrics: Advanced Age, Dementia, and Driv-
ing.” A discussion of the physician’s role, ethics, and com-
munication issues.
www.psychiatryweekly.com/aspx/article/articledetail.
aspx?articleid=984
Talking to Seniors and Their Family about Dementia
and Driving
Educational pamphlet by Mark Rapaport (2007).
http://docs.google.com/gview?a=v&q=cache:8BVwrfg
pLOwJ:www.rgpc.ca/best/GiiC%2520Resources/GiiC/
pdfs/5%2520Talking%2520to%2520seniors%2520about%
2520driving.pdf+rappoport+dementia+driving&hl=en&
gl=us
VA Government Pamphlet
Dementia and Driving handout.
www1.va.gov/vhapublications/ViewPublication.
asp?pub_ID=1162
Transportation alternatives
Agency on Aging
Assists in finding local resources for aging in the commu-
nity.
www.n4a.org/
American Public Transportation Association (APTA)
Helps locate a local transportation provider in your com-
munity.
www.publictransportation.org/systems/
American Administration on Aging (AOA)
Eldercare locator. Assists in finding resources in your
community for older adults.
www.eldercare.gov
Community Transportation Association (CTAA)
Information on transportation in the United States.
www.ctaa.org/ntrc/
ITNAmerica
Novel older adult transportation system that provides
24/7 rides to seniors.
www.itnamerica.org/.
National Center on Senior Transportation
Links to many transportation agencies.
http://seniortransportation.easterseals.com/site/
PageServer?pagename=NCST2_trans_care
696 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
Seniors on the MOVE
Assists older adults with relocation to another commu-
nity.
www.seniorsonthemoveinc.com/
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 Chapter 30
Elder Abuse and Mistreatment
Elliott Schulman1, Ashley Roque2, and Anna Hohler3
1
Lankenau Institute for Medical Research, Lankenau Medical Center, Wynnewood, PA, USA
2
Boston University School of Medicine, Boston, MA, USA
3
Department of Neurology, Boston University School of Medicine, Boston, MA, USA

Summary
• Physical, emotional, financial, and sexual abuse, along with neglect, are all types of elder abuse.
• Risk factors for mistreatment include being female, advanced age, low income, comorbid medical issues, and social
isolation.
• Elders with dementia and cognitive impairments are more likely to become victims, perhaps due to decreased ability to
communicate and defend themselves from their caregivers.
• Burnout, stress, and individual factors put caregivers and nursing home staff at risk for becoming abusive.
• EM screening is recommended for all geriatric patients. Accurate documentation of history and recognition of physical
signs of abuse are important in identifying elder abuse.
• Interventions for EM include education for both the patient and caregiver, adult protection services, support groups,
and respite care.

Introduction elder abuse is difficult, as research studies suggest that

Abuse affects all age groups, spares no sociodemographic
boundaries, and can contribute to health problems rang-
ing from depression to coronary artery disease. Abuse and
neglect may be associated with migraine and pseudosei-
zures (Alper et al., 1993; Tietjen et al., 2007). A history of
abuse may influence disease presentation and response to
treatment. A significant portion of neurologic patients are
elderly, a group that is at particular risk for mistreatment.
Elder mistreatment (EM) is defined as abuse or neglect of
either an individual over 65 years of age, or an adult who
is physically or mentally disabled. As neurologists, it is
imperative to identify the mistreatment and provide the
appropriate resources for our patients.
An estimated 1.01 million elders became victims of
various types of domestic elder abuse in 1996. Women
make up 68.3% of elder abuse victims (National Center on
Elder Abuse, 1996). These numbers are thought to grossly
underestimate the actual rates of EM. This epidemic of
EM is estimated to cost Americans tens of billions of dol-
lars annually in healthcare, social services, investigative,
and legal costs (National Committee for the Prevention
of Elder Abuse (NCPEA) official website). EM also influ-
ences the survival of our patients. Individuals who expe-
rience mistreatment are at a higher risk of 1 year mortality
(Dong et al., 2009). Reliably assessing the prevalence of
only one in four elder abuse incidents is reported (Tatara,
1990). Several reasons for this exist, including under
reporting because of physical or mental disability, and
fear of the consequences of reporting. By recognizing this
issue and addressing it as part of each evaluation, neu-
rologists can positively influence patient care.
Definitions of elder mistreatment
Elder abuse can fall into several different categories. Indi-
viduals can be placed in a disadvantaged position both
by what is done to them and by what is not provided for
them. Table 30.1 defines the types of abuse and neglect
and provides examples.
The cycle of mistreatment
Typically, EM does not occur continually, but instead
occurs sporadically. The caregiver may be caring between
episodes, which contributes to the lack of reporting. The
abused elder may perceive that the situation will improve
with time. The abuse becomes more severe as the care-
giver tries to meet the ever-increasing physical and cogni-
tive demands of the individual.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

699
700 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient

Table 30.1 Various forms of elder abuse Neglect is the most common form of EM (55%). Physical
Type Definition Examples abuse is the most common reported form of abuse (14.6%),
followed by financial (12.3%), emotional (7.7%), and sex-
Physical Willful act carried Slapping, hitting, kicking,
ual abuse (0.3%) (National Center on Elder Abuse, 1996).
abuse out with the intent of striking with objects,
causing pain or injury pinching, pushing, pulling
hair, and physically
restraining Individual risk factors of elders
Emotional Willful act executed to Verbal aggression, threats
abuse cause emotional pain, of institutionalization, Individual risk factors for becoming a victim of EM
injury, or mental anguish social isolation, humiliating include advanced age (over the age of 75) and income less
statements, insults
than $10,000 a year (Mass.Gov, 2010; Jones et al., 1997).
Financial Misappropriation Theft of checks or money,
Comorbid medical issues in the elderly can also
abuse of elderly person’s or coercion to deprive the
assets for personal elderly person of assets increase the risk of abuse. Common medical problems
or monetary gains, or (such as forcible transfer of that increase the risk of abuse include depression, frailty,
failure to use funds to property, forgery, fraud) physical impairment, and dementia (Jones et al., 1997;
restore health and well- Utley, 1999; Cooper et al., 2009). Elderly who experience
being of the elder depression are at increased risk of abuse because depres-
Sexual abuse Nonconsensual sexual Suggestive talk,
sion may cause a decrease in self-care and self-protection
activity with an elderly forced sexual activity,
(Halphen and Dyer, 2010). One study found that elders
person touching, or fondling
with a nonconsenting or with dementia were ten times more likely to be the vic-
incompetent person tims of abuse than other elders (Cooney et al., 2006). Cog-
Elder neglect Failure of designated Failure to provide adequate nitive impairment may decrease elderly patients’ abili-
caregiver to meet the food, clothing, shelter, ties to defend themselves, remove themselves from an
elderly person’s physical medical care, hygiene, abusive situation, or make them unable to communicate
and mental well-being social stimulation, or
the abuse to others. Elderly persons with cognitive and
needs emotional support
physical impairment are increasingly reliant on their care-
Source: Adapted from Ahmad and Lachs (2002) with permission of givers for help with performing activities of daily living.
Cleveland Clinic Journal of Medicine. Increased reliance can cause informal caretakers to expe-
rience significant stress that increases the risk that they
will abuse the elderly patient under their care (American
Risk factors for elder mistreatment Psychological Association, 2003).
Social isolation has also been shown to put the elderly
Being female increases the risk for abuse among both at an increased risk for mistreatment. In these situations,
older and younger individuals. Abuse of elderly females the abuser prevents the elder from interacting with oth-
may represent a continuum of violence against females ers, and the elder becomes completely dependent on
throughout the lifespan (Hightower, 2010). Elderly women the abuser. This may stop the elder from reporting the
have a greater chance than men of being widowed, losing abuse due to fear of institutionalization or abandonment
social support, and not being financially independent. In (Jayawardena and Liao, 2006; Halphen and Dyer, 2010).
many countries, women are assigned lower social sta-
tuses and have a decreased voice in decision making. All
these factors may contribute to the greater incidence of Caregiver risk factors
risk of abuse among elder females (Daichman et al., 2010).
In one study, investigators postulated that women suffer Caregivers who have disabling conditions, such as addic-
more serious injuries than men when abused; therefore, tion to alcohol or drugs, sociopathic personalities, or a
the abuse would be more likely to come to the attention history of mental illness, have higher rates of being per-
of protective services. Males, on the other hand, made petrators of abuse. Those with dementia, mental retarda-
up the majority of those who were abandoned (National tion, and a history of experiencing abuse and violence
Center on Elder Abuse, 1996). themselves are also more likely to be abusers (Jones et
The oldest elders (80 years and over) were abused al., 1997). Numerous studies have shown that caregivers
and neglected at 2–3 times the rate of the general elderly who are financially dependent on the abused also show a
population. The median age of elder abuse victims is 77.9 greater risk for becoming abusers (Jones et al., 1997; Utley,
years. In 1996, 66.4% of the reported victims of domestic 1999; Halphen and Dyer, 2010). Caregivers who have
elder abuse were white, 18.7% were African American, employment problems, personal illness, or low income
and 10.4% Hispanic (National Center on Elder Abuse, may take out their frustrations on the elders under their
1996). care, leading to mistreatment (Jones et al., 1997).

In almost 90% of EM episodes with a known perpe-
trator, the perpetrator is a family member. Two thirds of
the perpetrators are adult children or spouses (National
Center on Elder Abuse, 1996). Overall, men were the per-
petrators of abuse and neglect 52.5% of the time. Of the
cases of abuse and neglect, males were the most frequent
perpetrators of abandonment (83.4%), physical abuse
(62.6%), emotional abuse (60.1%), and financial/material
exploitation (59%). The age category with the most perpe-
trators was those from 41 to 59 years (38.4%), followed by
those less than 40 years of age (27.4%) (National Center on
Elder Abuse, 1996).
Verbal abuse was associated with a poor premorbid
relationship and social isolation of the caregiver. The
longer the caregiver had been tending to the elderly, the
higher the risk of physical abuse (Cooney and Mortimer,
1995). Neglectful situations arise more commonly when
there is a lack of resources.
Caregiver burnout
“Burnout” may be a risk factor for physical abuse
(Cooney and Mortimer, 1995). Evidence suggests that
those who physically abused elders were under mental
distress (Cooney and Mortimer, 1995; Cooper et al., 2009).
The longer the caregiver is taking care of the elderly indi-
vidual, the higher the risk of physical abuse.
Often informal caregivers take complete responsi-
bility for an elderly patient without appropriate train-
ing. They are not educated on the disease process, what
behaviors to expect, how to deal with difficult behavior,
or the resources that are available to them. As a result,
they may have difficulty meeting both their own needs
and the needs of the patient. These caregivers often feel
hopeless, frustrated, angry, and “burned out,” which can
lead them to use physical force or other abusive behaviors
(American Psychological Association, 2003).
It is important to determine the degree of assistance
the elderly require. Caregivers should be carefully ques-
tioned regarding whether they are overwhelmed, have
a social support system, or have adequate free time for
themselves (Cooper et al., 2009).
Special situations
Nursing homes
Nursing home residents are at higher risk of EM
because of cognitive impairment and physical limita-
tions. In addition, many are unable to report abuse, for
fear of reprisal (Lindbloom et al., 2007). A 1987 survey
of nursing home staff found that 36% had witnessed
at least one episode of physical abuse in the preced-
ing 12 months, and 40% had committed at least one
episode of psychological or verbal abuse over this
time period (Pillemer and Moore, 1989). Psychological
Elder Abuse and Mistreatment 701
abuse is likely to be more prevalent than physical abuse
and may take the form of isolation or intimidation
(Tarbox,  1983). Neglect may manifest as malnutrition
and dehydration. Often caregivers experience almost
daily abuse, including verbal and physical assault (Pil-
lemer and Moore, 1989). When staffing was inadequate,
caregivers were more likely to be abusive to nursing
home residents. Burnout was another risk factor for
abuse. Workers at risk for being abusive were often
stressed, while those who ignored the yelling or push-
ing by residents had positive work experiences and had
a stable personal life (Shaw, 1998). The following list
provides some abuser characteristics.
Characteristics of abusers in nursing homes
• Lower job satisfaction
• Workload stress
• Burnout
• History of domestic violence or mental illness
• Drug or alcohol abuse
• Inadequate staffing
(Lindbloom et al., 2007)
Screening for abuse
The American Medical Association (AMA) recom-
mends that all physicians routinely inquire about the
mistreatment of elderly patients (American Medical
Association, 1982). If there is a suspicion of abuse,
the patient and caregiver should be interviewed sepa-
rately. The patient will feel more comfortable talking
about their relationship with the caregiver and will
be less likely to fear retribution from the caregiver
(Swagerty and Brickley, 2005). AMA guidelines are
listed here.
AMA guidelines for screening (1982)
1 Are you alone a lot?
2 Has anyone ever failed to help you take care of yourself
when you needed help?
3 Are you afraid of anyone at home?
4 Have you ever signed any documents that you did not
understand?
5 Has anyone ever threatened you?
6 Has anyone ever touched you without your consent?
7 Has anyone at home ever hurt you?
Reports of abuse occurring in 5% of the elderly prob-
ably understate the prevalence (Figure 30.1). This sug-
gests that only the most serious abuse is being detected or
reported (Cooper et al., 2008).
Research studies have been undertaken to deter-
mine the most effective screening strategy. A con-
sensus has not yet been reached, but several of the
available methods have been tested for accuracy. In
fast-paced settings, such as emergency rooms or busy
outpatient clinics, brief instruments to assess potential
702 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
Reported abuse
Unidentified and
unreported abuse
Figure 30.1 Iceberg table. Source: NEAIS study, pp. 2–4; www
.ncea.aoa.gov/Main_Site/Library/Statistics_Research/National_
Incident.aspx.
mistreatment are generally used to determine whether
further assessment is required. Comprehensive assess-
ment protocols and guidelines are designed for set-
tings such as the Adult Protective Services (APS)
and ombudsman interviews, in which more in-depth
assessment is performed (Fulmer et al., 2004). In gen-
eral, patients respond more readily to questionnaires
that are then reviewed during the office visit (Glass et
al., 2001). Before screening the patient for abuse, the
physician should inform the patient of any manda-
tory requirement to report abuse to protective agencies
(Boston Medical Center, 2009).
An elderly person is 2–3 times more likely to visit a
healthcare professional than someone of a younger age.
Therefore, the healthcare field provides an opportune
setting for identifying and intervening in elder abuse
(Swagerty et al., 1999). However, identifying victims of
EM is usually difficult. Healthcare professionals, social
service agencies, and police departments often assume
the responsibility of identifying, reporting, and inter-
vening in elder abuse (Fulmer et al., 2004). In spite of
this, many healthcare professionals experience diffi-
culty in identifying the victims of elder abuse and feel
uncomfortable intervening in cases of abuse. Table 30.2
lists some typical signs of abuse. In one study, 90% of
physicians reported that EM was difficult to detect, and
only 2% of all cases of suspected EM were reported by
physicians (Fulmer et al., 2004). Clinicians should have
specific training on how to assess for elder abuse and
how to refer or report these cases (Campbell et al., 2000).
Because of the limited number of elders who report
abuse to authorities, the AMA recommends EM screen-
ing for all geriatric patients.
Two important factors in identifying elder abuse are
taking an accurate history and recognizing physical signs
of abuse (Swagerty et al., 1999).
When taking a history, the physician should try to get
a good sense of the patient’s daily life. Several important
Table 30.2 Red flags for abuse
Type of abuse Signs and symptoms
All types Frequent unexplained crying
Unexplained fear or suspicion of persons in the home
Physical Bruises, lacerations
Bone fractures
Laboratory findings of medication overdose or
underutilization of prescribed drugs
Sexual Bruises around breasts or genital area
Unexplained venereal disease
Emotional/ Signs of agitated or emotional upset
psychological Sudden change in behavior
Extreme withdrawal and noncommunication or
nonresponsiveness
Neglect Dehydration
Malnutrition
Untreated bedsores
Poor personal hygiene
Unattended or untreated health problems
features should be obtained from the history (Swagerty
et al., 1999).
• Medical problems/diagnoses
• Detailed description of home environment (adequacy
of food, shelter, supplies, medication, and so on)
• Accurate description of events related to injury or trau-
ma (instances of rough handling, confinement, or verbal
or emotional abuse)
• History of prior violence
• Description of prior injuries and events surrounding them
• Description of berating, threats, or emotional abuse
• Improper care of medical problems, untreated injuries,
poor hygiene, or prolonged period before presenting for
medical attention
• Depression or other mental illness
• Extent of confusion or dementia
• Drug or alcohol abuse
• Quality/nature of relationships with caregivers
• Other social contact, the patient has, besides the caregiver
Documentation and legal requirements
In the 1990s, elder abuse became a criminal offense. With
some variation among states, certain types of emotional
elder abuse and elder neglect are subject to criminal pros-
ecution, depending on the perpetrator’s conduct, intent,
and the victim’s injuries.
States differ on who is required to report suspected elder
abuse although the list of mandatory reporters is grow-
ing. Typically, medical personnel, nursing home workers,
peace officers, emergency personnel, public officials, social
workers, counselors, and clergy are listed as mandatory
reporters, and that responsibility is spreading to financial
institutions and other entities that work with seniors.

Reporting
Reporting suspected elder abuse is mandatory in all
states except Colorado, New Jersey, New York, North
Dakota, South Dakota, and Wisconsin. In Delaware,
Indiana, Kentucky, New Mexico, North Carolina, Rhode
Island, Texas, and Wyoming, anyone who suspects EM
is required to report the abuse. In other states, only
people of certain occupations, including healthcare
workers, are considered mandatory reporters. Even if
the patient is competent and requests that the abuse not
be reported, the physician is required to report abuse
under the mandatory reporting laws. Reporting abuse
is not considered a breach of patient confidentiality. In
28 states, failure to report suspected abuse is punish-
able by law (Jayawardena and Liao, 2006; Halphen and
Dyer, 2010).
Health professionals are required to report abuse if
they have a reasonable cause to believe it is occurring.
Suspicion of abuse is an adequate threshold to report to
protective agencies. Also, in most states, reporters are
protected from civil and criminal litigation (Jayawardena
and Liao, 2006).
If the patient is being abused by the caregiver or
someone in the general community, the report should be
made to the local APS. Initially, a verbal report should
be made immediately by calling the Elder Abuse Hot-
line. A written report of abuse should then be sent to the
appropriate agency within 48 hours. Physician’s offices
and hospitals generally keep copies of the Elder Abuse
Mandated Reporting Form on file. If the suspected
abuse is occurring in a long-term care institution, the
report should be made to the ombudsman by calling
the Department of Public Health. If there is concern that
immediate action is required to prevent further harm,
the reporter should notify law enforcement and protec-
tive agencies (Jayawardena and Liao, 2006; Halphen
and Dyer, 2010). A referral to social work may also be
appropriate to ensure ongoing assessment and support
of the elder.
The physician should inform patients that they have a
duty to report the abuse to protective agencies and should
involve patients in the reporting process as much as pos-
sible. Information pertaining to the suspected abuse
should be recorded in the medical record.
Documentation of abuse in the medical record
1 Complete, objective details of injuries/conditions based
on clinical findings and observations.
2 Patient’s account of injuries/conditions. Use direct
quotes in quotation marks whenever possible, including
specifics of incident(s).
3 Medical, nursing, and social work assessments.
4 Treatment and discharge plans, including referrals to
medical, nursing, or social work staff. Do not include
names of any confidential shelters or details of any safety
planning.
Elder Abuse and Mistreatment 703
5 Specific details of any mandated reports, including
name of reporter, type of report, and date of reporting,
where applicable.
6 Copies of reports themselves should not be included in
the medical record.
Great care must be taken in recording information per-
taining to the abuse. Summaries and general statements
are not considered strong evidence by law enforcement
agencies. If there is any physical evidence of abuse, it is
best to take photographs. If photographic evidence is not
possible, it is best to draw the injuries and provide a record
of color, induration, and size (Halphen and Dyer, 2010).
Interventions for the abused
Education
Competent elders have the right to reject the services
offered by protective agencies (Mass.Gov, 2010). If this
occurs, the physician’s main role is to educate the elder
on how to live as safely as possible. The physician should
gather information on the patient’s unmet needs and refer
the patient to the appropriate resources. Patients who
experience abuse can be referred to local support groups,
individual counseling, safety planning services, and cri-
sis intervention services (Chez, 1999). Patients should
be given the number for the National Domestic Violence
Helpline. In elder abuse situations when the victim is
deemed incompetent and is at the risk of serious harm,
intervention is court-ordered (Mass.Gov, 2010).
Adult protective services
Interventions provided by the APS include receiving
reports of adult abuse, exploitation, or neglect; investi-
gating these reports and subsequent case planning; and
monitoring. The APS may also provide or arrange for the
provision of medical, social, economic, legal, housing, law
enforcement, or other protective, emergency, or support-
ive services (National Center on Elder Abuse About Adult
Protective Services). It is APS policy that interventions be
as unrestrictive as possible; thus, in-home and commu-
nity-based services are preferred to placement in a long-
term care center (Mass.Gov, 2010).
Intervention for caregivers: education
and support
Instruction in behavior management
techniques
All caregivers should be instructed in how to handle dif-
ficult situations that may arise. Research has shown that
the behaviors that are most troubling to caregivers are
wandering, personality changes, paranoia, and aggres-
sive behavior. Classes, groups, and materials have all
been developed to provide caretakers with techniques on
704 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
dealing with these difficult situations. These behaviors
are usually the result of pain and discomfort, being expe-
rienced by the elder. If caregivers are taught to recognize
this, they can respond appropriately by eliminating the
source of discomfort (Nerenberg, 2002).
While communicating with the abuser, the physician
should not pass judgment on him or her. After being
accused of EM, abusers may react with feelings of denial,
guilt, blame, frustration, lack of understanding, and
indifference. Educational services should include reduc-
ing stress by improving coping skills. These include an
understanding of developmental changes with aging
(Chez, 1999). Knowledge of the progression, prognosis,
and treatment of disease may ease the caregiver’s anxiety
(Nerenberg, 2002). Caregivers should also be educated on
the importance of receiving treatment for mental health
and substance abuse (Jones et al., 1997).
The patient and caregiver should both be informed on
what is considered abuse and the laws/regulations on
elder abuse. Knowing these laws may stop some caregiv-
ers from becoming abusers (Chez, 1999).
A vital step in preventing caregiver stress and burnout
is ensuring that caregivers are made aware of the vari-
ous resources available to them. Numerous materials, fact
sheets, brochures, articles, courses, and websites provide
information and training to caregivers. Fifteen states have
comprehensive state-funded caregiver support programs.
These programs offer respite care and referral sources,
family consultation, support groups, care management,
education, and training. In 2000, the Older Americans
Act Amendments enacted the National Family Caregiver
Support Program (NFCSP), which increased the amount
of support services available to informal caregivers.
Another helpful resource for elder caregivers is the
support group. These groups are organized by both pri-
vate and public sponsors and provide an environment for
caregivers to meet and discuss the difficulties associated
with caring for elderly patients. These groups help care-
givers understand the behaviors that frustrate them, iden-
tify their “triggers,” and instruct them on stress-reducing
practices. Caregivers learn to work through the nega-
tive feelings they have about their roles in caring for the
elderly (Nerenberg, 2002).
Respite care
Respite care is another intervention to prevent burnout
and stress in caregivers and is a central part of the social
policy enacted to help prevent elder abuse. Respite
care provides relief or rest for informal caregivers and
reduces stress (de la Cuesta-Benjumea, 2010). Numer-
ous respite services are available to caregivers. Included
in some of these programs are volunteers or employ-
ees who provide relief to the caregivers. Adult day care
centers also give elders opportunities to participate
in social, recreational, or therapeutic programs. Other
programs provide temporary care for several days in
residential care facilities, nursing homes, or hospitals
(Nerenberg, 2002).
Case management
Case management is a model for providing services
that was developed for persons with various medical
and social needs. A case manager performs compre-
hensive “functional assessments” on patients to deter-
mine the types of interventions and assistance they
require. They then help coordinate the patient’s care,
assisting the patient and the family in accessing the
resources and services they require (Table 30.3). They
closely monitor the patient and intervene as necessary
(Nerenberg, 2002).
Table 30.3 Addressing caregiver burnout
Risk factors for caregiver burnout Caregiver resuscitation
Caregiver unclear on patient Regular evaluation of situation
prognosis and expectations for by provider
disease progression
Caregiver lack of financial resources Financial resources optimized
Caregiver lack of social support and Respite care coordination
respite
Patient with significant behavioral, Optimization of medication,
cognitive, or physical disabilities treatment, and assistant
devices
Source: Hohler (2010).
Future directions
Researchers can contribute to the current understanding
of caregiver stress and its relationship to abuse in the fol-
lowing ways.
1 Improve the reliability and validity of studies on the re-
lationship between caregiver stress and elder abuse.
2 Conduct research on the impact of providing support
to caregivers and its effect on EM, and identifying effec-
tive caregiver coping strategies (Nerenberg, 2002).
Summary
Abuse is a common problem in the elderly that will likely
increase as the population ages. By providing education
to caregivers and the abused, improving identification
of abuse, and intervening in EM cases, physicians act as
advocates for the elderly patient. Physicians should take
on the role of empowering elders to advocate for them-
selves and to protect their rights (Daichman et al., 2010).
Research is needed in this field to improve our under-
standing of the development and prevention of EM.

Vignettes
Case 1
A 75-year-old woman is brought to the emergency
department (ED) from her nursing home for fever. She
has a history of a left middle cerebral artery stroke with
right-sided weakness and mild aphasia. On examination,
she reports that she lies in bed most of the day, as the
nursing home is understaffed. She requires assistance to
get to the bathroom and is not always able to get help.
She has frequent accidents as a result. She complains of
pain on her backside. The attending ED calls the facil-
ity, where they report that she has had fever, confusion,
and agitation for the past 3 days. When asked to clarify
her medications, the nurse reports that she has missed
several doses of her BP meds. The nurse reports that
she has been in bed most of the day for the past 2 weeks
because “it takes a lot of work to sit her up and walk
her.” BP is 210/90, HR is 110, and is febrile. On examina-
tion, the patient is alert and oriented to person and place,
but has difficulty with the date. She has some difficulty
remembering her medications but thinks they may have
been missed on several occasions. She is able to follow
commands but has some difficulty with attention. She
has some difficulty with naming and slowness with rep-
etition. She is noted to have right-sided weakness of her
face and arm, with some increase in tone on the right. She
is able to stand with assistance. A stage 4 decubitus ulcer
is noted on her backside that appears infected.
This patient is suffering from neglect. She is missing her
medications and is not being assisted in her toileting. As a
result, she is hypertensive and has a decubitus ulcer that
is infected. The ED staff should document the situation,
including the call to the nursing home, and should con-
tact the ombudsman to report the nursing facility.
Case 2
An 82-year-old Parkinson’s patient is dropped off in
the ED by her son. She is an accurate historian, with
no evidence of dementia or delusions. She lives with
her son, who is her primary caretaker. Her son controls
the finances and does not provide her with enough care
and supervision at home. She is left to sit much of the
day, without assistance to the bathroom. She has fallen
numerous times and sustained a recent contusion to
the head. She reports that her son yells at her and tells
her to clean herself and fix her own meals. He provides
minimal gait assistance, stating that she needs to “learn
how to walk.” He has witnessed many falls and does not
assist her. Her Parkinson’s disease symptoms are pro-
gressing rapidly.
This case illustrates how neglect can have a direct impact
on the physical health of the patient. A thorough discus-
sion with the patient about neglect is imperative, and an
investigation by elder protective services is required. This
Elder Abuse and Mistreatment 705
patient will need to be cared for in an environment where
her physical and emotional needs can be met.
Case 3
An 85-year-old male is brought to the ED for a fall. He is
experiencing impaired cognition and difficulty ambulat-
ing. He reports that his son pushed him in the house dur-
ing an argument; he fell and hit his head. His son reports
that the patient was being loud and was frustrating him,
and he wanted him to be quiet. The patient has moderate
Alzheimer’s disease. The patient has a head CT scan per-
formed that reveals a right subdural hemorrhage.
This case illustrates physical abuse that is likely a result
of caregiver burnout. The case should be reported to Elder
Services, and the caregiver should be counseled about
burnout and given resources and education. The patient
should be transferred to a safe environment.
Appendix
Additional screening instrument
Hwalek-Sengstock Elder Abuse Screening Test (H-S/
EAST) (Hwalek et al., 1991)
1 Do you have anyone who spends time with you, taking
you shopping or to the doctor?
2 Are you helping to support someone?
3 Are you sad or lonely often?
4 Who makes decisions about your life, such as how you
should live or where you should live?
5 Do you feel uncomfortable with anyone in your family?
6 Can you take your own medication and get around by
yourself?
7 Do you feel that nobody wants you around?
8 Does anyone in your family drink a lot?
9 Does someone in your family make you stay in bed or
tell you, you are sick when you know you are not?
10 Has anyone forced you to do things you did not want
to do?
11 Has anyone taken things that belong to you without
your consent?
12 Do you trust most of the people in your family?
13 Does anyone tell you that you give them too much
trouble?
14 Do you have enough privacy at home?
15 Has anyone close to you tried to hurt you or harm you
recently?
Resources
For those being abused
National Center on Elder Abuse
302-831-3525
www.ncea.aoa.gov
706 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
For healthcare professionals
American Academy of Neurology online CME training
“Recognizing Abuse in Your Neurology Patients”
w w w. a a n . c o m / e d u c a t i o n / w e b c m e / i n d e x . c f m ?
event=program:info&program_id=5
CDC Elder Maltreatment
www.cdc.gov/violenceprevention/eldermaltreatment/
National Institute of Justice/Elder Abuse
http://www.ojp.usdoj.gov/nij/topics/crime/elder-
abuse/welcome.htm
For caregivers
ThisCaringHome.org
www.thiscaringhome.org
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 Chapter 31
Advocacy in Geriatric Neurology
Glenn Finney1 and Anil K. Nair2
1
Department of Neurology, McKnight Brain Institute, Gainesville, FL, USA
2
Clinic for Cognitive Disorders and Alzheimer’s Disease Center, Quincy Medical Center, Quincy, MA, USA

Summary
• Initial milestones for senior advocacy include the creation of social security, the establishment of the AARP (American
Association of Retired Persons), and the passage of Medicare.
• Prominent patient advocacy organizations include The American Heart Association, The National Parkinson Foundation,
Parkinson’s Action Network, and The Alzheimer’s Association. Advocacy for elder abuse is also developing.
• The federal legislative process is reviewed.
• Learning about your legislators’ backgrounds and beliefs as well as thoroughly researching your legislative proposal is
essential to successful advocacy.
• A list of talking points to consider when meeting with legislature on the topic of geriatric neurology is included.

Introduction arguably be the passage of the Social Security Act in

Before the twentieth century, most of the elderly in our
society were cared for quietly at home by their families.
Quiescence, followed by senescence, was the expectation
of people as they entered the so-called “golden years.”
However, the twentieth century saw a disruption of many
of the traditional ways of looking at family and aging,
both for good and for ill. The aging of the baby boomer
generation at the beginning of the twenty-first century
brought to the forefront the efforts of the preceding cen-
tury in advocacy for and by senior citizens in America. As
an increasing percentage of our total population consists
of people aged 55 and older, issues of economic security
and health become dominant. Many of the changes and
actions of the twentieth century have set the stage for
senior advocacy in the twenty-first century. This chapter
provides a brief overview of some of the highlights of leg-
islative and nongovernmental organization advocacy for
the elders of our society.
Beginnings: senior advocacy and
social security
Advocacy by and for seniors in America is difficult
to trace to its beginnings, although the first landmark
legislative triumph for the geriatric population could
1935. Although various pension schemes had been
around as far back as the American Revolutionary War,
this landmark piece of legislation was the first pro-
gram designed to protect the elderly from penury in
their senior years. It was a response to sky-high pov-
erty rates of more than 50% among seniors (Patterson,
1981). Some cite President Franklin Delano Roosevelt’s
championing of social security as part of the New Deal
as the first instance of presidential advocacy for the
elderly (Achenbaum, 1986). Frances Perkins, President
Roosevelt’s Secretary of Labor, was the chief architect
of the plan for social security and was herself in her
mid-50s at its passage (Downey, 2009). This part of
the New Deal faced head on the growing predicament
of a population that was beginning to outlive the tra-
ditional age of work and the grave threat of poverty
faced by seniors who had made enough through the
years for their immediate needs but had nothing left for
years—sometimes decades—of retired life. They had
no incoming stream of revenue, and their traditional
form of supportive care, children and other relatives,
was stretched to the breaking point by the widespread
financial devastation of the Great Depression. While
the national and global economy recovered from the
economic upheaval, something about the relation-
ship of family, society, and the elderly fundamentally
changed.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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708 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
Rise of organized senior advocacy:
advent of the American Association of
Retired Persons
AARP started out as the American Association of Retired
Persons. Founded for retired people aged 50 and older, it
was designed to advocate on issues for retired seniors. It
was formed in 1958 by the retired educator Ethel Percy
Andrus, having evolved from Andrus’s National Retired
Teachers Association, founded in 1947 (Ohles et al., 1997).
In 1999, as part of the organization’s recognition that
some seniors continued to work well past 50 years of age;
the association changed its name officially to its initials
AARP. AARP claims around 40 million members and is
one of the largest and best-known senior advocacy orga-
nizations in America. This kind of action, with seniors
banding together to promote their rights and care for their
own needs, was a watershed in elder advocacy. Seniors
refused to accept retirement and aging as the end of a pro-
ductive, active life, but rather sought the rights and the
tools to continue being prosperous and active well after
the traditional age for such matters.
Passage of Medicare: a major geriatric
advocacy milestone
Multiple attempts to develop a national health insurance
program were made throughout the twentieth century,
only to fail each time. However, one initiative that did
succeed transformed the landscape of health care for the
elderly: Medicare. Enacted through the Social Security
Act of 1965 as part of President Lyndon Baines Johnson’s
Great Society program, Medicare was the first program
to provide comprehensive health coverage for senior citi-
zens. The bill was signed into law at the Truman Library,
with former President Harry S. Truman and his wife in
attendance; the Trumans then received the first Medi-
care cards, in recognition of the President’s leadership in
health care during his presidency (Centers for Medicare &
Medicaid Services History).
The rising of rights movements
The 1970s saw several advocacy movements come to the
fore of American life. On the elder front, 1970 saw the birth
of the Gray Panthers, founded by Maggie Kuhn in that
year when she was forced to retire at the age of 65 (Centers
for Medicare & Medicaid Services). Indeed, a hot topic for
senior advocacy throughout the 1970s was the fight against
age discrimination, especially in the workplace. This new
militancy and legally aggressive stance by the aged reflected
the zeitgeist of the late 1960s and 1970s. Although the
approach of advocacy groups mellowed appreciably from
the 1980s on, the more assertive stance that elder advocates
assumed in the 1970s remained a part of elder advocacy.
Elders win prescription drug support
Medicare’s ability to provide health care was greatly
augmented by the passage of the Medicare Prescription
Drug, Improvement, and Modernization Act, signed into
law by President George Walker Bush on December 8,
2003. Although this act significantly expanded coverage
for care to seniors, the budgetary compromises required
to gain passage of the bill left a “donut hole” in which
seniors were often forced to pay thousands of dollars a
year for prescription drugs. This problem was exacerbated
by the dissolution of previously offered prescription drug
plans for the elderly in favor of the so-called Part D plans
(referring to the prescription drug benefit’s designation as
Part D of Medicare). Physicians and seniors often strug-
gled to find ways to cover the last several months’ worth
of medications as the end of the year slowly came. Some
pharmaceutical companies provided relief for patients in
the donut hole, but these often were strictly limited by
finances, making them no real solution to the problem.
However, seniors continued to advocate for closing the
donut hole. On March 23, 2010, President Barack Hussein
Obama signed the Patient Protection and Affordability
Care Act of 2010 (PPACA), which included a number of
provisions designed to gradually close the donut hole for
prescription drugs for seniors.
Ongoing areas of Medicare advocacy
in 2010
Closing the prescription “donut hole” remains a large part
of the present elder advocacy activities (Brown, 1998).
Other elder advocacy issues that are commonly champi-
oned in relation to Medicare are access to care, especially
ensuring availability and lack of barriers to specialty care
or care by a physician of the elder’s choice, and control of
premiums on Medicare that are financially hazardous to
seniors on a fixed income. Another rising area of advo-
cacy interest is provision of a long-term care benefit for
seniors requiring skilled nursing care.
Patient advocacy organizations
Formed during the twentieth century, most of the promi-
nent patient advocacy organizations addressing dis-
eases of aging started with mandates for education and
research into the diseases afflicting the elderly. Over time,
many branched out into patient outreach and services
and, of course, became more active in advocating to state

and federal governments for the needs of seniors afflicted
with or at risk for these diseases.
Have a heart
One of the earliest examples of a patient advocacy orga-
nization dealing with a disease that disproportionately
strikes the elderly is the American Heart Association
(AHA). Founded in New York City in 1915 as the Asso-
ciation for the Prevention and Relief of Heart Disease, its
main purpose at the time was to redress ignorance and
change perception of heart disease. At that time, heart
disease was viewed as unavoidable, and the only treat-
ment was believed to be bed rest. The AHA made great
strides over the many decades of its existence. In the mid
1990s, it focused on the challenge of stroke by forming a
new division, the American Stroke Association. The ded-
ication of the AHA to stroke prevention became perhaps
most evident with its selection of a neurologist, Ralph
L. Sacco, MD, MS, FAAN, FAHA, as its president-elect
in 2009 (American Heart Association). The American
Stroke Association partners with many other organiza-
tions in its efforts, including the American Academy of
Neurology.
Senior advocacy on the move
The National Parkinson Foundation (NPF) is one of the
oldest patient advocacy groups to address diseases of
the elderly—in this case, Parkinson’s disease and related
disorders. Founded sometime before 1957 by Mrs. Jeanne
C. Levey in Dade County, Florida, the foundation lost its
original charter in a flood of the Dade County Courthouse.
The NPF subsequently received a state charter in Florida
in 1957, which the organization uses as its official year of
incorporation (Parkinson.org.). In 1991, Joan Samuelson
founded a new network to specifically advocate for more
attention from the federal government for Parkinson’s dis-
ease, the Parkinson’s Action Network (PAN). It has been
an active advocacy group for this disease that impacts a
disproportionate number of seniors and has teamed up
in the past both with other patient advocacy groups and
with the American Academy of Neurology (Parkinson’s
Action Network PANs History).
Elder advocacy on my mind
The neurodegenerative disease that affects the largest
number of elders is Alzheimer’s disease. The first patient
advocacy group for Alzheimer’s disease was incorporated
on April 10, 1980, under the name of the Alzheimer’s Dis-
ease and Related Disorders Association. It later came to be
Advocacy in Geriatric Neurology 709
known as the Alzheimer’s Association. The Alzheimer’s
Association has several advocacy avenues for seniors and
those who care for them, including a yearly Alzheimer’s
Health Policy Forum in Washington, D.C. (Alz.org.).
Another active Alzheimer’s patient advocacy group is the
Alzheimer’s Foundation of America, which was founded
as a consortium of organizations to ensure quality of
care and excellence in service for Alzheimer’s disease
(Alzheimer’s Foundation of America).
Emerging threat to elderly: elder abuse
An emerging area of senior advocacy is in the area of
elder abuse. At the turn of the century, in part because of
the aging of the baby boom generation, it became more
obvious that some seniors were being abused by caregiv-
ers, often spouses or adult children, but sometimes other
care providers (Cooper et al., 2008). Health-care educa-
tion and provision of resources through the US govern-
ment’s Administration on Aging have been the front line
of advocacy on this sensitive issue, but more is likely to
develop in future.
The federal legislative process: how a
bill becomes a law
Although Article One of the US Constitution establishes
and defines the legislative branch of the federal gov-
ernment, it does not specify an exact protocol for cre-
ating laws. Instead, the two chambers of Congress—the
House of Representatives and the Senate—have come to
develop and use a very similar process for passing bills
into laws.
Along each step of this process, numerous opportuni-
ties arise to defeat a bill. Simple inaction can (and often
does) “kill” a bill. Once a bill has been defeated, it cannot
be reintroduced to Congress until the next congressional
session. Notably, only 10% of bills introduced to Congress
even make it out of committees for a full chamber vote,
and only 5% of the total bills introduced become laws,
although congressional productivity varies considerably
year to year.
The Process (House and Senate)
• Only a member of Congress may introduce a bill. A
sponsor introduces a bill; additional members may sign
on as cosponsors.
• Bills are referred to committees and subcommittees
with jurisdiction over the bill subject. Because committees
conduct research and hold hearings on the bills referred
to them, they also represent a prime opportunity for ad-
vocacy involvement.
• The House and the Senate have very different floor pro-
tocols. In the House, for example, discussion per legislator is
710 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
often limited and must be germane to the bill at hand. In the
Senate, however, entire bills can be amended to other bills.
Bills may also be filibustered—that is, one senator can talk
about a bill until time runs out, thereby “killing” the bill.
• Conference committees consist of legislators from both
the House and the Senate. Bills are sent to a conference
committee when both chambers approve different ver-
sions of the same bill. After a conference committee recon-
ciles the differences, the bill is sent back to both chambers
for a final vote, but it can be amended.
• A bill passed by both the House and the Senate then
becomes a law if the president signs it. If the president ve-
toes a bill, that bill may still become a law if a two-thirds
majority in both chambers votes to override the veto. A
pocket veto occurs when the president does not sign the
bill within ten days and Congress adjourns during that
time. A pocket veto cannot be overridden.
• A bill may be “killed” at any point during this process.
A bill makes it to the next step only if it has survived or
bypassed the previous one.
Keys to effective advocacy
Learn about your legislators
Before meeting with your members of Congress, it is best
to learn about their background, political beliefs, and top
issues.
Learn your legislator’s background
• Visit congress.org or similar websites to gather infor-
mation about offcials.
• Each legislator’s profile contains the following infor-
mation:
Length in office
Residence
Marital status
Previous occupation
Previous political experience
Education
Age
Birthplace
Religion
Percentage of votes received in their last election
Washington, D. C., address
Local office address
Current committee appointments
• Take the time to review all this information, as it may
be crucial to making a lasting connection during your
visit.
Note: The AHDA finds the biographical information
supplied by www.congress.org to be useful but does not
endorse the editorial content posted on this website.
Learn your legislator’s political beliefs and top issues
One of the best ways to learn about your members of Con-
gress is to review their official website. A Google search of
their name typically finds the right website. If not, you
can search using the appropriate link below:
• US House of Representatives: www.house.gov
On the website, the “Search for your legislator by zip
code” function is located in the top-left corner of your
screen.
• US Senate
Select your state using the “Find Your Senators” drop-
down menu in the top-right corner of your screen.
• Official websites for members of Congress are geared
toward informing their constituents about their top issues
and promoting past successes.
To be an effective advocate, one has to reach the listener
and make the audience care enough to take the action you
want. An advocate should also understand the context
and follow the rules of the legislative process, including
no harsh words, surprises, or assumptions. In speaking
with a legislator, start with common ground. Demon-
strate passion and commitment to the issues, and be both
credible and knowledgeable about the issue.
Effective advocacy during a legislative visit
Legislative visits offer a more substantial opportunity to
present a case for your issue. For that reason, legislative
advocacy requires a bit more preparation.
The first step is to understand what legislative out-
come your action plan requires. Are you trying to get a
new legislation passed? Are you asking for funding? Are
you trying to modify an existing proposal or law? When
you know what you are trying to achieve, you need to do
some research. Are other individuals or groups interested
in the same objective? Can you support existing legisla-
tion? Have other efforts been undertaken in the past? It is
important to assess potential partnerships and know the
context in which you will be making your request.
When you know what you want and have done your
research, the next step is to know how your local sys-
tem of government works so that you direct your efforts
appropriately. After you have identified your legislative
targets, you are ready to get to work! You have many
media for communicating your request—phone, e-mail,
letters, faxes, and in-person meetings. It is important to
consider which medium will best communicate your
point while making the best use of your own time. Some-
times a quick phone call or e-mail is ideal. At other times,
it may be worthwhile to meet with your legislator in per-
son. Whatever your course, use the following resources
to help you.
If you live outside the United States, you may need to
spend some additional time researching your own state
or national system to determine where legislative advo-
cacy is appropriate. In addition, many of these techniques
may work in other settings (educational systems, medical
and academic centers, and so on) where direct advocacy
is needed.

Being an effective advocate depends on being profes-
sional, courteous, positive, direct, clear, concise, factual,
credible, and specific. Always do your homework. Find
out where a bill is in the legislative process. Always fol-
low up with information you have promised. Visit or call
a legislator with an offer to be of assistance in the future.
Follow the KISS rule: keep fact sheets, letters, and testi-
mony short. Be sure to include contact information on fact
sheets and letters. Stay in contact with your legislator—it
is the key to establishing a relationship of mutual trust.
Treat members of the legislature as friends and intelligent
citizens. Attend legislative hearings, committee meetings,
budget mark-up sessions, and floor votes on your issues,
if appropriate. Always, always be truthful and reason-
able, and realize that everyone thinks their issue is the
most important one being considered. Thank legislators
for meeting with you and for their consideration, even if
your comments are not well received. Treat members of
the legislature as you would like to be treated.
It is common sense what not to do at these visits. Do
not give inaccurate information or purposely lie. Never
be rude to a legislator and/or his or her aide. Do not make
moral judgments based on a vote or an issue. Do not hold
grudges or be argumentative or abrasive. Do not inter-
rupt when someone is obviously busy. Do not cover more
than one subject in a contact unless asked. Do not blame
legislators for all the things that go wrong in government.
Do not be offended if someone forgets your name or who
you are, even if it is just 5 minutes after your visit.
Talking points
Use the same key messages you would for press contacts
when you have the opportunity to meet with a legislator
and/or his or her staff. Unlike a media interview, how-
ever, legislative visits offer a more substantive opportu-
nity to present a case for your issue. For that reason, leg-
islative advocacy requires a bit more preparation. Have
talking points memorized when you meet a legislator.
Talking points to consider when meeting government
officials about geriatric neurologic care are legion. The
main points are summarized next.
Geriatric neurology talking points
Congress should appropriate more funds for geriatric
neurology:
• To improve the integration and coordination of geriat-
ric neurology, mental health, and rehabilitative services
• To provide specialized geriatric care, especially includ-
ing the development of primary geriatric neurology cen-
ters at the federal and state levels
• For community-based research in geriatric neurol-
ogy, with emphasis on clinical research based on the
community for prevention and treatment, including ex-
ploration into the causes of geographic and racial dispari-
ties in geriatric neurologic care delivery
Advocacy in Geriatric Neurology 711
• To improve reimbursement practices for geriatric neu-
rologic care (particularly on-call reimbursement for neu-
rologists) to promote specialized care.
Congress should promote public awareness campaigns
regarding geriatric neurologic diagnosis, prevention,
and treatment.
Congress should support public and professional edu-
cation regarding geriatric neurologist as a primary or
principal care provider for the elderly.
Neurologists receive training in the delivery and inter-
pretation of diagnostic imaging tests.
Neurologists are the experts in the clinical use of neu-
roimaging, receiving extensive training in the anatomy,
physiology, and pathology of the nervous system. Based
on this training and daily clinical experience, neurologists
are in the best position to define and interpret appropriate
neuroimaging studies.
Neurologists provide their patients with high-quality
imaging and diagnosis.
No credible evidence indicates that imaging by neu-
rologists is being conducted inappropriately or is result-
ing in inaccurate diagnoses. In fact, a study reported in
the Journal of the American Medical Association (JAMA) in
April 1998 showed that neurologists were asked to inter-
pret computed tomography (CT) scans for signs of stroke
performed as well as radiologists.
Restricting neurologists’ diagnostic testing privileges
would reduce patient access to timely, convenient test-
ing, and disrupt the important continuity of care.
The American College of Radiology (ACR) asserts that
there is a shortage of radiologists. In certain parts of the
country, patients already face long waiting periods for
critical imaging studies. Restricting neurologists’ ability
to provide imaging services could substantially aggravate
this problem, resulting in significant delays and reduced
quality of care.
Restricting imaging self-referral access will not lower
health care costs.
JAMA published a study in September 1995 showing
that reduced reimbursement for self-referred services
did not result in a lower rate of self-referral. Even though
physicians received less money for their services, they
continued to provide the tests—because their patients
needed the service, regardless of the price.
National Institutes of Health (NIH)/National Institute
of Neurological Disorders and Stroke (NINDS) has
greatly aided in the understanding and treatment of
neurologic disorders.
Since Congress doubled funding for NIH, NINDS-
supported research has led to the identification of more
than 100 genes associated with neurologic diseases.
712 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient
Therapeutic strategies based on gene discoveries that are
already moving into human clinical testing include ones
for ALS, Huntington’s disease, ataxias, and muscular
dystrophy.
Recent NIH/NINDS appropriations have severely
impaired its ability to sustain these advances.
Federal research funding has been inadequate for some
disabling neurologic disorders. For example, funding
has been especially poor for migraine and other primary
headache disorders when considering disease prevalence,
disease-associated disability, and disease-associated eco-
nomic burden. Migraine afflicts 36 million Americans.
One in 25 Americans experiences prolonged headaches
15 or more days per month.
Few federal expenditures have paid off more than sup-
port of the NIH and NINDS.
A recent comprehensive review of all Phase III clini-
cal trials supported by the NINDS found that, estimated
conservatively, the economic benefit in the United States
from just eight of these trials exceeded $15 billion over
the course of 10 years. The study also found that new dis-
coveries from the trials were responsible for an estimated
additional 470,000 healthy years of life. These programs
prove their worth every day.
Congress should increase NIH funding.
This is the amount authorized by Congress when it
reauthorized the NIH in 2006.
Funding is also needed to complete Phase II of the Por-
ter Neuroscience Research Center.
Even with recent funding issues, the NIH continues
to streamline and improve research efforts. Examples
include Phase I of the John Edward Porter Neuroscience
Research Center, which houses neuroscientists from 11
NIH Institutes and Centers that have intramural neuro-
science programs.
Sustainable growth rate talking points
Physicians are the only providers subject to the Medi-
care Sustainable Growth Rate (SGR).
The SGR cuts payments to physicians if growth in
Medicare patients’ use of services exceeds the annual
growth in the US gross domestic product (GDP).
Medicare payments have not kept pace with physician
costs since 2001.
Multiple studies have shown that physician accep-
tance of new Medicare patients is declining. Further
cuts in annual updates will result in physicians tak-
ing fewer new Medicare patients and fewer physicians
participating in Medicare. Both of these effects will
have a negative impact on access to care for Medicare
beneficiaries.
Ask to support legislation to avert pending Medicare
physician payment cuts.
Ask the legislator to support the MedPAC’s recom-
mendation that Medicare physician reimbursement
be based on the Medical Economic Index, which mea-
sures annual practice cost increases. Paying physicians
according to the actual costs associated with treating
patients is necessary to maintain consistent access to
providers.
The AAN also asks that the policy of including the cost
of physician-administered drugs in the SGR be elimi-
nated, as these drugs are clearly not “physician services”
as defined by the law.
References
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American Heart Association. History of the American Heart Associa-
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(accessed on September 01, 2012).
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Cambridge, MA: Harvard University Press.
 Index
α-synuclein 209, 314–315, 320
AAION see arteritic anterior ischemic
optic neuropathy
AAMI see age-associated memory
impairment
AARP see American Association of
Retired Persons
AARS see Apparent Affect Rating Scale
abnormal motor movements 80
abstract thinking 92
acamprosate 607
ACC-001 580
acetylcholinesterase inhibitors (AChEIs)
352, 508, 557–558, 561–564
ACI-24 581
acoustic neuroma 533
acquired immunodeficiency syndrome
see HIV/AIDS
acquired neuropathies 501–507
ACS see delirium
activities of daily living (ADLs)
Alzheimer’s disease 201
driving impairment 688
mild cognitive impairment 188
acute angle-closure glaucoma 406, 491
acute confessional state 303–304
acute confusional state (ACS)
see delirium
acute inflammatory demyelinating
polyradiculoneuropathy (AIDP)
501–502
acute intracranial thrombotic stroke 530
acute motor sensory axonal neuropathy
(AMSAN) 501–502
acute symptomatic seizures 373
acute viral encephalitides 464–465
acyclovir 432
AD see Alzheimer’s disease
AD8 screening interview 91, 94–95
adenocarcinoma 533
ADLs see activities of daily living
Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.
ADPKD see autosomal dominant
polycystic kidney disease
Adult Protective Services (APS) 701, 702
advanced glycation end products (AGEs)
10, 13–14, 30
advocacy 706–711
Alzheimer’s disease 708
American Association of Retired
Persons 707
American Heart Association 708
concepts and definitions 706
diagnostic testing 710
elder abuse and mistreatment 708
federal legislative process 708–709
historical development 707
keys to effective advocacy 709–711
learning about legislators 709
legislative visits 709–710
Medicare and Medicaid 707, 711
NIH/NINDS support 710–711
Parkinson’s disease 708
patient advocacy organizations 707–708
prescription drug support 707
senior advocacy and social security 706
sustainable growth rate 711
talking points 710–711
understanding and treatment of
neurologic disorders 710–711
AEDs see antiepileptic drugs
affect assessment 88, 92–93
affitopes 580–581
age-associated memory impairment
(AAMI) 187
age-related macular degeneration (AMD)
75, 403–404
AGEs see advanced glycation end
products
aggression
Alzheimer’s disease 201
behavioral problems 619–620
psychopharmacology 591–592
aging
ancient versus modern environments
28–31
antagonistic pleiotropy 4, 8
apoptosis 15
autophagy 10, 14–15
brain size and neuronal loss 38–39
brain tumors 58–61
cardiovascular disease 24–26
cellular senescence 15–16
central nervous system infections 474
cerebrovascular disease 5, 23, 40, 42,
52–56, 301–302
cognitive changes in aging 28
cognitive reserve 123
concepts and definitions 3–5, 37–38
dementia and cognitive impairment
26–27, 40–52
demographic shifts 6–7
depression 295–297, 298
dietary or calorie restriction 4–5, 9–10,
15, 17–23, 32
diseases of aging 5–6, 24–32
disposable soma theory of aging 8–9
driving impairment 682–684
economic impacts 6–7
endocrine dyscrasia 16–17
evolutionary perspectives 4, 7–10,
17–18, 28–31
exercise and lifestyle 22–23, 669,
674–675
existential aspects of aging 298
expressive art therapies 628–629
functional changes to nervous system
37–67
gait disorders 127–128
genetic theories 9–10, 19
glycation, AGEs and AGE receptors 10,
13–14, 30
health care implications 3–36
historical perspectives 7–10
713
714 Index
aging (Continued)
immunosenescence 474
infections and inflammation of the
CNS 62–63
inflammation 13
lifestyle perspectives 5, 22–23, 28–31,
32
macroscopic changes 40
microscopic vascular pathology 40
mitochondria 10–13
mortality rates 5–6, 9
movement disorders 27–28, 56–58
normal aging and disease 38, 39–40
obesity 5, 23
oxidative stress 4, 9, 10–13
pharmacodynamics 590
pharmacokinetics 586–590
phenotypes of aging 10–17
polyphenols 23–24
prevention of diseases of aging 6–7,
32–33
promotion of diseases of aging 28–32
psychopharmacology 584, 586–590
sarcopenia 15
sensory disorders 395–396, 400
sleep disorders 348
synaptic and dendritic changes 39
trauma 63
vertigo and dizziness 378
white matter changes 39
agitation 591–592
agoraphobia 602
agraphias 91–92
AHA see American Heart Association
AHEI see Alternate Healthy Eating Index
AICA see anterior inferior cerebellar
artery
AIDP see acute inflammatory
demyelinating
polyradiculoneuropathy
AIDS see HIV/AIDS
AION see anterior ischemic optic
neuropathy
alcohol
dependence 606–607
diet and nutrition 649, 652, 657
gait disorders 131
withdrawal 607–608
alprazolam 600
ALS see amyotrophic lateral sclerosis
Alternate Healthy Eating Index (AHEI)
653
Alzheimer’s disease (AD) 200–207
advocacy 708
aging 26–27, 39–40, 41–43
amyloid hypothesis 572–581
amyloid imaging 162–168
behavioral problems 615–616, 622–623
biomarkers 204
changes in normal aging 39–40
clinical features and diagnostic
evaluation 200–203
clinical laboratory investigations 172,
173, 202
cognitive reserve 118–120, 122–123
concepts and definitions 184–185, 200
cortical atrophy 140–141
delirium 477–478
depression 297
diagnostic criteria 42–43, 202–205, 555
diet and nutrition 645, 646–651
differential diagnosis 189–195, 201,
203–205, 208, 212–213, 245, 283–285,
334–335
driving impairment 685–686, 688, 693
elder abuse and mistreatment 704
epidemiology 205
epilepsy 370
evidence-based pharmacologic
treatment 555–560
exercise and lifestyle 667–671,
673–675, 676
expressive art therapies 630–639
functional imaging 146–156
genetics 205–206
hippocampal atrophy 138–140
immunotherapy 554, 572–583
macroscopic appearance 41
medical foods 560
microscopic findings 41–42
neurologic examination 201–202
neuropsychology 111
olfactory disorders 440
preclinical stage 203
primary prevention or treatment
556–557
prodromal features 195
secondary prevention or treatment 555,
557–560
sleep disorders 351–352
structural neuroimaging 138–141
symptomatic therapy 557–558
symptoms 200–201
ventricular enlargement 141
visual disorders 419
white matter changes 141
amaurosis fugax 406–407
aMCI see amnestic mild cognitive
impairment
AMD see age-related macular
degeneration
American Association of Retired Persons
(AARP) 707
American Heart Association (AHA) 708
amnestic mild cognitive impairment
(aMCI)
aging 44, 48
amyloid imaging 164, 167
concepts and definitions 184, 187,
189–190
diagnostic criteria 188, 191
gait disorders 127
predictors of outcomes 193–195, 196
structural neuroimaging 140–141
treatment 195
AMPK signalling pathway 18–21
AMSAN see acute motor sensory axonal
neuropathy
amyloid hypothesis
amyloid-β plaques and neurofibrillary
tangles 39–40, 41–42
exercise and lifestyle 668–669
immunotherapy 572–581
amyloid imaging 137, 162–169
biomarkers 162–163
(11)C labeled agents 137, 163
case studies 165–167
concepts and definitions 137, 162–163
(18)F labeled agents 137, 164–165
mild cognitive impairment 192
amyloid precursor protein (APP) 206, 572
amyotrophic lateral sclerosis (ALS) 493
aging 50–51, 57
diagnostic criteria 494
differential diagnosis 334–335
epidemiology and clinical features 494
neurologic examination 73
treatment and prognosis 494–495
AN1792 573–577
anaplastic astrocytomas 59
aneurysms 519, 521–527
anhedonia 290–291, 295
animal prion diseases 276–277
anosmia 75
anoxic encephalopathy 55
antagonistic pleiotropy 4, 8
antecedent control model 621
anterior inferior cerebellar artery (AICA)
426–427
anterior ischemic optic neuropathy
(AION) 408–412
anterior odontoid screw fixation 537–538
anti-amyloid-β 572–581
antibiotics 461–462
antidepressants 593–597
adverse effects and drug interactions
594–595
clinical usage 595–597, 602–603, 607, 609
indications 595
pharmacokinetics and
pharmacodynamics 593–594

antiepileptic drugs (AEDs) 374–375
antihypertensive therapy 307
antioxidants
aging 11, 12–13, 23–24
diet and nutrition 646–647, 651,
653–654
anti-platelet therapy 307
antipsychotics 590–593
adverse effects and drug interactions
591
clinical usage 591–593
indications 591
pharmacokinetics and
pharmacodynamics 590–591
anxiety
dementia with Lewy bodies 218
Mental Status Examination 93
Parkinson’s disease 317
Parkinson’s disease dementia 218
psychopharmacology 597–603
anxiolytics 597–603
adverse effects and drug interactions
598–599
clinical usage 599–600, 608
indications 599
monitoring treatment 600
pharmacokinetics and
pharmacodynamics 597–598
apathy 93
aphasias
neurologic examination 73–74, 89, 91
neuropsychology 103
ApoE see apolipoprotein E
apolipoprotein E (ApoE) gene 173,
192–193
apoptosis 15
APP gene 206, 572
Apparent Affect Rating Scale (AARS) 634
aprosodia 73
APS see Adult Protective Services
aqueductal stenosis (AS) 281
argyrophilic grain disease 352
aripiprazole 563
arrhythmias 362
art therapy 632–636
arterial spin labeling (ASL) 154, 156
arteriosclerosis 40, 53
arteriovenous malformation (AVM)
522–523
arteritic anterior ischemic optic
neuropathy (AAION) 408, 410–412
AS see aqueductal stenosis
aseptic meningitides 462–463
ASL see arterial spin labeling
aspirin 307, 565
astrocytomas 58–59
astrogliosis 371
ataxia 128, 131, 132
atherosclerosis 26, 40, 52–53
atlantoaxial subluxations 386
attention 90, 101–102
atypical pain 546
audiometry 398, 422, 433–434
auditory agnosia 436
auditory disorders 398–399, 419–436
central hearing disorders 436
cerumen impaction 419–420
clinical laboratory investigations 398
conductive hearing disturbances
419–422
herpes zoster oticus 429–432
neurologic examination 77–78
noise-induced hearing loss 423–425
objective tinnitus 420–421
ototoxicity 432–433
presbycusis 423
sensorineural hearing disturbances
422–436
subjective tinnitus 423, 424, 433–436
sudden deafness 423, 425–428
superficial siderosis 428–429
auditory hallucinations 436
automatic speech 102
autonomic dysfunction 362–363
autonomic failure 318, 319, 362–363
autophagy 10, 14–15
autosomal dominant polycystic kidney
disease (ADPKD) 522
AVM see arteriovenous malformation
β-blockers 326–327
β-carotene 646, 654–655
bacterial brain abscesses 466–467
bacterial meningitidis 62, 460–462, 463
BAER see brainstem auditory evoked
response
balance
cerebrovascular disease 302
normal pressure hydrocephalus
282–283
vertigo and dizziness 378–394
ballooned neurons 48–49
bapineuzumab 576–579
basilar impression 386
Bayes’ theorem 171–172
BBB see blood–brain barrier
BCB see blood–cerebrospinal fluid
barriers
BDNF see brain-derived neurotrophic
factor
behavioral problems 613–627
aggravating factors 617–620
Alzheimer’s disease 615–616, 622–623
antecedent control 621
Index 715
behavior assessment 88
caregiving 619–622
clinical repercussions 614
common behavioral problems 614
concepts and definitions 613
confusion 618
delirium 618
disinhibition 107–108, 201
environmental interventions 621
environmental stressors 619
evidence-based treatment research 622
family/caregiver education and
training 621–622
frontotemporal dementia 616–617,
623–624
good care/comfort care model 620
individualized approaches to
treatment 622
learning theory 621
Lewy body dementia 616, 623
management techniques 702–703
medication-induced 618
nonpharmacologic treatment 620–624
pain 619
Parkinson’s disease 617, 624
prevalence rates 613–614
primary progressive aphasia 261–262
psychosocial interventions 622
rationale for nonpharmacologic
approaches 614–615
unmet needs 620–621
vascular dementia 616, 623
behavioral variant frontotemporal
dementia (bvFTD)
aging 48
behavioral problems 616–617
clinical features 239–240
clinical–pathologic correlation 244
concepts and definitions 185, 239
diagnostic criteria 246
differential diagnosis 239
functional imaging 151
structural neuroimaging 141
benign paroxysmal positional vertigo
(BPPV) 379–381
bent spine syndrome 129
benzodiazepines 597–603, 608, 609–610
BF-227 163
bibliotherapy 637–639
bilateral vestibular loss (BVL) 384–385
Binswanger syndrome 227, 230–231
biometrics 72
blood-oxygenation-level-dependent
imaging (BOLD) 154–155
blood–brain barrier (BBB) 459, 474
blood–cerebrospinal fluid barriers (BCB)
459
716 Index
body mass index (BMI) 23
BOLD see blood-oxygenation-level-
dependent imaging
Bonnet syndrome 413–414, 415–416
botulinum toxin 327–328
BPPV see benign paroxysmal positional
vertigo
brachial plexopathy 499–500
brain-derived neurotrophic factor
(BDNF) 288, 668
brain reserve model 118–120
brain size 38–39
brain tumors see neurooncology
brainstem auditory evoked response
(BAER) testing 425, 427–428, 434
brainstem strokes 386–388
branch retinal artery occlusion (BRAO)
407–408
Broca’s aphasia 73–74, 103
bupropion 609
burning mouth syndrome 442
burnout 700, 703
buspirone 597–600
bvFTD see behavioral variant FTD
BVL see bilateral vestibular loss
(11)C labeled agents 137, 163
C-reactive protein (CRP) 175, 176, 411–412
CAA see cerebral amyloid angiopathy
CAD-106 581
CADASIL 225, 227–228, 230–231
caffeine 649, 652
calcium 652, 657–658
calculation abilities 92
calorie restriction see dietary or calorie
restriction
CAM see confusion assessment method
camptocormia 316–317
canalolith-repositioning procedures 381
cancer
neuromuscular disorders 499–500,
510–511
neurosurgical care 539
see also neurooncology
carbamazepine 374–375, 543
cardiac syncope 361–362, 365
cardiovascular disease (CVD)
aging 24–26
diet and nutrition 646, 656, 658
exercise and lifestyle 668
physical examination 73
caregiving
behavioral problems 619–622
burnout 700, 703
driving impairment 690–691
elder abuse and mistreatment 699–700,
702–703
carotid angioplasty and stenting (CAS)
307–308, 530
carotid endarterectomy (CEA) 307–308,
528–530
carotid occlusive disease 528–530
carotid sinus hypersensitivity (CSH) 216,
361
carotid surgery 307–308
cART see combination antiretroviral
therapy
CAS see carotid angioplasty and stenting
case management 703
cataracts 75, 401
catatonia 602
catechins 654–655
cautious gait 129
CBD see corticobasal degeneration
CBGD see corticobasal ganglionic
degeneration
CDR see Clinical Dementia Rating
CEA see carotid endarterectomy
cellular senescence 15–16
central gustatory disturbances 441–443
central hearing disorders 436
central nervous system (CNS) infections
459–476
acute viral encephalitides 464–465
blood–brain barrier 459, 474
concepts and definitions 459–460
cutaneous herpes zoster and
complicated zoster syndromes
469–470
HIV/AIDS in the aging population
471–473
immunosenescence 474
infectious meningitidis 460–464
intracranial abscesses 466–468
myelitides and spinal canal infections
468–469
septic encephalopathy 470–471
central nervous system (CNS) lesions
385–386, 436
central nervous system (CNS) lymphoma
533
central olfactory disturbances 438–440
central retinal artery occlusion (CRAO)
407–408
central visual disturbances 414–419
cerebellar ataxia syndromes 389–390
cerebellar examination 82–83
cerebellar strokes 386–388
cerebellar tremor 329
cerebral amyloid angiopathy (CAA)
aging 40, 42, 53–55
immunotherapy 572, 579
cerebral aneurysms 527
cerebral injury 178–179
cerebral perfusion 668
cerebrolysin 566
cerebrospinal fluid (CSF)
central nervous system infections
460–464, 468–469
chronic subdural hematomas 520–521
clinical laboratory investigations
172–179
dementia with Lewy bodies 213
frontotemporal dementia 246
immunotherapy 577
mild cognitive impairment 192, 194
normal pressure hydrocephalus
281–282, 532–533
Parkinson’s disease 320
prion diseases 272–273
vertigo and dizziness 391–392
cerebrovascular accidents (CVAs)
neurologic examination 73, 76–77, 83
neuropsychology 104, 107
cerebrovascular disease (CVD) 301–311
aging 5, 23, 40, 42, 52–56, 301–302
Alzheimer’s disease 200, 210
atypical presentations 302–303
biologic changes with aging 301–302
clinical laboratory investigations 170,
175–176
clinical presentations 302
concepts and definitions 301
depression 296
gustatory disorders 442
hospitalization 302, 303
Mental Status Examination 87–88
neurologic examination 74
normal pressure hydrocephalus 282
specific diseases 303–309
treatment and outcome data 306–309
vascular cognitive impairment 224–235
vascular depression hypothesis 309
see also individual disorders
cerumen impaction 419–420
cervical venous hum 421
cervicogenic headache 485, 490–491
characteristic model of memory 105
Charcot–Marie–Tooth (CMT) syndrome
506–507
CHEIs see cholinesterase inhibitors
chemotherapy 464, 534, 535–536
CHF see congestive heart failure
Chiari malformations 386
CHMP-2B gene 245
cholesterol-lowering agents 513–514
cholinesterase inhibitors (CHEIs) 215–219
chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) 503
chronic subdural hematomas 519,
520–521

chronic traumatic encephalopathy 63
chronic wasting disease (CWD) 276–277
CIND see cognitive impairment no
dementia
CIPD see chronic inflammatory
demyelinating
polyradiculoneuropathy
circadian rhythms 347, 348
CJD see Jakob–Creutzfeldt disease
CK-BB see creatine kinase
Clinical Dementia Rating (CDR) scale 94,
187, 190
clinical laboratory investigations 170–180
Alzheimer’s disease 172, 173, 202
Bayes’ theorem 171–172
body fluids used 172
cerebral injury 178–179
cerebrovascular disorders 175–176
concepts and definitions 170–171
delirium 177, 481
depression 176–177
epilepsy 373
frontotemporal lobar degeneration 172,
173–174
genetic disorders 178
headaches 176
hemorrhage 175
HIV/AIDS 177
infarction 175
Jakob–Creutzfeldt disease and prion
disorders 172, 174
laboratory test interpretation 171–172
Lewy body disease 172, 173
normal pressure hydrocephalus 174
paraneoplastic disorders 177–178
Parkinson-plus syndromes 174–175
Parkinson’s disease 173, 174
secondary dementia 172–173
sensory disorders 398
syncope 363–364
vascular cognitive impairment 172, 173
vasculitis 175–176
clock-drawing test 92, 108–110
clonus 82
clopidogrel 565
clorazepam 564
closed-angle glaucoma 405
closed head injury 370
Clostridium botulinum toxin 422
clozapine 563
cluster headaches 485, 488
CMT see Charcot–Marie–Tooth
CMV see cytomegalovirus
CNS see central nervous system
coenzyme Q10 652–653
coffee 649, 652, 655–656
cognitive impairment see individual disorders
cognitive impairment no dementia
(CIND) 187, 188, 224–226
cognitive rehabilitation 675
cognitive reserve 118–125
brain reserve model 118–120
concepts and definitions 118–121
exercise and lifestyle 673–674
implications for diagnosis and
prevention 123
neural markers in healthy elderly and
Alzheimer’s patients 122
neural markers in healthy young and
older adults 121–122
neural markers in young, healthy
adults 121
cognitive status assessment see
Mental Status Examination;
neuropsychology
cognitive training 674–675
coiled bodies 336–337
combination antiretroviral therapy
(cART) 463, 471–473
communication 88–89, 102–104
competency 100
complicated zoster syndromes 469–470
comprehension 102–103
compression fractures 519, 539–542
computed tomography angiography
(CTA) 523–524, 528–529, 531
computed tomography (CT)
aneurysms 523–525
auditory disorders 421, 429
central nervous system infections 461,
466, 469
chronic subdural hematomas 520–521
compression fractures 540
infarction 175
neuromuscular disorders 498
normal pressure hydrocephalus 282,
532–533
odontoid fractures 536–537
stroke 528
concentration 90, 101–102
concrete thinking 107
conditioning 105
conduction aphasia 104
conductive disturbances
auditory 419–422
gustatory 440–441
olfactory 437
visual 400–402
confusion 618
confusion assessment method (CAM) 481
congestive heart failure (CHF) 362
consciousness level 87
construction skills 92
coordination tests 82–83
Index 717
cortical atrophy 140–141
cortical deafness 436
corticobasal degeneration (CBD) 343–345
aging 48–50
clinical features 343–344
concepts and definitions 313, 343
diagnostic testing 344
differential diagnosis 334–335, 343, 344
epidemiology 343
neuropathology 345
structural neuroimaging 142
treatment 344–345
corticobasal ganglionic degeneration
(CBGD) 112–113, 174–175, 352
corticobasal syndrome (CBS) 239, 242
corticosteroids 508–509, 514–515
corticotropin-releasing factor (CRF) 288,
292–295
CR see dietary or calorie restriction
cranial nerves 74–78
cranial neuropathies 76
craniocervical junction syndromes 386
CRAO see central retinal artery occlusion
creatine kinase (CK-BB) activity 179
creative aging 628–629
CRF see corticotropin-releasing factor
CRP see C-reactive protein
cryptococcal meningitis 464
cryptococcosis 62
CSF see cerebrospinal fluid
CSH see carotid sinus hypersensitivity
CT see computed tomography
cutaneous herpes zoster 469–470
CVAs see cerebrovascular accidents
CVD see cardiovascular disease
CWD see chronic wasting disease
cyclophosphamides 509, 511
cyclosporines 511
cytochrome P450 (CYP450) 587–589, 594,
599
cytomegalovirus (CMV) 464–465
DA see dopamine
dairy products 652, 657
dance therapies 636–637
Dandy’s syndrome 384–385
DASH see Dietary Approaches to Stop
Hypertension
DAT see dopamine transporter
DBS see deep brain stimulation
de Kooning, Willem 635
declarative memory 105
decompressive hemicraniectomy 531
deep brain stimulation (DBS)
Parkinson’s disease 320, 546–550
progressive supranuclear palsy 339
tremor disorders 328
718 Index
deep tendon reflexes 81–82
default mode network (DMN) 155–156
delirium 477–484
behavioral problems 618
cerebrovascular disease 302, 303–304
clinical laboratory investigations 177,
481
clinical presentations 481–482
concepts and definitions 477
confusion assessment method 481
diagnostic criteria 479, 481
epidemiology 477–478
etiology 480–481
future directions and research 483
medication-induced delirium 480
neuropsychology 113
pathophysiology 478
psychopharmacology 592
risk factors 478–480
treatment 482–483
visual disorders 419
dementia with Lewy bodies (DLB)
208–223
aging 40, 46–47
clinical features 208, 214, 217–219
clinical laboratory investigations 173
cognition and function 215–216
concepts and definitions 185, 208
diagnostic criteria 47, 209–214
differential diagnosis 203–205, 208–214,
317–318, 334–335
dopamine transporter SPECT imaging
211
evidence-based pharmacologic
treatment 561–562
falls and dysautonomia 219
fluctuating cognition 210, 218
frequency 209
functional imaging 151–152
genetics 214–215
improving diagnostic accuracy 210–211
microscopic and macroscopic
appearances 46–47
mood disorders 218
neurochemistry 209
neuropathology 208–209
neuropsychology 112
olfactory disorders 439
parkinsonism 218–219
predictors of treatment response
216–219
psychopharmacology 592
REM sleep behavior disorder 210–211
revised consensus diagnostic criteria
211–214
severe neuroleptic sensitivity 211
sleep disorders 353
structural neuroimaging 142
treatment 215–219
visual disorders 418–419
dementias see individual disorders
dendrites 39
depression 287–300
aging 295–297, 298
Alzheimer’s disease 297
cerebrovascular disease 309
clinical laboratory investigations
176–177
common factors promoting late-life
depression 295–297
dementia with Lewy bodies 218
diagnostic criteria 290–291
epidemiology 287
evolutionary perspectives 289–290
exercise and lifestyle 672
existential aspects of aging 298
inflammation 296–297
interactive depressive matrix 293–294
lifestyle perspectives 298
mechanistic integration 288–289
media representations 288
Mental Status Examination 92–93
mild cognitive impairment 191
monoamine deficiency hypothesis
291–292
multifaceted separation-distress
hypothesis 289
neuropsychology 113
neuroscientific overview 291–292
pain 296
Parkinson’s disease 317, 319
Parkinson’s disease dementia 218
problem space of depression 287–289
psychopharmacology 593–597
social brains 292–295
syndrome versus chemical imbalance
288
treatment 297–298
dermatomal sense 81
dermatomyositis 510–511
dexamethasone 462
DHA see docosahexaenoic acid
diabetes mellitus
neuromuscular disorders 500–501,
505–506
syncope 363
vascular cognitive impairment 232
diabetic amyotrophy 500–501
diabetic neuropathies 505–506
diet and nutrition 645–666
alcohol 649, 652, 657
Alzheimer’s disease 645, 646–651
antioxidants 646–647, 651, 653–654
B vitamins 647, 650, 651, 653, 656
coenzyme Q10 652–653
coffee, tea and caffeine 649, 652,
655–656
concepts and definitions 645–646
dairy products 652, 657
dietary patterns 649–650, 653, 658–659
fish and unsaturated fatty acids
647–648, 650, 651–653, 655, 658–659
fruit, vegetables and fiber 647, 650, 651,
655, 656–657
Parkinson’s disease 645, 651–653
stroke 645, 653–659
Dietary Approaches to Stop
Hypertension (DASH) 650–651,
658–659
dietary or calorie restriction (DR/CR)
aging 4–5, 9–10, 15, 17–23, 32
calorie restriction mimetics 20–22, 32
evolutionary and animal models 17–19
genes and pathways 19
mammalian target of rapamycin 18–22
variants and mutants 22
diffuse Lewy body disease (DLBD) 27–28
diffusion tensor imaging (DTI) 142
diffusion-weighted imaging (DWI)
central nervous system infections
466–467
degenerative dementias 141
prion diseases 273–274
stroke 528
digital subtraction angiography (DSA)
523–524
disability 127
discrimination tests 81
disease modifying treatment 246–247
disequilibrium see balance; vertigo and
dizziness
disinhibition 107–108, 201
disposable soma theory of aging 8–9
disulfuram 607
Dix–Hallpike maneuver 379–380
dizziness see vertigo and dizziness
DLB see dementia with Lewy bodies
DLDB see diffuse Lewy body disease
DMN see default mode network
docosahexaenoic acid (DHA) 647–648,
651
donepezil 195, 216, 558–563, 566
dopamine (DA) neurons 17
dopamine transporter (DAT) imaging
211, 344
DR/CR see dietary or calorie restriction
drama therapies 636–637
driving impairment 681–697
activities of daily living 688
aging drivers 682–684
caregiver burden and concerns 690–691

clinical assessment of older drivers
684–689
cognitive changes and assessment
683–686, 687–688
concepts and definitions 681–682
driving restriction and driving
retirement 689–691
interventions to promote safety and
mobility 692–693
legal ramifications 691–692
medical assessment 686
mobility/strength changes and
assessment 684, 687
performance-based evaluations 688
physician decision on whom to report
691–692
physician requirements to report at
risk elders 691
road tests 689
road traffic accident statistics 681–682
role of geriatric neurologist 693
sensory changes and assessment
682–683, 686–687
simulators 688
social implications 689–690
support and resources 693–695
drug-induced tremor 328–329
DSA see digital subtraction angiography
DTI see diffusion tensor imaging
DWI see diffusion-weighted imaging
dysarthria 73
dysautonomia 219
dyskinesias 316–317, 319
dysmetria 82–83
dysphasias 102
dystonias 316–317, 333–334, 343
EBT see evidence-based treatment
ECG see electrocardiography
ECT see electroconvulsive therapy
education 673–674, 702–703
EEG see electroencephalography
eicosapentaenoic acid (EPA) 647–648, 651
Einstein Aging Study 127–128
ELD see external lumbar drainage
elder abuse and mistreatment 698–705
advocacy 708
caregivers 699–700, 702–703
case management 703
case studies 704
concepts and definitions 698–699
cycle of mistreatment 698
documentation and legal requirements
701–702
future directions 703
incidence and prevalence 698
interventions 702–703
neglect 699–701
nursing homes 700
reporting 702
resources 704–705
risk factors 699–700
screening for abuse 700–701, 704
signs and symptoms 701
special situations 700
electrocardiography (ECG) 360, 363–364
electroconvulsive therapy (ECT) 596, 602
electroencephalography (EEG)
corticobasal degeneration 344
epilepsy 372–373
prion diseases 272
sleep disorders 346–347
syncope 360, 364
electrolytes 657–658
electromyography (EMG) 347
electrooculography (EOG) 347
elimination half-life 590
EMG see electromyography
emotional abuse 699–701
encoding 105–106
end-of-life care 6–7
endocrine dyscrasia 16–17
endothelial nitric oxide synthase (eNOS)
25–26
environmental interventions model 621
environmental stressors 619
EOG see electrooculography
EPA see eicosapentaenoic acid
ependymomas 60
epilepsy 369–377
clinical diagnosis 371
clinical laboratory investigations 373
clinical studies of drug therapy
374–375
concepts and definitions 369
differential diagnosis 359–360, 372–373
epidemiology 369–370
etiology of geriatric epilepsy 370–371
mechanisms of seizures 371
syndromes and seizure classification
373
treatment 374–375
epileptic vertigo 385–386
epileptic visual hallucinations 415
episodic ataxia syndromes 390
episodic memory 104–106, 105
Epworth sleepiness scale (ESS) 347
erythrocyte sedimentation rate (ESR) 176,
411–412
ESS see Epworth sleepiness scale
essential tremor (ET)
concepts and definitions 312–313,
325–326
differential diagnosis 314, 325–326
Index 719
pathophysiology 326
treatment 326–328
ethical issues 195–196
evidence-based pharmacologic treatment
Alzheimer’s disease 555–560
concepts and definitions 554
dementia with Lewy bodies 561–562
frontotemporal dementia 561
medical foods 560
overall approach to pharmacotherapy
of dementia 562–564
Parkinson’s disease dementia 566–567
primary prevention or treatment 555–557
pseudobulbar affect 567–568
secondary prevention or treatment 555,
557–560
symptomatic therapy 557–558
vascular dementia 565–566
evidence-based treatment (EBT) 622
evolutionary perspectives
aging 4, 7–10, 28–31
depression 289–290
executive function
Alzheimer’s disease 200
Mental Status Examination 92
neuropsychology 106–108
exercise and lifestyle 667–680
aging 5, 22–23, 28–31, 32
cognitive rehabilitation 675
concepts and definitions 667
depression 298
disease progression 670–671
education and lifetime cognitive
experiences 673–674
impact of exercise in older age 669–670
later-life cognitive experiences and
cognitive training 674–675
lifetime exercise and dementia 668–669
lifetime social support and dementia
risk 676
mental exercise 672–675
non-AD dementia syndromes 671–672
physical exercise 667–672
potential modifying factors 672
primary prevention 668–669, 673–674,
676
secondary prevention 669–670, 674–
675, 676
social interaction 675–676
tertiary prevention 670–671, 675, 676
expressive art therapies 628–641
Alzheimer’s disease 630–639
art therapy 632–636
concepts and definitions 628–629
creative aging 628–629
dance/movement and drama therapies
636–637
720 Index
expressive art therapies (Continued)
frontotemporal dementia 633, 635–636
music therapy 629–632
Parkinson’s disease 637
poetry/bibliotherapy, storytelling and
reminiscence 637–639
expressive speech 102
external lumbar drainage (ELD) 532–533
extracellular amyloid deposition 572
extraocular movements 76
extraparenchymal abscesses 468
(18)F labeled agents 137, 164–165
facial droop/asymmetry 77
facial movement 77
facial pain syndromes 519, 542–546
facial recognition 110
falls
cerebrovascular disease 302
dementia with Lewy bodies 219
gait disorders 126–127, 129
Parkinson’s disease dementia 219
syncope 365
familial Jakob–Creutzfeldt disease (fCJD)
174, 267, 270, 274
fatal familial insomnia (FFI) 267, 270,
274–275, 353
fCJD see familial Jakob–Creutzfeldt
disease
FDDNP 164
FDG-PET see positron emission
tomography
federal legislative process 708–709
FFI see fatal familial insomnia
fiber 647, 656–657
financial abuse 699–700
fish 647–648, 650, 655
FLAIR see fluid attenuated inversion
recovery
flavonoid 654–655
florbetaben 165
florbetapir 164–165
fluctuating cognition 210, 218
fluid attenuated inversion recovery
(FLAIR) 273–274, 466, 535
fluoxetine 564
flutemetamol 164
fMRI see functional magnetic resonance
imaging
focal motor neuron disease 495–496
folic acid 647, 656
Folstein Minimental State examination
283–284
fragile X ataxia tremor syndrome
(FXTAS) 389–390
frontal gait 128, 131
frontal lobe injuries 108
frontotemporal dementia (FTD) 239–250
behavioral problems 616–617, 623–624
clinical–pathologic correlation 243–245
concepts and definitions 185, 239
diagnostic criteria 245–246
differential diagnosis 190, 203–205, 239
epidemiology 239
evidence-based pharmacologic
treatment 561
expressive art therapies 633, 635–636
functional imaging 240–241
genetics 245
neuropsychology 111–112, 241
pathology 242–245
sleep disorders 352
structural neuroimaging 141–142,
240–241
subtypes 239–245
treatment 246–247
see also individual spectrum disorders
frontotemporal lobar degeneration
(FTLD)
aging 40–41, 48–51
ALS-dementia 51
amyotrophic lateral sclerosis 50–51, 57
clinical laboratory investigations 172,
173–174
corticobasal degeneration 48–50
differential diagnosis 239, 245–246
FTLD-tau and tauopathies 48, 243, 246
FTLD-ubiquitin 50–51
functional imaging 151
Pick’s disease 48
progressive supranuclear palsy 49–50
fruit 647, 650, 651, 655
FTD see frontotemporal dementia
FTLD see frontotemporal lobar
degeneration
functional disorders 129
functional imaging 136–137, 146–161
Alzheimer’s disease 146–156, 162–168
cognitive reserve 120, 121–123
concepts and definitions 136–137, 146
corticobasal degeneration 344
dementia with Lewy bodies 151–152,
211, 212–213
frontotemporal dementia 240–241
frontotemporal lobar dementia 151
mild cognitive impairment 147–149,
162–167, 192–193
normal pressure hydrocephalus 282
Parkinson’s disease 315
primary progressive aphasia 254–255,
257–258, 259–260
progressive supranuclear palsy 338
vascular dementia 152
see also individual techniques
functional limitations 100
functional magnetic resonance imaging
(fMRI)
cognitive reserve 121–122
dementia 137, 146, 154–156
mild cognitive impairment 192–193
perfusion fMRI using arterial spin
labeling 156
response to memory tasks 155
resting state fMRI 155–156
fungal meningitides 463
fused in sarcoma (FUS) pathology 243
FXTAS see fragile X ataxia tremor
syndrome
gamma-aminobutyric acid (GABA) 288,
292
gabapentin 327
GAD see generalized anxiety disorder
gag reflex 78
gait disorders 126–135
adverse outcomes 126–127, 129
aging of walking 127–128
case discussions 131–133
clinical classification 128–129
epidemiology 126
etiology, diagnosis and workup
130–131
expressive art therapies 632
historical perspective 126
neurologic examination 83–84
normal pressure hydrocephalus
282–283
performance-based tests 130
progressive supranuclear palsy 333
psychogenic gait disorders 129
quantitative assessment 129
timed gait 129–130
walking while talking 130
galantamine 558, 559–563
gantenerumab 580
GBM see glioblastomas multiforme
GCA see giant cell arteritis
gender 672
general appearance 88
generalized anxiety disorder (GAD) 600,
602
genetic testing 173, 178
genetics
aging 9–10, 19
Alzheimer’s disease 205–206
clinical laboratory investigations 178
dementia with Lewy bodies 214–215
frontotemporal dementia 245
Parkinson’s disease dementia 214–215
prion diseases 267, 270, 274–275
progressive supranuclear palsy 337–338

genome-wide association studies
(GWAS) 206
Gerstmann–Sträussler–Scheinker (GSS)
267, 270, 274
GFR see glomerular filtration rate
giant cell arteritis (GCA) 410–412, 485,
489–490
glaucoma 75, 404–406, 491
glial neoplasms 58–60
glioblastomas 59
glioblastomas multiforme (GBM)
533–534
gliosis 371
globus pallidus interna (GPI) 550
glomerular filtration rate (GFR) 590
glycation 10, 13–14, 30
good care/comfort care model 620
GPI see globus pallidus interna
grasp strength 632
GSS see Gerstmann–Sträussler–Scheinker
Guillain–Barré syndrome 501–502
gustatory disorders 398–399, 440–443
burning mouth syndrome 442
central gustatory disturbances 441–443
cerebrovascular disease 442
clinical laboratory investigations 398
conductive gustatory disturbances
440–441
Parkinson’s disease 442–443
presbygeusia 441–442
sensorineural gustatory disturbances
441–443
HAD see HIV-associated dementia
hallucinatory misperceptions 396–397
haloperidol 482, 592
HAND see HIV-associated
neurocognitive disorders
HD see Huntington’s disease
head injuries 370
head and neck examination 72
headache 485–492
classification 486
clinical approaches 486–487
clinical laboratory investigations 176
concepts and definitions 485–486
etiology 486
migraine 390–391, 414–415, 485, 487
neurooncology 534
primary headache disorders 485–489
secondary headache disorders 485–486,
489–491
treatment 487–491
hearing see auditory disorders
Heidenhain variant of Jakob–Creutzfeldt
disease 415
hemicrania continua 485, 488–489
Index 721
hemiparetic gait 131, 133 immediate memory 104
hemorrhage 175, 386–388, 427 immunosenescence 474
hemorrhagic stroke 490, 527–528 immunotherapy
hereditary motor and sensor neuropathy active immunotherapies in clinical
(HMSN) 506–507 development 580–581
herpes simplex virus (HSV) 62, 464–465 active versus passive immunotherapy
herpes zoster oticus 429–432 572, 575–581
HHV see human herpes viruses Alzheimer’s disease 554, 572–583
higher-level gait disorders 128 AN1792 573–577
hippocampal atrophy 138–140 bapineuzumab 576–579
HIV-associated dementia (HAD) 471–472 clinical experience with anti-amyloid-β
HIV-associated neurocognitive disorders 573
(HAND) 471–473 clinical experience with passive
HIV/AIDS immunization 576–580
central nervous system infections 459, concepts and definitions 554
463, 465, 471–473 follow-up studies 574
clinical laboratory investigations 177 future directions 581
delirium 479 mechanisms of anti-amyloid-β
HMSN see hereditary motor and sensor immunotherapy 575–576
neuropathy passive immunotherapies in clinical
hospitalization 302, 303 development 579–580
house-drawing test 109–110 preclinical studies with anti-amyloid-β
HPA see hypothalamic-pituitary-adrenal 572–573
HPG see hypothalamic–pituitary–gonadal second-generation immunotherapies
HSV see herpes simplex virus 574
human herpes viruses (HHV) 464–465 vasogenic edema 578–579
human immunodeficiency virus see impulse-control disorders 317
HIV/AIDS IMRT see intensity modulated radiation
Huntington’s disease (HD) 57–58 treatment
hyperlipidemia 307 incidental PSP 337
hypertension 231–232, 307 inclusion body myositis 512–513
hyperviscosity syndrome 427 incontinence 302
hypnic headaches 485, 489 infarction 54–55, 175
hypoglossal nerve 78 infectious diseases
hypoglycemia 360 aging 6, 62–63
hypophonia 334 auditory disorders 427,
hyposmia 439 430–432
hypothalamic-pituitary-adrenal (HPA) bacterial meningitis 62
axis 288, 292, 294 central nervous system infections
hypothalamic–pituitary–gonadal (HPG) 459–476
axis 8, 16–17 cryptococcosis 62
hypotonia 79 epilepsy 371
hypoxic encephalopathy 55 toxoplasmosis 62
vertigo and dizziness 381, 383
IADLs see instrumental activities of viral infections 62
daily living infectious meningitidis 460–464
iatrogenic Jakob–Creutzfeldt disease inflammation
(iCJD) 174, 270, 275–276 aging 13, 62–63
IC see intracranial depression 296–297
ICP see intracranial pressure exercise and lifestyle 668
ictal hallucinations 397 informant assessment 90–91,
ideomotor apraxia 344 94–95
idiopathic polyneuropathy 506 Informant Questionnaire on Cognitive
idiopathic vestibulopathy 381–383 Decline in the Elderly (IQCODE)
illusory misperceptions 396–397 91, 95
imbalance see balance; vertigo and initiation 107
dizziness insight 89
722 Index
insomnia
fatal familial insomnia 267, 270,
274–275, 353
psychopharmacology 600, 603
instrumental activities of daily living
(IADLs) 688
insulin-signaling pathways 668
intelligence quotient (IQ) 119–121
intensity modulated radiation treatment
(IMRT) 535
interleukins 13, 16, 23
internal carotid artery (ICA) 522
intracerebral hematoma 531
intracranial abscesses 466–468
intracranial aneurysms 522–525
intracranial pressure (ICP) 460, 462–463,
465–466
intracranial thrombotic stroke 530
intraparenchymal hemorrhages 55
intravenous immunoglobulin (IVIG) 580
IQ see intelligence quotient
IQCODE see Informant Questionnaire on
Cognitive Decline in the Elderly
ischemic stroke 490, 527–528
isolated, apparently unprovoked
epileptic events 373
IVIG see intravenous immunoglobulin
Jakob–Creutzfeldt disease (CJD)
aging 41, 51
clinical aspects 269–271
clinical laboratory investigations 172,
174
concepts and definitions 268–269
diagnostic criteria 271
diagnostic tests for sCJD 272–274
differential diagnosis 278
familial CJD 174, 267, 270, 274
genetic prion diseases 267, 270,
274–275
history of CJD nomenclature 267–268
iatrogenic CJD 174, 270, 275–276
molecular classification of sCJD 277–278
molecular and pathologic findings 277
overview of human prion diseases 267
prion decontamination 276
proteinase-sensitive proteinopathy 278
sleep disorders 353
sporadic CJD 174, 267, 269–274, 277–278
structural neuroimaging 142–143
treatment 278
variant CJD 51, 174, 270, 275–276
visual disorders 415
judgment 92
kinetic/action tremor 324
Kooning, Willem de 635
Kuru 270, 275
kyphoplasty 540–542
laboratory investigations see clinical
laboratory investigations
Lambert–Eaton myasthenic syndrome
(LEMS) 509–510
lamotrigine 374–375
language and speech
corticobasal degeneration 344
Mental Status Examination 88–89, 91–92
neurologic examination 73, 73–74
neuropsychology 102–104
primary progressive aphasia 253–254,
256–262
late-life migrainous accompaniments
414–415
late-onset hereditary myopathies 515
LDL see low density lipoprotein
learning theory 621
LEMS see Lambert–Eaton myasthenic
syndrome
level of consciousness 87
levetiracetam 375
levodopa
evidence-based pharmacologic
treatment 564
Parkinson’s disease 317, 318–319,
320–321
progressive supranuclear palsy 334,
338–339
Lewy body dementia (LBD)
behavioral problems 616, 623
clinical laboratory investigations 172,
173
differential diagnosis 190, 213–214
see also individual spectrum disorders
life expectancy 5–6, 9
lifestyle see diet and nutrition; exercise
and lifestyle
light touch 81
lipopolysaccharides (LPS) 470–471
lithium 488
logopenic variant primary progressive
aphasia (lvPPA) 251–252, 253,
258–260
longstanding overt ventriculomegaly in
adults (LOVA) 281, 285
long-term memory 104–105
loudness 73
LOVA see longstanding overt
ventriculomegaly in adults
low density lipoprotein (LDL) 25
lower-level gait disorders 128
LPS see lipopolysaccharides
LRRK2 mutations 315, 338
lumbosacral plexopathy 500–501
macular degeneration 75
magnesium 658
magnetic resonance angiography (MRA)
490–491, 523–524
magnetic resonance imaging (MRI)
Alzheimer’s disease 138–141, 146
auditory disorders 427, 429, 434
central nervous system infections
468–469
chronic subdural hematomas 520–521
compression fractures 540
corticobasal degeneration 344
dementia with Lewy bodies 213
epilepsy 372–373
exercise and lifestyle 668, 670
infarction 175
mild cognitive impairment 192–193
neuromuscular disorders 498
neurooncology 534–535
normal pressure hydrocephalus
282–283, 532–533
odontoid fractures 536–537
Parkinson’s disease 547
prion diseases 273–274
progressive supranuclear palsy 338
stroke 528
major depressive disorder (MDD) 290–291
malignant gliomas 533–534, 536
mammalian target of rapamycin (mTOR)
9, 10–12, 16, 18–22
MAOIs see monoamine oxidase inhibitors
MAPT gene 243, 245, 337–338
MAV see migraine-associated vertigo
maxillomandibular advancement (MMA)
procedure 351
MCA see middle cerebral artery
MCI see mild cognitive impairment
MDD see major depressive disorder
mean wakefulness test (MWT) 347
media representations of depression 288
medical foods 560
Medicare and Medicaid 7, 707, 711
medication history 72
medication-induced behavioral problems
618
medication-induced delirium 480
medication-induced visual hallucinations
415
medication overuse headache (MOH)
485, 489
Mediterranean diet 649–650, 659
medullary strokes 78
memantine 216–217, 557–558, 560–562,
566–567
memory
Alzheimer’s disease 200
cerebrovascular disease 302

functional imaging 155
Mental Status Examination 90–91,
92–93
neuropsychology 104–106
normal pressure hydrocephalus 283
Meniere’s disease 383–384
meningiomas 60–61, 533
Mental Status Examination 87–97
abstract thinking 92
attention, working memory and
concentration 90
behavior 88
calculation abilities 92
cognitive assessment 90–95
concepts and definitions 73, 85, 87
executive function 92
general appearance 88
informant-based tools 90–91, 94–95
insight 89
judgment and problem-solving 92
language 91–92
level of consciousness 87
memory 90–91, 92–93
mood and affect 88, 92–93
movement 88
observational and neuropsychiatric
assessment 87–89
orientation 90
perceptual disturbances 89
performance-based tools 90–91, 93–94
speech and communication 88–89
thought form/content 89
vascular cognitive impairment 226
visuospatial and construction skills 92
word list generation 92–93
metastatic lesions 60
MG see myasthenia gravis
microvascular decompression (MVD)
545–546
MID see multi-infarct dementia
middle cerebral artery (MCA) 522,
530–531
migraine 414–415, 485, 487
migraine-associated vertigo (MAV)
390–391
mild cognitive impairment (MCI)
aging 40–41, 44
amyloid imaging 162–167
biomarkers 191–193, 196
concepts and definitions 184, 187–189
diagnostic criteria 188, 190–191
diet and nutrition 650
differential diagnosis 184, 188–193, 201
driving impairment 685–686, 692
evidence-based pharmacologic
treatment 556, 557
exercise and lifestyle 669–670, 673, 675
functional imaging 147–149, 192–193
future directions 196
gait disorders 127
immunotherapy 581
neurologic examination 72
neuropsychology 110–111, 113–114
pathologic changes 191
predictors of outcomes 193–195
societal impacts and ethical issues
195–196
structural neuroimaging 192–193
subtypes 184, 187–188, 189–190
treatment 184, 195
Mini Cognitive Assessment Instrument
(Mini-Cog) 91, 93
mini-mental state examination (MMSE)
expressive art therapies 631
Mental Status Examination 91, 93
mild cognitive impairment 188
neuropsychology 99, 102
mitochondria 10–13
mixed pathology in dementia 47–48
MLST see Multiple Sleep Latency Test
MMA see maxillomandibular
advancement
MMSE see mini-mental state examination
MNDs see motor neuron diseases
MoCA see Montreal Cognitive
Assessment
modality model of memory 105
modified Rankin scale (mRS) 306
MOH see medication overuse headache
monoamine deficiency hypothesis 291–292
monoamine oxidase inhibitors (MAOIs)
318–319, 594–596
monoclonal antibodies 580
monounsaturated fatty acids (MUFAs)
647–648, 651
Montreal Cognitive Assessment (MoCA)
74, 91, 94, 165–167
mood disorders
dementia with Lewy bodies 218
expressive art therapies 632
Mental Status Examination 88, 92–93
Parkinson’s disease 317
Parkinson’s disease dementia 218
psychopharmacology 603–605
see also depression
mood stabilizers 603–605
adverse effects and drug interactions
604
clinical usage 604–605
indications 604
pharmacokinetics and
pharmacodynamics 603–604
mortality rates 5–6, 9
motion sickness 382
Index 723
motor examination 78–80
motor neuron diseases (MNDs) 493–497
amyotrophic lateral sclerosis 493,
494–495
clinical features 242
diagnostic criteria 494–496
differential diagnosis 239, 256
epidemiology and clinical features
494–496
focal motor neuron disease 495–496
functional imaging 151
olfactory disorders 440
pathophysiology 493–494, 496
post-polio syndrome 496–497
primary lateral sclerosis 493, 495
progressive muscular atrophy 493, 495
treatment 494–497
movement assessment 88
movement disorders see individual
disorders
movement therapies 636–637
MRA see magnetic resonance
angiography
MRI see magnetic resonance imaging
mRS see modified Rankin scale
MS see multiple sclerosis
MSA see multiple system atrophy
mTOR see mammalian target of
rapamycin
MUFAs see monounsaturated fatty acids
multi-infarct dementia (MID) 44–45
multiple sclerosis (MS) 388
Multiple Sleep Latency Test (MSLT) 347,
354
multiple system atrophy (MSA)
aging 56–57
clinical laboratory investigations 174–175
differential diagnosis 334–335
sleep disorders 353
syncope 362–363
muscle bulk 78
muscle disorders 510–513
muscle strength 79–80
muscle tone 78–79
music therapy 629–632
MVD see microvascular decompression
MWT see mean wakefulness test
myasthenia gravis (MG) 507–509
myelitides 468–469
myeloneuropathy 132
myocardial scintigraphy 212
NAION see nonarteritic anterior ischemic
optic neuropathy
naltrexone 607
naMCI see nonamnestic mild cognitive
impairment
724 Index
naming tests 91
NART see National Adult Reading Test
National Parkinson Foundation (NPF) 708
natural selection 8, 289–290
NAV4694 165
nerve root diseases 493, 497–499
neural compensation 120
neurally mediated syncope 361
neuritic plaques 42–43
neurodegenerative disease
aging 14–15, 26–27
Alzheimer’s disease 203
depression 297
epilepsy 370
gait disorders 131
olfactory disorders 439–440
structural neuroimaging 136, 138–145
see also individual disorders
neurofibrillary tangles (NFTs) 39–40,
41–42, 336
neurofibromas 61
neurogenesis 668
neuroimaging see amyloid imaging;
functional imaging; structural
neuroimaging
neuroleptic sensitivity 211, 217–218
neurologic examination 71–84
Alzheimer’s disease 201–202
coordination and cerebellar
examination 82–83
cranial nerves 74–78
focus on function 71–72
gait and posture 83–84
language evaluation 73–74
mental status testing 73
motor examination 78–80
physical examination 71, 72–73
reflexes 81–82
sensory examination 80–81
speech evaluation 73
neurologic gaits 128
neuromuscular disorders 493–516
acquired neuropathies 501–507
amyotrophic lateral sclerosis 493,
494–495
brachial and lumbosacral plexus
diseases 499–501
cholesterol-lowering agents 513–514
chronic inflammatory demyelinating
polyradiculoneuropathy 503
concepts and definitions 493
dermatomyositis 510–511
diabetic neuropathies 505–506
focal motor neuron disease 495–496
Guillain–Barré syndrome 501–502
hereditary motor and sensor
neuropathy 506–507
idiopathic polyneuropathy 506
inclusion body myositis 512–513
Lambert–Eaton myasthenic syndrome
509–510
late-onset hereditary myopathies 515
muscle disorders 510–513
myasthenia gravis 507–509
nerve root diseases 493, 497–499
neuromuscular junction disorders
507–510
paraneoplastic neuropathy 504–505
paraproteinemic polyneuropathy
503–504
peripheral nerve disorders 501
polymyositis 511–512
post-polio syndrome 496–497
primary lateral sclerosis 493, 495
progressive muscular atrophy 493, 495
specific toxins 513–515
steroid myopathy 514–515
toxic neuropathies 505, 513
see also motor neuron diseases
neuromuscular junction disorders
507–510
neuronal achromasia 48–49
neuronal loss 38–39
neurooncology
aging 58–61
glial neoplasms 58–60
meningiomas 60–61
metastatic lesions 60
neurofibromas 61
neurosurgical care 519, 533–536
primary CNS lymphomas 60
Schwannomas 61
neuropathic gait 131, 132
neuropathic tremor 329
neuropsychiatric symptoms
dementia with Lewy bodies 217–218
Mental Status Examination 87–89
Parkinson’s disease 317–318
Parkinson’s disease dementia 217–218
neuropsychology 98–117
attention, orientation and
concentration 101–102
cognitive disorders 110–113
cognitive domains 101–113
concepts and definitions 85–86, 98
diagnosis 100
executive abilities 106–108
frontotemporal dementia 241
functional limitations 100
interpretation of results 99
language and communication 102–104
normative data 98
preclinical diagnosis of dementia
113–114
standardized assessment 98–99
treatment 100–101
utility of neuropsychological
assessment 99–101
vascular cognitive impairment 226–227
verbal and episodic memory 104–106
visuospatial abilities 108–110
neurosurgical care 519–553
acute intracranial thrombotic stroke
530
aneurysms 519, 521–527
carotid occlusive disease 528–530
chronic subdural hematomas 519,
520–521
compression fractures 519, 539–542
concepts and definitions 519–520
decompressive hemicraniectomy 531
neurooncology 519, 533–536
normal pressure hydrocephalus
531–533
odontoid fractures 519, 536–539
pain 519, 542–546
Parkinson’s disease 519, 546–550
spontaneous intracerebral hematoma
531
stroke 519, 527–528
trigeminal neuralgia 519, 542–546
neurotrophic growth factors 668
NFTs see neurofibrillary tangles
nfvPPA see nonfluent/agrammatic
variant primary progressive aphasia
nicotine dependence 608–609
noise-induced hearing loss (NIHL)
423–425, 434, 436
nonamnestic mild cognitive impairment
(naMCI)
aging 44
concepts and definitions 184, 187,
189–190
gait disorders 127
predictors of outcomes 193–195
nonarteritic anterior ischemic optic
neuropathy (NAION) 408–410
nondeclarative memory 105
nonepileptic seizures (NES) 360, 372–373
nonfluent aphasia 344, 632
nonfluent/agrammatic variant primary
progressive aphasia (nfvPPA) 239,
241–242, 244, 252–256
nonrapid eye movement (NREM) sleep
346, 347, 352
nonsteroidal anti-inflammatory drugs
(NSAIDs) 485, 487, 498–499
normal aging 38, 39–40
exercise and lifestyle 669, 674–675
sensory disorders 396
sleep disorders 348

normal pressure hydrocephalus (NPH)
281–286
classification of hydrocephalus 281
clinical laboratory investigations 174
concepts and definitions 186, 281
demographics 281
diagnostic criteria 284
differential diagnosis 283–285
gait disorders 131, 133
neuroimaging 282
neurosurgical care 531–533
pathophysiology 281–282
prognostication 284
symptoms 282–283
treatment 284–285, 286–287
vertigo and dizziness 391–392
normative data 98
NPF see National Parkinson Foundation
NPH see normal pressure hydrocephalus
NREM see nonrapid eye movement
NSAIDs see nonsteroidal anti-
inflammatory drugs
Nuedexta 564, 567–568
nursing homes 700
nutrition see diet and nutrition
obesity 5, 23
objective tinnitus 420–421
observational assessment 87–89
obsessive–compulsive disorder (OCD)
602
obstructive sleep apnea (OSA) 318,
350–351, 353–354
OCD see obsessive–compulsive disorder
odontoid fractures 519, 536–539
office testing 398
olfactory disorders 398–399, 436–440
central olfactory disturbances 438–440
clinical laboratory investigations 398
conductive olfactory disturbances 437
neurologic examination 75
Parkinson’s disease 318, 439
presbyosmia 438
sensorineural olfactory disturbances
437
oligodendrogliomas 59–60
omega-3 fatty acids 647–648, 650, 651–652
open-angle glaucoma 405
optic nerve 75
oral candidiasis 440–441
orientation 90, 101–102
orthostatic hypotension 362, 364–365,
392–393
orthostatic tremor 325, 328
OS see oxidative stress
OSA see obstructive sleep apnea
otogenic dizziness 379, 392
ototoxicity 432–433
oxcarbazepine 375
oxidative stress (OS) 4, 9, 10–13
oxytocin 293
PACNS see primary angiitis of the CNS
Pagnini–McClure maneuver 380
pain
atypical pain 546
behavioral problems 619
depression 296
medical therapy 543
microvascular decompression 545–546
natural history 542–543
neurologic examination 81
neurosurgical care 519, 542–546
percutaneous procedures 543–544
stereotactic radiosurgery 544–545
PAN see Parkinson’s Action Network
panic attacks/disorder 602
PAP see positive airway pressure
paraneoplastic LEMS 510
paraneoplastic neurologic syndromes
(PNS) 177–178
paraneoplastic neuropathy 504–505
paraproteinemic polyneuropathy
503–504
parkinsonism
Alzheimer’s disease 201
dementia with Lewy bodies 218–219
gait disorders 130, 132–133
normal pressure hydrocephalus 283
Parkinson’s disease dementia 218–219
sleep disorders 353
tremor disorders 328
visual disorders 416
parkinsonism–dementia complex (PDC)
334–335
Parkinson-plus syndromes 174–175
see also individual spectrum disorders
Parkinson’s Action Network (PAN) 708
Parkinson’s disease dementia (PDD)
behavioral problems 617, 624
clinical features 214, 217–219
clinical laboratory investigations 173
cognition and function 215–216
differential diagnosis 212–214, 283–285,
317–318
evidence-based pharmacologic
treatment 566–567
falls and dysautonomia 219
genetics 214–215
mood disorders 218
neuropsychology 112
predictors of treatment response
216–219
sleep disorders 353
Index 725
structural neuroimaging 142, 142–143
treatment 215–219
Parkinson’s disease (PD)
advocacy 708
aging 27–28, 56
behavioral problems 617, 624
clinical features 214, 315–317
clinical laboratory investigations 173,
174
concepts and definitions 312, 314
deep brain stimulation 320, 546–550
diet and nutrition 645, 651–653
differential diagnosis 208, 212–214, 314,
317–318, 325–326, 334–335, 343
driving impairment 688
elder abuse and mistreatment 704
epidemiology 314
exercise and lifestyle 671–672
expressive art therapies 637
functional imaging 315
future directions 321
gustatory disorders 442–443
lesion surgery 320
neurologic examination 73
neuropsychiatric symptoms 317–318
neurosurgical care 519, 546–550
nonmotor features 318
olfactory disorders 318, 439
pathogenesis 314–315
prodromal features 315
psychopharmacology 592, 601–602
syncope 362–363
treatment 318–320
visual disorders 416–418
paroxetine 564
paroxysmal hemicranias 485, 488–489
PAS see Predementia Alzheimer’s Disease
Scale
patient advocacy organizations 707–708
PBA see pseudobulbar affect
PD see Parkinson’s disease
PDC see parkinsonism–dementia
complex
PDD see Parkinson’s disease dementia
Peabody Picture Vocabulary Test (PPVT)
120
penlight shadow test 398
pentoxyfylline 565–566
perceptual disturbances 89
percutaneous procedures 543–544
performance testing 90–91, 93–94,
130, 688
perfusion fMRI 156
periodic lateralized epileptiform
discharges (PLEDs) 465
periodic limb movements of sleep
(PLMS) 349–350, 352–354
726 Index
peripheral nerve disorders 501
peripheral nervous system (PNS)
infections 459
personality change 201
PET see positron emission tomography
PGRN mutations 245
phenotypes of aging 10–17
PHN see postherpetic neuralgia
phonation 73
physical abuse 699–701
physical examination
biometrics 72
cardiovascular assessment 73
head and neck examination 72
medications 72
neurologic examination 71, 72–73
physical exercise 667–672
PiB 163
PICA see posterior inferior cerebellar
artery
Pick’s disease see behavioral variant FTD
PIGD see postural instability gait
disorder
pinhole test 400
PINK1 mutations 315
PLEDs see periodic lateralized
epileptiform discharges
PLMS see periodic limb movements of
sleep
PLS see primary lateral sclerosis
PMA see progressive muscular atrophy
PML see progressive multifocal
leukoencephalopathy
PMR see polymyalgia rheumatica
PNS see paraneoplastic neurologic
syndromes; peripheral nervous
system
poetry 637–639
point-to-point movements 83
polymerase chain reaction (PCR)
461–463, 465, 468–469
polymyalgia rheumatica (PMR) 410
polymyositis 511–512
polypharmacy 480–481
polyphenols 23–24
polysomnography (PSG) 347
polyunsaturated fatty acids (PUFAs)
647–648, 650, 651–653, 658–659
ponezumab 579–580
position sense 81
positive airway pressure (PAP) therapy
351, 354
positive spontaneous visual phenomena
with blindness 413–414
positron emission tomography (PET)
Alzheimer’s disease 137, 146–152, 154
amyloid imaging 162–168
clinical applications 152
dementia with Lewy bodies 151–152,
212–213
frontotemporal lobar dementia 151
immunotherapy 577–578
mild cognitive impairment 147–149,
192–193
physiologic and pathologic brain
processes 146–149
presymptomatic AD risk evaluation
149–150
progressive supranuclear palsy 338
SPECT comparison 154
vascular dementia 152
posterior inferior cerebellar artery (PICA)
426–427, 522, 526
posterior odontoid screw fixation 538–539
posterior probability 171
posterior vitreous detachment (PVD)
401–402
postherpetic neuralgia (PHN) 469–470
post-polio syndrome 496–497
post-stroke dementia (PSD) 230–231
post-traumatic stress disorder (PTSD)
602–603
postural hypotension 392–393
postural instability gait disorder (PIGD)
316–317, 319
postural tremor 324
posture 83–84
potassium 658
PPVT see Peabody Picture Vocabulary
Test
preclinical silent vascular brain injury
230
Predementia Alzheimer’s Disease Scale
(PAS) 194
prednisone 511
pregabalin 327
presbycusis 423
presbygeusia 441–442
presbyopia 75, 400–401
presbyosmia 438
prescription drug support 707
presenilin proteins 206
PRGN mutations 338
primary angiitis of the CNS (PACNS)
175–176
primary CNS lymphomas 60
primary headache disorders 485–489
primary lateral sclerosis (PLS) 493, 495
primary progressive aphasia (PPA)
251–266
assessment of speech–language
function 260–261
associated cognitive, behavioral and
neurologic deficits 254, 257, 259
behavioral problems 617
clinical features and neurobiologic
correlates 241–242, 252
concepts and definitions 185, 239, 251
diagnostic criteria 251–252
differential diagnosis 239
functional imaging 151, 254–255,
257–258, 259–260
logopenic variant 251–253, 258–260
neurologic examination 73–74
neuropathology 255–256, 258
neuropsychology 111–112
nonfluent agrammatic variant 239,
241–242, 244, 252–256
semantic variant 239, 241–244, 252–253,
256–258
speech–language profile 253–254,
256–262
structural neuroimaging 141–142,
254–255, 257–258, 259–260
treatment 261–262
primary writing tremor 328
primidone 326
priming phenomena 105
primitive reflexes 82
prion diseases 267–280
animal prion diseases 276–277
clinical aspects 269–271
clinical laboratory investigations 172,
174
concepts and definitions 186, 267,
268–269
diagnostic criteria 271
diagnostic tests for sCJD 272–274
differential diagnosis 278
epidemiology 267
genetics 267, 270, 274–275
history of CJD nomenclature
267–268
molecular classification of sCJD
277–278
molecular and pathologic findings 277
overview of human prion diseases 267
prion decontamination 276
proteinase-sensitive proteinopathy 278
sleep disorders 353
treatment 278
see also Jakob–Creutzfeldt disease
prior probability 171
PRNP gene 267–269, 274–275, 415
problem-solving 92
procedural memory 105
progressive cortical atrophy 616
progressive multifocal
leukoencephalopathy (PML) 62
progressive muscular atrophy (PMA)
493, 495

progressive supranuclear palsy (PSP)
49–50, 332–342
biochemistry 337
clinical features 242
clinical laboratory investigations
174–175
clinical–pathologic correlation 244–245
clinical presentation 332–334
concepts and definitions 313
diagnostic criteria 332–333
differential diagnosis 239, 334–335, 343
epidemiology 332
functional imaging 338
genetics 337–338
historical perspective 332
incidental PSP 337
macroscopic pathology 336
microscopic pathology 336–337
mixed pathology 337
neurologic examination 73
neuropathology 336–337
neuropsychology 112
prognosis 339
sleep disorders 352
structural neuroimaging 142, 338
treatment 247, 338–339
variants 334
proinflammatory cytokines 13, 16–17, 23
proliferative vitreoretinopathy (PVR) 402
pronator drift 80
propranolol 326–327
proteinase-sensitive proteinopathy
(PSPr) 278
PSD see post-stroke dementia
pseudobulbar affect (PBA) 567–568
PSG see polysomnography
PSP see progressive supranuclear palsy
PSPr see proteinase-sensitive
proteinopathy
psychiatric disorders 392
psychodrama 637
psychogenic gait disorders 129
psychogenic nonepileptic seizures
372–373
psychogenic pseudosyncope 360
psychogenic tremor 329
psychopharmacology 584–612
adverse effects and drug interactions
585–586, 591
aging 584, 586–590
antidepressants 593–597, 602–603, 607,
609
antipsychotics 590–593
anxiolytics and sedative–hypnotic
drugs 597–603, 608
clearance and excretion 590
diagnostic criteria 584
distribution 587
elimination half-life 590
metabolism 587–589
mood stabilizers 603–605
pharmacodynamics 590, 591
pharmacokinetics 586–591
screening for psychotropic use 585
substance-related disorders 605–610
treatment adherence 586
treatment effectiveness 584–585
treatment initiation 586
psychosis 590–593
psychosocial interventions 622
PTSD see post-traumatic stress disorder
public awareness campaigns 710
PUFAs see polyunsaturated fatty acids
pulsatile tinnitus 420–421
pupillary reactions 76
pure word deafness 436
PVD see posterior vitreous detachment
PVR see proliferative vitreoretinopathy
quetiapine 563
radiation therapy (RT) 500, 534–536
radiculopathies 493, 497–499
radionuclide cisternography 532
rapid alternating movements 83
rapid eye movement behavior disorder
(RBD) 353
dementia with Lewy bodies 210–211
epilepsy 372
olfactory disorders 439
Parkinson’s disease 315, 319–320
progressive supranuclear palsy 334
visual disorders 417
rapid eye movement (REM) sleep 346,
347–348, 352
rapid eye movement sleep without
atonia (RSWA) 315, 319–320, 334
RAS see Rhythmic Auditory Stimulation
RBD see rapid eye movement behavior
disorder
reactive oxygen species (ROS) 10–13
reading assessment 91
recurrent stroke 232–233
reflexes 81–82
release hallucinations 397
REM see rapid eye movement
reminiscence 637–639
remote memory 105
repetition 91, 103
respite care 703
resting tremor 324
restless leg syndrome (RLS) 348–349,
353–354
retinal artery occlusion 407–408
Index 727
retrieval 105–106
retrochiasmal visual field defects 415–416
Rhythmic Auditory Stimulation (RAS) 632
rigidity 79
risk prognostication scores 365
rivastigmine 559–563, 566
RLS see restless leg syndrome
road tests 689
Romberg test 83
ROS see reactive oxygen species
RSWA see rapid eye movement sleep
without atonia
RT see radiation therapy
SAH see subarachnoid hemorrhage
Saint Louis University Mental Status
(SLUMS) 91, 94
saliva 441
sarcopenia 15
SASP see senescence-associated secretory
phenotype
SBT see short blessed test
Schwannomas 61
sCJD see sporadic Jakob–Creutzfeldt
disease
SDH see subdural hematomas
secondary dementia 172–173
secondary headache disorders 485–486,
489–491
sedative–hypnotic drugs 597–603
adverse effects and drug interactions
598–599
clinical usage 599–600
indications 599
monitoring treatment 600
pharmacokinetics and
pharmacodynamics 597–598
seizures 359–360, 370–373, 534
selective serotonin reuptake inhibitors
(SSRIs)
depression in the elderly 297
Parkinson’s disease 319
psychopharmacology 594–597,
602–603, 607
self-monitoring and assessment 107
semantic dementia (SD)
behavioral problems 617
expressive art therapies 635–636
neuropsychology 111–112
structural neuroimaging 141–142
semantic memory 105
semantic variant primary progressive
aphasia (svPPA) 239, 241–244, 252,
256–258
Semont liberatory maneuver 381
senescence-associated secretory
phenotype (SASP) 30
728 Index
senile cataracts 401
senior advocacy see advocacy
sensorineural disturbances
auditory 422–436
gustatory 441–443
olfactory 437
visual 402–414
sensory ataxia syndromes 388–389
sensory disorders 395–458
aging 395–396, 400
auditory disorders 398–399, 419–436
categorization by modality and level of
dysfunction 399
clinical laboratory investigations 398
concepts and definitions 395–398
distortions and other misperceptions
396–398
driving impairment 682–683
gustatory disorders 398–399, 440–443
neurologic examination 80–81
olfactory disorders 398–399, 436–440
sensorineural disorders 396
sensory deficits 396
visual disorders 75, 398–419
septic encephalopathy 470–471
serotonin-selective reuptake inhibitors
(SSRIs) 177
sertraline 564
SES see socioeconomic status
severe neuroleptic sensitivity 211
sexual abuse 699–701
SGR see sustainable growth rate
short blessed test (SBT) 91, 93–94
short-lasting unilateral neuralgias with
conjunctival tearing (SUNCT) 485,
488–489
short-term memory 104
shunt valves 284–285, 286–287
SIADH see syndrome of inappropriate
antidiuretic hormone
sight see visual disorders
single photon emission computed
tomography (SPECT)
corticobasal degeneration 344
dementia 137, 152–154
dementia with Lewy bodies 211,
212–213
mild cognitive impairment 192–193
PET comparison 154
visual disorders 413
sirtuins (SIRT) 12, 21–22
situation-related seizures 373
SIVD see subcortical ischemic vascular
dementia
sleep disorders 346–356
Alzheimer’s disease 351–352
circadian rhythms 347, 348
clinical approaches 353–354
concepts and definitions 346–347
disorders of sleep in the elderly
348–351
epilepsy 372
fatal familial insomnia 267, 270,
274–275, 353
insomnia 600, 603
napping and excessive daytime
sleepiness 348, 354
nonrapid eye movement sleep 346,
347, 352
normal aging 348
obstructive sleep apnea 318, 350–351,
353–354
Parkinson’s disease 315, 318, 319–320
periodic limb movements of sleep
349–350, 352–354
prion diseases 267, 270, 274–275, 353
psychopharmacology 600, 603
rapid eye movement sleep 346,
347–348, 352
restless leg syndrome 348–349, 353–354
sleep architecture 347, 348
slow-wave sleep 346, 347, 352
synucleinopathies 218
tauopathies 334, 352
treatment 349, 351
see also rapid eye movement behavior
disorder
slow-wave sleep (SWS) 346, 347, 352
SLUMS see Saint Louis University Mental
Status
small vessel disease 40, 53, 172
smell see olfactory disorders
social anxiety disorder 603
social brains 292–295
social interaction
driving impairment 689–690
exercise and lifestyle 675–676
expressive art therapies 630–631, 632
social security 6–7, 706
societal impacts 195–196, 690–691
socioeconomic status (SES) 119
SOD see superoxide dismutases
sodium restriction 384
solanezumab 579
spasticity 78–79, 128–129
spatial cognition 109
SPECT see single photon emission
computed tomography
speech see language and speech
spinal accessory nerve 78
spinal canal infections 468–469
spontaneous intracerebral hematoma 531
sporadic Jakob–Creutzfeldt disease
(sCJD) 174, 267, 269–274, 277–278
SSRIs see serotonin-selective reuptake
inhibitors
stage model of memory 105–106
standardized neuropsychological
assessment 98–99
statins 513–514
stereotactic radiosurgery 544–545
steroid myopathy 514–515
STN see subthalamic nucleus
storage 105–106
storytelling 637–639
stress 294–295, 672
striatal deformities 316
stroke
bottom of form 305
carotid surgery, endarterectomy and
stenting 307–308
cerebrovascular disease 304–309
classifications 305
diet and nutrition 645, 653–659
epilepsy 371
etiology and clinical subtypes 305
expressive art therapies 631–632
headache 490
neurologic examination 75
neurosurgical care 519, 527–528
novel therapies 308–309
outcome data 306–307
risk factors 304
stroke care 305–306, 307
vascular cognitive impairment 224,
230–233
vertigo and dizziness 386–388
structural neuroimaging
Alzheimer’s disease 138–141
cognitive reserve 120, 121–123
concepts and definitions 136
cortical atrophy 140–141
corticobasal degeneration 344
degenerative dementias 136, 138–145
dementia with Lewy bodies 142, 213
frontotemporal dementia 141–142,
240–241
hippocampal atrophy 138–140
mild cognitive impairment
192–193
normal pressure hydrocephalus 282
parkinsonian dementias and Jakob–
Creutzfeldt disease 142–143
Parkinson’s disease dementia 142
primary progressive aphasia 254–255,
257–258, 259–260
progressive supranuclear palsy 338
vascular cognitive impairment 227
ventricular enlargement 141
white matter changes 141
see also individual techniques

subarachnoid hemorrhage (SAH) 55–56,
522–527
subcortical ischemic vascular dementia
(SIVD) 45, 225
subcortical vascular dementia (SVD) 227,
230–231
subdural hematomas (SDH) 63, 519,
520–521
subependymomas 60
subjective light touch 81
subjective tinnitus 423, 424, 433–436
substance-related disorders
alcohol dependence 606–607
alcohol withdrawal 607–608
benzodiazepine dependence 609–610
concepts and definitions 605
diagnosis 606
nicotine dependence 608–609
psychopharmacology 605–610
subthalamic nucleus (STN) 549–550
sudden deafness 423, 425–428
SUNCT see short-lasting unilateral
neuralgias with conjunctival tearing
superficial siderosis 428–429
superoxide dismutases (SOD) 10–11
survival 127
sustainable growth rate (SGR) 711
svPPA see semantic variant primary
progressive aphasia
swallowing 632
SWS see slow-wave sleep
symptomatic localization-related
epilepsy 373
synapses 39
syncope 357–368
autonomic dysfunction 362–363
cardiac syncope 361–362, 365
clinical features 358–359
clinical laboratory investigations
363–364
definition and classification 357
differential diagnosis 359, 372
elderly patients 365
epidemiology 357–358
epilepsy and/or seizures 359–360
neurally mediated syncope 361
nonepileptic seizures 360
postsyncopal symptoms 359
prodromal features 358–359
prognosis and economic impact 364
psychogenic pseudosyncope 360
risk prognostication scores 365
symptoms 359
treatment 364–365
types 357–358, 361–363
syndrome of inappropriate antidiuretic
hormone (SIADH) 470
tacrine 558
tai chi 637
task-specific tremor 325
taste see gustatory disorders
tauopathies
aging 48
corticobasal degeneration 345
frontotemporal dementia 243, 246
sleep disorders 352
TBI see traumatic brain injury
TCAs see tricyclic antidepressants
TDP-43 protein 243–244
tea 649, 652, 655
temperature sense 81
temporal model of memory 104–105
tension-type headaches 485, 488
TGN see trigeminal neuralgia
thalamotomy 320
thought form/content 89
thrombolysis 306–307
TIAs see transient ischemic attacks
ticlopidine 565
tilt table testing 360, 362–364
timed gait 129–130
TimeSlips 639
tinnitus 420–421, 423, 424, 433–436
TLOC see transient loss of consciousness
TN see trigeminal neuralgia
TNF-α see tumor necrosis factor
topiramate 327, 375
TOR signalling pathway 18–21
toxic neuropathies 505, 513
toxoplasmosis 62
Trail Making Test A/B 99
transient global amnesia (TGA) 372
transient ischemic attacks (TIAs)
cerebrovascular diseases 307–308
differential diagnosis 372
syncope 360, 361
vertigo and dizziness 387
visual disorders 414–415
transient loss of consciousness (TLOC)
357–359, 365
transmissible spongiform
encephalopathies (TSEs) 268
trauma 63
traumatic brain injury (TBI) 178–179
treatment adherence 586
treatment effectiveness 584–585
tremor disorders 324–331
cerebellar tremor 329
clinical characterization of tremor
324–325
concepts and definitions 312–313, 324
drug-induced tremor 328–329
essential tremor 312–313, 314, 325–327
orthostatic tremor 325, 328
Index 729
parkinsonism 328
Parkinson’s disease 315–317, 319
pathophysiology 326
primary writing tremor 328
psychogenic tremor 329
treatment 319, 326–329
tricyclic antidepressants (TCAs) 487,
594–596
trigeminal nerve injuries 76–77
trigeminal neuralgia (TGN) 485, 491, 519,
542–546
tuberculous meningitis 463–464
tufted astrocytes 336–337
tumor necrosis factor (TNF-α) 13, 16–17,
23
tumors see cancer; neurooncology
tuning fork tests 398
UB-311 581
ubiquitin 50–51
UFAs see unsaturated fatty acids
undetermined epilepsy 373
unilateral pulsatile tinnitus 420–421
unmet needs model 620–621
unsaturated fatty acids (UFAs) 647–648,
650, 651–653, 655, 658–659
urinary symptoms 283
V-950 581
valosin-containing protein (VCP) 244,
245
valproate 328–329
variant Jakob–Creutzfeldt disease (vCJD)
51, 174, 270, 275–276
varicella-zoster virus (VZV) 430–432,
469–470
vascular cognitive impairment (VCI)
224–238
aging 40, 44–46
clinical laboratory investigations 172,
173
concepts and definitions 185, 224–225
diagnostic criteria 227–230
differential diagnosis 190
epidemiology 225–226
evaluation 226–227
historical perspective 224–225
infarct size, number and location 44–45
Mental Status Examination 226
microscopic infarcts 45–46
neuropathology 40, 227
neuropsychology 226–227
primary prevention and risk factors
231–232
prognosis/outcome 234
recurrent stroke and cognitive decline
232–233
730 Index
vascular cognitive impairment (VCI)
(Continued)
secondary prevention 232–233
structural neuroimaging 227
subcortical ischemic vascular dementia
45
subtypes 227, 230–231
treatment 231–234
vascular dementia (VaD)
behavioral problems 616, 623
concepts and definitions 224–225
differential diagnosis 190, 229–231
epidemiology 225–226
evidence-based pharmacologic
treatment 565–566
exercise and lifestyle 671
functional imaging 152
neuropsychology 113
prognosis/outcome 234
treatment 233–234
vascular depression hypothesis 309
vascular parkinsonism 315, 335
vasculitis 54, 63, 175–176
vasogenic edema 578–579
VCI see vascular cognitive impairment
vCJD see variant Jakob–Creutzfeldt
disease
VCP see valosin-containing protein
vegetables 647, 650, 651, 655
velnacrine 559
venlafaxine 563
venous hum 421
ventral intermediate nucleus (VIM) 549
ventricular enlargement 141
verbal episodic memory 106
verbal memory 104–106
vertebroplasty 540–542
vertical gaze palsy 332–333
vertigo and dizziness 378–394
aging 378
benign paroxysmal positional vertigo
379–381
bilateral vestibular loss 384–385
cerebellar ataxia syndromes 389–390
CNS structural lesions 385–386
craniocervical junction syndromes 386
diagnosis and diagnostic tests 380, 382,
384–385, 387–391, 393
differential diagnosis 380–382, 384–388,
390–392
epileptic vertigo 385–386
episodic ataxia syndromes 390
mechanisms 379–382, 384–390
Meniere’s disease 383–384
migraine-associated vertigo 390–391
multiple sclerosis 388
normal pressure hydrocephalus 391–392
otogenic dizziness 379, 392
postural or orthostatic hypotension
392–393
prognosis 381
psychological causes of dizziness 392
sensory ataxia syndromes 388–389
symptoms 379, 382–385, 387–393
treatment 381–393
types and classification of dizziness
378–379
vascular causes 386–388
vestibular neuritis 381–383
very low density lipoprotein (VLDL) 25
vestibular neuritis 381–383
VH see visual hallucinations
vibration sense 80–81
vicious circle hypothesis 11
videonystagmography (VNG) 382
VIM see ventral intermediate nucleus
viral encephalitides 464–465
viral infections 62
viral meningitides 462–463
visual disorders 398–419
age-related macular degeneration 75,
403–404
Alzheimer’s disease 419
amaurosis fugax 406–407
anterior ischemic optic neuropathy
408–412
central visual disturbances 414–419
clinical laboratory investigations 398
conductive visual disturbances
400–402
delirium 419
dementia with Lewy bodies 418–419
distortions and other misperceptions
397–398
glaucoma 404–406
hallucinations due to central pathology
415–416
Heidenhain variant of Jakob–
Creutzfeldt disease 415
late-life migrainous accompaniments
414–415
neurologic examination 75, 75–76
parkinsonism 416
Parkinson’s disease 416–418
positive spontaneous visual
phenomena with blindness 413–414
posterior vitreous detachment 401–402
presbyopia 400–401
retinal artery occlusion 407–408
senile cataracts 401
sensorineural visual disturbances
402–414
visual hallucinations (VH) 397–398
Alzheimer’s disease 419
Bonnet syndrome 413–414, 415–416
delirium 419
dementia with Lewy bodies 418–419
due to central pathology 415–419
epileptic VHs 415
medication-induced 415
Parkinson’s disease 317, 319,
416–418
retrochiasmal visual field defects
415–416
visuoperception 108–109
visuospatial abilities 92, 108–110
vitamins and vitamin supplementation
298, 646–647, 650–651, 653–656, 658
VLDL see very low density lipoprotein
VZV see varicella-zoster virus
WAIS see Wechsler Adult Inventory Scale
walking while talking (WWT) 130
WAT see Word Accentuation Test
Wechsler Adult Inventory Scale (WAIS)
120, 121–122
Wechsler Memory Scale (WMS) 188
weight loss 318
Welander distal myopathy 515
Wernicke’s aphasia 73–74, 104
Wernicke–Korsakoff syndrome (WKS)
41, 51–52
West Nile virus (WNV) 464–465
whispered voice test 398
white matter 39, 141
Wide Range Achievement Test (WRAT)
120
WKS see Wernicke–Korsakoff syndrome
WNV see West Nile virus
Word Accentuation Test (WAT) 120
word list generation 92–93
working memory 90, 104
WRAT see Wide Range Achievement Test
WWT see walking while talking
xerostomia 441
Z-scores 98
zidovudine 513
Figure 2.1 Apical dendrite (arrow head) and cell body (arrow) of
pyramidal neuron, hippocampus CA1, mouse brain (Golgi stain).

Figure 2.2 Dendritic spines, mouse brain, hippocampus CA1

(Golgi stain).

Figure 2.3 Activated cortical microglia in older person without

cognitive impairment; antibody to class II major histocompatibility
antigen (MHCII).

(a) (b)

Figure 2.4 Alzheimer’s disease brain showing

(a) narrowing of gyri and widened sulci, and
hippocampal atrophy with enlargement of
lateral ventricles, especially temporal horn (b).

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.
(a) (b)

Figure 2.5 Neurofibrillary tangles:

(a) hippocampus CA1 (modified
Bielschowsky stain); (b) frontal
cortex (immunohistochemistry
with antibodies to paired helical
filament).

Figure 2.6 Ghost tangles, hippocampus CA1 (modified Bielschowsky

silver stain).

(a) (b)

Figure 2.7 Neuritic plaque

pathology in AD. (a) Three
NPs in the neocortex on H&E
stain are difficult to see. (b) The
same NPs are easily visualized
on modified Bielschowsky
silver stain.

(a) (b)

(c) (d)

Figure 2.8 Amyloid pathology

in AD. (a) Numerous amyloid
immunostained plaques
in the cortex at low power.
(b) Leptomeningeal arterioles
also may show amyloid
deposition. (c, d) Higher
power of plaque pathology
using amyloid immunostain.
 (a) (b)

Figure 2.9 An old lacunar infarct in the

anterior thalamic nucleus: (a) gross coronal
brain slab; (b) histologic appearance of old
infarct with few macrophages and cavitation.

(a) (b)

Figure 2.10 Subcortical ischemic vascular

disease. Both (a) gross and (b) histologic
brain sections show lacunar infarcts
and enlarged perivascular spaces
predominantly in the caudate in a person
with vascular parkinsonism.

(a) (b)

Figure 2.11 Substantia nigra

neurons with multiple LBs:
(a) classic dense concentric
appearance with peripheral
halo on H&E; (b) LB halo stains
darker using antibodies to
α-synuclein.
(a) (b)

(c)

Figure 2.12 Cortical LBs in the superior

temporal cortex. (a) H&E stain shows an
eosinophilic cytoplasmic inclusion without a
clearly defined halo. (b) Low-magnification
view showing numerous α-synuclein-
immunostained cortical LBs. (c) Cortical LBs
may stain uniformly or show a peripheral
halo with α-synuclein immunostain.

Figure 2.13 Corticobasal degeneration: ballooned neuron (neuronal

achromasia) on H&E stain.

Figure 2.14 Tau-immunopositive astrocytic plaques are

characteristic of CBD (AT8 immunohistochemistry).
 (a)

(b) (c)

Figure 2.15 Progressive supranuclear

palsy: neurofibrillary tangle (NFT)
pathology. (a) Globose NFT with
basophilic filamentous appearance (H&E).
(b) NFT in SN highlighted with tau
immunohistochemistry. (c) Antibody to
4-repeat tau isoforms labels two NFT.

(a) (b)

Figure 2.16 PSP: astrocytic pathology.

(a) Tau-immunoreactive tufted astrocyte in
the subthalamic nucleus (AT8 antibody).
(b) Coiled bodies that immunolabel with
antibodies specific to 4-repeat tau.

(a)

Figure 2.17 FTLD-TDP: TDP-43 immunoreactive

inclusions in the neurons of the dentate layer (b)
of hippocampus. (a) Low magnification
shows diffuse nuclear staining and numerous
TDP-43 positive inclusions (arrows). (b) High
magnification shows cytoplasm inclusions with
nuclear clearing in affected neurons.
Figure 2.18 Atherosclerosis, the Circle of Willis. Note the Figure 2.19 Fusiform aneurysm of the basilar artery. Artery is
asymmetric involvement of vertebral arteries, extension into dilated and tortuous and may compress and distort the brain stem.
basilar artery, and posterior cerebral arteries.

Figure 2.20 Arteriolosclerosis: hyaline thickening of two small

vessels in the deep white matter. Note that the upper vessel
appears occluded.

(a) (b)

Figure 2.21 Cerebral amyloid

angiopathy. (a) Cortex
involves small-size and
medium-size arteries,
(c) (d)
arterioles, and capillaries
(arrows; small arrow also
shows dysphoric change).
(b) Leptomeninges vessels.
(c) Amyloid alternating
with amyloid-free regions.
(d) “Double-barrel”
appearance from separation
of endothelium from the
affected muscularis. (a–c, Aβ
immunostain.)
Figure 2.22 Charcot–Bouchard aneurysm; note the
markedly thinned region of the vessel wall.

(a) (b) (c)

Figure 2.23 Amyotrophic

lateral sclerosis. (a) Pallor of
the lateral corticospinal tracts
of spinal cord on myelin
stain. (b) Low and (c) high
magnification show CD8
immunostained macrophages
indicative of degeneration.

Figure 2.24 Amyotrophic lateral sclerosis anterior horn cell with a

Bunina body.
(a) (b)

(c)

Figure 2.25 Amyotrophic lateral sclerosis.

Hyaline inclusions in an anterior horn
motor neuron on H&E (a) and ubiquitin
(b). (c) Skein-like inclusions in the anterior
horn cells in ALS also stain with antibodies to
ubiquitin.

Figure 2.27 Glioblastoma: histologic appearance of

pseudopalisading necrosis.

Figure 2.26 Glioblastoma multiforme: gross appearance with

variegated necrotic-appearing mass without definite borders.

Figure 2.28 Metastatic adenocarcinoma: cortical lesion appears well

demarcated and necrotic.
Figure 7.3 3D hippocampal atrophy maps
showing the amount of atrophy (in %)
accumulated over a 3-year period in
cognitively normal elderly patients who
remained cognitively normal for 6 years
or longer since baseline (NL–NL) and
cognitively normal elderly patients who
were diagnosed with amnestic MCI at
3 years and AD at 6 years (NL–MCIAD).

Figure 7.4 Cortical atrophy in AD. Relative

to patients with amnestic MCI, patients
with very mild AD show extensive cortical
atrophy of the entorhinal, parahippocampal,
inferior, and lateral temporal cortices, with
disease changes spreading next to the
parietal and frontal association cortices (left
column). The pattern is strikingly similar to
the amyloid deposition described in Braak
and Braak amyloid stage B (right column).
 92 AD < 104 NC

48 mm 40 mm 32 mm 24 mm 16 mm 8 mm 0 mm −8 mm
Figure 7.7 FDG PET in 92 AD
and 184 MCI participants
from the Alzheimer’s Disease
Neuroimaging Initiative
(ADNI; Mueller et al., 2006;
Jack et al., 2008a), compared
with 104 cognitively normal
184 MCI < 104 NC elderly controls. Top images
show typical patterns of
glucose hypometabolism in
Alzheimer’s disease (AD),
compared with normal. Bottom
48 mm 40 mm 32 mm 24 mm 16 mm 8 mm 0 mm −8 mm images show similar AD-like
patterns, but to a less spatial
and intensity extent in MCI.
0.005 7 e-16
See Langbaum et al. (2009) for
p value
methodology details.

(a)

Figure 7.8 FDG PET in 298

participants with varying
48 mm 40 mm 32 mm 24 mm 16 mm 8 mm 0 mm −8 mm degrees of MCI and AD, and
cognitively normal elderly from
(b) ADNI ( Mueller et al., 2006;
Jack et al., 2008a). (a) Areas
of correlated FDG PET
binding representing glucose
hypometabolism associated
with CDR scores. (b) Areas
of correlated FDG PET
binding representing glucose
hypometabolism associated
with MMSE scores. Regions
associated with cognitive
48 mm 40 mm 32 mm 24 mm 16 mm 8 mm 0 mm −8 mm impairment are similar to those
associated with a diagnosis
0.005 1 e-15 of clinical AD (Figure 7.7).
p value See Langbaum et al., 2009 for
methodology details.
 Left lateral Right lateral

Parietal Parietal
Prefrontal Prefrontal

Temporal Temporal
Figure 7.9 Regions of the brain with
abnormally low CMRgl in young adult
carriers of two copies of the APOE ε4-allele Right medial
Left medial
and their relationship to brain regions with
abnormally low CMRgl in patients with Cingulate Cingulate
probable AD. Purple areas are regions in
which CMRgl was abnormally low only
in patients with AD. Bright blue areas are
regions in which CMRgl was abnormally
low in both the young adult e4 carriers
and patients with probable AD. The muted
blue areas are regions in which CMRgl
was abnormally low only in the ε4 carriers.
Source: Reiman et al. (2004). Reproduced
with permission from National Academy of
Sciences.

(a)

Figure 7.10 Individual FDG-PET

scans in a patient with (a) normal
cognition, (b) MCI, (c) AD, (b)
(d) bvFTLD, and (e) DLB. Images
on the left are individual FDG-
PET CMRgl binding, showing
areas of significant glucose
hypometabolism compared
with normal controls (blue). An
automated algorithm was used (c)
to transform individual patient
images into the dimensions of
a standard brain and compute
statistical maps of significantly
reduced glucose metabolism
relative to 67 normal control
subjects (mean age 64 years). Red- (d)
outlined regions represent areas
of mean hypometabolism seen in
FDG-PET scans from 14 patients
with AD (mean age 64 years),
compared with the same 67
normal controls. On the right are
raw FDG-PET color maps from
(e)
the same corresponding patients.
Here we can see the use of FDG-
PET for identifying disease-
specific patterns of glucose
metabolism for clinical use in
individual patients, to assist with
diagnostic decision-making.
 Amyloid negative

L A P R

Amyloid positive

L A P R

Figure 7.13 Falsely colored amyloid images

for cases 1, 2 and 3. Top row is images
from Ms. JW, middle row from Mr. PS and
Amyloid positive bottom row from Ms. EC. Even though there
images further highlight the significant
differences in accumulation of amyloid, it is
recommended that black and white images
L A P R be used in diagnostic visual evaluation and
rating of amyloid images. This is to minimize
machine and operator factors involved in
producing false color images leading to
greater inter rater variability.

(a) “Refolding” model

PrPC PrPSc

(b) “Seeding” model

PrPC PrPSc

Very, Rapid Rapid

Figure 9.11 Voxel-based morphometry (VBM) demonstrating the very
topographic distribution of left-hemisphere cortical atrophy in slow
three PPA cohorts (red = nonfluent/agrammatic, blue = semantic,
and green = logopenic). Courtesy of S.M. Wilson and M.L.
Gorno-Tempini.
Figure 9.12 Models for the conformational conversion of PrPC to PrPSc.
(a) The “refolding” model. The conformational change is kinetically
controlled, a high-activation energy barrier preventing spontaneous
conversion at detectable rates. Interaction with exogenously
introduced PrPSc causes PrPC to undergo an induced conformational
change to yield PrPSc. This reaction could be facilitated by an enzyme
or chaperone. In the case of certain mutations in PrPC, spontaneous
conversion to PrPSc may occur as a rare event, explaining why
familial CJD or GSS arises spontaneously, albeit late in life. Sporadic
CJD may come about when an extremely rare event (occurring in
about one in a million individuals per year) leads to spontaneous
conversion of PrPC to PrPSc. (b) The “seeding” model. PrPC and
PrPSc (or a PrPSc-like molecule, light) are in equilibrium, with
PrPC strongly favored. PrPSc is stabilized only when it adds onto
a crystal-like seed or aggregate of PrPSc (dark). Seed formation is
rare; however, once a seed is present, monomer addition ensues
rapidly. To explain exponential conversion rates, aggregates must
be continuously fragmented, generating increasing surfaces for
accretion. Reproduced from Weissmann C et al. (2002).
 PRNP –8 –M 129V E219K

(a) Codons 1 23 50 100 150 200 231 254

PrPC Protein
Cu2+ X Y
Y
αA αB αc

β1 β1 S-S GPI
(b)

PrPSC Type Type Protein

membrane
PrPSC 1 2 X Y
Y

Cell
82 97 αB αc

(c) S-S GPI

P1 D2L

(d)

Figure 9.13 The prion protein. (a) The prion protein gene (PRNP) is located on the short arm of the human chromosome 20. The nonpathogenic
polymorphism includes deletion of one of the octarepeat segments, methionine–valine polymorphism at the 129 position, and glutamine–
lysine polymorphism at position 219. (b) Post-translational modification truncates the cellular prion protein (PrPC) at positions 23 and 231 and
glycosylates (Y) at positions 181 and 197. The phosphatidylinositol glycolipid (GPI) attached to serine at position 231 anchors the C-terminus
to the cellular membrane. The intracellular N-terminus contains five octarepeat segments, P(Q/H)GGG(G/-)WGQ (blue blocks), that can bind
copper ions. The central part of the protein contains one short α-helical segment (α-helix A encompassing residues 144–157 [green block]), flanked
by two short β-strands (red blocks): β1(129–131) and β2(161–163). The secondary structure of the C-terminus is dominated by two long α-helical
domains: α-helix B (residues 172–193) and α-helix C (residues 200–227), which are connected by a disulfide bond. The blue arrows indicate
binding sites of the protein X within α-helices B and C. The dashed frame marks a segment between positions 90 and 150, which is crucial for the
binding of PrPC to PrPSc. (c) PrPSc has increased β-sheet content (red dashed block). (d) Unlike PrPSc, which is anchored to the membrane, GSS
amyloidogenic peptides are truncated and excreted into the cellular space, where they aggregate and fibrillize into GSS amyloid deposits. This
example is an 8-kDa PrP fragment associated with the most common GSS/P102L mutation. A synthetic form of this peptide (90–150 residues),
exposed to acetonitrile treatment to increase β-sheet content, is the only synthetically generated peptide that, when injected intracerebrally into
P102L-transgenic mice, is able to induce the GSS disease. Source: Geschwind (2011). Reproduced with permission from Elsevier.

Figure 9.14 Neuropathology of prion disease. (a) In sCJD, some brain areas may have no (hippocampal end plate, left), mild (subiculum, middle),
or severe (temporal cortex, right) spongiform change. Haematoxylin and eosin (H&E) stain. (b) Cortical sections immunostained for PrPSc in sCJD:
synaptic (left), patchy/perivacuolar (middle), or plaque type (right) patterns of PrPSc deposition. (c) Large Kuru-type plaque,
H&E stain. (d) Typical “florid” plaques in vCJD, H&E stain. Source: Budka (2003). Reproduced with permission from Oxford University Press.
 Trigeminal (Gasserian) ganglion

Figure 22.17 Schematic of the trigeminal nerve and its three divisions, V1, V2, and V3, and their respective sensory territories. Ophthalmic
(blue V1); maxillary (red V2); mandibular (pink V3). © Barrow Neurological Institute.

Figure 22.25 Schematic of the commonly used targets for DBS, including the globus pallidus interna, subthalamic nucleus, and ventral
intermediate nucleus of the thalamus and adjacent structures. © Barrow Neurological Institute.
 Screen Week 78 Screen Week 78

(a) –0.09 (b) –0.33

treated patients
Bapineuzumab
4.0

(c) 0.06 (d) 0.25

treated patients
Placebo

0.0

Figure 23.711C-PIB PET images in two bapineuzumab-treated (a, b) and two placebo-treated (c, d) patients. Average 11C-PIB PET changes

from baseline to week 78 are shown at the top center of each panel for each patient (a–d). The scale bar shows the PiB uptake ratios relative
to the cerebellum. Source: Rinne et al. (2010). Reproduced with permission from Elsevier.

Left hippocampus Right hippocampus

(a) Hippocampus 5.2 5.2
5.1 5.1
Volume (mm3)

Volume (mm3)
5 5
4.9 4.9
4.8 4.8
4.7 4.7
4.6 4.6
Baseline 6 months 1 year Baseline 6 months 1 year

(b) Caudate nucleus

Left caudate nucleus Right caudate nucleus
4.9 5.3

4.8 5.2
Volume (mm3)

Volume (mm3)

4.7 5.1

4.6 5

4.5 4.9

4.4 4.8
Baseline 6 months 1 year Baseline 6 months 1 year

(c) Thalamus Thalamus

15.00
Exercise
Volume (mm3)

14.50 Stretching

14.00

13.50

13.00
Baseline 6 months 1 year
Figure 28.1 Brain region examined using MRI, and graphs demonstrating 1-year effects of aerobic exercise versus a stretching control in
cognitively healthy older adults (n = 120). (a) Example of hippocampus segmentation and graphs demonstrating an increase in hippocampus
volume for the aerobic exercise group and a decrease in volume for the stretching control group. The Time by Group interaction was
significant (p < 0.001) for both left and right regions. (b) Example of caudate nucleus segmentation and graphs demonstrating the changes in
volume for both groups. Although the exercise group showed an attenuation of decline, this did not reach significance (both p > 0.10).
(c) Example of thalamus segmentation and graph demonstrating the change in volume for both groups. None of the changes were significant
for the thalamus. Error bars represent SEM. Source: Erickson et al. (2011). Reproduced with permission of National Academy of Sciences.
(a)

2 3
4
1 5

(b) Change in segment 1 (genu)

Younger Older

0.01

0
Δ Mean diffusivity*

–0.01

–0.02

–0.03

(c) Younger Older

0.02
Δ Fractional anisotropy

0.01

Figure 28.3 Midsagittal slice showing corpus callosum subsegmented

–0.01
(a) and 6-month cognitive training-induced improvements over
baseline in genu (likely connecting prefrontal regions) in white matter
–0.02 microstructure, as measured by mean free diffusion of water (b) and
Intervention Control directional rate (anisotropy) of water diffusion (c) for younger and older
adults (n = 32). *units of measurement for Mean Diffusivity. Source:
*10–9m2/s Lovden et al. (2010). Reproduced with permission of Elsevier.