International Journal of Gerontology 11 (2017) 210e214

Contents lists available at ScienceDirect

International Journal of Gerontology

journal homepage: www.ijge-online.com

Review Article

Post-stroke Dementia: Epidemiology, Mechanisms and Management

Gwo-Chi Hu a, b, Yi-Min Chen a, b *
a b
Department of Rehabilitation Medicine, Mackay Memorial Hospital, Taipei, Taiwan, Department of Neurology, Mackay Memorial Hospital, Taipei,
Taiwan

a r t i c l e i n f o s u m m a r y

Article history: Post-stroke dementia (PSD) is a clinical entity that encompasses all types of dementia following an index
Received 7 December 2016 stroke, which may affect up to one third of stroke survivors. Unlike physical disability after stroke,
Received in revised form cognitive function usually worsens over time and are often overlooked with detrimental impacts on the
10 April 2017
quality of life of survivors. The risk factors for post-stroke dementia are multifactorial and includes
Accepted 7 July 2017
Available online 10 August 2017
genetic predisposition, demographic factors (like older age and lower education status), pre-stroke
cognitive and functional status, prior transient ischemic attack or stroke, vascular risk factors, charac-
teristics and medical diseases associated with complications of stroke. Neuroimaging determinants are
Keywords:
dementia,
global cerebral atrophy or regional atrophy like hippocampal atrophy or medial temporal lobe atrophy,
mechanism, white matter lesions and changes, silent infarcts, lacunar infarcts and microbleeds. The mechanism of
risk factors, post-stroke dementia remains unknown and its neuropathology is poorly defined. Post-stroke dementia
stroke, patients may benefit from target treatment of dementia with anti-dementia drugs as well as prevention
treatment and treatment of strokes. This review focus on the epidemiology, presumed mechanisms, recent studies
on biomarkers, diagnostic workup and promising management strategies with functional outcome for
post-stroke dementia.
Copyright © 2017, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier
Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

1. Introduction 2. Definition

Stroke is the leading cause of disability and the second leading
cause for dementia worldwide. Out of approximately 15 million
people suffering stroke every year; about 5 million, one third, are
left with permanent disability.1 A big increase in the prevalence of
post-stroke dementia (PSD) has been observed in recent years due
to increase in stroke in aging population and to decline in mortality
from stroke with modern treatments. Cognitive decline symptoms
are often overlook in stroke survivors leading to increased rates of
mortality and institutionalization. Because of their dependency and
negative financial impact upon their families and healthcare pro-
viders, PSD is a major public health issue and its prevention playing
the crucial role. This review article discusses the epidemiology,
implications, risk factors, mechanism and current management
strategies for PSD. (see Fig. 1).
* Corresponding author. Department of Neurology, Mackay Memorial Hospital,
No. 92, Sec. 2, Zhongshan N. Rd., Taipei City 10449, Taiwan.
E-mail address: jenny.4102@mmh.org.tw (Y.-M. Chen).
The dementia that occurs after a stroke, irrespective of the
presumed cause, and the final diagnosis of PSD should be delayed
to at least 6 months after stroke according to American Psychiatric
Association's Diagnostic and Statistical Manual of Mental Disorder.
PSD may impact all aspects of cognitive functions, but attention and
executive function is the most affected domains. A study suggested
that the presumed etiology of poststroke dementia was vascular
dementia in two-thirds of patients and Alzheimer's disease in
one-third.2
3. Incidence and prevalence
There are many studies about the incidence and prevalence of
PSD but comparisons are difficult owing to variations in the criteria
for the diagnosis of dementia, patient characteristics, stroke sub-
type, methodology, and duration of follow up. Various tools are
available to screen and assess cognition, they are not PSD-specific.
The most commonly used diagnostic criteria and tools are devel-
oped by National Institute of Neurological Disorder and Stroke-

http://dx.doi.org/10.1016/j.ijge.2017.07.004
1873-9598/Copyright © 2017, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Post-stroke Dementia
Fig. 1. The mechanisms on post-stroke dementia. AD ¼ Alzheimer's disease.
Vascular Cognitive Impairment (NINDS-VCI), Association Inter-
nationale pour la Recherche  et l’Enseignement en Neurosciences
for VaD and Diagnostic and Statistical Manual of Mental Disorders.
The incidence of PSD over time course is non-linear, being higher in
the first 6 months after stroke.3 A study in Italy found that 21.5%
patients developed dementia after stroke during 4-year follow-up.4
In the Rochester study, the relative risk of dementia after stroke was
8.8 after 1 year, then declined progressively to 4.2 after 3 years, 3$5
after 5 years, 2.5 after 10 years, and 2.0 after 25 years.5 In addition,
many studies demonstrated that previous or recurrent strokes were
correlated to a high risk of PSD.6,7 A systematic and meta-analysis
found that 10% of patients had dementia before the first stroke,
10% developed dementia soon after the first stroke and more than
30% had developed dementia after recurrent stroke.6 The preva-
lence of PSD ranges from 6 to 32% with the prevalence around 28%
at 3 months point of time after stroke.6,7
4. Characteristics of PSD
4.1. Demographics characteristics
Increasing age is commonly a recognized risk factor for PSD.8
There was no significant relationship between gender and the
risk of PSD, although some found female sex to be higher risk. A
lower education level was an independent predictor of PSD in most
studies.9 Pre-stroke functional and cognitive status prior to the
stroke were also predictors for PSD.10 Desmond et al. suggested that
severe neurological deficit diagnosed at onset of stroke is associ-
ated with a high risk of PSD.11 Other vascular risk factors such as
hypertension, diabetes mellitus, atrial fibrillations, and myocardial
infarctions are also independent risk factors of PSD.12 Hyperten-
sion, the biggest risk factor for stroke, is also a leading risk factor for
vascular dementia and Alzheimer's disease.13 In the Framingham
Heart Study, the chronicity of hypertension was inversely related to
the cognitive functioning.14 The Honolulu Asia Aging Study showed
cognitive benefit from blood pressure lowering especially in the
middle age JapaneseeAmerican men.15 The Study also found that
211
diabetes was associated with increased risk of total dementia
(relative risk 1.5 [95% CI 1.01e2.2]), Alzheimer's disease (AD; 1.8
[1.1e2.9]) and vascular dementia (VaD; 2.3 [1.1e5.0]).16 The influ-
ence of hyperlipidemia, hyperhomocysteinemia, alcohol con-
sumption, and cigarette smoking on PSD remains unproven. In
addition, some studies have found that medical illnesses such as
seizure, sepsis, arrhythmia, hypotension, and congestive heart
failure might be associated with high risk of PSD.17,18
4.2. Stroke characteristics
Stroke pathogenesis and the neuroanatomical structures and
locations determine the risk of PSD. In the Framingham study, large
artery infarcts, lacunar infarcts, and infarcts of unknown origin
were associated with high risk of PSD.19 A systematic meta-analysis
revealed hemorrhagic stroke also related to increased risk of
PSD.6,20 Chronic brain ischemia from hypoperfusion induced by a
variety of cardiovascular deficits can cause nerve cells damage and
protein synthesis abnormalities that might increase risk of further
dementia.21 Dementia can even be caused by nonefocal neuro-
logical changes found in patients with transient ischemic attack
(TIA).22 In addition neuroimaging studies suggested that infarction
in strategic locations in the brain plays an important role in the risk
of PSD. These lesions include infarctions at dominant thalamus,
angular gyrus, deep areas of frontal lobe, medial temporal lobe,
hippocampus and left hemispheres to multiple infarctions in both
brain hemispheres.23
4.3. Neuroimaging characteristics
The neuroimaging abnormalities correlating with PSD are
cerebral atrophy, silent and multiple infarctions, white matter
lesions, and cerebral microbleeds commonly seen by computerized
tomography (CT) and magnetic resonance imaging (MRI). Laakso
et al. found medial temporal atrophy both in vascular dementia and
Alzheimer's disease.24 Silent brain infarction is the finding of
cerebral infarction on brain images in the absence of stroke clinical
212
symptoms. The Rotterdam Scan Study found silent brain infarcts as
an independent predictor of PSD.25 Severe white matter changes on
neuroimages indicates increased risk of PSD.26 These White matter
hyperintensities may be caused by a variety of factors including
ischemia, gliosis, micro-hemorrhages and damage to small blood
vessel walls. Pantoli suggested that both white matter lesions and
lacunar infarctions are predictors of cognitive decline after stroke.27
In addition, two large studies also showed that multiple cerebral
microbleeds are associated with cognitive impairment in stroke
survivors.28,29
Functional imaging by Fluorine-18-Fluorodeoxyglucose Positron
Emission Tomography (FDG-PET) evaluates the cerebral blood flow
and glucose metabolism and is useful in the differentiation be-
tween vascular dementia and Alzheimer's disease. A large cohort
study using positron emission tomography showed that increased
Alzheimer's disease-like Pittsburg compound B retention and
medial temporal atrophy were associated with dementia after
stroke/TIA.30 Liu et al. used Pittsburgh Compound B (PiB) positron
emission tomography to investigate patients with stroke or TIA
who had a more progressive cognitive decline. They found that
concurrent amyloid pathology was found in about one fifth of the
patients.31
Functional magnetic resonance imaging (fMRI) can detect
disruption of cholinergic pathways and major hubs of large-scale
networks in patients with PSD.32 Additionally, advanced multi
diffusion tensor imaging (DTI) has been shown to better correlate
with cognitive deficits (particularly executive functions) supporting
the notion that cognitive dysfunction in the vascular cognitive
impairment (VCI) spectrum is due to the disruption of subcortical
white matter pathways.33 One longitudinal study demonstrated the
predictive value of DTI for cognitive decline as well as atrophy of
mesial temporal lobe.34
4.4. Genetic characteristics
Genetic factors might be independent risk factors of PSD. Most
of them are related to lipid metabolism, angiotensin, and inflam-
mation.35 Genes such as a-1-antichymotrypsin polymorphism,
angiotensin-converting enzyme gene and Apolipoprotein E (APOE)
gene have been studied.36,37 There is evidence showing APOE e4 is
associated with the risk of AD and vascular cognitive impairment.38
Morris et al. found that NOS3 TT genotype increased the risk of
incident dementia compared with the GG genotype.39 The most
common form of inherited vascular dementia is cerebral autosomal
dominant (CADASIL) and cerebral autosomal recessive arteriopathy
with subcortical infarcts and leukoencephalopathy (CARASIL)
which are linked to NOTCH3 and HTRA1 gene.
4.5. Biomarkers characteristics
The sensitive CSF biomarkers for Alzheimer's disease, such as
Ab-42 peptide and tau protein, show lowest specificity for vascular
dementia. Recent studies showed significantly elevation of matrix
degrading metalloproteinases (MMPs) such as gelatinase B (MMP-
9) in vascular dementia. Other CSF markers associated with
vascular dementia and indirectly PSD are a-1 antitrypsin, plas-
minogen activator inhibitor-1, and apolipoprotein H.40 Serum bio-
markers such as advanced glycation end products (sRAGE), b-
secretase enzyme (BACE1) and APOE genotypes have been sug-
gested to correlate with poststroke cognitive impairment.41
A common variant (29.5%) (polymorphism) of alpha-2-
macroglobulin leads to increased risk of Alzheimer's disease.
Currently, no specific biomarkers have been proven to discriminate
Alzheimer's disease from PSD.
G.-C. Hu, Y.-M. Chen
4.6. Mechanism
The mechanism of PSD remains unclear. The pathological sub-
strates associated with post-stroke or vascular dementia are poorly
understood and remain controversial for several reasons. There is
considerable overlap between the neuropathological data of cere-
brovascular disease and Alzheimer's disease.42 The heterogeneous
nature of cerebrovascular lesions may have an effect on cognition
through various mechanisms including altered blood flow and
oxygen supply, chronic inflammation, disruption of axonal tracts, or
altered cortical connectivity.43 Some studies provide the patho-
logical evidence of a substrate (clasmatodendrosis), which con-
tributes to the development of dementia in stroke survivors, mostly
of vascular origin. The clasmatodendrosis (morphological attribute
of irreversibly injured astrocytes) was reported to link to white
matter hyperintensities and frontal white matter changes. These
clinicopathological findings provide a novel association between
irreversible astrocyte injury and disruption of gliovascular in-
teractions at the bloodebrain barrier in the frontal white matter
and cognitive impairment in elderly post-stroke survivors.44 The
neuritic plaque which is one of the main pathologic manifestations
of Alzheimer's disease increased as the aggravation of atheroscle-
rosis suggesting the correlation between stroke and Alzheimer's
disease.28
Medical comorbidities can cause cerebral hypoxia or ischemia
leading to cerebral hypoperfusion, which serves as a basis for some
cases of PSD.18 Gasecki et al. suggested that decline in cerebrovas-
cular reserve capacity and increased vascular degenerative changes
in hypertensive patients may lead to the development of micro-
hemorrhages, micro-infarcts, and hyper-dense white matter le-
sions. It can also affect the cerebral vaso-reactivity and auto-
regulatory capacity. Zhang and colleagues found that diabetes-
exacerbated PSD might be associated with abnormal phosphory-
lation of tau and generation of amyloid beta in the brains of animal
models (see Fig. 1).45
Inflammatory and immune processes are directly involved in
the pathogenesis of PSD. A study demonstrated that decreased
cytokines such as interleukin-6 and interleukin-8 are associated
with changes in both gray and white matters, suggesting inflam-
matory and immune factors contributing to the pathogenesis of
dementia per se. The possible biomarkers reported having an as-
sociation with dementia were tumor necrosis factor-a, interleukin-
1, interleukin-10, sE-Selectin, vascular endothelial cell adhesion-1,
nerve microfilament proteins, a-Synuclein, and g-Synuclein.46 In
a recent study, patients with vascular dementia were found to have
increased serum somatostatin and decreased neuron-specific
enolase with the lower content than that in control group up to 6
months after stroke.47
4.7. Management strategies
Prevention of primary and secondary stroke is of utmost
importance in PSD management strategies. Aggressive manage-
ment of pre-stroke risk factors by medications and lifestyle changes
plays important role in the prevention for PSD.48 Antiplatelet or
anticoagulant, antihypertensive and lipid-lowering agents are
commonly used to treat risk factors. Early and optimal treatments
for strokes when they occur and early rehabilitation are the next
crucial intervention. In addition, cognitive impairment can benefit
from treatment of neuropsychiatric symptoms as well as cognitive
training.
4.7.1. Blood pressure lowering agents
Several controlled trials have showed that antihypertensive
medication could decrease the risk both vascular dementia and
Post-stroke Dementia
Alzheimer's disease.49 The exact mechanism is unclear but could be
either due to a neuroprotective effect or result of pressure lowering
by antihypertensive medication. Most studies suggested angio-
tensin II receptor blockers, angiotensin-converting enzyme in-
hibitors and calcium channel blockers prevent cognitive decline in
patient with hypertension. Blockade of the renineangiotensin
system by angiotensin II receptor blockers or angiotensin-
converting enzyme inhibitors can prevent onset of dementia.
Inhibiting of neuronal calcium influx by calcium channel blockers
can have a protective effect on cognitive decline as the disturbance
of the intracellular calcium homeostasis is central to the patho-
physiology of neurodegeneration. A systematic review showed four
randomized controlled trials had benefit of antihypertensive drugs
on cognitive decline: SYST-EUR (Systolic Hypertension in Europe
Study) I and II, with a 55% reduction in dementia risk; HOPE (Heart
Outcomes Prevention Evaluation), with a 41% reduction in cogni-
tive decline associated with stroke; and PROGRESS (Perindopril
Protection against Recurrent Stroke Study), with a 19% reduction in
cognitive decline.49
4.7.2. Lipid lowering agent
Recent studies indicated the pleiotropic effects of statin might
benefit cognitive function by pro-endothelial activity, stabilization
of atherosclerotic plaques, anti-inflammation and inhibition of
thrombogenesis. But, there is no established role for statin in pre-
vention and treatment of dementia as two large clinical trials
demonstrated no cognitive improvements while a small trial found
mixed results.
4.7.3. Cholinesterase inhibitors and Memantine
Both Alzheimer's disease and vascular dementia patients have
cholinergic deficit and experience improvement after being treated
with cholinesterase inhibitors. Memantine, an N-Methyl-D-aspar-
tate (NMDA) receptor antagonist was proposed to have a neuro-
protective effect in both Alzheimer's disease and vascular
dementia.50
4.7.4. Phosphodiesterase inhibitor (PDE)
These drugs inhibit the action of phosphodiesterase and reduce
breakdown of cyclic adenosine monophosphate (cAMP). A meta-
analysis showed that cilostazol, a PDE-3 inhibitor with several
pleiotropic activities can improve mild cognitive impairment.51
Other PDE inhibitors, such as pentoxifylline and related agents
pentifyline, propentofylline, and triflusal were being studied as
possible treatment for dementia.52
5. Other medications
The role of non-steroidal anti-inflammatory drugs in dementia
is related to amyloid-induced inflammatory reaction. Despite some
epidemiological studies revealing reduced risk of developing de-
mentia in non-steroidal anti-inflammatory drugs treated patients,
but increased risk of cardiovascular events has also been found in
these patients.53 Some studies have found the use of vitamin E is
associated with reduce risk of PSD.54 A combined comprehensive
physical and psychosocial approach may be associated with good
functional outcome in PSD patients.
In conclusion, chronic brain changes related with advancing age
compromise the cognitive reserve and increase the risk of post-
stroke dementia (PSD) when vascular attacks occur or recur. After
intervention for acute stroke, early and optimal intervention should
be directed to post-stroke dementia (PSD) in the window before
dementia sets in. Detailed clinical and neuropsychological assess-
ment after stroke is the crucial in order to estimate the prognosis
and program for secondary prevention. The current barriers for
213
earlier identification of PSD is lack of uniform diagnostic criteria,
PSD-specific assessment tools and precise biochemical marker.
Lastly, future researches might shed light on the pathophysiology
and might come up with new diagnostic neuroimaging techniques
and bio-markers in addition to cognitive assessment tool for early
recognition of PSD.
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