Dementia And Neuropsychiatry

Dr. Pichai Roj, Tu R3

Hippocampus
Hippocampal formation - subiculum - hippocampus - dentate gyrus

Thalamic and midline structures involved in memory

1.Primary area
Frontal lobes Parietal lobes Temporal lobes Occipital lobes

Association areas
1.Parieto-occipito-temporal association areas 2.Prefrontal association area 3.Limbic association area

Functions of the parieto-occipitotemporal cortex in the nondominant hemisphere Interpreting music Nonverbal visual experiences Visuospatial

2.Prefrontal association area

Planning Elaboration of thoughts Received preanalyzed data Working memories

Frontal Subcortical Circuits

DLPF cortx Lat Orbital cortx Ant Cingulate cortx caudate(DL) GP(lat DM) caudate(VM) GP(med DM) nuc accumbens GP(rostrolat)

Thal (VA,MD)

Thal (VA,MD)

Thal (MD)

Arch Neurol 1993;50:873-880.

Frontal lobe syndromes

Dorsolateral: Executive dysfunction Orbitofrontal: Disinhition, Anosmia Medial frontal / anterior cingulate: apathy

Orbitofrontal syndrome
Disinhibition Impulsive Mood changes: Lability, irritability, hypomania, mania

Medial frontal syndrome

Apathy loss of generative thought transcortical motor aphasia( preserved repetition, comprehension) contralateral neglect Akinetic mutism ( unilateral--> transient, bilateral--> permanent)

3.Limbic association area

Anterior pole of the temporal lobe Ventral portion of the frontal lobe Cingulate gyrus

Behavior,emotions and motivation

Classification of memory systems( by time )

1.Short-term memory - sec to min 2.Intermediate long-term memory - days to weeks and then lost

3.Long-term memory
- yrs ,lifetime

Long term memory

Declarative
Episodic Semantic Skills

Procedural

Classical conditioning Others

Approach To Dementia

Whom should we suspect?

Cognitive domain Short-term memory Examples Forgetting date, misplacing objects, repeating questions

Language

Difficulty naming familiar objects or people and understanding language

Getting lost in previously familiar surrounding, having trouble driving Loss of ability to balance checkbook, plan travel Sadness, aggression, socially inappropriate behavior

Visuospatial skills

Complex cognition Emotion and personality

DSM IV criteria for dementia

Multiple cognitive deficit include memory impairment and at least one Aphasia Apraxia Agnosia Disturbance in executive function Severe impair occupation or social Exclude course of delirium Etiology may related medical condition ,substance abuse or combination

Approach Dementia
Subcortical dement Cortical dementia severity Speed impair
Neuropsychology deficit

Mild to moderate Slow Frontal memory (recall impairment)

More severe early Normal Dysphasia ,agnosia ,dyspraxia Depression less

neuropsychiatry Apathy depression

Motor abnormal Dysarthria ,EPS pathology

Gegenhalten ,less

Striatum ,thalamus Cortical area

Cortical vs Subcortical
Cortical
AD FTD

Subcortical
VaD PD, PSP, Huntingtons disease, Wilsons disease, SCA Hydrocephalus WM diseases Etc.

Approach Dementia
Anterior: FTD Posterior: AD Clinical course: -Progessive -Treatable

Reversible dementia
D E M E N T I A Drugs Emotional disorders Metabolic and endocrine disorders Eye and ear dysfunction Nutritional deficiencies Tumors, trauma Infections Atherosclerosis, Alcohol

Neurodegenerative disease
Alzheimers disease Frontotemporal dementia, CBD Parkinsonian dementia ;Parkinsons disease dementia ,DLB ,MSA

DDx cognitive impairment

Aging change? MCI Delirium Depression (pseudodementia) Amnestic syndrome Dementia

History Definite onset (can be dated) Duration before consulted Rapid progression Pts complaint of cognitive loss Pts description of cogitive loss Family awaren of dysfunction&severity Loss of social skills Hx psychopathology

Dementia
Unusual Long Unusual Variable (minimal) Vague Variable (usual in later stage) Late uncommon

Depression
Usual Short Usual Emphasized Detailed Usual Early common

Examination
Recent:remote memory loss Specific memory loss (patchy) Attention&concentration Dont know answers Near miss answers Performance on tasks of similar difficulties Pts emotional reaction to symptoms

Dementia
Recent>remote Uncommon Often poor Uncommon Variable(common in later stages) Consistent

Depression
Equal Common Often good Common Uncommon Variable

Variable (unconcerned Great distress in later stages)

Examination (2)
Pts affect

Dementia

Depression

Pts efforts in attempting to perform tasks Pts efforts to cope with dysfunction

labile., blunt or Depressed depressed Great Small

Maximal

Minimal

Feature
Onset

Delirium
Acute, often at night

Dementia
Insidious Generally stable over course of day Months to years Clear Usually normal

Course over 24 Fluctuating with lucid hours intervals during day, worse at night Duration Consciousness Attention Hours to weeks Reduced Globally disordered Hypoalert or hyperalert, Distractible Fluctuates over course of day

Feature
Orientation

Delirium
Usually impaired for time, tendency to mistake unfamiliar for familiar place and persons Disorganized Illusions and hallucinations (usually visual) Incoherent, hesitant, slow or rapid Always disrupted Either or both are present

Dementia
Often impaired

Thinking Perception

Impoverished Usually normal

Psychomotor activity Speech Sleep-wake cycle Physical illness or drug toxicity

Often normal Difficulty in finding word Often fragmented sleep Often absent, esp in AD

INVESTIGATE Routine CBC ,ERS ,Urea or creatinine electrolyte ,Liver function test calcium ,glucose ,Vitamin B12 and folate ,Thyroid funtion test ,syphilis Common CT or MRI brain Occasional HIV ,CSF ,EEG ,SPECT

Biomarker in AD
Tau level AB 1-42 Neuropile Biomarker -elevated -decease -thread protein -nonspecific for AD and other -accurate differential AD from normal elderly subjects

Neuropsychiatry Test

MENTAL STATUS EXAMINATION

Drowsy Obtundation Stupor coma

DDX Stuporous
Akinetic mutism : a state of silent , alert appearing immobility. The patients eyes are open and may follow environmental events. There are regular sleep-wake cycles. He may be inert or may have occasional brief movements - Large frontal lobe injuries - Bilateral cingulate gyrus damage - Midbrain

 Locked-in syndrome : The patient mute and paralyzed. The patient can communicate by eye movement. Intellectual function is not impaired Bilateral pontine lesions

Attention
Forward digit span : the numbers are given at a rate of one per second in a monotonous voice. 7 is normal. < 5 is abnormal

 Individuals with normal attention perform the test perfectly Toxic or metabolic disorder Increased ICP Frontal lobe disorder Focal lesion of the posterior R hemisphere

Memory
1.Learning - examiners name,3 words ,3 objects 2.Backward memory - backward spelling ,serial subtraction

3.Delayed recall - 30 minutes

4.Retrograde memory
- retrieve knowledge from the past

Non-verbal memory
Patients are asked to copy several figures ; a few minutes later the patients must reproduce the drawings from memory Design fluency test

Language
Spontaneous speech : aphasia Language comprehension Repetition : pt with shortened digit span will be able
to repeat only brief phrases. Conversely, the digit span is a repetition test, pt with repetition disturbances will have abnormal digit spans.

Naming : adequte vision must be ensured before the

test. Low and high frequency words

Reading Writing

Word list generation

Asking the patient to think of as many members of a specific category ( category fluency ) or as many words beginning with a specific letter ( semantic fluency ) as possible in 1 minute Normal 12-24 animal names, <12 is abnormal Normal 10-20 words beginning with the letter F , < 10 is abnormal

 Word list generation is sensitive to anomia and word finding disturbances, lexical search abnormalities associated with frontal subcortical systems dysfunction and psychomotor retardation

Visuospatial skill
Visuospatial abilities Spatial attention Perception Construction Visuospatial problem solving Visuospatial memory

 Construction tasks are the most widely used screening tests of visuospatial ability. Clock drawing Copying figures of increasing complexity

Tests of copying

 Injury of the posterior aspect of the R hemisphere produces the most severe visuospatial deficits Dysfunction of frontal, occipital or L parietal lobe can affect drawing abilities The R hemisphere mediates the external configuration The L hemisphere mediates the internal details

Clock Drawing Test

Calculation
In MSE : addition, multiplication, subtraction and division One or 2 digit tasks : 16 + 32, 15 x 3 100-7: at least 5 serial It is determined by pts education and occupational history. Damage to the posterior aspect of the L hemisphere

Abstraction
This skill refer to the patients ability to derive a general principle from a specific example. Similarity Difference Similariy : identify the class or category of which 2 items are members Difference : identify the salient distinguishing feature between 2 similar items

 Depends on the patients education These tests are culturally biased Abstraction is sensitive to many types of brain dysfunction Task failure is a nonspecific indicator of cerebral dysfunction Common in frontal systems disorders

Judgment and insight

To yield ecologically valid results that meaningfully relate to the individual s everyday decisions Questions : insight into their own conditions, their plans for the future and their understanding of their own limitation best demonstrate their insight and judgment Orbitofrontal damage

Frontal subcortical systems tasks

Alternating programs

Copying multiple loop figures

Serial hands sequence

the pt is then asked to say aloud fist, slap, cut

Mild Cognitive Impairment (MCI)

Mild Cognitive Impairment

Memory complaint by the patient, family or physician Normal ADLs Normal global cognitive function Objective memory impairment or impairment in one other area of cognitive function as evidence by score 1.5-2.0 SD below the age appropriate mean Clinical Dementia Rating Scale Not demented

MCI
Increase risk AD 12-15% per years Normal risk 1-2 % per year Non amnestic MCI or MCI with multiple domain impairment risk dementia not complete Neuropathological change ; choline acetyltranferase deficit and loss of cholinergic basal forebrain

Common causes of dementia in practice

AD: 50-60% VAD: ??? DLB FTD Others: 5-10%

Dementia
Early amnesia Yes Fluent aphasia Apraxia Agnosia Parkinsonian features Visual hallucination Fluctuation

No

Atherosclerotic Hx Behavioral Focal neurologic changes signs, motor signs Nonfluent aphasia

AD

DLB

VaD

FTD

ALZHEIMERS DISEASE
Most cases are sporadic Familial autosomal dominant form
MEMORY LOSS, APHASIA, APRAXIA AND VISUOSPATIAL ABNORMALITIES = HALLMARKS PRIMARY MOTOR AND SENSORY FUNCTIONS USUALLY NORMAL

 Alzheimers disease : more than memory loss -Decline in cognitive -Loss of ADL -Non-cognitive symptoms -Psychiatric symptoms

Cognitive Deficits
Dysphasia : anomia ,aphasia Dyspraxia Disorientation Impaired calculation Impair judgement and problem-solving

NON-COGNITIVE NEURO SIGNS

- ODOUR THRESHOLD RECOGNITION

- FRONTAL RELEASE SIGN - IMPAIRED STEREOGNOSIS AND GRAPHESTHESIA - SPEED OF GAIT LENGTH OF STEPS

PSYCHIATRIC SYMPTOMS
Anxiety ,depression ,blunted affect Hallucination ,delusion Physical and verbal aggressive ,repetitive mannerism ,uncooperativeness

Behaviour problem in dementia

Verbal aggressive Physical aggressive/agitation Sleep disturbance Restlessness Wandering Apathy /withdrawal 54% 42% 38% 38% 30% 27%

Vascular Dementia
Relation between dementia and CVD: onset within 3 mo. of stroke, abrupt onset ,stepwise decline Complex interaction Vascular etiologies: cerebrovascular disease, and other vascular risk factors Changes in the brain: infarcts, white matter lesion (WMLs), atrophy Cognitive, behavior and other neurological deficit Criteria for VaD : Cerebrovascular disease and its effect on cognitve expands Mixed AD and CVD common VAD not diagnosis until at least 3 months after stroke

NIND-AIREN Criteria for VAD

Require elements 1. dementia with memory def. and >or= 2 in cognitive domains 2. Hx of CVD 3. elements 1+2, relationship stroke and dementia, abrupt onset or stepwise decline in cognitive func., or fluctuating course, and/or brain imaging finding document damaged.

Categories of VAD
Multi-infarct dementia (MID) which develops gradually mini-strokes or transient ischaemic attacks (TIAs see below) ,MID affects the cerebral cortex, which is the outer Subcortical vascular dementia (Binswangers disease or lacunar) which involves vascular damage to the nerve cell fibres (deep white matter) by affecting the sheath nerve fibres in the brain (demyelination). Strategic VaD : thalamic dementia

NINDS-AIREN criteria
Supportive informations 1. Hx risk factors of CVD 2. Hx falling or gait disturbance 3. Early urinary incontinence wo urological conditions 4. Frontal lobe / extrapyramidal feature 5. Pseudobulbar feature

Diagnostic Labeling
Possible VAD; inclusion criteria by clinical evaluation, neurological ex, cognitive impairment, documented MMSE or Capacity Screen Examination, Hx stroke+ neuro def Propable VAD ; above + neuroimaging CT/MRI Definite VAD; above+ neuroimaging+ neuropathology

Clinical presentation
Small vessel disease Lacunes & white matter infarction = WHITE MATTER DISEASE Motor & Cognitive Executive Slowing Forgetfulnes Mood Changes Dysarthria Urinary Symptoms Short- Stepped Gait

type1 type2 type3 type4 type5 type6 type7 type8

Multi infarct , large sized artery Single/multi infarct, basal ganglia, thalamus, angular gyrus Multi subcortical lacunar, deep penetrating artery , most common Binswanger s subcortical leukoencephalopathy Combine small/ large infarct, subcortical and cortical ICH CADASIL Mixed with AD

Subcortical Arteriosclerotic Encephalopathy (SAE)

Bingswanger disease -young patients with HT (50-60) -gradual stepwise progression with stroke -gradual cognitive impairment ;memory deficit ,apathy ,and slow thinking -motor abnormalities ;clumsiness ,slow action ,and gait disturbance.Reflex asymmetry ,extensor plantar response ,frontal lobe sign

Cerebral Autosomal Domonate Arteriopathy with Subcortical Infracts and Leukoencephalopathy (CADASIL)
Mid- adult life; mean 43.3 yrs Clinical manifestations; migrain with aura, seizure, organic psychiatric symp. Negative asso CVD risk factors, arteriosclerosis Subcortical dementia ,momory and frontal deficit

Imaging lesion and Clinical symptoms

Size and number of lesion not explain cognitive function Strategically location cause cognitive disorder -Thalamic lesion :dominant hemisphere -language deficit ,retrograde amnesia if bilateral cause memory loss ,frontal deficit -basal ganglia (globus pallidus,head caudate) -fronatal lobe disease ,apathy ,abulia -disihbition ,aggressive ,psychotic feature

Dementia with Lewy Bodies

Cortical Lewy bodies (CLB) typically found in Parkinsons disease and dementia with Lewy bodies (DLB) CLBdemonstrated using alpha-synuclein immunohistochemistry Lewy body counts were increased nearly 10-fold in the neocortex, limbic cortex, and amygdala

- 3 core diagnostic features

1. Fluctuating confusion 2. Persistent visual hallucinations 3. Spontaneous Parkinsonism

(Probable = 2/3

Possible = 1/3)

Clinical feature
Dementia in association with :
- fluctuations in cognition (especially attention and alertness) - visual hallucinations (typically well formed) - mild spontaneous Parkinsonism

Supportive features :
repeated or unexplained falls syncope or transient loss of consciousness neuroleptic sensitivity syndrome hallucinations in other modalities systematised delusions

Galton and Hodges, 1999

 Dementia :attention ,frontal-executive ,and visuospatial deficits ,short term memory better than AD ,100% Fluctuating cognition :variable altered level of attention or arousal ,60-80% Visual hallucination :recurrent ,variable degree ,50-75% Parkinsonism :spontaneous ,rigidity ,and bradykinesia ,intention tremor ,80-90%

 Cognitive and neuropsychiatric feature appearing within 1 year of motor sign Dopaminergic provoke psychosis Antipsychotic agents induce motor disabilities Sensitivity reaction to neuroleptic drugs

Frontotemperal dementia
Clinical course during the first 2 years is as follows: Psychiatric abnormalities

Patients with orbitofrontal dysfunction become aggressive and socially inappropriate. They may steal or demonstrate obsessive or repetitive stereotyped behaviors.
Patients with dorsomedial or dorsolateral frontal dysfunction may demonstrate a lack of concern, apathy, or decreased spontaneity. Patients may be depressed early in the disease. These mood changes can predate amnesia.

 Speech and language abnormalities often begin early and progress rapidly. Patients usually have relatively little limb apraxia and/or visuospatial dysfunction, thus distinguishing them from patients with diffuse bihemispheric impairment. Even memory impairment is relatively less severe than speech/language and behavioral changes. Incontinence can occur early. Parkinsonism, with its concomitant history of rigidity and gait impairment, can occur.

 General neurologic examination may include some of the following abnormalities: Primitive reflexes such as grasp, suck, and snout (not palmomental reflex, which is often present in healthy individuals; Sjogren, 1997) Akinesia, plastic rigidity, or paratonia on motor examination (Beversdorf, 1998) Resting tremor (uncommon; its presence suggests Parkinson disease or a Parkinson-plus syndrome)

 Mental status/neuropsychological examination may reveal the following: Verbal output that is often nonfluent Most patients have difficulty in naming common objects or pictures (anomia). Spontaneous speech can be sparse yet "fluent" in character, with preserved grammar. Perseveration Relatively preserved visuospatial and visual orientation skills

Clinical
Risk factors

VaD
Transient ischemic attack, strokes, Atherosclerotic risk factors: DM, HT Sudden or insidious Slow or stepwise Neurologic deficits Early abnormalities Slightly impaired early Markedly impaired early Subcortical >7 Less

AD

Onset Progression Neuro signs Gait Memory Executive function Type of dementia Hachinski Ischemic Score Neuroimaging

Insidious Gradually progressive Normal Normal Prominent Impaired in later stage Cortical <4

Infarction, white matter lesions Normal or hippocampal atrophy

Clinical difference
Tremor Motor symptoms Axial involvement : postural instability, masked face Parkinsonism signs at dementia diagnosis Response to levodopa Less

DLB

PDD
More often Unilateral at onset Less

Bilateral More often

25-50%

All cases

Poor

Good

Cognitive impairment Before or within 1 yrs of parkinsonism

After parkinsonism > 1 yrs at least


Parkinsonism Fluctuation Verbal memory

DLB
93.8 50-75 semantic memory 31.3

AD

delirium episodic memory

Executive function
Attention, visuospatial function, constructional abilities Visual hallucination

Neuroleptics

Extrapyramidal

Clinical differences
Onset Early behavioral symptoms Early socially inappropriate behaviors Memory problems Language problems Visuospatial problems Motor signs Mood Most < 75 yrs Common Common

FTD

AD
markedly with age Unusual Later stage Presenting symptom Always associated with memory problems More Less Sadness, anhedonia, apathy, insomnia, guilty Inappetite Typically delusion of misidentification and persecutory (in moderate to severe cases)

Appetite Psychotic symptoms

Initially intact can occur as an isolated cognitive entity in PPA Less More often Irritability, anhedonia, withdrawal, alexithymia, euphoria,, no suicidal idea and guilt appetite, weight gain, CHO craving Rarely persecutory delusion, maybe jealous, somatic, religious and often bizarre

NPH
6th-7th decade 50%: known causes, 50% idiopathic Improvement after shunting 30-50% of idiopathic and 50-70% of secondary NPH Triad: gait difficulty, subcortical cognitive problems, urinary incontinence

NPH
Examination: Mild spasticity of lower extremities BBK present Strength leg preserved Cognitive impairment: Prominent attention, memory impairment, executive, frontal lobe dysfunction Subcortical dementia

Diagnostic tests
Neuropsychological assessment Neuroimaging techniques: CT, MRI CSF removal Cisternography Measurement of cerebral blood flow and metabolism Pressure monitoring and hydrodynamic tests

Prognostic factor for shunting

Gait disturbance Brief symptom duration Lack of dementia at the onset Positive - Lumbar punture and CSF drainage

Increase adequctal flow on MRI CSF dynamic study isotope cistenography Biomarker E-4 alles of ApoE gene

Management
Nonpharmacologic treatment Patient, caregiver & healthcare workers education Caregiver support Patient psychological treatment Financial &legal issues Pharmacologic treatment Cognitive symptoms Non-cognitive symptoms: neuropsychiatric problems

Antiamyloid Therapies
No antiamyloid therapies are currently available. Immunization reduces pathological signs of AD in transgenic mice that have APP mutation. This clinical trial was interrupted when encephalitis developed in 6 % of the patients. Inhibitors to and secretase are under active study.

Cholinesterase inhibitors

AChEI in AD
Efficacy in mild to moderate AD AChEI in moderate to severe AD AChEI in VaD AChEI in DLB AChEI in dementia associated PD

Cholinergic dysfunction and AChI in VaD

1. 2. Cholinergic structures are vulnerable to ischemic damage. Localized stroke interrupt cholinergic bundle that extend from nucleus basalis to cerebral cortex and amygdala 3. Loss of cholinergic neurons in 40% of VaD with reduced acetylcholine activity in cortex, hippocampus, striatum and CSF

Pharmacologic Rx in VaD
Aspirin Pentoxifylline Posatirelin Propentofylline Nicergoline Nimodipine Memantine AChIs

Memantine
N-methyl-D-aspartate antagonist Interfere glutamatergic excitotoxicity improvement on the function on hippocampal neurons Moderate-to-severe AD (alone and combine with AChE inhibitors).

Management of DLB
Target symptom include : - EPS - Cognitive impairment - Neuropsychiatric features (hallucination depression , sleep disorder, behavioral disturbance ) - ANS

 Antiparkinsonian drug : lowest dose of levodopa monotherapy Neuroleptic agent : provoke severe EPS 50% in DLB, increase MR 2-3 times low dose atypical antipsychotic drugs Cholinesterase inhibitor : significant improved in fluctuating cognitive impairment, visual hallucination, apathy, anxiety, sleep disturbance

Health Maintenance and General Medical Treatment

Exercise Control hypertension and other medical conditions Annual immunization against influenza Dental hygiene Use of eye-glasses and hearing aids Nutrition, hydration, and skin care.

Imaging Brain

AD

AD

CADASIL IMAGING

Diagnosis ;MRI; numerous small deep infarction with diffuse myelin loss and pallor hemispheric WM ,internal capsule and basal ganglia ,and lacunar infract

Multiple infraction

Multiple subcortical infraction

Strategic infraction

FTD

Hydrocephalus

Hydrocephalus

hydrocephalus

Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy

Creutzfeldt-Jakob disease
Basal ganglia and cortical-subcortical involvement

Von Economo encephalitis

Progressive Supranuclear palsy

Progressive Supranuclear palsy

imaging atrophy of midbrain (substantia nigra) and pontine tegmentum with abnormally enlarged prepontine cistern variable atrophy of globus pallidus some cases show atrophy of frontotemporal regions with enlarged lateral ventricles and third ventricle some cases show atrophy of motor cortex

MSA

(A) Hyperintense rim in the outer margin of putamen (black arrow), putaminal hypointensity and atrophy (white arrow) in a patient with MSA-p.
(B) Hyperintensity of the middle cerebellar peduncles (black arrow) and hot-cross bun sign (white arrow) in a patient with MSA-c on a T2-weighted image of 1.5-T MRI.

Wilsons disease

Hallervordan-Spatz disease

Hallervordan-Spatz disease

END