POST-STROKE
DEMENTIA
Pr. Riadh Gouider
Department of Neurology - Alzheimer
Centre
Razi Hospital –Tunisia- Tunisia
Concept-Historical Overview
1684
Thomas Willis (1684)
The earliest clinical
description of
vascular dementia
1894
Biswanger(1894)
1895
Alzheimer (1895)
“ arteriosclerotic brain degeneration ”
1974
Hachinski (1974)
“ Multi infarct
dementia”
Concept
Vascular Cognitive Impairement spectrum
Ischemic stroke
C
V
D
Brain
at risk
MCI
Vascular
cognitive
disorder
(Pre-dementia)
Moderate
Dementia
Severe
Dementia
Vascular-Dementia
(VaD)
Al-Qazzaz NK et al.2014
Concept
Vascular Cognitive Impairement spectrum
VCI
VASCULAR
DEMENTIA
POST-STROKE
DEMENTIA
Al-Qazzaz NK et al.2014-Modified
Concept
Relationship : Cognitive Impairment and CVD
DEMENTIA
VCI-ND
VaD
MIXED
AD
MCI
Al-Qazzaz NK et al.2014-Modified
Epidemiology
Stroke
7% after 1 year
48% after 25 years
16–18%
Pendlebury ST et al. 2010
Epidemiology
Brain at
risk

MCI
Post-stroke MCI
(after First stroke):

At 3 months:
 17-92%
Moderate
Dementia

Severe
Dementia
Post-stroke dementia
(after First stroke):


Cumulative incidence:
1.7-3%/year
At 25 years: 48%
17-66% (5-11% in the first 15 months)
Brainin et al. 2014
Prevalence of VaD
RAZI HOSPITAL COHORT
All Dementias
• VaD = 311 / 2521 patients
226
201
311
=> 12.33%
(mixed dementia not included)
• 184 Men/ 127 Women
• Mean Age : 72 y (42 to 90 y)
Vascular dementias
Degenerative
dementias
1638
Secondary dementias
Dementia of
undetermined origin
Risk Factors
Demographic
 Age
 Sex
 Ethnicity
Stroke factors
 Previous/recurrent
cerebrovascular accident
(CVA)/TIA
Vascular risk factors
•
•
•
•
•
•
•
Hypertension
Atherosclerosis
Diabetes mellitus
Low blood pressure
Coagulopathies
Peripheral vascular disease
ApoE4
•
•
•
•
•
•
Cigarette smoking
Hypercholesterolemia
Ischemic heart disease
Atrial fibrillation
Elevated homocysteine
Myocardial infarction (MI)/angina
systemic inflammation
Vascular Risk Factors
RAZI HOSPITAL COHORT
N
% (/311)
Hypertension
79
24.5%
Diabetes
38
12.2%
Dyslipidemia
24
7.7%
Diagnosis
1.
Clinical Evaluation
2.
Cognitive Assessement
3.
Neuroimaging
4.
Biomarkers
5.
Neurpathology
Pathogenic factors
1. Volume of brain destruction
2. Location of vascular lesions
3. Number of cerebrovascular lesions
Volume of Brain destruction
Tomlinson 1970:
 All patient with loss 100 ml brain volume: dementia
 Demented patients:more frequent infarcts > 20 ml than
controls

Small infarcts: possible contribution to dementia

Concept of strategic sites of infarcts

VaD: mean volume of infarcted brain loss:39-47ml
Pathogenic factors
1.Volume of brain destruction
2. Location of vascular lesions
3. Number of cerebrovascular lesions
Classification according to major morphologic
lesions
Small vessel disease
 Ischemic white matter
degeneration
 Cribriform atrophy of white
matter
 Lacunar infarction in
subcortical nuclei and WM
 Granular atrophy of cortex
Large vessel disease
 Very extensive or multifocal
infarction
 Critically sited infarcts
Hypoperfusion lesions
 Hippocampal sclerosis
 Laminar cortical necrosis
Rare local vascular disease
 CADASIL
 Cerebral amyloidosis
 Cerebral vasculitis
 Antiphospholipid antibody
syndrome
Strategic Infarct Syndrome
Vascular
territory
Structures
affected
Clinical features
anterior
cerebral artery
medial frontal
cortex
frontal behaviours
(apathy,disinhibition,hyperorality,
inappropriate sexuality,emotional
lability);memory changes
middle
cerebral artery
angular gyrus
Alexia, agraphia, fluent aphasia, memory
changes,abnormal spatial awareness
middle
cerebral artery
Boundary regions
cerebral
convexity cortical
"watersheds"
Amnesia, apraxia, aphasia agnosia hemineglect, visual disturbances
posterior
cerebral artery
hippocampus
posterior
cerebral artery
medial thalamic
nuclei
Amnesia, anomia, visual field
disturbances, confusion
memory impairment (especially memory
acquisition); inattention
Al-Qazzaz NK et al.2014-Modified
Pathogenic factors
1. Volume of brain destruction
2. Location of vascular lesions
3. Number of cerebrovascular lesions
Number of cerebrovascular lesions

Basic concept: multiple small infarcts

Mean number:
5.8 - 6.7 VaD
3.2 in non demented

Additional factors (age,education level..) for intellectual
decline
Pathogenic Factors
Cerebral microinfarcts
Age
Vascular causes
Education
Atherosclerosis
Lacunar state
Genetics
Microvascular
disease
Withe matter lesions
Vascular
risk factors
ApoE…4
Reduced….
Multiple microinfarcts
Cerebrovascular
disorders
Additional
pathologies
Neuronal synapse loss
Cerebral atrophy
Cognitive
impairment
Dementia
MECHANISMS

PSCI:


Immediately after stroke
Delay cognitive impairment becomes apparent
Olesen J et al.2012

Alzheimer disease pathogenesis: contributions to the 1/3
demented cases after stroke → overlap between VCI and AD
Feigin VL et al. 2014
MECHANISMS
Main mechanisms on post-stroke cognitive impairment
Jia-Hao Sun et al. 2014
Clinical Evaluation
STROKE
DEMENTIA
Brainin et al. 2014
Clinical Evaluation
Time
Time
to
assessment
STROKE
Dynamic
process
IMMEDIATE
DEMENTIA
Stroke endpoint: 90 days?
VCI-MCI
DELAYED
POST-STROKE
DEMENTIA
Brainin et al. 2014
Clinical Evaluation
Time
STROKE
Space
unique
recurrent
STROKE
Large vessel
Infarct
Lacunar
Strategic
Infarct
Subcortical Infarcts/
Leucopathy
Brainin et al. 2014
Clinical Evaluation
History of vascular risk factors / cardivascular disease
Others: migraine, depression
Cognitive complaint
Onset - progression

Others:



Gait disturbance
Urinary incontinence
Focal neurological signs
Brainin et al. 2014
Clinical Evaluation
RAZI HOSPITAL COHORT VaD

Mean age at onset: 69.76 years (41-89)

Mean diagnosis time: 2.27 years

Presenting symptoms
80
70
60
50
40
30
20
10
0
Memory
disorders
Behavioral
disorders
Language
disturbances
Mood disorders
Confusion
Clinical Evaluation
Diagnostic criteria

Hachinski Ischemia Scale

Ischemic Scale of Rosen

DSMIII,DSMIII-R, DSMIV

International classification of diseases (ICD10)


State of California Alzheimer’s Disease Diagnostic and Treatment
Centers (ADDTC)
(Chui et al 1992)
National Institute of Neurological Disorders and stroke - Association
Internationale pour la Recherche et l’enseignement en Neurosciences
(NINDS-AIREN)
Brainin et al. 2014
Clinical Evaluation
The Hachinski Ischemia Score
Feature
Abrupt onset
Stepwise deterioration
Fluctuating course
Nocturnal confusion
Relative preservation of personality
Depression
Somatic complaints
Emotional incontinence
History of hypertension
History of strokes
Evidence of associated atherosclerosis
Focal neurological symptoms
Focal neurological signs
Score
2
1
2
1
1
1
1
1
1
2
1
2
2
Score ≥ 7 - VaD
Score ≤4 – AD
Brainin et al. 2014
Clinical Evaluation
The NINDS-AIREN Criteria
Diagnosis of dementia

Cognitive decline (memory and two other domains)

Impaired functional abilities as a result of cognitive decline
Evidence of cerebrovascular disease (CVD)

Focal neurological signs consistent with stroke

Brain CT or MRI required
Relationship between dementia and CVD


Temporal association between the two – abrupt onset of
dementia after CVD event
Sudden stepwise cognitive deterioration
Brainin et al. 2014
Cognitive Assessment
MMSE
MoCA
Montreal Cognitive Assessment
ACE-R
Addenbrooke’s Cognitive Examination Revised
Clinician versus neuropsychologist
Al-Qazzaz NK et al.2014-Modified
Cognitive Assessment
RAZI HOSPITAL COHORT VaD

MMSE (Tunisian adapted version of Folstein’s MMS)

Five-word screening test (Tunisian adapted version of Dubois’ 5-word)

Free and clued selective reminding test (Tunisian adapted version of
the Grober et Bushke)

Frontal Assessment Battery (Tunisian adapted version)

Digit span

Clock drawing test

Neurpsychiatric Inventory (NPI)

Geriatric depression scale (GDS)
Cognitive Assessment
RAZI HOSPITAL COHORT VaD
Free and clued selective reminding test
Cognitive Assessment
Ischemic stroke
Vascular cognitive disorder
(Pre-dementia)
•Pre-stroke
•cognitive
functioning
MCI
•Slowed
cognitive
flexibility
•Perceptual
disorder
•Impaired
retrieval
Pre-existing executive funnctioning
Dregan A et al.2013
Pre-existing White matter lesions
Kliper E et al.2014
Moderate
Dementia
•Reduced
episodic
memory
function
Severe
Dementia
•Executive function impairment
•Poor recall with better recognition
declining to amnesia
•Slow psychomotor function
•Depression
•Decline of activities in daily living
•Eventual global severe impairment
Cognitive properties
Brain
at risk
Vascular-Dementia
(VaD)
Al-Qazzaz NK et al.2014-Modified
Neuropsychological testing in VaD

Specificity of cognitive profile: debated
Overlap with AD / ≠ AD?

No correlation between extent of ischaemic
lesion and severity or pattern of neuropsychological impairment

Neuropsychological pattern: not adopted as a
diagnostic feature
PREDICTORS FOR PSCI

Imaging predictors:

Silent infarcts

Global cerebral atrophy

Medial-temporal lobe atrophy

White matter changes

Size and location of infarct lesion

Involvement of fibre tracts connecting centres of functional networks

Multiple strokes

FDG PET: non-systematic changes in metabolism in infarcted areas (≠
Typical pattern of AD)
Yang J et al. 2014
Brain Imaging of VaD
Multiple large
vessel infarcts
Strategic thalamic infarct
Brain Imaging of VaD
CADASIL
Biswanger’s Disease
AD vs VaD vs Mixed dementia (MD):
Clinicoradiologic correlations in MRI
RAZI HOSPITAL - MRI STUDY

Purpose: To investigate the contribution of MRI medial
Temporal lobe Atrophy (MTA) and White Matter
Hyperintensities (WMH) in the cognitive decline

50 patients included : 15 AD, 20 VaD,15 MD

Methods:
 visual rating of MTA according to the Scheltens scale
 WMH rated semiquantitatively with the Age-Related
White Matter Changes Rating Scale (ARWMC scale)
RAZI HOSPITAL - MRI STUDY
Results

MTA mean score was
 2 in AD patients,
 1.61 in VaD patients
 3.25 in MD patients
No significant difference
in MTA between AD and VaD groups
5/20 Patients with VaD had significant MTA with worse
performance in the tests of executive functioning (considered
to be a major characteristic of VaD)
RAZI HOSPITAL - MRI STUDY
Results

Total WMH mean score
 5.33 in AD group,
 8.05 in VaD group
 8.27 in MD group
No correlations between MTA and WMH in AD
and VaD patients
PREDICTORS FOR PSCI

Biomarkers:

APOE4 polymorphism: controversial data

Renin-angiotensin level: conflicting data

B secretase enzyme and receptor levels for advanced glycation
end product (assessed 2 weeks after stroke)

Erythrocyte sedimentation rate (ESR), CRP and IL-6

Indolamine 2,3-dioxygenase activity

kynurenine/tryptophan ratio

Homocysteine, vitamin B12 and folic acid levels
M. Brainin et al. 2014
Apolipoprotein E
Polymorphism in the Tunisian population
Genotypes (%)
Jemaa et al., 2006
Smach MA et al. 2008
E3/E3
E3/E4
E3/E2
E4/E4
E4/E2
E2/E2
E3
E4
E2
CTRL 233
AD
0
CTRL 38
71,2
14,2
12,4
0,4
1,4
0,4
84.6
8.1
7.3
0
0
0
0
0
0
0
0
0
73,6
13,2
9,4
1,9
1,9
0
84,9
9,5
5,7
AD
48,4
32,3
3,3
10,7
5,4
0
66,2
29,9
4,4
69
18,3
7
2,8
1,4
1,4
81,6
12,6
5,6
58
41,7
35
8,3
13,3
1,7
0
63,3
31,6
5
CTRL 48
68,7
14,5
16,6
0
0
0
84,3
7,3
8,3
AD 48
CTRL 64
AD 158
37,5
41,7
16,6
4,17
0
0
66,6
25
8,3
65.63
28.13
4.68
1.56
0
0
82.03
15.62
2.35
51,98
34,81
0,63
10,75
0
1,89
69,62
28,16
2,21
73
CTRL 71
Achouri-Rassas et al. 2011
Fekih-Mrissa et al., 2014
OUR SERIES
Allele frequency (%)
AD
Managment of
Poststroke Dementia
MANAGMENT

No unequivocally efficacious treatment

Some used in AD have shown some positive effects on PSCI:
significant improvement on executive function

Cholinesterase inhibitors :

Memantine: possible neuroprotective effect by reducing the
excitotoxicity but still uncertain
M. Brainin et al. 2014
Involvement of cholinergic pathways
in VaD
Cholinergic pathways in
healthy brain
White matter hyperintensities
in VaD
Selden NR, et al. Brain, 1998.
Overlap Between AD and VaD
Cholinergic deficit
AD
Probable
Amyloid plaques
Genetic factors
Neurofibrillary tangles
Possible
Mixed
Possible Probable
Mixed
Amyloid plaques
Genetic factors
Neurofibrillary tangles
Stroke/TIA
Hypertension
Diabetes
Hypercholesterolemia
Heart disease
VaD
Stroke/TIA
Hypertention
Diabetes
Hypercholesterolemia
Heart disease
Kalaria RN, Ballard C. Alzheimer Dis Assoc Disord, 1999.
Dement Geriatr Cogn Disord 2005;20:338–344
- Combined analysis of 2 randomized, doubleblind,
placebo-controlled, 24-week studies (307,308)
- 1219 patient
- NINDS-AIREN criteria
- Donepezil 5mg/10mg/placebo
Donepezil in VaD: Cognition
Benefit in Global function: improved CIBIC-plus(5mg) CDR-SB (10mg)
Romàn et al 2005.
Lancet 2002; 359: 1283–90
GAL-INT-6
24 weeks
Galantamine 24mg daily
592 patients
NINDS-AIREN
MMSE 10-24
MRI or CT evidence of VaD
ADAS-cog Scores (6 Months)
3
Mixed D Placebo (n = 87)
Deteriorated
Probable VaD Placebo (n = 67)
2
Mean change
+/- SE in
ADAS-cog/11
1
0
-1
-2
Baseline
Improved
1
2
3
4
5
6
D = 2.2
p = 0.013
Time (months)
Cognition: improvement in scores on the ADAS-cog scale versus placebo
Stroke 2002, 33:1834-1839
28 weeks
Memantine 24 mg daily
321 patients
NINDS-AIRNS
MMS 12-20
MRI or CT evidence of VaD
ADAS-cog
Mean change from baseline
1
*
0
-1
-2
 Memantine (20
mg/day)
 Placebo
-3
0
Worsening
ADAS-cog score difference
2
Improvement
ITT, LOCF
12
28
Week
Significant Benefit on Cognition: improvement of ADAS-cog
Orgogozo et al., Stroke 2002
PREVENTION PSD



Prevention of vascular risk factors
Treatment of brain lesions
Aspirin: protection of cognitive decline and higher cognitive
performances

Non significant superiority of association Aspirin-
Dipyridamole on reduction of cognitive impairement risk
Ihara M et al. 2014
Primary prevention
Treatment of vascular risk factors
1.Teart HTA optimally
2. Treat diabetes
3. Control hyperlipidaemia
4. Tobacco + alcool
5. Anticoagulants for atrial fibrillation
6. Antiplatelet therapy
7. Carotid endarterectomy for severe ( 70 %) stenosis
8. Dietary control
9. Lifestyle (stress, weight…)
10. stroke + TIA : NMDA, ca++, antioxidants
11. Rehabilitation
Secondary prevention
Early diagnosis and treatment of acute stroke.
Prevention of stroke recurance: PROGRESS
Perindopril (ACE inhibitor) showed strikingly beneficial
effects in reducing the risk of dementia and cognitive
impairment in pts with recurrent stroke
CONCLUSION

Need for guidelines of a standardized neuropsychological protocol
after stroke

Need to greater understanding of the cognitive domains vulnerable
to impairment after stroke and description of ‘natural history’ of
cognitive change post-stroke

Published clinical trials not promising: little is known whether PSCI
can be prevented using pharmacological agents

Appropriate vascular risk management is associated with a long-term
reduced risk of cognitive impairment
Ihara M et al. 2014
60