Imaging Biomarkers in Predicting MCI and Dementia

Ronald C. Petersen, Ph.D., M.D.

Alzheimers Disease Research Center

Mayo Clinic College of Medicine Rochester, MN
Mild Cognitive Impairment Symposium
Miami January 18, 2014

Disclosures
Pfizer, Inc. and Janssen Alzheimer
Immunotherapy : Chair DMC

Roche: Consultant Merck: Consultant

Funding

National Institute on Aging: U01 AG006786 P50 AG016574 U01 AG011378

Introduction to the Recommendations from the National Institute on Aging-Alzheimers Association Workgroups on Diagnostic Guidelines for Alzheimers Disease
Clifford R. Jack, Jr, Marilyn S. Albert, David S. Knopman, Guy M. McKhann, Reisa A. Sperling, Maria C. Carrillo, Bill Thies, Creighton H. Phelps

Alz and Dementia, 2011

2012 MFMER | 3238583-3

Hypothetical Model of Dynamic Biomarkers of the Alzheimers Pathological Cascade

A Tau-meditated neuronal injury and dysfunction Brain structure Memory Clinical function

Abnormal

Biomarker magnitude
Normal

Cognitively normal

MCI

Dementia

Clinical disease stage

Jack et al: Lancet Neurol 2010

Criteria Approach

Clinical criteria Biomarkers Molecular neuropathology

CSF AB42 Amyloid imaging

Measures of neuronal injury

Structural, e.g., MRI Functional, e.g., FDG PET CSF tau

Alzheimers Disease Spectrum

Preclinical AD

MCI Due to AD

Dementia Due to AD

The Diagnosis of Dementia Due to Alzheimers Disease:

Recommendations from the National Institute on Aging-Alzheimers Association Workgroups on Diagnostic Guidelines for Alzheimers Disease
Guy M. McKhann, David S. Knopman, Howard Chertkow, Bradley T. Hyman, Clifford R. Jack, Jr, Claudia H. Kawas, William E. Klunk, Walter J. Koroshetz, Jennifer J. Manly, Richard Mayeux, Richard C. Mohs, John C. Morris, Martin N. Rossor, Philip Scheltens, Maria C. Carrillo, Bill Theis, Sandra Weintraub, Creighton H. Phelps

Alz and Dementia, 2011

2012 MFMER | 3238583-7

Dementia Due to AD
Diagnostic category Probable AD dementia Probable AD with evidence of path AD Possible AD dementia atypical with path Dementia unlikely AD Biomarker probability of AD etiology Uninformative/ available Intermediate Highest High consider secondary A (PET or CSF) Neuronal injury (tau, FDG, sMRI)

Conflicting/ indeterminant or unavailable ? Positive Positive Positive Positive Positive

Lowest

Negative

Negative

McKhann et al: 2011

2012 MFMER | 3219504-8

Alzheimers Disease Spectrum

Preclinical AD

MCI Due to AD

Dementia Due to AD

The Diagnosis of Mild Cognitive Impairment Due to Alzheimers Disease:

Recommendations from the National Institute on Aging-Alzheimers Association Workgroups on Diagnostic Guidelines for Alzheimers Disease
Marilyn S. Albert, Steven T. DeKosky, Dennis Dickson, Bruno Dubois, Howard H. Feldman, Nick C. Fox, Anthony Gamst, David M. Holtzman, William J. Jagust, Ronald C. Petersen, Peter J. Snyder, Maria C. Carrillo, Bill Thies, Creighton H. Phelps

Alz and Dementia, 2011

2012 MFMER | 3238583-10

MCI Due to AD
Diagnostic category MCI MCI due to AD intermediate likelihood MCI due to AD high likelihood MCI unlikely due to AD Biomarker probability of AD etiology Uninformative A (PET or CSF) Neuronal injury (tau, FDG, sMRI)

Conflicting/ indeterminant or unavailable Positive Untested Untested Positive

Intermediate Intermediate

Highest

Positive

Positive

Lowest

Negative

Negative

Albert et al: 2011

2012 MFMER | 3219504-11

Alzheimers Disease Spectrum

Preclinical AD

MCI Due to AD

Dementia Due to AD

3047674-12

Toward Defining the Preclinical Stages of Alzheimers Disease:

Recommendations from the National Institute on Aging-Alzheimers Association Workgroups on Diagnostic Guidelines for Alzheimers Disease
Reisa A. Sperling, Paul S. Aisen, Laurel A. Beckett, David A. Bennett, Suzanne Craft, Anne M. Fagan, Takeshi Iwatsubo, Clifford R. Jack, Jr, Jeffrey Kaye, Thomas J. Montine, Denise C. Park, Eric M. Reiman, Christopher C. Rowe, Eric Siemers, Yaakov Stern, Kristine Yaffe, Maria C. Carrillo, Bill Thies, Marcelle Morrison-Bogorad, Molly V. Wagster, Creighton H. Phelps

Alz and Dementia, 2011

2012 MFMER | 3238583-13

Preclinical AD
Diagnostic category Stage 1 Stage 2 Stage 3 Stage 0 A (PET or CSF) Positive Positive Positive Negative Neuronal injury Negative Positive Positive Negative Clinical Negative Negative Positive Negative

Sperling et al: 2011

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NIA-AA Preclinical AD Staging in Relation to Our Hypothetical Model of Biomarkers

Preclinical Stage
Abnormal

Biomarker magnitude

Neuronal injury

Cognitive symptoms

Cut points
Normal Cognitively normal MCI Dementia

Clinical disease stage

Do the Criteria Work?

Mayo Clinic Study of Aging (MCSA)

3047674-16

Mayo Olmsted County Study of Aging

(U01 AG006786)

CP1265413-14

Mayo Clinic Study of Aging

Population-based study of 30004000 nondemented persons age 50-89 years in Olmsted County, MN

CP1265413-14

Mayo Clinic Study of Aging

2004 Oct.
Enrollment F-U Cycle 2 F-U Cycle 3 F-U Cycle 4 F-U Cycle 5 Data analysis F-U Cycle 6 Data analysis F-U Cycle 7 Data analysis Replen cohort Replen cohort Replen cohort Replen cohort

06

08

10

12

14

F-U = follow-up
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Mayo Clinic Study of Aging

70 year olds
2004 Oct
Enrollment F-U Cycle 2 F-U Cycle 3 F-U Cycle 4 F-U Cycle 5

06

08

10

12

14

n=2000

F-U Cycle 6 F-U Cycle 7

50 year olds
2011
Enrollment

12

13

14

F-U Cycle 2

n=2000

F-U Cycle 3

F-U = follow-up
2013 MFMER | 3270183-20

Evaluation
Consent form Blood draw Clinical evaluation Nurse/SC interview
Participant Family history Current medications Demographic information Memory & orientation Medical history & risk assessment Neuropsychiatric inventory Study partner Clinical dementia rating Functional assessment (FAQ)

Neurological evaluation
Neurological history Short test of mental status Modified Hachinski scale Prime MD (physician form) Neurological examination and modified UPDRS

Cognitive assessment
Memory Logical memory (delayed) Visual reprod (delayed) AVLT Executive function Trails A & B Digit symbol substitution Visuospatial Picture completion Block design Language Boston naming test Category fluency

Consensus conference
CP1333643-2

Resources Acquired

4000 non-demented subjects

3000 cognitively normal 800 MCI

2500 quantitative MRI scans ~ 4000 DNA samples ~ 4000 frozen plasma/serum samples
plus annual samples

Clinical and performance measures

Extension of MCSA

Add new subjects older cohort Add 1000+ subjects younger cohort Continue annual clinical follow-ups Continue serial MRI scans Collect annual plasma/serum Perform 800 CSFs Perform 1200 FDG-PET scans Perform 1200 PiB PET scans

So, How Do the Criteria Fare in the General Population?

MCI Due to AD

Assessing Biomarkers in the Community

Biomarker negative
Amyloid neg FDG PET/MRI neg

Amyloid positive Neurodeg neg

Amyloid pos FDG PET/MRI neg

Amyloid pos Neurodeg pos

Amyloid pos FDG PET/MRI pos

Neurodegen only
Amyloid neg FDG PET/MRI pos

All MCI MCSA

Population Frequencies
50 40

30

%
20 10 0 Biom neg Amyloid only Amyloid + neurodeg Neurodeg only sNAP
2013 MFMER | 3270183-27

Petersen et al: Ann Neuro, 2013

MCSA aMCI
Annual Rates of Change
50%
MCI Biom neg

NL

8%
Dementia

NL

36%

MCI Amyloid positive

0%
Dementia

42%
5%
NL
MCI Amyloid + Neurodegen

64%

17%
Dementia

36%
NL

MCI Neurodegen only (sNAP)

22%
Dementia

78%

42%

Petersen et al: Ann Neuro, 2013

Risk of Dementia Following Reversion to Normal

100

Cumulative incidence of dementia (%)

80
60 40 20 0 0

MCI with reversion vs normal HR = 6.6; P<0.001 MCI no reversion vs normal HR = 28.8; P<0.001 Normal

Years of follow-up

2014 MFMER | 3320580-29

aMCI
60 50 40 MCSA ADNI

% 30
20 10 0 Biom neg Amyloid only Amyloid + Degenerative neurodeg only

Petersen et al: Ann Neuro , 2013

2013 MFMER | 3270183-30

Preclinical AD

Preclinical AD
Diagnostic category Stage 1 Stage 2 A (PET or CSF) Positive Positive Neuronal injury Negative Positive

Clinical Negative Negative

Stage 3
Stage 0

Positive
Negative

Positive
Negative

Positive
Negative

Sperling et al: 2011

Pre-clinical Normal
Population Frequencies
Jack et al., Ann Neurol, 2012

NIA-AA Preclinical AD Staging in Relation to Our Hypothetical Model of Preclinical Biomarkers Stage
Abnormal
Biomarker magnitude

0
43%

1
16% A

2
12% Neuronal injury

3
3% Cognitive symptoms

Cut points Normal Cognitively normal Clinical disease stage MCI Dementia

Jack et al: Lancet Neuro, 2010

Preclinical Alzheimers Disease and Its Outcome

A Longitudinal Cohort Study
Stephanie J. B. Vos; Chengjie Xiong; Pieter Jelle Visser; Mateusz S. Jasielec; Jason Hassenstab; Elizabeth A. Grant; Nigel J. Cairns; John C. Morris; David M. Holtzman; Anne M. Fagan

Lancet Neurology 12:957, Oct 2013

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Preclinical Alzheimers Disease and Its Outcome: A Longitudinal Cohort Study

Lancet Neurology 12:957, Oct 2013

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Pre-Clinical AD Stages
Neuroimaging vs CSF
50 40 30 Jack et al: MCSA, 2012 Vos et al: 2013

%
20
10

0
Stage 0 Stage 1 Stage 2 Stage 3 SNAP

Uncl

Petersen, L Neur 2013

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Preclinical Progression to MCI/Dementia

Mayo Clinic Study of Aging
50 40 30 % 20 10 0 Stage 0 Stage 1 Stage 2 Stage 3 SNAP

Knopman et al., 2012

2012 MFMER | 3205603-38

Progression to CDR >/= 0.5 by Preclinical Alzheimers Disease Stage

1.0
Normal Stage 1 Stage 2 Stage 3 SNAP Group

Cumulative incidence probability

0.8 0.6

St 3

St 2

0.4 0.2 0.0 0 2 4 6 8 10 12

St 1 SNAP NL

14

Follow-up (years)
Vos et al: Lancet Neurol 12:957, 2013
2013 MFMER | 3309417-39

Amyloid-first and Neurodegenerationfirst Profiles Characterize Incident Amyloid PET Positivity

Clifford R. Jack, Jr., Heather J. Wiste, Stephen D. Weigand, David S. Knopman, Val Lowe, Prashanthi Vemuri, Michelle M. Mielke, David T. Jones, Matthew L. Senjem, Jeffrey L. Gunther, Brian E. Gregg, Vernon S. Pankratz, Ronald C. Petersen Neurology, 2013; 81: 1732-1740

Figure 1. Flow chart.

The CN groups in blue are the focus of this paper.

Jack et al, Neurology, 2013

Changes in Imaging and Clinical Measures By Amyloid Status

2013 MFMER | 3266631-43

2013 MFMER | 3263944-44

Figure 1.
Linear trend of performance on the verbal memory composite (A) and the visual memory composite (B) for HA-A, HA-A+, MCI-A, MCI-A+, and AD-A+ groups, from baseline to 36 months.
Lim YY et al, Brain 2013.
2013 MFMER | 3266631-45

Mayo Clinic Study of Aging

Role of amyloid status in progression from healthy control to MCI in the general population

2013 MFMER | 3266631-46

Role of Amyloid in Predicting Progression in Imaging and Cognitive Biomarkers

Amyloid positive vs. amyloid negative Imaging biomarkers PiB PET FDG PET MR ventricular volume Cognitive measures Global 4 cognitive domains

2013 MFMER | 3266631-47

BASELINE CHARACTERISTICS OF SUBJECTS WITH SERIAL DATA

Characteristic Age, years, median (IQR) Male, no. (%) APOE e4 carrier, no (%) Education, years, median (IQR) Short Test Score, median (IQR) Cognitive domain z-scores, median (IQR) Global Memory Language Attention Visuospatial PIB ratio, median (IQR) FDG ratio, median (IQR) Hippocampal volume, cm3, median (IQR) Hippocampal volume/TIV, median (IQR) Number of follow-up visits, % 1 2 3 4 5 Serial Cognitive Data (n = 484) 78 (75, 82) 269 (56) 120 (25) 14 (12, 16) 35 (34, 37) Serial Imaging Scans (n = 200) 78 (75, 82) 121 (60) 57 (28) 14 (12, 16) 35 (33, 37)

0.75 (0.16, 1.25) 0.70 (0.02, 1.38) 0.50 (-0.02, 1.02) 0.59 (-0.00, 1.11) 0.64 (0.02, 1.22) 1.38 (1.31, 1.63) 1.40 (1.30, 1.50) 7.0 (6.4, 7.5) 0.47 (0.43, 0.52)

0.71 (0.13, 1.23) 0.70 (-0.04, 1.32) 0.47 (-0.04, 0.99) 0.59 (0.02, 0.99) 0.61 (0.00, 1.20) 1.38 (1.30, 1.61) 1.40 (1.30, 1.50) 7.0 (6.4, 7.5) 0.47 (0.42, 0.52)

261 (54) 181 (37) 29 (6) 10 (2) 3 (1)

171 (86) 28 (14) 1 (0) 0 (0) 0 (0)

Change in STMS by PiB Over Time

2.9 2.7 2.5 2.3 2.1 1.9 1.7 1.5 1.3 0.0 0.5 1.0 1.5 2.0 Age=75, PIBAge=75, PIB+ PIB, P=0.002 Age=82, PIBAge=82, PIB+

Short Test of Mental Status

Time (years)

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Change in Global Cognition by PiB Over Time

2.0
Age=75, PIBAge=75, PIB+ PIB, P=0.02 Age=82, PIBAge=82, PIB+

Global z-score

1.5 1.0

0.5
0.0 -0.5 0.0 0.5 1.0 1.5 2.0

Time (years)

2014 MFMER | 3320580-50

Change in Attention by PiB Over Time

2.0
Age=75, PIBAge=75, PIB+ PIB, P=0.005 Age=82, PIBAge=82, PIB+

Attention z-score

1.5 1.0

0.5
0.0 -0.5 0.0 0.5 1.0 1.5 2.0

Time (years)

2014 MFMER | 3320580-51

ApoE and PiB Cognitive Measures

Global z-score
APOE4+, PIB+ APOE4+, PIBAPOE4-, PIB+ APOE4-, PIB-

Attention z-score

Short Test Mental Status

-0.1

0.0

0.1

-0.1

0.0

0.1

-1.0

-0.5

0.0

0.5

Annual change

2014 MFMER | 3320473-52

Change in PiB Levels by PiB Over Time

2.9 2.7 2.5 2.3 2.1 1.9 1.7 1.5 1.3 0.0 0.5 1.0 1.5 2.0 Age=75, PIBAge=75, PIB+ PIB, P0.001 Age=82, PIBAge=82, PIB+

PiB ratio

Time (years)

2014 MFMER | 3320580-53

Change in Ventricular Volume by PiB Over Time

Ventricular volume (cm3)
Age=75, PIBAge=75, PIB+ PIB, P=0.001 50 40 Age=82, PIBAge=82, PIB+

60

30 0.0 0.5 1.0 1.5 2.0

Time (years)

2014 MFMER | 3320580-54

ApoE and PiB Imaging Biomarkers

PIB
APOE4+, PIB+ APOE4+, PIBAPOE4-, PIB+ APOE4-, PIB-

Ventricular volume

0.01

0.01

0.03

0.05

Annual change

2014 MFMER | 3320473-55

Education, PBI by ApoE Interaction and Hippocampal Volume

Education (12 vs 16 yr)

Among ApoE4 - / PIB +

Among ApoE4+ / PIB + PIB + ApoE4 + vs PiB ApoE4Among PiB + APOE4 + Among PiB - APOE4+ HV/TIV (P25 vs P75) 0 1 2 3 4 5 6

Hazard ratio

2014 MFMER | 3320473-56

Evolving Field on Biomarkers

Pre-clinical
Amyloid alone slow progression Amyloid plus neurodegeneration Amyloid plus ApoE4 additive

MCI
Amyloid alone slow progression Amyloid plus neurodegeneration

Mayo Clinic AD Research

Rochester
Brad Boeve Dave Knopman Cliff Jack Val Lowe Bob Ivnik Mary Machulda

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Michelle Mielke
Rosebud Roberts Walter Rocca Shane Pankratz

Nilufer Taner-Erketin
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Jenny Whitwell
Kejal Kantarci Joe Parisi Eric Tangalos

Scottsdale
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Thank You