Rost Et Al 2022 Post Stroke Cognitive Impairment and Dementia

Circulation Research
STROKE AND NEUROCOGNITIVE IMPAIRMENT COMPENDIUM
Post-Stroke Cognitive Impairment and Dementia

Natalia S. Rost , Amy Brodtmann , Matthew P. Pase, Susanne J. van Veluw , Alessandro Biffi , Marco Duering,
Jason D. Hinman , Martin Dichgans
ABSTRACT: Poststroke cognitive impairment and dementia (PSCID) is a major source of morbidity and mortality after stroke
worldwide. PSCID occurs as a consequence of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage.
Cognitive impairment and dementia manifesting after a clinical stroke is categorized as vascular even in people with comorbid
neurodegenerative pathology, which is common in elderly individuals and can contribute to the clinical expression of PSCID.
Manifestations of cerebral small vessel disease, such as covert brain infarcts, white matter lesions, microbleeds, and cortical
microinfarcts, are also common in patients with stroke and likewise contribute to cognitive outcomes. Although studies of
PSCID historically varied in the approach to timing and methods of diagnosis, most of them demonstrate that older age,
lower educational status, socioeconomic disparities, premorbid cognitive or functional decline, life-course exposure to vascular
risk factors, and a history of prior stroke increase risk of PSCID. Stroke characteristics, in particular stroke severity, lesion
volume, lesion location, multiplicity and recurrence, also influence PSCID risk. Understanding the complex interaction between
an acute stroke event and preexisting brain pathology remains a priority and will be critical for developing strategies for
personalized prediction, prevention, targeted interventions, and rehabilitation. Current challenges in the field relate to a lack of
harmonization of definition and classification of PSCID, timing of diagnosis, approaches to neurocognitive assessment, and
duration of follow-up after stroke. However, evolving knowledge on pathophysiology, neuroimaging, and biomarkers offers
potential for clinical applications and may inform clinical trials. Preventing stroke and PSCID remains a cornerstone of any
strategy to achieve optimal brain health. We summarize recent developments in the field and discuss future directions closing
with a call for action to systematically include cognitive outcome assessment into any clinical studies of poststroke outcome.
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Key Words: brain ischemia ◼ cerebral hemorrhage ◼ cognitive dysfunction ◼ dementia ◼ subarachnoid hemorrhage ◼ white matter
S
troke remains a leading cause of disability in the (ICH),20,24,25 and aneurysmal subarachnoid hemorrhage
United States and around the world.1,2 The devel- (SAH)26,27 (Figure 1). There is growing recognition that
opment of effective acute treatments has resulted the risk and temporal trajectory of PSCID is determined
in global trends showing improvement in stroke out- by an interplay of multiple factors including modifiable
comes.3–5 Yet, poststroke cognitive impairment and and nonmodifiable risk factors, comorbidities, index
dementia (PSCID) remain highly prevalent and dis- stroke characteristics (eg, ischemic versus hemorrhagic),
abling.6–10 Cognitive deficits are present in over 70% of features of the acute infarct or hemorrhage (eg, size,
stroke survivors, depending on stroke type, definition, and location, multiplicity), and the overall burden of preexist-
time point of assessment,8,11 (Table 1) and are associated ing brain injury9,28–30—aspects that will be discussed in
with disability,12,13 dependency,14 and morbidity15,16; thus, detail below.
posing a major burden to patients, caregivers, and health Given the frequency and variety of factors that are
care systems. As such, there is a critical need for an accu- implicated in initiating or accelerating cognitive dys-
rate diagnosis, timely intervention, and optimal prevention function in elderly people, understanding the underlying
of PSCID. mechanisms of PSCID is of paramount significance if we
PSCID may occur as a consequence of acute isch- are to develop accurate prediction models and effective
emic stroke (IS),23 as well as intracerebral hemorrhage treatments.30,31 Acute ischemic or hemorrhagic insults to
Correspondence to: Natalia S. Rost, MD, MPH, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, 175 Cambridge St, Suite 300, Boston, MA
02114, Email nrost@partners.org or Martin Dichgans, MD, LMU Klinikum, Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich
81377, Germany, Email martin.dichgans@med.uni-muenchen.de
For Sources of Funding and Disclosures, see page 1265.
© 2022 American Heart Association, Inc.
Circulation Research is available at www.ahajournals.org/journal/res
1252 April 15, 2022 Circulation Research. 2022;130:1252–1271. DOI: 10.1161/CIRCRESAHA.122.319951

Rost et al Poststroke Cognitive Impairment and Dementia
STROKE AND NEUROCOGNITIVE

a brain with preexisting microvascular or neurodegenera-
IMPAIRMENT COMPENDIUM
Nonstandard Abbreviations and Acronyms tive disease can initiate a series of pathological events
leading to variable trajectories of cognitive decline (Fig-
AD Alzheimer disease ure 1).29,32 Still, the relative contributions of vascular
AGES Age, Gene/Environment Susceptibility and neurodegenerative disease to PSCID largely vary
Reykjavik Study between subjects and are often difficult to determine.33,34
ASPIS Austrian Polyintervention Study to Also, lack of consensus on how and when to diagnose
Prevent Cognitive Decline After Isch- PSCID following an acute stroke32,35–37 has posed chal-
emic Stroke study lenges for research and providing guidance to clinicians.
Aβ amyloid β protein Below, we review the current concept of PSCID with an
BBB blood-brain barrier emphasis on aspects relevant to diagnosis, prevention,
BP blood pressure and management.
CogFAST Cognitive Function After Stroke study
DEMDAS Determinants of Dementia After
Stroke study DEFINITION AND CLINICAL FEATURES
DISCOVERY Determinants of Incident Stroke Cog- Poststroke cognitive impairment (PSCI) encompasses
nitive Outcomes and Vascular Effects cognitive impairments manifesting in the 3 to 6
on Recovery Study months after incident stroke. It includes not only defi-
HBC Heart-Brain Connection study cits specific to the stroke lesion site, such as aphasia
ICD International Classification of Diseases or memory deficits, impairments arising from strate-
ICH intracerebral hemorrhage gic infarcts in the hippocampi, thalami, and key corti-
IS ischemic stroke cal regions,38 but also those that may have preceded
ISGC International Stroke Genetics the stroke. Higher-order visuospatial, attentional,
Consortium and executive dysfunction, which are more associ-
J-STARJapan Statin Treatment Against Recurrent ated with canonical vascular cognitive impairment
Stroke trial (VCI), are frequently detected on poststroke cogni-
LAST Life After Stroke Trial tive screening. Hence, PSCI is often conflated with
MoCA Montreal Cognitive Assessment
VCI. Some researchers use the terms early and late
(or delayed) PSCID to differentiate the cognitive defi-

MRI magnetic resonance imaging
cits detected in the immediate poststroke period from
NfL neurofilament light chain
those that develop over the proceeding months.39
NICE Nimodipine in preventing Cognitive However, these distinctions are arbitrary and poorly
impairment in Ischemic Cerebrovascu-
defined. While this is not problematic when explaining
lar Events trial
the nature of the deficits in a clinical setting, the lack
NVU neurovascular unit
of consensus in terms of disease definition (eg, the
OR odds ratio inclusion of cases with transient ischemic attack, prior
OXVASC Oxford Vascular Study stroke, or preexisting dementia) has impeded PSCID
PRoFESS Prevention Regimen for Effectively research.
Avoiding Second Strokes trial Vascular risk factors confer both increased risk of
PROGRESS Perindopril Protection Against Recur- stroke and cognitive impairment, and community-based
rent Stroke Study studies of individuals having serial cognitive testing
PSCI poststroke cognitive impairment before and after incident stroke revealed increased
PSCID poststroke cognitive impairment and cognitive impairment before their stroke as well as
dementia accelerated cognitive decline afterwards.32,40 The past
REGARDS Reasons for Geographic and Racial 2 decades have seen a concerted effort to harmonize
Differences in Stroke study the description and testing of PSCID,28,41 but more work
SAH subarachnoid hemorrhage needs to be done to improve crosstalk between the
SPS3 Secondary Prevention of Subcortical fields of stroke and cognitive neurology. Current terms
Stroke Study are dependent on the patient’s individual cognitive tra-
STROKOG Stroke and Cognition Consortium jectory and impose arbitrary divisions between post-
SVD small vessel disease stroke cognitive deficits directly related to the acute
VCI vascular cognitive impairment brain lesion, cognitive impairments that may be extant
VCID vascular cognitive impairment/dementia years after stroke, and more diffusely defined post-
VICCS Vascular Impairment of Cognition stroke dementia, where cognitive decline is required
Classification Consensus Study to occur within a predefined time period following the
stroke.
Circulation Research. 2022;130:1252–1271. DOI: 10.1161/CIRCRESAHA.122.319951 April 15, 2022 1253

Table 1. Stroke Characteristics, Risk Factors for and Rates of PSCID

Timing of Risk factors

diagnosis Stroke
PSCID rate poststroke subtype Stroke characteristics Clinical Radiographic
Pendlebury 12%–20.3%* (hos- Variable IS, HS HS, left hemisphere, stroke Older age, lower education Leukoaraiosis, atrophy, infarct
and Rothwell7 pital based) severity, prior stroke, level, prior cognitive decline, volume, MTLA
multiple strokes, recurrent functional disability, diabe-
7.4% (population-
stroke, dysphasia tes, AF
based)
Wong et al17 73% 3 mo SAH Aneurysmal SAH NA Delayed cerebral infarction
Douiri et al18 24% 3 mo IS, ICH, Anterior circulation infarct Older age, Black race, SES Lacunar infarcts, large-artery
SAH atherosclerosis
Mok et al19 4.4% 3y IS, TIA NA Older age, hypertension, Multiple lacunar infarcts, WMH
diabetes
Moulin et al20 14.2% 1y ICH Lobar location Older age Superficial siderosis, cortical
atrophy, higher CMB count
Biffi et al21 19% 6 mo ICH Lobar location Older age, APOE e2 variant Hematoma volume
Arba et al22 34% 1y IS, HS, Stroke severity Older age, hypertension, NA
TIA diabetes, leg paralysis
Pendlebury 34.4% (NIHSS 1y IS, ICH, Stroke severity, prior Age, previous stroke, dys- Leukoaraiosis
and Rothwell8 score >10) TIA stroke phasia, baseline cognition,
low education, premorbid
8.2% (NIHSS
dependency, diabetes
score <3)
5.2% (TIA)
Lo et al9 44% (global) 2-6 mo IS, HS, Prior stroke Hypertension, diabetes, AF, NA
TIA CHF
Koton et al10 23.3% ≥1y IS Stroke severity, no. of re- Systolic BP, hypertension NA
current strokes medication use
Shown is a selection of recent studies reporting rates of PSCID diagnosis in patients with variable stroke subtypes without prestroke dementia and an ascertained
stroke event. AF indicates atrial fibrillation; APOE, apolipoprotein E; BP, blood pressure; CHF, congestive heart failure; CMB, cerebral microbleed; HS, hemorrhagic
stroke; ICH, intracerebral hemorrhage; IS, ischemic stroke; MTLA, medial temporal lobe atrophy; NA, not available; NIHSS, National Institutes of Health Stroke Scale
score; PSCID, poststroke cognitive impairment/dementia; SAH, subarachnoid hemorrhage; SES, socioeconomic status; TIA, transient ischemic attack; and WMH, white
matter hyperintensities.
*First-ever or recurrent stroke included.
Classification and Diagnostic Criteria better encompass the spectrum of cognitive disorders
associated with all forms of cerebral vascular brain
PSCI has been defined as all problems in cognitive
injury.41,43,45 The lack of consensus has been identified
function that occur following a stroke, irrespective of
as an obstacle to accurate prevalence46 and cognitive
the (stroke) etiology.28 In contrast, poststroke demen-
trajectory11 estimation.
tia is defined as immediate and/or delayed cognitive
decline that begins within 6 months after a stroke
and that does not reverse (encompasses dementia Cognitive Profile
that develops within 6 months of stroke in patients).41 Deficits related to the incident stroke are heterogenous,
Even the terms used to describe cognitive disorders with lesion-specific impairments often being superim-
due to vascular etiologies differ. Diagnostic and Sta- posed on impairments resulting from more diffuse vascu-
tistical Manual of Mental Disorders-V used the terms lar brain injury.47 Domain-specific impairments resulting
mild and major neurocognitive disorder42; the Interna- from the acute insult include disorders of attention such
tional Society for Vascular Behavioral and Cognitive as neglect in patients with right hemispheric stroke,48
Disorders43 and the VICCS (Vascular Impairment of aphasia syndromes arising from lesions in language
Cognition Classification Consensus Study)41 guide- networks, and memory impairments, most prominent
lines use mild vascular cognitive disorder and vas- in insults affecting paramedian thalami.38 These may
cular dementia or major vascular cognitive disorder; be differentiated from the underlying cognitive profile
and the International Classification of Diseases, Tenth of VCI, which is characterized by attentional, executive,
Revision (ICD-10)44 does not include a specific defini- and visuospatial dysfunction, and by slowed processing
tion of either PSCI or VCI but includes a definition of speed. These impairments likely arise as vascular patho-
vascular dementia. Only the VICCS guidelines specify logical brain burden. Especially white matter dysfunc-
poststroke dementia as a subtype of major VCI, and tion,49 disproportionately impacts widely distributed brain
none use the term PSCI explicitly. VCI criteria perhaps networks such as attention and visuospatial function.


Figure 1. Risk factors and trajectories of poststroke cognitive impairment/dementia (PSCID).

A variety of acute ischemic or hemorrhagic insults to a brain with preexisting microvascular or neurodegenerative disease can initiate a series
of pathological events leading to variable trajectories of cognitive decline. Both the risk and temporal trajectories of PSCID are determined by a
complex interplay of multiple factors including modifiable and nonmodifiable risk factors, index stroke characteristics, and the overall brain health
(Illustration Credit: Ben Smith). AD indicates Alzheimer disease; ePVS, enlarged perivascular spaces; ICH, intracerebral hemorrhage; IS, ischemic
stroke; PET, positron emission tomography; and SAH, subarachnoid hemorrhage. *Level of cognitive function at the time of stroke. Note that some
individuals experience cognitive decline before stroke.
While poststroke delirium is a common clinical occur- Although, the most recent European Stroke Organisa-
rence,50 its association with future PSCID is not well tion joint guidelines found limited evidence for any clini-
understood. Poststroke delirium can take months to cal prediction tools for PSCI or delirium.28 Furthermore,
resolve, and most neuropsychologists defer assess- the presence of delirium further confounds any diagno-
ment until at least 3 months following inpatient delirium, sis of PSCID.
making a temporal association difficult. Many research-
ers regard poststroke delirium as evidence of preexist-
ing cognitive impairment, and posit that it is associated Lesion Location and PSCID
with increased risk of poststroke cognitive decline.51 The concept of strategic infarction—infarcts located
Acute stroke lesion topography may also be linked to in regions critical for cognitive processing or stra-
poststroke delirium risk, with lesions in supratentorial tegic locations—causing vascular dementia remains
regions and those supplied by the anterior circulation contested, but most authors agree that lesion loca-
having higher rates of poststroke delirium diagnosis.52 tion is critical for PSCI. In the largest multicohort

lesion-symptom mapping study to date, left fronto- appear to decline in stroke survivors. Interestingly, visual
temporal and thalamic, and right parietal, infarcts were memory may not be similarly affected.59 There is recent
found to be strongly associated with PSCI,53 echoing a evidence that executive impairments—considered a
prior study where global cognitive impairment was most core feature of progressive VCI—stabilize or improve
associated with left angular gyrus and left basal ganglia following stroke,60 which may, in part, reflect risk factor
white and gray matter infarction.54 Posterior circulation management. However, many stroke survivors exhibit
strokes, especially brain stem infarcts, are less associ- cognitive impairments that endure or progress in the
ated with PSCID,7 although intriguing associations with years following their incident stroke.
posterior circulation and vertebrobasilar stenoses have
been reported, posited to result from hippocampal and
posterior cingulate cortical hypoperfusion. However, EPIDEMIOLOGY
lesion location alone does not predict poststroke cogni-
tive outcome, prompting some authors to suggest that
Demographic and Vascular Risk Factors
more sophisticated paradigms should be used, such as Stroke and dementia share several modifiable risk fac-
combining lesion location and lesion network mapping tors, including education and traditional cardiovascular
to improve prediction.55,56 risk factors, such as high blood pressure (BP), smok-
The strong associations with strategic infarction ing, and diabetes.61,62 However, decades of research
and PSCI contrast with the predictors of poststroke have shown that the risk factors for PSCID are more
dementia. Prior clinical or silent stroke, multiple, recur- nuanced than those for either stroke or dementia
rent, large or severe strokes, hemorrhagic stroke, left- alone.
hemispheric stroke, and the presence of aphasia have Older age is associated with faster cognitive decline
consistently been associated with 1- and 5-year risk poststroke. For example, in the REGARDS study (Rea-
of poststroke dementia.7,8 Most of the left-hemispheric sons for Geographic and Racial Differences in Stroke),
stroke risk may be attributable to aphasia: the dementia each 1-year increase in baseline age was associated
odds ratio (OR) of aphasia is almost three times higher with a 17% higher odds of cognitive impairment per
than stroke side.7 year of follow-up.63 These findings dovetail with those
Cognitive screening tools are heavily weighted to of nonstroke cohorts, whereby older age is a strong
language-based tasks. Almost all tests require adequate risk factor for the incidence of cognitive impairment.64
hearing and vision, proficiency in their delivered lan- A 2009 synthesis of the available evidence found that
guage, and depend on intact oral comprehension and stroke survivors with low education were 1.8 times
expression. Most researchers have used the mini-men- more likely to experience poststroke dementia.7 Stroke
tal state exam or the Montreal Cognitive Assessment survivors with high education may be better able to
test (MoCA) for their global cognitive screen, which are compensate for vascular brain injury, thus maintaining
insensitive to higher-level attentional problems, and nei- a higher level of function for longer.
ther incorporate mood and behavioral measures which The CogFAST study (Cognitive Function After
profoundly impact activities of daily living. Hence, the Stroke) reported that the presence of three or more car-
findings that PSCI primarily relate to strategic infarct diovascular risk factors was associated with a 3.6-fold
locations in the left middle cerebral artery territory may increase in the risk of poststroke dementia in an elderly
in part be a function of the very tests used to measure population.65 With respect to individual vascular risk fac-
this impairment. tors, prevalent diabetes and atrial fibrillation have been
linked to a higher risk of poststroke dementia across
studies; diabetes and atrial fibrillation are associated
Time Course with a 1.5- and 1.9-fold increase in dementia risk,
Cognitive performance is dynamic due to the dueling respectively.7 In addition to contributing to the index
effects of native mechanisms of recovery, second- stroke, atrial fibrillation may increase the risk of silent
ary neurodegeneration, and recurrent cerebrovascular brain infarction or more widespread cerebral small ves-
events. For most published studies, cognitive impair- sel disease (SVD) perhaps as a result of microthrombi
ment has been examined at a single time point after or hemodynamic challenges to cerebral autoregulation,
stroke11,46; thus, there are surprisingly few longitudi- which in turn may contribute to the risk of cognitive
nal studies of poststroke cognitive trajectories. Over- impairment.66,67 Diabetes may also exacerbate the over-
all cognitive performance may stabilize over the initial all burden of brain SVD. For instance, a neuropatho-
12 months, and there is evidence that both genetic57,58 logical analysis of more than 1.300 autopsied patients
(APOE e4 carrier status) and stroke factors, most with diabetes found that diabetes increased the odds
prominently stroke severity,8 mediate poststroke cogni- of brain infarcts, particularly lacunes, but not Alzheimer
tive trajectories. Verbal memory and processing speed disease (AD) pathology.68 As detailed below, the burden


of SVD appears to be a key predictor of dementia in likely contributing factors. These results point towards
patients with stroke. the importance of refining our understanding of PSCID
SVD burden can contribute to cognitive impairment risk factors and translating those findings into improved
and dementia in persons with and without stroke alike.7,69– outcomes for patients.
71
Since SVD can affect multiple brain regions and show
variable involvement of specific white matter tracts, SVD
can affect multiple cognitive domains, including execu- Stroke Characteristics Associated With PSCID
tive function, processing speed, and memory.69,72 Meta- Risk
analysis suggests that the presence of leukoaraiosis and Several characteristics of the stroke itself are predic-
atrophy are associated with a 2.3- and 2.2-fold increase tive of poststroke dementia, including stroke severity
in poststroke dementia risk, respectively.7,8 and lesion volume. For example, one study indicates that
Neuropathologies that are comorbid with cerebrovas- severe stroke advances dementia onset by ≈25 years,
cular disease likely hasten dementia onset in stroke sur- mild stroke advances dementia onset by 4 years, and
vivors.73,74 Persons with mixed neuropathological findings transient ischemic attack by about 2 years.8 Two weeks
(eg, SVD and AD) are 3 times more likely to have demen- after stroke, lesion volume explains high variance in left
tia than persons with just one neuropathologic diagno- motor deficits and language but little variance in verbal
sis (eg, SVD alone).75 Medial temporal lobe atrophy (a and spatial memory.83 This may be because cognitive
common feature of AD) is a strong risk factor for post- functions that are widely distributed throughout cortical
stroke dementia.7 Patients with stroke or SVD who have regions, such as memory and attention, may be less sus-
evidence of Aβ (amyloid β) deposition experience more ceptible focal insults.
rapid cognitive decline than those without Aβ.76,77 Thus, There also appears to be an interplay between infarct
preclinical AD appears to increase the risk of dementia in location and number. Multiple infarcts have long been
patients with stroke; further research is needed to inves- described as a cause of vascular dementia, often mani-
tigate other comorbid proteinopathies. festing clinically as a stepwise or fluctuating deterioration
High BP and smoking, while related to both stroke in cognitive function.84 Pooled analysis of the available
and dementia risk more generally,61,78 have not been data also suggests that having multiple strokes leads
consistently associated with the risk of PSCID.7,8 Inter- to a 2.8-fold increased risk of poststroke dementia.7,8
estingly, the REGARDS study reported that stroke sur- With respect to infarct location, left-hemisphere strokes
vivors with hypertension, as compared to those without, confer an increase in risk (OR=1.4).7 Since most indi-
experienced a slower decline in executive function.63 BP viduals are left-hemisphere dominant for language and
is highly dynamic and its relationship with PSCID likely since language underpins performance on many neuro-
depends on several factors including the timing of mea- psychological tasks, left-hemisphere stroke may result in
surements relative to the stroke, chronicity of hyperten- cognitive deficits that are more easily detected by formal
sion, and medication use. The PROGRESS (Perindopril neuropsychological testing. Furthermore, as language is
Protection Against Recurrent Stroke Study) randomized essential for many activities of daily living and as impair-
controlled trial (RCT) showed that antihypertensive ther- ment to activities of daily living is required for a dementia
apy reduced the risk of cognitive decline relative to pla- diagnosis, left-hemisphere strokes resulting in aphasia
cebo, particularly in participants with recurrent stroke.79 may lower the threshold for dementia diagnosis. Even
Although more research is needed, greater BP variability when multiple strokes are present, the spatial distribu-
in the early phase poststroke has been associated with tion of those lesions may be important in causing cog-
cognitive impairment.80,81 nitive impairment. The AGES (Age, Gene/Environment
As detailed above, several of the known risk factors SusceptibilityReykjavik Study) reported that, compared
for poststroke dementia are potentially modifiable, sug- to participants without infarcts, persons with multiple
gesting that targeted interventions or management plans infarcts in the same location did not display poorer
could reduce the risk of poststroke dementia. Indeed, the memory, processing speed, or executive function.85 In
Framingham Heart Study found that the risk of dementia contrast, multiple infarcts across multiple locations (eg,
in stroke survivors has been declining over the past 3 cortical and subcortical regions) were associated with
decades.82 Between 1977 and 1983, the 5-year rela- poor performance across all three measured cognitive
tive risk of developing dementia was 9 times higher abilities. Imaging studies have shown that patients with
in stroke survivors than in individuals free of stroke. deficits across multiple cognitive domains tend to have
Between 2004 and 2008, it was only 40% greater. This damage to so-called ‘cross-road’ regions where multiple
risk reduction could in part relate to improved detection white matter pathways overlap.83
of milder strokes. However, improved stroke treatment Data comparing the risk of PSCID between intracra-
and management and more successful prevention of nial hemorrhage and IS subtypes have been inconclusive.
secondary ischemic events, including recurrent stroke, A 2009 review found that hemorrhagic strokes were not
covert brain infarcts, and white matter injury, are also predictive of poststroke dementia.7 However, this finding

was likely underpowered, with only 15 dementia cases cerebral amyloid angiopathy.91,92 However, the relation-
contributing to the pooled effect. A more recent investiga- ship between APOE and dementia risk in stroke sur-
tion found that, in the population-based OXVASC (Oxford vivors has been equivocal.29 A recent analysis of the
Vascular Study), the risk of poststroke dementia was 4.5 Oxford Vascular Study cohort found that ε4 homozygos-
times higher following hemorrhagic as compared to 2.5 ity was present in 1.7% of stroke survivors. Such individ-
times higher for IS.8 However, this difference in risk was uals displayed a 2.9-fold increase in dementia risk over
less marked after adjustment for stroke severity and no 5 years (relative to ε3/ε3 carriers).57 In contrast, ε4 het-
longer statistically significant after excluding cases with erozygosity was not associated with an increase in post-
transient ischemic attack. When comparing data from stroke dementia risk. Further work is needed to uncover
the general population to data from a Danish medical the genetics of PSCID beyond genes related to common
database comprising 279,349 stroke survivors, the risk brain pathologies in the general population.
of dementia within ten years was 1.6 times higher after
IS and 2.6 times higher after intracerebral or SAH.86 Dif-
ferences in dementia risk between ischemic and hemor- NEUROPATHOLOGY
rhagic stroke survivors are not fully understood but may The neuropathological lesion types associated with
stem from differences in the underlying disease process strokes include large (territorial) infarcts, multiple infarcts,
and thus susceptibility (eg, genetic factors or the pres- ICHs, SAHs, hemorrhagic infarcts, and secondary brain
ence of cerebral amyloid angiopathy), the nature and atrophy after stroke. Besides the impact of lesion type,
extent of brain injury related to a specific stroke sub- size, and location itself, there are other neuropathological
type (ie, often more severe following ICH), diffuse type substrates associated with cognitive decline after stroke
of brain injury that can induce extended involvement and that are incompletely understood and appear to be com-
multiple phases (eg, delayed cerebral ischemia after plex. First, there are immediate effects on brain health
SAH), or availability or sequelae of acute stroke interven- caused by the tissue changes that arise due to vessel
tions (often more invasive following hemorrhage).86 occlusion or vessel rupture. This cascade of events may
Meta-analysis has identified several stroke com- include excitotoxicity, oxidative stress, blood-brain bar-
plications as predictors of PSCID, including hypoxic- rier (BBB) dysfunction, inflammation, and cell death.93 In
ischemic episodes (OR=2.4), incontinence (OR=3.6), addition, vasogenic edema and hemorrhages may occur
acute confusion (OR=3.3), dysphasia (OR=4.1), early in the affected tissue as a result of delayed microvascu-
seizures (OR=5.4), recurrent stroke (OR=2.4), and lar damage and BBB leakage.
abnormal electroencephalogram findings (OR=2.7).7 Besides these direct detrimental effects on the brain
Complications such as incontinence may be associated parenchyma, it has become increasingly clear that pre-
with dementia because they exacerbate functional limi- existing structural brain changes, and in particular SVD
tations or are associated with greater injury severity or lesions, are major contributors to the occurrence of
diffuse parenchymal injury. cognitive impairment or dementia after stroke.30 These
include changes to the small vessels themselves (eg,
arteriolosclerosis and cerebral amyloid angiopathy), as
Genetic Contributions to PSCID well as their manifestations such as microbleeds, micro-
Genome-wide association studies as well as studies infarcts, lacunar infarcts, enlarged perivascular spaces,
on familial cases of stroke and dementia have pro- and white matter lesions (Figure 2; Table 2).
vided major insight into the genetic underpinnings and Of these, microinfarcts and white matter lesions,
mechanisms of stroke, SVD, and AD dementia.87–89 typically visible as white matter hyperintensities on brain
However, genome-wide association studies studies magnetic resonance imaging (MRI), appear to be the
for VCI are lacking. most relevant due to their widespread effects on tissue
Given the huge sample sizes required for genome- integrity.65,94 On neuropathological examination of the
wide association studies, candidate gene approaches brain postmortem, chronic microinfarcts are recognized
have been used to examine risk factors for vascular on standard hematoxylin and eosin sections as focal
dementia and PSCID. A 2015 meta-analysis of genetic areas of tissue injury with evidence of cell loss and glio-
polymorphisms for vascular dementia located 69 stud- sis, sometimes with cavitation, ranging from 100 μm to
ies, including 4462 cases and 11 583 controls.90 Over- a few mm in diameter. Microinfarcts are considered the
all, 5 polymorphisms were found to associate with most abundant form of silent brain infarction and their
vascular dementia, including APOE ε4. However, with accrual over time can significantly impact brain structure
the exception of APOE ε4, these findings require repli- and function by disrupting connected areas beyond the
cation in larger studies. actual visible lesion boundaries.95–98
The APOE ε4 allele is the strongest genetic risk The neuropathology of white matter hyperintensi-
factor for late-onset AD.88 Moreover, genetic variation ties is inherently heterogenous and includes white
in APOE has been associated with SVD markers and matter rarefaction, ischemia, inflammation, BBB


Figure 2. Neuropathological substrates of small vessel disease.
leakage, myelin breakdown, axonal injury, loss of oli- increases in vascular Aβ accumulation as a result of
godendrocytes, and perivascular space dilation.99,100 impaired perivascular Aβ clearance may contribute
Autopsy studies that directly compared white matter to the formation of cerebral amyloid angiopathy and
tissue in cases that developed dementia compared dementia.104,105 Additional studies are needed to fur-
to cases that did not develop dementia poststroke ther elucidate the neuropathological substrates and
have revealed BBB disruption (eg, loss of pericytes pathophysiological mechanisms that are implicated in
and fibrin extravasation) and irreversible astrocyte the development of PSCID.
injury (in the form of clasmatodendrosis).94,101 Coexist-
ing neurodegenerative changes such as parenchymal
Aβ plaques and neurofibrillary tau tangles have also PATHOPHYSIOLOGY
been implicated.65,93,102,103 It is likely that there may be Given the wide range of clinical stroke events, patho-
synergistic effects between stroke, SVD, and neurode- physiology of PSCID varies extensively. All IS subtypes
generative pathologies. For example, stroke-induced (SVD, cardioembolism, large-artery atherosclerosis, or
strokes of other determined or undetermined cause),
Table 2. Neuropathological Characteristics of Preexisting
as well as ICH (lobar or deep) and SAH can cause vas-
Small Vessel Disease Changes Contributing to Poststroke
Cognitive Impairment/Dementia cular cognitive impairment or dementia (VCID)62; con-
sequently, PSCID is recognized as major VCID, along
Lesion Neuropathological characteristics
with other traditionally outlined mechanisms including
Arterioloscle- Hyaline thickening of arterioles, loss of vascular smooth multiinfarct dementia, strategic infarct dementia, sub-
rosis muscle cells, and luminal narrowing
cortical ischemic dementia, hemorrhagic dementia, and
Cerebral amy- Deposition of amyloid β in the walls of leptomeningeal
loid angiopathy arteries, cortical arterioles, and capillaries, loss of vascu-
mixed dementia.38 Although mechanistic considerations
lar smooth muscle cells of interaction between stroke and neurodegenerative
Microbleeds Acute phase: extravascular intact or lysed erythrocytes/ pathology apply across the full spectrum of VCID, the
Subacute phase: blood-breakdown products, including underlying disease biology linked to acute stroke insult
biliverdin, hematoidin, and hemosiderin/Chronic phase: is still poorly understood. Major knowledge gaps relate
iron-positive hemosiderin-laden macrophages
to the impact of (1) specific stroke subtypes and syn-
Microinfarcts Acute phase: tissue pallor with hypoxic (ie, eosinophilic
or red) neurons/ Subacute phase: macrophages, reac-
ergistic effects of preexisting AD or SVD pathology, (2)
tive astrocytes/ Chronic phase: tissue puckering or cavi- stroke lesion characteristics (size, topography, multiple
tation with a rim of reactive fibrillary astrocytes lesions versus single strategic infarct) and poststroke
Lacunar infarcts Tissue cavitation with evidence of neuroinflammation progression of chronic neurodegeneration and SVD
in the form of macrophages and perilesional reactive
pathology, (3) the combined effect of patient vascu-
astrocytes
lar risk profile, antecedent comorbidities, and func-
Enlarged peri- Fluid and extracellular matrix-filled dilated peri-arteriolar
vascular spaces spaces
tional baseline, (4) genetic susceptibility, and (5) acute
White matter Rarefaction of the white matter, loss of myelin, axonal
stroke interventions and poststroke course on cogni-
injury injury, oligodendrocyte loss, reactive astrocytes, macro- tive outcomes.30,106
phages, dilated perivascular spaces, blood-brain barrier While these questions are being addressed by
leakage, neuroinflammation
ongoing large-scale research efforts,107–110 cognitive

dysfunction following an acute stroke event is gener- NEUROCOGNITIVE ASSESSMENT

ally caused by (1) direct injury to the brain structures

Neurocognitive assessment of PSCID is usually moti-
critical for cognitive function (eg, a single strategic
vated by one of two overarching goals, namely either
lesion involving eloquent regions such as thalamus or
to (1) screen stroke patients at large for presence of
basal ganglia),53,54 (2) disruption of the structural and
PSCID; or (2) diagnose PSCID in specific individuals,
functional connections in the brain (eg, large lesions,
characterize its presentation and follow its evolution
multiple lesions of key brain gray matter structures
over time.134,135 Several considerations guiding cognitive
or lesions largely impacting white matter),111–115 and
testing apply equally to both clinical applications. Reli-
(3) global brain dysfunction due to acute inflamma-
able diagnosis of PSCID is predicated on application of
tion, neurotoxicity, and metabolic disarray.116–121 Fur-
standardized neuropsychological testing instruments,
thermore, significant variation exists in interindividual
allowing for both consistent screening practices across
ability to compensate for both acute injury as well
patients with stroke and meaningful longitudinal follow-
as preexisting vascular and neurodegenerative bur-
up for individuals. Both screening and in-depth exami-
den of disease, a concept known as brain reserve or
nation of cognitive function should capture information
resilience. Some factors contributing to brain reserve,
on multiple cognitive domains, including at a minimum
such as age are also known to affect risk of PSCID
general orientation, memory, and executive function.134,135
(Figure 1), with compensatory mechanisms including
More in-depth testing aimed at definitive diagnosis and
vascular remodeling and angiogenesis being possibly
longitudinal follow-up should further capture detailed
attenuated in the aging brain, and resulting in more
information on language, and visuospatial processing.
extensive tissue damage and hence accelerated cog-
Table 3 shows a practical framework to approach cog-
nitive decline poststroke.93
nitive screening and more in-depth assessment during
At the cellular level, acute stroke related injury
the natural history of cognitive impairment and recovery
ultimately impairs function of the neurovascular unit
following acute stroke.
(NVU), the smallest building block of the brain paren-
In the hyperacute setting (Emergency Department
chyma at the center of the vast majority of brain dys-
and/or Neurocritical Intensive Care Unit) the approach
function.122–124 The NVU is comprised multiple cell
should entirely be focused on PSCID screening.29 Most
types, including neurons, glia, and vascular cells,125
experts recommend using tests requiring <5 minutes
which coordinate the unit’s critical role in cere-
for administration, such as the Mini-Cog or abbreviated
bral blood flow regulation and in maintaining intact
forms of the MoCA test.135–137 The National Institute for

brain parenchymal milieu, as the BBB’s main build-
Neurological Disorders and Stroke and the Canadian
ing block.126,127 The NVU is commonly implicated in
Stroke Network previously convened an expert working
VCID, or mechanisms of mixed dementia,128 as life-
group and devised recommendations for neurocogni-
long damage to the cerebral vasculature by untreated
tive assessment standards in the diagnosis and study
hypertension, diabetes, or smoking leads to microvas-
of VCID.134 Based on available evidence we recommend
cular dysfunction. This in turn causes BBB dysregu-
using the National Institute for Neurological Disorders
lation, impaired clearance, and unauthorized entry of
and Stroke-Canadian Stroke Network 5-minute proto-
blood-borne neurotoxic molecules into the brain.124,129
col including the Orientation, Memory and Phonemic
Reduction of resting cerebral blood flow and accumu-
fluency MoCA subtests for PSCID screening in the
lation of neurotoxic plasma proteins (fibrinogen, plas-
acute setting.134,138,139 Of note, the brief screening tests
minogen, thrombin etc) accelerate neuronal injury and
advocated above have proven validity in assessment of
neurodegeneration even in the absence of the known
older adults, but current evidence for their use in PSCID
Alzheimer’s toxin (Aβ); although, dysregulation of the
screening is far more limited.135
NVU may accelerate Aβ accumulation through dimin-
In the hyperacute setting it is further advocated
ished clearance and increased production of Aβ.130,131
to screen for delirium, which affects 25% to 40% of
These 2 pathways (Aβ independent and Aβ depen-
patients during the acute period, and has implications
dent) are considered to be synergistic in contributing
for longer-term cognitive outcomes.140 The confusion
to cognitive impairment/dementia.124,129
assessment method has proven accuracy for diagno-
The NVU’s ability to withstand cerebrovascular insults,
sis of delirium after stroke, and a modified version for
proteinopathy, metabolic disarray, or inflammatory burden
intensive care unit use incorporates picture-based, non-
is thought to underlie what has recently been termed as
verbal responses to aid in assessment of patients with
brain health.129 Conversely, the NVU’s failure portends
aphasia or other language disorders.141,142 Upon the
susceptibility to stroke, dementia, or other detectable
patient having achieved medical stabilization more in-
brain diseases.128 Given significant overlap between risk
depth assessment for cognitive performance can be pur-
factors for stroke, dementia, and PSCID, preserving the
sued, usually in a stroke unit setting. In these instances,
NVU integrity through common preventive measures
administering a detailed, full neuropsychological testing
holds promise to promote optimal brain health.132,133


Table 3. Proposed Framework for Neurocognitive Assessment of PSCID
Acute stroke care
Time from stroke onset (onset to 7 d)* 8–90 d 3–12 mo 1 y and beyond
Setting ED/ICU/Stroke Unit Rehabilitation Facility Stroke Clinic Primary Care Stroke Clinic Primary Care Neurocognitive Clinic
Assessment approach Screening only Diagnosis (if positive prior screening) vs ongoing screening
Screening test Yes Yes Based on clinic context
In-depth testing No If positive prior screening (or research purposes)
Delirium screening Yes Based on clinic context
ED indicates emergency department; ICU, intensive care unit; and PSCID, poststroke cognitive impairment/dementia.
*Based on individual patients’ clinical context and local practice patterns, the acute stroke care phase may be considered completed before 7 d or last consider-
ably longer.
battery is generally unfeasible. Experts, therefore, recom- leukoaraiosis,148 MRI is the most informative method and
mend using a validated global cognition screening test, thus the main focus of this section.
with preference (based on currently available evidence) An emerging theme in longitudinal imaging studies of
given to the MoCA or Oxford Cognitive Screen. The stroke survivors is secondary neurodegeneration, that is,
MoCA has the largest body of literature supporting its neurodegeneration in remote brain regions distant from
use, although the validated cutoff (<26) has shown to the infarct (Figure 3A).149 Selective cortical thinning was
have very high sensitivity and specificity for PSCID.143,144 found 6 months poststroke in regions connected to sub-
The Oxford Cognitive Screen, however, does offer some cortical infarcts.150,151 Increased iron deposition in the
advantages, such as domain-specific results and finger- ipsilateral thalamus after nonthalamic stroke likewise
pointing response to aphasia-related testing bias.145 suggests remote degeneration.152 MRI studies have fur-
Stroke survivors screening positive in the hyperacute ther shown widespread white matter changes 6 months
and acute settings should be administered a detailed poststroke in the ipsilateral hemisphere, which were found
neuropsychological testing battery in the subacute set- to correlate with circulating levels of serum neurofila-
ting (ideally within the first 90 days of stroke), usually in ment light chain (NfL), providing biomarker evidence for
a dedicated rehabilitation facility or at outpatient stroke neuroaxonal degeneration.153 Functional and structural
neurology follow-up.29 The National Institute for Neu- brain network studies complement the effort to under-
rological Disorders and Stroke-Canadian Stroke Net- stand these widespread effects after stroke154,155 and can
work working group generated recommendations for 2 unravel compensatory and recovery mechanisms.156
detailed neuropsychological testing protocols lasting 60 There are multiple parameters from baseline MRI with
and 30 minutes, respectively, that can be readily applied predictive value for cognitive outcome after stroke, the
to assessment of PSCID (Table 4).134 most consistent factor being brain atrophy.106 A recent,
These batteries include tests with population norma- large collaborative study on almost 3000 stroke survi-
tive data, validated versions in several languages, and vors systematically assessed the effect of infarct location
can also be used for longer-term clinical and research on PSCID using voxel-based lesion-symptom mapping.53
purposes in the months and years following acute This study found infarcts in the left frontotemporal lobes,
stroke.146,147 While screening for prestroke cognitive left thalamus, and right parietal lobe to be strongly asso-
impairment is rarely feasible in the hyperacute and acute ciated with PSCI and provided maps assigning infarcts
settings, in-depth evaluation of PSCID in the subacute to PSCID risk strata based on anatomic location.53 These
setting should include assessment for premorbid cogni- maps are available for public access (https://metavci-
tive performance to inform the diagnostic process.29 This map.org/features/software-tools/location-impact-
is best achieved by use of informant standardized ques- score/) and serve as an example of research findings
tionnaires, with different versions of Informant Ques- translating into clinical applications.
tionnaire on Cognitive Decline in the Elderly being used Identification and precise quantification of preexisting
extensively in both clinical and research settings.24 comorbid diseases may aid the prediction of PSCI and
inform on underlying mechanism. Among the most rel-
evant factors in patients with stroke is cerebral SVD (see
NEUROIMAGING section on neuropathology above). Aside from being a
Neuroimaging is a key research tool in PSCID with major cause of stroke, SVD has been recognized as one
increasing value for clinical application. Imaging offers of the most frequent comorbidities in patients with other
mechanistic insight into pathophysiology and adds to stroke causes (Figure 3B). A recent meta-analysis has
prediction models of outcome. While computed tomog- highlighted the association between white matter hyper-
raphy is widely available and can be applied to approxi- intensities, a hallmark of SVD on MRI, and PSCID as well
mate parameters of clinical relevance, such as infarct as other long-term outcomes.71 White matter hyperintensi-
volume, brain volume, preexisting infarcts and severity of ties can be assessed quantitatively by lesion segmentation

Table 4. NINDS-CSN Neuropsychological Testing Batteries precise indicators of PSCID likely mandate incorpora-
for PSCID* tion of the affected regions and pathways in the brain
Domain Test provided by imaging techniques, fluid biomarkers can
60-min protocol provide a rapid, easily accessible, and potentially valu-
Global Mini-mental state Exam able tool that may function as both risk and prognostic
Orientation MoCA 6-item orientation
biomarkers.164 Varying poststroke injury cascades may
influence the development of PSCID, including inflam-
Executive Semantic fluency (animal naming)
mation, neuroaxonal injury, vascular injury, and the acti-
Phonemic fluency (Controlled Oral Word As-
sociation)
vation of neurodegenerative pathways.30 Recent reports
indicate that windows into each of these processes are
WAIS-III digit symbol coding
available in peripheral blood.
Trail making test (A and B)
Neuroaxonal injury, as measured by circulating levels
Visuospatial Clock drawing
of NfL, provide the most robust measure that is likely to
Rey-Osterrieth figure be associated with PSCID. Blood NfL levels rise rapidly
Language Boston naming test, short form in the days and weeks after acute stroke and several
Memory HVLT-R studies associate blood NfL levels with prognosis as
Depression CES-D measured by the modified Rankin Scale.153,165–168 Sepa-
Apathy Apathy evaluation scale rately, blood NfL levels are associated with AD and cog-
Other neuropsychiatric NPI-Q nitive impairment from cerebral SVD.169–172 As PSCID
30-min protocol
is, in part, driven by the extent of axonal injury resulting
from stroke, layered upon any preexisting neuroaxonal
Global Mini-mental state exam
injury, circulating NfL levels are poised to achieve a role
Orientation MoCA 6-item orientation
in evaluating risk of PSCID and establishing prognostic
Executive Animal naming
expectations of cognitive impairment after stroke.
Controlled Oral Word Association Beyond the structural injury to the brain caused by
WAIS-III digit symbol coding stroke, PSCID is likely to be accelerated by pathways
Memory HVLT-R implicated in neurodegeneration including Aβ and
Depression CES-D-10 tau accumulation. Low plasma Aβ ratios (42:40) and
plasma total tau have both been shown to be predic-
Other neuropsychiatric NPI-Q

tive of future cognitive decline and postmortem evi-
CES-D indicates Center for epidemiological; studies-depression scale; CSN,
Canadian Stroke Network; HVLT-R, Hopkins verbal learning test; revised; MoCA, dence of AD pathology in otherwise cognitively intact
Montreal Cognitive Assessment; NINDS, National Institute of Neurological Disor- individuals.173–177 Posttranslational modifications of tau,
ders and Stroke; NPI-Q, Neuropsychiatric Inventory, Questionnaire Version; and specifically phosphorylation events that are thought to
PSCID, poststroke cognitive impairment/dementia.
*Adapted from Hachinski et al134 with permission. Copyright ©2006, Wolters promote its accumulation into neurofibrillary tangles are
Kluwer Health, Inc. activated by stroke178 and of particularly high sensitivity
in detecting Alzheimer’s pathology.179 Plasma phospho-
or semi-quantitatively by rating scales that can be used tau 181 and phospho-tau 217 detect clinical AD with
routinely in clinical practice. The impact of other MRI mani- high sensitivity and thus deserve to be explored as risk
festations of SVD,157 such as cerebral microbleeds,158 on biomarkers for PSCID.180–182
stroke outcome is currently being investigated. Also, there At its core, stroke is fundamentally a vascular injury and
is increasing recognition of diffusion MRI markers as pre- as such, indirect measures of impaired BBB permeability
cise and reliable metrics of SVD burden.159,160 such as fibrinogen levels and aquaporin-4 have also been
The role of preexisting AD pathology in PSCID implicated in PSCID.183–185 Similarly, changes in angiogenic
remains controversial. Studies using the AD imaging hall- signaling have been implicated in the aging process186 and
marks medial temporal lobe and hippocampal atrophy as can be easily measured in blood. Elevations of circulat-
potential predictors of PSCID have been inconclusive.7 ing levels of angiogenic signaling molecules may implicate
Notably, hippocampal atrophy might also be driven by a failure of angiogenesis and poor collateral blood flow
other factors, such as SVD.161 Also, imaging studies pathways in individuals at risk for PSCID.187
combining positron emission tomography with tracers Finally, inflammation is a well-recognized cause and
directed at Aβ did not find amyloid pathology to be a key consequence of stroke and likely contributes to PSCID
factor for the development of PSCID.162,163 in selected individuals by synergizing with baseline levels
of inflammation measurable in plasma that are known to
associate with cerebral SVD.119,188 Thus, numerous fluid
FLUID BIOMARKERS biomarkers are likely to emerge as reliable risk and prog-
Emerging data suggest that important markers of nostic tools for PSCID serving to augment clinical and
PSCID may be found in the peripheral blood. Though imaging-based assessments.


Figure 3. Advanced magnetic resonance (MR) imaging and circulating biomarkers facilitate understanding of poststroke
cognitive impairment and dementia (PSCID) mechanisms.
A, Neuroimaging changes indicative of remote, secondary degeneration after stroke and links to elevated serum neurofilament light chain levels
in the (sub)acute and chronic phase. B, Embolic stroke (red) in a patient with atrial fibrillation and comorbid cerebral small vessel disease (SVD;
blue). CT indicates computed tomography; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; NfL, neurofilament light
chain; WMH, white matter hyperintensities.
on dementia incidence (2 trials) and incident mild cogni-

MANAGEMENT tive impairment (1 trial). In NICE and PROGRESS, there
Prevention was a modest effect of BP lowering therapy on the pre-
Despite strong epidemiological foundation for a role of vention of cognitive decline as defined by a ≥3-point drop
vascular risk factors in cognitive decline and demen- in the mini-mental state exam score. Overall, however, the
tia,132,189–191 there is limited evidence from RCTs that con- quality of evidence is insufficient to recommend inten-
trolling vascular risk factors through interventions would sive BP lowering solely for the prevention of PSCID.28
lower the risk of incident PSCID.28,189 The same applies to statin treatment,28 for which there
Few RCTs have examined the effects of intensive BP is limited information from the J-STAR trial (Japan Statin
management on cognitive decline and incident dementia Treatment Against Recurrent Stroke).196
in patients with a antecedent stroke: the NICE (Nimodip- Current guidelines recommend against the use of dual
ine in Preventing Cognitive Impairment in Ischemic Cere- antiplatelet therapy compared with single antiplatelet
brovascular Events),192 PRoFESS (Prevention Regimen therapy for the prevention of cognitive decline or demen-
for Effectively Avoiding Second Strokes),193 and SPS3 tia following lacunar infarction.28 The recommendation
(Secondary Prevention of SubCortical Stroke Study)194 is based on results from SPS3, which found short-term
trials included patients with a recent IS (maximum interval dual antiplatelet treatment (aspirin 325 mg plus clopi-
from stroke onset: 90 days), whereas the PROGRESS dogrel 75 mg versus aspirin 325 mg plus placebo) to
trial195 included patients with either IS or hemorrhagic have no beneficial effect on mild cognitive impairment
stroke within an interval up to 5 years from stroke onset. incidence or cognitive decline, while being associated
Compared to placebo, BP lowering therapy had no effect with an increased risk of bleeding.

Observational studies suggest lifestyle factors as a physical activity at goal levels, healthy diet consistent
target for dementia prevention, but there is insufficient with current guideline levels, body mass index <25 kg/
evidence from RCTs to recommend monitored lifestyle m2, BP<120/<80 mm Hg, total cholesterol <200 mg/
interventions solely for the prevention of PSCID.28 The dL, and fasting blood glucose <100 mg/dL) to maintain
ASPIS trial (Austrian Polyintervention Study to Prevent optimal brain health.132
Cognitive Decline After Ischemic Stroke) examined the
effects of a multidomain intervention that simultane-
ously targeted BP, lipid and glycemic control, healthy Symptomatic Treatment
diet, physical activity, and cognitive training.197 Another Currently, there is no pharmacological treatment
trial compared an intervention that combined advice on approved for PSCID. There have been several trials of
risk factor management with smoking cessation courses, cholinesterase inhibitors (galantamine, donepezil, or
physical activity, and healthy diet with usual care.198 Both rivastigmine) in patients with vascular dementia,203–205
trials recruited patients shortly after stroke but neither of but only one trial with a focus on PSCID.206 This trial
them found a significant effect on cognitive outcomes. randomized 50 patients, who had PSCI/no dementia at
The effects of physical activity on cognitive decline post- 3-month poststroke to either rivastigmine or placebo.
stroke were investigated in the LAST (Life After Stroke Within a treatment duration of 24 weeks, there was no
Trial)199 and MoveIT trial,200 but again, there was no clear benefit across the primary (executive function) and sec-
effect on cognitive outcomes. ondary outcomes (global cognitive function, activities
Overweight and obesity states are established risk of daily living, behavioral, and psychological symptoms).
factors for cognitive decline and dementia. Yet, disentan- A network meta-analysis of trials using cholinesterase
gling the influence of obesity from the influence of insu- inhibitors in patients with vascular dementia and other
lin resistance and other components of the metabolic VCI found some evidence that donepezil and galan-
syndrome on cognitive decline remains challenging and tamine may improve cognition but concluded that this
there are no interventional studies that have examined effect is unlikely to be clinically important.204 Memantine
the effect of weight reduction on the risk of cognitive is a glutamate N-Methyl-D- aspartate receptor antago-
decline. While low educational level is associated with nist that has been approved for symptomatic treatment
an increased risk of cognitive impairment and demen- in moderate to severe dementia due to AD. As for cho-
tia including in patients with a history of stroke,7,28 there linesterase inhibitors there is no evidence to suggest a
is uncertainty over the benefits of structured cognitive clinically relevant benefit of treatment with memantine
training as a single intervention for the prevention of cog- in patients with vascular dementia.207 Yet, many elderly
nitive decline and dementia after stroke.28 Overall, there patients with stroke have neurodegenerative disease
is a lack of methodologically robust and adequately pow- that may benefit from treatment with cholinesterase
ered studies in this area. inhibitors or memantine and stroke should not be a bar-
Some investigators have advocated the use of rier to considering treatment with these agents if there
animal-derived nootropics for the prevention of VCID. is a suspicion of concomitant AD.28,208
There was a small (N=503 patients) RCT in patients Cognitive rehabilitation, in particular interventions
with IS and a MoCA<25, who were randomized within based on relearning of compensatory strategies have
1-week poststroke to receive actovegin, a deprot- shown promise in small interventional studies.28,208
einized hemoderivative of calf blood, or placebo for However, there is continued uncertainty on the ben-
6 months followed by 6 months of standard therapy. efits of cognitive rehabilitation interventions due to a
Treatment with actovegin was found to be associated lack of methodologically robust trials.28 There is some
with significant improvements on the Alzheimer disease evidence that noninvasive brain stimulation might tran-
assessment scale-cognitive subscale when compared siently improve cognitive function poststroke but addi-
to placebo.201 However, the effect size was small, and tional data from sufficiently powered trials are needed to
there are some safety concerns causing uncertainty fully assess this therapeutic modality.209 As an important
over the benefits and risks of actovegin.28 aspect, treatment plans in PSCID should address comor-
Given the well-documented association between bidities, such as behavioral and psychological symptoms,
stroke, in particular severe stroke, and risk of demen- support for patients and caregivers, and maximizing
tia and an even higher risk of dementia in those with independence.28,38,208
recurrent stroke,7,8 there is strong reason to believe that
treatments with proven efficacy for stroke prevention
will also prevent cognitive decline.202 In light of this and FUTURE DIRECTIONS
the above data, the American Heart Association/Ameri- While substantial progress has been made in concep-
can Stroke Association provided specific recommenda- tualizing VCID,38,128 the precise mechanisms of PSCID
tions on risk factor management45,132 and recommends are insufficiently understood.35,106 The hypothesis that
checking health status with Life’s Simple 7 (nonsmoking, a specific stroke event may precipitate, accelerate, or


unmask cascades of neurodegeneration and microvas- available, there is growing interest in PSCID, and its
cular dysfunction in a vulnerable brain requires rigorous prevention, given the changing epidemiology of post-
investigation. Further, the recently proposed construct of stroke survivors—with older individuals surviving longer.
brain health purports protective factors that constitute The key to attaining population brain health is to reduce
brain’s ability to withstand the effects of acute insult or incidence of dementia by preventing stroke,202 modify
allow the brain to recover fully and rapidly to its prestroke the overall burden of cerebrovascular and cardiovascu-
level of function, that is, mechanisms of brain resilience in lar disease, and through that, augment potential brain
stroke.39,124,132 reserve and resilience39 of individuals and communities.
Considering the complexity of underlying disease pro- Therefore, the next step is to incorporate the mechanis-
cesses in PSCID, there is an urgent need for a coor- tic insights from the ongoing research efforts in PSCID
dinated, global research effort to close the existing and to develop personalized approach to diagnosis, man-
knowledge gaps in this field.30 A number of large-scale agement, and prevention of cognitive impairment and
international research consortia focus on understand- dementia after stroke, and though that, explore the new
ing VCID cause and developing treatable targets to frontiers in brain health.
lessen the burden of VCID worldwide including DEM-
DAS (Determinants of Dementia After Stroke Study),108
STROKOG (Stroke and Cognition Consortium),107 SVD ARTICLE INFORMATION
at target, HBC (Heart-Brain Connection), MarkVCID,109 Affiliations
the ISGC (International Stroke Genetics Consortium), J. Philip Kistler Stroke Research Center (N.S.R., S.J.v.V., A. Biffi) and Divisions of
Memory Disorders and Behavioral Neurology (A. Biffi), Department of Neurol-
and a Network on Understanding the Role of the Peri- ogy, Massachusetts General Hospital, Harvard Medical School, Boston. Florey
vascular Space in cerebral SVD.31 More recently, DIS- Institute of Neuroscience and Mental Health, University of Melbourne, Australia
COVERY (Determinants of Stroke Cognitive Outcomes (A. Brodtmann). Turner Institute for Brain and Mental Health, Monash University,
Melbourne, Australia (A. Brodtmann. M.P.P.). Harvard T.H. Chan School of Public
and Vascular Effects on Recovery), a prospective, multi- Health, Boston (M.P.P.). MassGeneral Institute for Neurodegenerative Disease,
center observational cohort study aiming to enroll 8000 Massachusetts General Hospital, Charlestown (S.J.v.V.). Institute for Stroke and
nondemented racially and ethnically diverse patients Dementia Research (ISD), University Hospital, LMU Munich, Germany (M. Duer-
ing, M. Dichgans). Medical Image Analysis Center and Department of Biomedical
with incident IS, ICH, and SAH admitted across 30 Engineering, University of Basel, Switzerland (M. Duering). Department of Neu-
high-volume US stroke centers has been funded by the rology, David Geffen School of Medicine, University of California Los Angeles
National Institutes of Health (www.discoverystudy.org). (J.D.H.). Department of Neurology, West Los Angeles VA Medical Center, CA
(J.D.H.). German Center for Neurodegenerative Diseases (DZNE), Munich, Ger-
DISCOVERY participants are followed for a minimum
many (M. Dichgans). Munich Cluster for Systems Neurology (SyNergy), Munich,
of 2 years with serial in-person and phone-based cogni- Germany (M. Dichgans).
tive and functional assessments, and with subgroups of
Acknowledgments
participants undergoing detailed MRI and positron emis- We thank Martin Bretzner, MD, Interventional Neuroradiology Clinical Fellow,
sion tomography imaging as well as blood collection for CHU de Lille (Université de Lille, Inserm U1172 - Lille Neuroscience and Cogni-
plasma biomarkers, genome sequencing, epigenetics, tion) and Postdoctoral Research Fellow at the J. Philip Kistler Stroke Research
Center (Massachusetts General Hospital and Harvard Medical School) for his
and gene expression studies.30 DISCOVERY aims to contribution in developing concept and illustrative framework of Figure 1.
understand cognitive decline and dementia in high-risk
US populations based on their stroke events type or the Sources of Funding
This work is, in part, supported by the National Institute for Neurological Disorders
underlying vulnerability to PSCID. Using this knowledge and Stroke (NINDS)/National Institute on Aging (NIA) U19NS115388.
and the findings from the multiple ongoing international
research studies in VCID, the global community must Disclosures
Dr Rost is, in part, supported by National Institute for Neurological Disorders
forge the future of personalized poststroke interventions
and Stroke (NINDS)/NIA U19NS115388 and she serves as Associate Edi-
to reduce overall burden of PSCID and related disability. tor of Stroke. A. Brodtmann serves on the editorial boards of Neurology and
Furthermore, we propose to consider cognitive outcomes International Journal of Stroke. She has received consultancy fees from Biogen
Australia Scientific Advisory Board and the Roche Diagnostics Australia Scien-
after stroke using harmonized timing and methods of
tific Advisory Board. Her research is funded by the National Health and Medical
assessments for patients of all stroke subtypes (IS, ICH, Research Council (NHMRC) and the National Heart Foundation. M.P. Pase is a
and SAH) as the new standard for all clinical trials of scientific advisor to the Alzheimer’s Disease Drug Discovery Foundation (ADDF).
His salary is funded by a National Heart Foundation of Australia Future Leader
poststroke outcomes.
Fellowship (GTN102052) and an NHMRC Investigator grant (GTN2009264)
As population ages globally, brain health is becom- with research funding from the NIA, NHMRC, Australian Research Council
ing one of the most important concepts to embrace as (ARC), ADDF, Heart Foundation, Dementia Australia, and Alzheimer’s Associa-
tion. S.J. van Veluw receives funding from the National Institutes of Health (NIH),
part of the public health priorities to optimize quality of
the Alzheimer’s Association, American Heart Association, and the Netherlands
life and to control health care costs worldwide.210 Brain Organization for Scientific Research. Her lab is also supported by a sponsored
health implies optimal function and freedom from neuro- research agreement from Therini Bio. M. Duering is an employee of MIAC AG,
has received honoraria for lectures from Sanofi Genyzme and Bayer Vital GmbH,
logical injury, which is intimately connected to prevention
and served as consultant for Hovid Berhad and Roche Pharma. J.D. Hinman is,
of PSCID. While no personalized prediction of trajec- in part, supported by NINDS/NIA U19NS115388. The other authors report no
tories of cognitive impairment after stroke is currently conflicts.

16. Ganesh A, Luengo-Fernandez R, Wharton RM, Gutnikov SA, Silver LE,

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Rost Et Al 2022 Post Stroke Cognitive Impairment and Dementia

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Circulation Research

STROKE AND NEUROCOGNITIVE IMPAIRMENT COMPENDIUM

Post-Stroke Cognitive Impairment and Dementia

1252 April 15, 2022 Circulation Research. 2022;130:1252–1271. DOI: 10.1161/CIRCRESAHA.122.319951

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(or delayed) PSCID to differentiate the cognitive defi-

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Table 1. Stroke Characteristics, Risk Factors for and Rates of PSCID

Timing of Risk factors

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Figure 1. Risk factors and trajectories of poststroke cognitive impairment/dementia (PSCID).

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dysfunction following an acute stroke event is gener- NEUROCOGNITIVE ASSESSMENT

ally caused by (1) direct injury to the brain structures

forms of the MoCA test.135–137 The National Institute for

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Other neuropsychiatric NPI-Q

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on dementia incidence (2 trials) and incident mild cogni-

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16. Ganesh A, Luengo-Fernandez R, Wharton RM, Gutnikov SA, Silver LE,

4422(09)70236-4 2022;93:232–237. doi: 10.1136/jnnp-2021-327557

1266 April 15, 2022 Circulation Research. 2022;130:1252–1271. DOI: 10.1161/CIRCRESAHA.122.319951

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Association Stroke Council, Council on Epidemiology and Prevention, 10.1016/j.jacc.2019.04.034

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post stroke cognitive decline. Int J Stroke. 2015;10:513–518. doi: 10.1161/STROKEAHA.111.643726

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