Vascular Dementia

Disclosures

•  AGA Medical •  Orasi Medical •  NINDS •  National Institute on Aging •  Alzheimer’s Association

Post-stroke Neuropsychiatric Problems

•  Depression •  Anxiety •  Apathy •  Pathologic laughing and crying •  Aggression •  Psychosis •  Mania •  Obsessive-compulsive disorder •  Cognitive problems

Dementia

Working definition: An acquired and persistent impairment in intellectual function with problems in at least three of these areas: – Memory – Language – Visuospatial skills – Emotions and personality – Complex cognition

Dementia

•  The impairment is sufficient to interfere with usual social and occupational activities

•  Dementia is not always progressive or irreversible

Stroke and Dementia Terminology

• Multi-infarct dementia • Vascular dementia • Vascular cognitive impairment • Vascular mild cognitive

impairment

Dementia Frequency

•  66-70 % Alzheimer’s •  10-25% vascular dementia (#2 for today) •  Largest group may be mixed – BrainNet Europe Consortium 53% of 3,300

autopsied brains – Similar numbers from smaller series in US – Up to 40% Alzheimer’s / vascular – Depends on the criteria

Qiu2007,Schneider2007,Kovacs2008

Vascular Dementia

•  Location – Multiple locations – A key location producing deficits in multiple

areas of cognition – Diffuse pathology: typically slows more than

disconnects •  Size: 50-100cc of brain or more

associated with dementia

Classification

•  Multi-infarct dementia •  Strategic infarct dementia •  Subcortical ischemic dementia •  Hypoperfusion dementia •  Mixed (usually with Alzheimer’s) ***************************** •  Hemorrhagic dementia •  Dementia due to specific arteriopathies •  Vascular mild cognitive impairment

Multi-infarct dementia

•  Cumulative cognitive deficits from multiple strokes

•  Depends on: – Number of strokes – Location – ? total volume of infarcted brain (50-100cc +)

•  Most commonly recognized

Strategic infarct dementia

•  Angular gyrus •  Genu of the internal capsule •  Thalamus •  Caudate •  Cerebellum

Angular gyrus infarct

•  Dominant hemisphere – Gerstmann’s (L-R disorientation, finger

agnosia, acalculia, agraphia) – Fluent aphasia

•  Non-dominant hemisphere – Visuospatial disturbance – Attentional disturbance/neglect

Internal capsule - genu infarct

•  Acute confusional state •  Chronic attentional deficits •  Apathy •  Psychomotor slowing •  Verbal memory deficits

Thalamic infarct

•  Language •  Verbal memory •  Visuospatial processing •  Personality change •  Apathy •  May have bilateral thalamic injury – Paramedian artery or venous

Chui2007

Caudate stroke

•  Abulia / apathy •  Agitation / hyperactivity •  Attentional deficits •  Language problems (left) •  Neglect (right)

Cerebellar infarct

•  Working memory •  Verbal memory •  Visual-spatial function •  Executive function

Schmahmann 1998, 2006

Subcortical ischemic dementia

•  Often grouped together as “subcortical” or small vessel disease

•  Includes both small infarcts (lacunae) and more diffuse white matter disease

Lacunar infarcts and cognition

•  16 patients with single symptomatic lacunar infarct -- deep white matter

•  Scattered, excluding genu of internal capsule, 11 on L and 5 on R

•  “Not right”, “different”, “tired” •  Normal on most neuropsych testing

VanZandvoort1998

Lacunar infarct

•  All had deficits in attention and the speed of mental processing

•  Trouble with complex or multiple tasks, and time pressure

Van Zandvoort 1998, J. Anderson 2008

White matter disease

AKA •  Leukoaraiosis •  Senile leukoencephalopathy •  Progressive subcortical vascular

encephalopathy •  Subcortical ischemic leukoencephalopathy •  Subcortical arteriosclerotic encephalopathy •  Lacunar dementia •  Binswanger’s disease (encephalitis subcorticalis

chronica progressiva) Filley 2001, Schmahmann 2008


Common risk factors:

– Age – Hypertension – Diabetes – Atherosclerotic

disease

Pathology includes:

– Demyelination – Axonal loss – Gliosis

– Assumed to be ischemic

Filley 2001, Schmahmann 2008


•  Only modest correlation of white matter burden with cognitive performance

•  Correlates better with transition from normal cognitive function to MCI, than from MCI to dementia

•  White matter burden correlates with rate of decline in population studies


Most affected: •  Motivation •  Processing speed •  Executive function •  Memory (retrieval rather than encoding) •  Common instruments like the MMSE

may be less useful in this setting •  Association with depression

Chui 2007

Bohnen, N. I. et al. Neurology 2009;72:1411-1416

Disrupted periventricular cholinergic projection axons are presented by a dashed line.

Modified from:

Global hypoperfusion

Affecting: •  Memory •  Attention •  Language •  Motivation/apathy •  Praxis •  Visuospatial function

Evolution of dementia

•  Demons and other evil spirits •  Not syphilis •  Hardening of the arteries •  Alzheimer’s disease •  Alzheimer’s + vascular and other mixed

pathologies

Stroke and Alzheimer’s

Alzheimer’s associated with:

– Diabetes – Hypertension – Atrial fibrillation – Elevated cholesterol – Elevated homocysteine – Inflammation

– High serum viscosity – High fibrinogen – Prior stroke/TIA – Excessive alcohol – Smoking

De La Torre 2002, Qui 2007

Alzheimer’s Disease

Better with: Increased Education: Reduced risk /

delayed onset / modified course /testing effect?

Mentally stimulating activities Social interactions Physical activity

Qui 2007, Wilson 2009

Stroke/Alzheimer’s Genetics

•  APOE 4/4 –prior stroke/TIA gives 5x risk of developing Alzheimer’s

•  Genes with potential link to Alzheimer’s include – TNF alpha polymorphism with CT or TT

genotype) – Angiotensin converting enzyme gene – Lipoprotein lipase gene – Beta-fibrinogen gene – Nitric oxide synthase lll gene – Low-density lipoprotein gene


•  Alzheimer's disease pathology includes: – Capillary abnormalities – BBB changes – Arteriolar lipohyalinosis – Amyloid angiopathy (98%) – Wallerian degeneration

•  Vascular changes were described by Alzheimer

Schmahmann 2008


•  Overlap clinically, genetically, and pathophysiologically

•  The more we know the greater the overlap

•  Insight into the complexity and variability of both Alzheimer’s and vascular injury

Vascular risk factors •  Hypertension: reduced risk of dementia

with treatment with antihypertensives ~ longer than 5 years under age 75 compared with untreated hypertensive subjects and normotensive controls

Hoffman Neurology 2009

•  Weak to no evidence for statins, reducing BP (without prior cerebrovascular disease), nonsteroidals, B12, specifically for cognitive decline

Bowler 2007, Cochrane 2006, 2009

General Treatment of Dementia

•  Counseling and education •  Planning: job, living situation, $$$,

caregivers… •  Attention to driving •  Attention to driving •  Attention to driving •  Avoid drugs that worsen mental status

(benzodiazepines, anticholinergic drugs…)

Behavioral Problems

– Glasses/hearing aids – Lights – Reorientation – Protect sleep – Control stimulation – Pictures/familiar objects from home – Calendars/schedules – Memory books

Behavioral Problems

Caregiver response: – Identify the problem – Reassurance – Redirection/distraction – Calm approach

Stay Calm

If you can stay calm while everyone around you panics, you should stop and wonder if you really understand the situation

Anonymous

Symptomatic Treatment

•  Depression – SSRI’s, trazodone, nefazodone, ECT, TMS

•  Psychosis – Newer antipsychotics: olanzapine,

risperidone – Smallest dose, limited time – Little evidence of benefit in trials

•  Anxiety – SSRI’s, buspirone

Symptomatic Treatment

Agitation/aggression – Environment – Treat medical illness – Atypical antipsychotics – Valproic acid, carbamazepine, beta-

blockers – Buspirone – Trazodone

Behavioral issues

•  Importance of exercise •  Staying mentally active •  Staying active socially

Cognitive Treatment

•  Dopamine agonists •  Stimulants •  Acetylcholinesterase inhibitors

Cognitive Treatment •  Acetylcholinesterase inhibitors for cognition

and behavior –  limited evidence for donepezil, rivastigmine, and

galantamine –  cautious interpretation given mixed dementias in

study –  off-label use (for the moment)

•  Memantine -- NMDA antagonist –  modest and conflicting evidence– may have

cognitive benefit in mild to moderate VaD •  CDP-choline -- limited benefit over short-term •  The benefits are subtle

Cochrane Database of Systematic Reviews 2005-9

Summary

•  Review of some of the cognitive effects of vascular disease

•  Appreciation of the interaction of vascular disease and Alzheimer’s

•  Limited options for treatment •  Emphasizes the need for risk factor

modification and prevention

Evaluation of the patient

Folstein MMSE

•  Questions (Total of 30 points) •  Orientation (10 points)

–  Patient identifies time and place •  Registration (3 points) and Recall (3 points)

–  Patient recalls objects at 1 and 5 minutes •  Attention and Calculation (5 points)

–  Patient spells a word backwards or serial 7’s •  Language (8 points)

–  Tests processing language •  Visual-spatial: pentagons (1 point)

MMSE: Educational and Age Norms

•  Fourth Grade Education – Ages 18 to 69: Median MMSE Score 22-25 – Ages 70 to 79: Median MMSE Score 21-22 – Age over 79: Median MMSE Score 19-20

•  Eighth Grade Education – Ages 18 to 69: Median MMSE Score 26-27 – Ages 70 to 79: Median MMSE Score 25 – Age over 79: Median MMSE Score 23-25

•  High School Education – Ages 18 to 69: Median MMSE Score 28-29 – Ages 70 to 79: Median MMSE Score 27 – Age over 79: Median MMSE Score 25-26

•  College Education – Ages 18 to 69: Median MMSE Score 29 – Ages 70 to 79: Median MMSE Score 28 – Age over 79: Median MMSE Score 27 Crum1993

www.bethanygrp.org

Frontal Assessment Battery

•  Standardized test •  Age standardized norms available •  18 points

www.bethanygrp.org

FrontalAssessmentBaCery

Approach to the patient

Diagnostic studies •  Electrolytes, renal function, liver

function, CBC, TSH, B12 •  MRI or CT scan in most patients

Selected patients •  Lumbar puncture

–  May eventually have useful CSF profiles of tau, phospho-tau, amyloid-beta, metalloproteinase 9,light neurofilament subunit of myelin

•  Toxicology •  RPR, HIV… •  Genetic testing •  EEG •  Neuropsychological testing •  Functional imaging •  Stroke evaluation

Bibl2007,2008

Hachinski Ischaemia Score

•  Abrupt onset 2 •  Stepwise deterioration 1 •  Fluctuating course 2 •  Nocturnal confusion 1 •  Relative preservation of

personality 1 •  Depression 1 •  Somatic complaints 1 •  Emotional incontinence 1

•  History of hypertension 1 •  History of strokes 2 •  Evidence of associated

atherosclerosis 1 •  Focal neurological

symptoms 2 •  Focal neurological signs 2

HachinskiVC,“CerebralbloodflowindemenAa.”ArchNeurol.1975;32:632‐7.

NINDS - AIREN criteria for the diagnosis of vascular dementia

1. Dementiadefined by cognitive decline from a previously higher level of functioning and manifested by impairment of memory and of two or more cognitive domains (orientation, attention, language, visuospatial functions, executive functions, motor control, and praxis), preferable established by clinical examination and documented by neuropsychological testing; deficits should be severe enough to interfere with activities of daily living not due to physical effects of stroke alone.

Exclusion criteria: cases with disturbance of consciousness, delirium, psychosis, severe aphasia, or major sensorimotor impairment precluding neuropsychological testing. Also excluded are systemic disorders or other brain diseases (such as AD) that in and of themselves could account for deficits in memory and cognition.

2. Cerebrovascular disease, defined by the presence of focal signs on neurologic examination, such as hemiparesis, lower facial weakness, Babinski sign, sensory deficit, hemianopia, and dysarthria consistent with stroke (with or without history of stroke), and evidence of relevant CVD by brain imaging (CT or MRI) including multiple large vessel infarcts or a single strategically placed infarct (angular gyrus, thalamus, basal forebrain, or PCA or ACA territories), as well as multiple basal ganglia and white matter lacunes, or extensive periventricular white matter lesions, or combinations thereof.

3. A relationship between the above two disorders, manifested or inferred by the presence of one or more of the following: (a) onset of dementia within 3 months following a recognized stroke; (b) abrupt deterioration in cognitive functions; or fluctuating, stepwise progression of cognitive deficits.

II. Clinical features consistent with the diagnosis of probable vascular dementia include the following:

(a) Early presence of gait disturbance (small-step gait or marche a petits pas, or magnetic, apraxic-ataxic or parkinsonian gait); (b) history of unsteadiness and frequent, unprovoked falls; (c) early urinary frequency, urgency, and other urinary symptoms not explained by urologic disease; (d) pseudobulbar palsy; and (e) personality and mood changes, abulia, depression, emotional incontinence, or other subcortical deficits including psychomotor retardation and abnormal executive function.

III. Features that make the diagnosis of vascular dementia uncertain or unlikely include (a) early onset of of memory deficit and progressive worsening of memory deficit and progressive worsening of memory and other cognitive functions such as language (transcortical sensory aphasia), motor skills (apraxia), and perception (agnosia), in the absence of corresponding focal lesions on brain imaging; (b) absence of focal neurological signs, other than cognitive disturbance; and (c) absence of cerebrovascular lesions on brain CT or MRI.

IV. Clinical diagnosis of possible vascular dementia may be made in the presence of dementia (section I-1) with focal neurologic signs in patients in whom brain imaging studies to confirm definite CVD are missing; or in the absence of clear temporal relationship between dementia and stroke; or in patients with subtle onset and variable course (plateau or improvement) of cognitive deficits and evidence of relevant CVD.

V. Criteria for diagnosis of definite vascular dementia are (a) clinical criteria for probable vascular dementia; (b) histopathologic evidence of CVD obtained from biopsy or autopsy; (c) absence of neurofibrillary tangles and neuritic plaques exceeding those expected for age; and (d) absence of other clinical or pathological disorder capable of producing dementia.

VI. Classification of vascular dementia for research purposes may be made on the basis of clinical, radiologic, and neuropathologic features, for subcategories or defined conditions such as cortical vascular dementia, subcortical vascular dementia, BD, and thalamic dementia. The term "AD with CVD" should be reserved to classify patients fulfilling the clinical criteria for possible AD and who also present clinical or brain imaging evidence of relevant CVD. Traditionally, these patients have been included with VaD in epidemiologic studies. The term "mixed dementia," used hitherto, should be avoided.

Reference Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993 Feb;43(2):250-60.

Vascular Dementia

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