Vascular Cognitive Impairment Continuum 2016

Vascular CognitiveImpairment

Eric Smith, MD, MPH

ABSTRACTPurpose of Review: This article provides a diagnostic framework for vascular cog-nitive impairment, discusses prevalence and relationships to other neurodegenerativepathologies, and provides advice on diagnostic workup and management.Recent Findings: Vascular cognitive impairment is the second most common causeof cognitive impairment and frequently coexists with other neurodegenerative neu-ropathologies. Three new diagnostic criteria have been published recently; commondiagnostic elements include the need to classify cognitive impairment as mild cog-nitive impairment or dementia and to link the cognitive impairment to evidence ofclinically significant cerebrovascular disease. Vascular cognitive impairment may befurther subclassified into poststroke vascular cognitive impairment and nonstrokevascular cognitive impairment, most commonly caused by cerebral small vesseldisease, which may only be recognized on neuroimaging.Summary: Vascular cognitive impairment is a potentially treatable common causeof cognitive impairment, progression of which may be slowed or halted by secondaryprevention of vascular disease.

Continuum (Minneap Minn) 2016;22(2):490–509.

INTRODUCTIONVascular cognitive impairment is thesecond most common cause of demen-tia and may be the most preventableand treatable cause. Vascular cognitiveimpairment is commonly encounteredin two forms. In poststroke vascular cog-nitive impairment, the cognitive im-pairment is the immediate and directconsequence of a symptomatic stroke.In nonstroke-related vascular cognitiveimpairment, the cognitive impairmentis the consequence of clinically hard-to-detect cerebrovascular disease, whichmay be evident only on neuroimagingwith CT or MRI. Additionally, vascularcognitive impairment is a frequentcontributor to mixed dementia, accom-panied by other neuropathologies suchas Alzheimer pathology. This articlesummarizes the classification, diagno-sis, and management of vascular cog-nitive impairment.

CLASSIFICATION OF VASCULARCOGNITIVE IMPAIRMENTClassification criteria for vascular cogni-tive impairment have been publishedby the International Classificationof Diseases, Tenth Revision (ICD-10),1

National Institute of NeurologicalDisorders and Stroke-AssociationInternationale pour la Recherche etl’Enseignement en Neurosciences(NINDS-AIREN),2 State of CaliforniaAlzheimer’s Disease Diagnostic andTreatment Centers (ADDTC),3 AmericanHeart Association/American Stroke As-sociation (AHA/ASA),4 the InternationalSociety of Vascular Behavioural and Cog-nitive Disorders (Vas-Cog),5 and in theDiagnostic and Statistical Manualof Mental Disorders, Fourth Edition(DSM-IV)6 and Fifth Edition (DSM-5).7

Common elements of recent criteriaare given in Table 6-1. All of these clas-sification schemes require that some

Address correspondence toDr Eric Smith, University ofCalgary, Room C1261, FoothillsMedical Centre, 1403 29 St NW,Calgary, AB, Canada,[email protected] Disclosure:Dr Smith serves as a boardmember of the QualityOversight Committee of theAmerican Heart Associationand as an assistant editor forStroke. Dr Smith receives grantsupport from the AlzheimerSociety of Canada, theCanadian Institutes of HealthResearch, the CanadianPartnership Against Cancer,and the Heart and StrokeFoundation of Canada andreceives research supportfrom McMaster University.Unlabeled Use ofProduct/InvestigationalUse Disclosure:Dr Smith discusses theunlabeled/investigationaluse of cholinesteraseinhibitors for the treatmentof vascular dementia.* 2016 American Academyof Neurology.

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TABLE 6-1 Recent Classification Criteria for Vascular Cognitive Impairment

AHA/ASA4 Vas-Cog Society5 DSM-57

Cognitive criteria Discriminates between vascularmild cognitive impairmentand vascular dementia

Discriminates betweenmild and major vascularcognitive disorder (dementia)

Discriminates betweenmild and major vascularneurocognitive disorder

Criteria forprobable vascularcognitiveimpairment

There is imaging evidence ofcerebrovascular diseaseand either:

Either: The criteria are metfor major or mildneurocognitive disorder.

There is a clear temporalrelationship betweena vascularevent (eg, clinical stroke) andonset of cognitive deficits.

The onset of cognitive deficitsfollows one or more strokesor there are physical signsconsistent with stroke.

The clinical features areconsistent with a vascularetiology, as suggested byeither of the following:

OR

OR

Onset of the cognitivedeficits is temporallyrelated to one or morecerebrovascular events.

There is a clear relationshipin the severity and pattern ofcognitive impairment andthe presence of diffuse,subcortical cerebrovasculardisease pathology.

If history of stroke or transientischemic attack is absent, then thereis evidence of cognitive decline inspeed of information processing,complex attention or frontalexecutive functions, accompaniedby one or more of: gaitdisturbances, urinary symptoms,or personality and mood changes.

OR

There should be no history ofgradually progressivecognitive deficits before orafter stroke that suggest thepresence of a nonvascularcognitive disorder (eg,Alzheimer disease).

There should be neuroimagingevidence of either large vesselinfarct, strategically placed singleinfarct(s) or intracerebralhemorrhages(s), multiple (morethan two) lacunar infarcts outsidethe brainstem, or extensive andconfluent white matter lesions.

Evidence for decline isprominent in complexattention (includingprocessing speed) andfrontal-executive function.

There should not be evidenceof other nonvascular cognitive,medical, psychiatric, or neurologicdisorders sufficient to explain thecognitive impairment (includingAlzheimer disease).

There is evidence ofthe presence ofcerebrovascular diseasefrom history, physicalexamination, and/orneuroimaging consideredsufficient to account fortheneurocognitivedeficits.

The symptoms are notbetter explained byanother brain diseaseor systemic disorder.

Probable vascularneurocognitive disorderis diagnosed if one ofthe following is present;otherwise possiblevascular neurocognitivedisorder shouldbe diagnosed:

Clinical criteria aresupported byneuroimaging evidenceof significantparenchymalinjury attributed tocerebrovascular disease(neuroimaging supported).

Continued on page 492

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degree of cognitive impairment shouldbe present along with evidenceVfrom some combination of history,physical examination, cognitive pro-file, and diagnostic testing, includingneuroimagingVof a vascular contribu-

tion to the cognitive impairment. Theterm vascular cognitive impairment isintended to encompass all forms of cog-nitive impairment, not only dementia,and to include all cases where vascu-lar disease contributes to impairment,

TABLE 6-1 Recent Classification Criteria for Vascular Cognitive Impairment Continued from page 491

AHA/ASA4 Vas-Cog Society5 DSM-57

OR

The neurocognitivesyndrome is temporallyrelated to one ormore documentedcerebrovascular events.

OR

Both clinical and genetic(eg, cerebral autosomaldominant arteriopathywith subcorticalinfarcts andleukoencephalopathy)evidence ofcerebrovasculardisease is present.

Criteria forpossible vascularcognitiveimpairment

Meets criteria except thatthere is no clear relationshipbetween the vasculardisease and the cognitiveimpairment, there isinsufficient information(eg, neuroimaging studiesare not available), severeaphasia precludes accuratecognitive assessment, orthere is evidence ofother neurodegenerativeconditions (eg, Alzheimerdisease) in addition tocerebrovascular disease.

Meets criteria except thatneuroimaging is not available.

Clinical criteria are metbut neuroimaging isnot available and thetemporal relationshipof the neurocognitivesyndrome with one ormore cerebrovascularevents is notestablished.

Classificationwhen otherpotential causesare present (ie,mixed disease)

Possible vascularmild cognitiveimpairment or dementiashould be diagnosed whenthere is evidence of otherneurodegenerative conditions.

Vascular mild/major cognitivedisorder with concomitantAlzheimer disease may bediagnosed when the patientadditionally meets criteria forprobable or possible AD.

Not specificallyaddressed.

AHA/ASA = American Heart Association/American Stroke Association; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition; Vas-Cog = International Society of Vascular Behavioural and Cognitive Disorders.


Vascular Cognitive Impairment


including in cases where it is not thesole contributor. More recent classifica-tion systemsVthe AHA/ASA, Vas-Cog,and DSM-5Vdistinguish between vas-cular mild cognitive impairment (MCI)(or minor vascular neurocognitivedisorder in the DSM-5) and vasculardementia (or major vascular neurocog-nitive disorder in the DSM-5).

AHA/ASA and Vas-Cog criteria fur-ther classify vascular cognitive impair-ment as probable or possible basedon the completeness of the diagnos-tic workup and the presence or absenceof evidence for competing causes ofdementia, such as Alzheimer disease(AD). In practice, probable vascularcognitive impairment may be the mi-nority of cases because comorbid pa-thologies such as AD are commonlyidentified, or at least cannot be ruledout with certainty.

AHA/ASA, Vas-Cog, and DSM-5 cri-teria acknowledge that vascular cog-nitive impairment may come in theform of poststroke vascular cognitiveimpairment or nonstroke forms of vas-cular cognitive impairment, such asthat caused by subcortical ischemicdisease. This distinction is importantas it makes clear that the absence of aclinical history of stroke does not ex-clude vascular cognitive impairment.Indeed, neuroimaging and neuropa-thology studies have established thatclinically silent, or ‘‘covert,’’ cerebro-vascular disease becomes extremelycommon with aging, is associated withcognitive impairment and the presenceof dementia, and is sufficient to causeclinically relevant cognitive impairment.

Furthermore, Vas-Cog criteria sub-classify vascular cognitive impairmentaccording to cerebrovascular pathology(Table 6-2). It is important to recog-nize that the vascular pathologies un-derlying vascular cognitive impairmentare extremely diverse (including arterio-sclerosis, cerebral amyloid angiopathy,

atheroembolism, cardiac embolism,hypoperfusion, and hemorrhage) suchthat patient prognosis and manage-ment must be highly individualized.With appropriate case-specific man-agement of the vascular risk factorsrelevant to the patient’s vascular pa-thology, it may be possible to arrestprogression of vascular cognitive im-pairment by preventing further cere-brovascular injury.

DIAGNOSIS AND DIAGNOSTICTESTINGThe diagnosis of a patient with possi-ble vascular cognitive impairment maybe considered to consist of three stages.First, a determination should be madeof whether evidence of cognitive im-pairment exists, including classificationas MCI or dementia. Second, a workupfor the presence of vascular diseaseshould be completed, including itslocation, severity and underlyingcauses, and risk factors. Third, consid-eration should be given as to whetherthe vascular disease is sufficient topartly or wholly explain the cogni-tive impairment.

Assessing CognitiveImpairment in VascularCognitive ImpairmentThe assessment for cognitive impair-ment should follow the same prin-ciples for assessment of MCI anddementia as provided in the article‘‘The Mental Status Examination inPatients With Suspected Dementia’’ byMurray Grossman, MD, FAAN, andDavid J. Irwin, MD,8 and in the article‘‘Mild Cognitive Impairment’’ byRonald C. Petersen, PhD, MD,9 in thisissue of Continuum. The sensitivityfor detecting vascular cognitive im-pairment is enhanced by the use ofscreening or assessment tools thatinterrogate executive function and

KEY POINTSh Diagnostic criteria for

vascular cognitiveimpairment are basedon the presence ofcognitive impairmentand vascular diseaseas well as a clinicaljudgment that thevascular disease iscausing the impairment.

h The term vascularcognitive impairmentencompasses all severityof cognitive impairmentcaused by vasculardisease, including mildcognitive impairmentand dementia.

h Vascular cognitiveimpairment may besubclassified aspoststroke vascularcognitive impairment,which refers to thedirect immediateconsequence ofclinical stroke, or asnonstroke vascularcognitive impairment,which is most commonlycaused by cerebral smallvessel disease.

h Vascular cognitiveimpairment has manyvascular causes. Thecause of the vasculardisease should beidentified so thatfurther progressionor recurrence canbe prevented.



KEY POINTh The clinical assessment

for vascular cognitiveimpairment can beconceived as athree-stage processthat includes thefollowing steps:(1) assess for cognitiveimpairment; (2) assessthe presence, severity,and cause of vasculardisease; and (3) assesswhether the vasculardisease is sufficient tocause the impairment,in whole or in part.

TABLE 6-2 Vascular Pathology of Vascular Cognitive Impairmenta

b Parenchymal Lesions of Vascular Etiology

Large vessel atherothromboembolic disease

Multiple infarcts

Single strategically placed infarct

Small vessel disease

Multiple lacunar infarcts

Ischemic white matter damage

Dilated perivascular spaces

Microinfarcts

Microhemorrhages

Hemorrhage

Intracerebral hemorrhage

Multiple microbleeds

Subarachnoid hemorrhage

Hypoperfusion

Hippocampal sclerosis

Laminar cortical necrosis

b Types of Vascular Pathologies

Atherosclerosis

Cardiac, atherosclerotic, and systemic emboli

Arteriolosclerosis

Lipohyalinosis

Cerebral amyloid angiopathy

Vasculitis

Venous collagenosis

Arteriovenous fistulae

Hereditary angiopathies (eg, cerebral autosomal dominant arteriopathywith subcortical infarcts and leukoencephalopathy [CADASIL])

Berry aneurysms

Miscellaneous vasculopathies (eg, moyamoya disease)

Cerebral venous thrombosis

a Modified with permission from Sachdev P, et al, Alzheimer Dis Assoc Disord.5 journals.lww.com/alzheimerjournal/Abstract/2014/07000/Diagnostic_Criteria_for_Vascular_Cognitive.2.aspx. B 2014Lippincott Williams & Wilkins.




http://journals.lww.com/alzheimerjournal/Abstract/2014/07000/Diagnostic_Criteria_for_Vascular_Cognitive.2.aspx

http://journals.lww.com/alzheimerjournal/Abstract/2014/07000/Diagnostic_Criteria_for_Vascular_Cognitive.2.aspx

processing speed, which are frequentlyaffected in patients with vascular cog-nitive impairment. For example, theMontreal Cognitive Assessment (MoCA)tool appears to be a more sensitivetool for vascular cognitive impairmentthan the Mini-Mental State Examination(MMSE), attributed to the relativelygreater degree of executive functionassessment on the MoCA (www.mocatest.org).10,11 When clinical un-certainty persists despite the use of avalidated bedside cognitive screeningtool, neuropsychological testing isoften helpful. The cognitive profileof vascular cognitive impairment isfurther described later in this article.

Assessing the Presence ofCerebrovascular Disease inPatients With VascularCognitive ImpairmentThe determination of the presence ofcerebrovascular disease may be basedon a combination of history, examina-tion, and diagnostic testing such asneuroimaging. The clearest evidenceof cerebrovascular disease is when aclinical history of stroke exists. How-ever, the physician should be surethat the diagnosis of stroke is wellsupported by clinical history, medicalrecords, physical examination showingneurologic signs consistent with paststroke (such as aphasia, dysarthria,hemianopia, or other focal neurologicsigns) and, if needed or availablefrom previous stroke workup, neuro-imaging evidence of cerebral infarc-tion or hemorrhage consistent with thesigns and symptoms. Patient-reportedhistory of stroke is generally reli-able; however, nonspecific neurologicsymptoms can sometimes be falselyreported as stroke, introducing diag-nostic confusion.

Identifying the presence of cere-brovascular disease is more difficult

when a history of stroke is absent.Neuroimaging can identify evidenceof silent strokes and other manifesta-tions of cerebral small vessel diseasethat are hard to detect clinically. Clini-cal history, signs, and symptoms maybe suggestive of nonstroke vascularcognitive impairment but are nothighly sensitive or specific and shouldnot be relied on to diagnose vascularcognitive impairment in the absenceof neuroimaging confirmation. Thesesigns and symptoms include frontalgait disorder, urinary incontinence,a stepwise progression of cognitiveimpairment with intervening static pe-riods, prominent executive dysfunc-tion and slowed processing speed onneuropsychological testing, and minorasymmetric neurologic signs such asincreased tone, reflex asymmetry, Ba-binski responses, or frontal release signs.5

The presence of vascular risk factorssuch as diabetes mellitus and hyperten-sion should increase suspicion for vas-cular cognitive impairment but shouldnot be taken as proof of its presence.

Neuroimaging is recommended bythe AHA/ASA as helpful for the diag-nosis of vascular cognitive impair-ment.4 Neuroimaging is useful notonly for identifying the presence ofcerebrovascular disease, but also thelocation and severity of the cerebro-vascular lesions, which help determinethe clinical significance of the lesions,including whether they are sufficientto account for the cognitive impair-ment. MRI is superior to CT for iden-tifying small infarcts and hemorrhagesand demonstrates more manifesta-tions of cerebral small vessel disease;therefore, MRI should be preferredover CT.12 In patients with a historyof stroke, neuroimaging should gen-erally identify the previous infarct orhemorrhage unless it is small. Inpatients with cerebral small vesseldisease, MRI may identify a range of

KEY POINTSh Cerebrovascular disease

should be diagnosed byhistory, examination,and diagnostic testing,including neuroimaging.

h Neuroimaging providesuseful evidence ofthe presence, location,and severity ofcerebrovascular disease.



http://www.mocatest.org

http://www.mocatest.org

manifestations, including small in-farcts, lacunae of presumed vascularorigin, white matter hyperintensi-ties, and others (Figure 6-1). A recentconsensus statement offers rec-ommendations for terms, defini-tions, and reporting of cerebralsmall vessel disease as a contributorto neurodegeneration.12

Assessing the RelationshipBetweenCerebrovascularDiseaseand Cognitive ImpairmentDetermining whether the identifiedcerebrovascular disease is sufficient toaccount for, in whole or in part, cog-nitive impairment may be the mostclinically difficult part of the assess-

ment for vascular cognitive impair-ment. Although general principlesrelating the location and severity ofcerebrovascular disease to the risk forcognitive impairment have beenestablished, there are no objectivelyderived models or risk scores to pre-dict the presence of cognitive impair-ment in individual patients based ontheir clinical characteristics and bur-den of cerebrovascular disease. There-fore, clinical judgment is requiredto determine whether identified cere-brovascular disease is clinically rele-vant, or merely an incidental finding.This judgment is difficult becausecerebrovascular disease is a common

KEY POINTh Because cerebrovascular

disease is commonand can be incidental,clinical judgment isneeded in individualpatients to determinewhether cerebrovascularlesions are sufficientto cause cognitiveimpairment in theaffected individual.

FIGURE 6-1 MRI manifestations of cerebral small vessel disease.

DWI = diffusion-weighted imaging; FLAIR = fluid-attenuated inversion recovery; GRE = gradientrecalled echo; SWI = susceptibility-weighted imaging.

Reprinted with permission from Wardlaw JM, et al, Lancet Neurol.12 www.thelancet.com/journals/laneur/article/PIIS1474-4422(13)70124-8/abstract. B 2013 Elsevier Ltd.




http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(13)70124-8/abstract

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(13)70124-8/abstract

accompaniment of aging that is fre-quently seen in nonimpaired individ-uals, as well as in impaired individuals(where it tends to be more severeand diffuse). For example, silentbrain infarcts, extensive white matterhyperintensities, and microbleeds,are frequently detected on MRI ofolder individuals without dementia(Table 6-3).14Y16

The clearest circumstance wherecerebrovascular disease can be defin-itively related to cognitive impairmentis in poststroke vascular cognitive im-pairment, where there is a clinicalhistory of stroke, preceded by the ab-sence of cognitive symptoms but im-mediately followed by cognitiveimpairment (Case 6-1). In this case,the diagnosis of vascular cognitive im-pairment is essentially certain. How-ever, a pitfall to avoid is to overlook ahistory of prestroke cognitive decline,which, if present, could indicateeither a competing neurodegenera-tive cause of dementia or a mixeddementia. Formal questionnaires such

as the Informant Questionnaire on Cog-nitive Decline in the Elderly (IQCODE)17

(Supplemental Digital Content 6-1,http://links.lww.com/CONT/A172) can beused to assess for prestroke cognitivedecline, or a careful clinical history ofperformance on instrumental activi-ties of living (such as driving, shop-ping, and handling finances) can beused to screen for prestroke cog-nitive disabilities.

The number, volume, and locationof infarcts or hemorrhages is relatedto the risk for poststroke cognitive im-pairment. Single, strategic locationshave been identified that are associatedwith poststroke cognitive impairmentwhen affected by stroke.18 Theselocations include left hemisphereperisylvian language areas, the thala-mus, midbrain, medial temporal lobe,and medial frontal lobe. Single strokesin these regions can cause cognitiveimpairment by affecting brain networkssustaining language, attention, ormemory. Cognitive impairment mayalso result from the combined effect

KEY POINTh In poststroke vascular

cognitive impairment,the link betweenstroke and subsequentvascular cognitiveimpairment shouldbe readily apparent.

TABLE 6-3 Prevalence of Cerebral Small Vessel Disease on Magnetic Resonance Imaging inthe General Population Without Dementiaa

AgeDecade

Infarcts

BeginningConfluent or ConfluentWhite MatterHyperintensitieson MRIb

Microbleedsc

Q1 infarct Q2 infarcts

T2*-WeightedGradient RecalledEcho (GRE)

Susceptibility-WeightedImaging (SWI)/High-SensitivitySequence

50Y59 5Y8% 1Y2% 1% 3% 12%

60Y69 7Y12% 2Y3% 1Y4% 5Y10% 15Y17%

70Y79 12Y23% 3Y6% 6Y14% 8Y16% 30Y31%

80+ 25Y38% 6Y9% 19% 18% 40%

MRI = magnetic resonance imaging.a Data are aggregated from multiple population-based studies.b As measured using the Fazekas scale.13c As can be seen from the table, susceptibility-weighted imaging (SWI) and other newer, high-sensitivity MRI sequences detect abouttwice as many microbleeds as older T2*-weighted gradient recalled echo (GRE) sequences.



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of multiple strokes affecting sufficientbrain regions, such as the prefrontallobes, involved in cognitive process-ing. This syndrome has been termedmulti-infarct dementia. By contrast,the clinician should generally be scep-tical of relating cognitive impairmentto single, small to moderately sizedinfarcts in brain regions outside theaforementioned strategic areas forcognitive processing. No single vol-ume threshold reliably discriminatespatients with poststroke vascular cog-nitive impairment versus those with-out because the cognitive effects ofinfarcts and hemorrhages depends onthe locations of the lesions as well astheir size.

Consensus criteria recommend thatthe diagnosis of nonstroke vascularcognitive impairment should be

based on a pattern of diffuse, severecerebrovascular disease.4,5 In mostcases, nonstroke vascular cognitiveimpairment is caused by subcorticalischemic cerebral small vessel dis-ease, also called Binswanger disease(Case 6-2). However, our understand-ing of the relationship between thelocation, extent, and severity of the ce-rebral small vessel disease and theresulting clinical syndromes is still in-complete; therefore, only general prin-ciples can be discussed. Silent braininfarcts and white matter hyperin-tensities on MRI predict risk for de-mentia in population-based studies, andsilent brain infarcts are associated withpresence of dementia in autopsy-basedstudies,19Y21 while the relationship ofcerebral microbleeds to cognition isless clear. Small infarcts in the thalamus

KEY POINTSh Location, as well as size

and severity, must betaken into accountwhen considering thecognitive consequencesof infarcts and othercerebrovascular lesions.

h The diagnosis ofnonstroke vascularcognitive impairmentshould be supportedby the presence ofdiffuse, severecerebrovascular disease.

Case 6-1A 71-year-old woman presented acutely withconfusion, vomiting, left hemianopia, lefthemiparesis, and skew deviation. Head CT wasunremarkable but CT angiography showed thatthe basilar artery was occluded due to thrombusformation on an atherosclerotic plaque. Thepatient was treated with IV tissue plasminogenactivator and endovascular thrombectomy. Thepatient’s motor and oculomotor findings resolvedafter treatment. However, the patient remainedcognitively impaired, with deficits in verballearning and recall. Diffusion-weighted MRI showedacute infarction (bright signal) in the right occipitaland bilateral medial temporal lobes (Figure 6-2).During follow-up 3 months later, the patientdescribed symptoms of persistent forgetfulnessthat interfered with shopping, finances, and driving.Poststroke vascular dementia was diagnosed.

Comment. Strategic infarctions in the bilateralmedial temporal lobes caused vascular dementia inthis case. Poststroke dementia has also beenassociated with infarcts in locations such as the leftperisylvian cortex, medial frontal lobe, or thalamus,or with the presence of multiple cortical infarcts.

FIGURE 6-2 Axial diffusion-weighted MRI of thepatient in Case 6-1 shows acuteinfarction (bright signal) in the rightoccipital andbilateralmedial temporal lobes.




may be more likely to affect cognitionthan small infarcts in other locations.Higher numbers of infarcts andhigher volumes of white matterhyperintensities are associated withhigher risk of cognitive impairment;however, exact thresholds are notwell defined and likely vary based onthe location of the lesions. To support adiagnosis of vascular cognitive impair-ment, the AHA/ASA recommends that‘‘diffuse, subcortical cerebrovasculardisease pathology’’ should be present,4

while the Vas-Cog Society recommendsthat at least three supratentorialbrain infarcts or ‘‘extensive and con-fluent’’ white matter hyperintensitiesshould be present.5 However, theserecommendations, while useful aids to

clinical judgment, have not been stud-ied for their validity in clinical practice.

Promising new MRI techniques notyet ready for clinical use may, in thefuture, allow better discrimination ofclinically relevant from less clinicallyrelevant cerebrovascular lesions byinterrogating their impact on brain net-work function. Subcortical infarctionand ischemic white matter demyelin-ation are presumed to cause cognitiveimpairment by disconnecting brain net-works subserving cognition. Recent MRItechniques have demonstrated thatwhite matter hyperintensities of pre-sumed vascular origin are associatedwith reduced structural brain con-nectivity measured using diffusion-tensor imaging,22 and that subcortical

Case 6-2A 65-year-old man presented with cognitive slowing, forgetfulness, and decreased gait speed that hehad experienced for approximately 1 year. He was no longer able to manage his own finances or dohis own shopping. He had a history of poorly controlled hypertension. The patient’s Montreal CognitiveAssessment (MoCA) score was 14 out of 30. Neurologicexamination showed mild hyperreflexia, a few beatsof clonus at each ankle, and a slow, unsteady gaitwith a shortened stride length but nearly normalbase width. Brain MRI showed severe white matterhyperintensities with multiple lacunae of presumedvascular origin (Figure 6-3). A diagnosis of probablevascular dementia caused by hypertensive smallvessel disease was given. Despite initiation of aspirin,improved blood pressure control, and a trial ofcholinesterase inhibition, progressive cognitivedecline ensued.

Comment. This case is consistent with vasculardementia due to diffuse subcortical cerebrovascularpathology, also called Binswanger disease. Despitethe absence of symptomatic stroke, the silent braininfarcts and white matter hyperintensities appearto be sufficient to cause cognitive decline. Therelatively young age at onset suggests that Alzheimerpathology is probably absent. However, the presenceof comorbid Alzheimer pathology cannot becompletely excluded as amyloid imaging studies inpatients with subcortical ischemic dementia showthat mixed dementia, with a contribution fromAlzheimer pathology, is relatively common.

FIGURE 6-3 Axial fluid-attenuated inversionrecovery (FLAIR) MRI of the patient inCase 6-2 shows severe white matter

hyperintensities (double arrow) with multiple lacunaeof presumed vascular origin (single arrow).



infarction is associated with remotecortical atrophy in connected areas.23

While neuroimaging remains themost useful diagnostic test to linkthe presence and severity of cerebro-vascular disease with the presence ofvascular cognitive impairment, theclinician must keep in mind that neu-roimaging does not have perfectsensitivity for all clinically relevantcerebrovascular lesions. Specifically,neuroimaging is unable to detect mi-croinfarcts, which are infarcts as smallas 0.2 mm in diameter that are visibleat autopsy in approximately one-quarter of all deceased elderly butin up to half of all deceased elderly pa-tients with dementia.24 These infarctsfall below the limit of spatial resolutionof clinical MRI. About half the time theyoccur in the absence of gross infarcts,such that neuroimaging may falsely sug-gest the absence of infarction.

When the patient’s neuropsycho-logical profile matches the locationand severity of cerebrovascular dis-ease, the case for clinically relevant ce-rebrovascular disease is strengthened.Most commonly, vascular cognitive im-pairment is associated with relativelygreater impairments in executive func-tion and processing speed than inepisodic memory for a given level ofoverall disability.4 By contrast, early ADis most often associated with episodicmemory impairment.25 However, it isimportant to recognize that some de-gree of memory impairment is verycommon in vascular cognitive impair-ment as well.4 Furthermore, the clini-cian should be aware that there can begreat variety in the spatial distributionand severity of cerebrovascular disease,which determines the neuropsycholog-ical profile. Therefore, there is no oneuniform pattern of neuropsycho-logical impairment in all patients withvascular cognitive impairment. For thisreason, a diagnosis of vascular cognitive

impairment should not be made basedon neuropsychological profile alone,but should be supported by otherevidence from clinical history, neuro-logic examination, and neuroimagingthat is consistent with vascular cognitiveimpairment. Nonetheless, neuropsy-chological testing may be very help-ful when uncertainty exists regardingthe clinical significance of cerebrovas-cular disease by identifying whetherthe neuropsychological profile ismore or less consistent with the iden-tified cerebrovascular lesions in thatindividual patient. Some vascular cog-nitive impairment diagnostic criteriarequire specific supportive clinical fea-tures, such as executive dysfunction,to be present to diagnose nonstrokevascular cognitive impairment,5,7 whileothers do not.1,4

The clinician’s case for clinicallyrelevant cerebrovascular disease canbe further strengthened if other mo-tor manifestations of cerebral infarc-tion or hemorrhage are identifiedbased on history and clinical exam-ination. Noncognitive manifestationsof cerebrovascular disease includefrontal gait disorder, lower-body par-kinsonism, apathy, depression, urinaryincontinence, spasticity, hyperreflexia,and frontal release signs.5 Addition-ally, behavioral disturbances such asapathy, depression, and emotional in-continence are frequent as well.5 Thepresence of these signs, in the absenceof competing nonvascular causes, sug-gests symptomatic cerebrovascular dis-ease with the implication that thecerebrovascular disease could also beaffecting cognition.

Nonatherosclerotic andNonarteriolosclerotic Causes ofVascular Cognitive ImpairmentThe next sections review two impor-tant causes of vascular cognitive

KEY POINTSh Microinfarcts are a

substrate for vascularcognitive impairment,but are only visible atautopsy because they aretoo small to see on MRI.

h Although patientswith vascular cognitiveimpairment oftenexhibit impairments inexecutive function andprocessing speed, othercognitive domains mayalso be affected.

h Motor signs that mayaccompany vascularcognitive impairmentinclude frontal gaitdisorder, lower bodyparkinsonism, apathy,depression, urinaryincontinence, spasticity,hyperreflexia, andfrontal release signs.




impairment unrelated to the conven-tional vascular factors that cause ath-erosclerosis and arteriolosclerosis:cerebral amyloid angiopathy andmonogenic inherited cerebrovascu-lar diseases.

Cerebral amyloid angiopathy. Ce-rebral amyloid angiopathy is causedby vascular "-amyloid deposition inthe cerebral cortex and leptomeninges,leading to fragility of the vessel wallwith rupture and bleeding in somepatients.26 Cerebral amyloid angi-opathy is the second most commoncause of intracerebral hemorrhagein elderly patients, after hypertensivevasculopathy. Because vascular amyloidtends to spare the arteries supplyingthe internal part of the brain, cerebralamyloid angiopathyYrelated hemor-rhages predominately occur in the super-ficial, lobar portions of the cortex andunderlying white matter, or in theadjacent subarachnoid space, withsparing of the basal ganglia and thebrainstem. This lobar pattern of hem-orrhages and superficial siderosis forms

the basis for clinical diagnosis duringlife (Table 6-4).27

The diagnosis of cerebral amyloidangiopathy is greatly aided by the useof MRI with hemorrhage-sensitivesequences such as susceptibility-weighted imaging (SWI), which allowsdemonstration of microbleeds causedby cerebral amyloid angiopathy. Posi-tron emission tomography (PET) am-yloid tracers bind to vascular amyloidas well as senile plaques, and, there-fore, cannot be used to distinguish be-tween vascular and parenchymalamyloid deposits.

Cerebral amyloid angiopathy andAD exist on a spectrum. Most pa-tients with AD have some amount ofvascular amyloid, although comparedto patients with cerebral amyloidangiopathyYrelated hemorrhage, thedeposits are more likely to be aroundcapillaries than within the walls ofarterioles. Patients with AD rarely havehemorrhagic strokes, although thefrequency of microbleeds is higherthan in non-AD controls. Conversely,

TABLE 6-4 Modified Boston Criteria for Cerebral AmyloidAngiopathy–Related Hemorrhagea

Probable Cerebral Amyloid Angiopathy

1. Age Q55

2. Either multiple hemorrhages restricted to lobar, cortical, orcortico-subcortical regions (cerebellar hemorrhage allowed) OR singlelobar, cortical, or cortico-subcortical hemorrhage and focal ordisseminated superficial siderosis

3. Absence of other cause of hemorrhage or superficial siderosis

Possible Cerebral Amyloid Angiopathy

1. Age Q55

2. Either single lobar, cortical, or cortico-subcortical hemorrhage OR focalor disseminated superficial siderosis

3. Absence of other cause of hemorrhage or superficial siderosisa Modified with permission from Linn J, et al, Neurology.27 www.neurology.org/content/74/17/1346.short. B 2010 American Academy of Neurology.



http://www.neurology.org/content/74/17/1346.short

http://www.neurology.org/content/74/17/1346.short

most patients with cerebral amyloidangiopathy do not have AD dementia.

Community-based autopsy studiesshow that cerebral amyloid angiopathyis associated with cognitive impair-ment and risk for dementia, evenafter accounting for the associationbetween cerebral amyloid angiopathyand AD (Case 6-3).28 Controlling forthe degree of coexisting Alzheimerpathology, cerebral amyloid angiopathywas associated with worse episodicmemory and perceptual speed.29 Thesecognitive impairments could be causedby cerebral amyloid angiopathyYrelated microinfarction, ischemicwhite matter demyelination, impairedvascular reactivity, or the cumulativeeffects of hemorrhages.30 There areno disease-modifying treatments forcerebral amyloid angiopathy.

Monogenic inherited causes ofvascular cognitive impairment. Thepresence of confluent white matterhyperintensities or multiple lacunaein excess of that expected by ageand not explained by conventionalvascular risk factors should promptconsideration of an inherited causeof vascular cognitive impairment, par-ticularly when a family history ispresent.31 The inherited cause ofvascular cognit ive impairment,which is the most commonly en-countered and best studied, maybe cerebral autosomal dominantarteriopathy with subcortical infarctsand leukoencephalopathy (CADASIL).CADASIL is an autosomal dominantdisease caused by mutations in theNOTCH3 gene. Affected patients de-velop migraine, lacunar stroke, andthen vascular cognitive impairmentdue to the cumulative effects of mul-tiple lacunar infarcts and extensivewhite matter hyperintensities. Thereare no disease-modifying treatments.Other inherited diseases that can

cause vascular cognitive impairmentinclude cerebral autosomal recessivearteriopathy with subcortical infarctsand leukoencephalopathy (CARASIL)(a CADASIL-like disease caused bymutations in HTRA1) and mutationsin the COL4A1 gene.31

PREVALENCE, NEUROPATHOLOGY,AND RELATIONSHIP TO OTHERNEURODEGENERATIVEDISEASESBoth clinical and autopsy data showthat vascular cognitive impairment isthe second most common cause oflater life dementia, after AD. Specialty-clinicYbased studies show that vascularcognitive impairment is the diagnosisin about 10% of patients, while mixeddementia with a vascular component,often in combination with AD, is thediagnosis in a similar or even greaterproportion of cases.32 Epidemiologicstudies are generally consistent withthe clinic-based studies in showingthat vascular dementia is the secondmost common cause of dementia.33

However, exact numbers on incidenceand prevalence are difficult to estab-lish because the different vascular de-mentia criteria appear to vary in theirsensitivity and specificity, inhibitingcross-cohort comparisons.

Autopsy-based neuropathologystudies of prevalence have a numberof advantages over clinic-based stud-ies. The autopsy allows quantitativeor semiquantitative measurement ofcerebrovascular lesions difficult toidentify on in vivo imaging, such asmicroinfarction, and allows quantita-tive assessment of comorbid patholo-gies such as neurofibrillary tangles,amyloid plaques, and Lewy bodies.Ideally, neuropathology studies wouldbe nested within community repre-sentative samples and have a highdegree of participation in the au-topsy arm to avoid the referral and

KEY POINTSh Cerebral amyloid

angiopathy is animportant cause ofvascular cognitiveimpairment, with effectsthat are independentof the degree ofaccompanying Alzheimerdisease pathology.

h Cerebral autosomaldominant arteriopathywith subcorticalinfarcts andleukoencephalopathy isthe most commoninherited monogeniccause of vascularcognitive impairment.

h Vascular cognitiveimpairment is thesecond most commoncause of cognitiveimpairment andfrequently coexists withother neurodegenerativepathologies asmixed dementia.




Case 6-3A 73-year-old man was seen for forgetfulness and apathy that had been present for approximately2 years. Activities of daily living were essentially preserved, with the exception of occasional minorerrors such as purchasing incorrect items at the grocery store. The patient’s Montreal CognitiveAssessment (MoCA) score was 24 out of 30. Scores on the Trail Making B test and a test of verbalrecall were one standard deviation below the mean compared to normative values. Brain MRIshowed six microbleeds on the gradient recalled echo (GRE) sequence, all in lobar locations(Figure 6-4A), and severe white matter hyperintensities on the fluid-attenuated inversion recovery(FLAIR) sequence (Figure 6-4B). Fluorodeoxyglucose positron emission tomography (FDG-PET)scan showed patchy hypometabolism, including in brain regions with microbleeds. However,metabolism in the posterior cingulate gyrus, a region typically affected by Alzheimer disease,was preserved, suggesting that Alzheimer disease was probably not the cause of the cognitiveimpairment. A diagnosis of probable vascular mild cognitive impairment was given, with cerebralamyloid angiopathy as the most likely vascular cause. Over the next 2 years, the patient progressedto mild dementia, with an essentially unchanged FDG-PET scan. Two years after the initialpresentation, the patient had a right parietal intracerebral hemorrhage (Figure 6-4C), typical ofcerebral amyloid angiopathy.

Comment. Probable cerebral amyloid angiopathy was diagnosed in this case on the basis ofthe Boston criteria (Table 6-4), which indicate that cerebral amyloid angiopathy is highly probablein patients with a lobar intracerebral hemorrhage and MRI evidence of one or more microbleedsrestricted to lobar locations. Patients with multiple lobar-only microbleeds, without hemorrhagicstroke, are also likely to have cerebral amyloid angiopathy, although the Boston criteria have notbeen validated in this setting. Neuropathology studies show that more severe cerebral amyloidangiopathy is a predictor of cognitive impairment, controlling for the degree of accompanyingAlzheimer pathology.

FIGURE 6-4 Axial MRI of the patient in Case 6-3 shows six microbleeds on the gradient recalled echo (GRE) sequence, allin lobar locations (A), and severe white matter hyperintensities on the fluid-attenuated inversion recovery(FLAIR) sequence (B). Two years after initial presentation, the patient had a right parietal intracerebralhemorrhage (C), typical of cerebral amyloid angiopathy.



selection bias that may affect clinic-based studies.

Cerebrovascular lesions commonlymeasured at autopsy include infarcts,hemorrhages, arteriolosclerosis, andatherosclerosis. Microinfarcts, whichmay be the most clinically relevantvascular neuropathologic lesion, canbe identified on histology but areusually not visible grossly or on invivo MRI.24 Conversely, it is impor-tant to recognize that some lesionsreadily visible on MRI, such as mi-crobleeds, may be hard to find atautopsy and that MRI white matterhyperintensities, which have such adramatic appearance on MRI, aredifficult to visualize at autopsy with-out special stains and, therefore, canbe overlooked.

Vascular pathology is extremelycommon at time of death, both inpersons with and without dementia,being present in roughly 80% ofbrains overall.34 By comprehensivelymeasuring both vascular as well ascomorbid neurodegenerative pathol-ogies it is possible to estimate, in anunbiased and objective manner, therelationship between vascular pathol-ogies and risk for dementia incommunity-based studies, while simul-taneously controlling for other pathol-ogies. Using this approach, autopsystudies consistently show that vascu-lar pathology, mostly consisting of man-ifestations of cerebral small vesseldisease such as small infarcts, indepen-dently predicts the risk of dementiaeven when accounting for Alzheimerand Lewy body pathology. These datasuggest that vascular pathology ac-counts for roughly one-quarter toone-third of dementia risk.35,36

The frequent co-occurrence ofAlzheimer and vascular pathology withdeleterious effects on cognition hasraised scientific interest in whetherthere are deeper, fundamental inter-

actions between these most commonpathologies of dementia. This interesthas been heightened by recent obser-vations that sporadic AD is associatedwith a failure of soluble amyloid-" (A")clearance37 and that soluble A" canexit the brain through vascular andperivascular clearance pathways.38 How-ever, autopsy studies generally showthat the burden of cerebrovascular andAlzheimer pathology are independentof one another and that effects onthe odds of dementia are additive, notmultiplicative.39 Thus, interactions be-tween cerebrovascular and Alzheimerpathology seem to be in their com-bined effects on brain cellular and net-work function, and not because onedisease directly causes the other; how-ever, note that this observation doesnot exclude a role for variance in (non-diseased) vascular clearance of A" inthe pathogenesis of AD.

MANAGEMENT OF VASCULARCOGNITIVE IMPAIRMENTManagement of vascular cognitive im-pairment may be categorized as pa-tient and caregiver support, cognitiverehabilitation for poststroke vascularcognitive impairment, consideration ofcognitive enhancing medications, andtreatment and secondary preventionof the causative cerebrovascular pro-cess. Recommendations for the man-agement of vascular cognit iveimpairment have been published bythe AHA/ASA.4

Personal and caregiver supportshould follow general principles ofmanagement for patients with MCIor dementia and should includeassessments of driving safety, safetyin the home, financial and medical ad-vanced planning, management ofneuropsychiatric complications, andpalliative care, as appropriate for theindividual patient.40

KEY POINTSh Vascular cognitive

impairment accountsfor up to one-third ofdementia risk.

h Patient and caregiversupport to maintainquality of life andprolong communityliving are importantaspects of vascularcognitive impairmentmanagement.




For patients with poststroke vascularcognitive impairment, cognitive re-habilitation may speed or improve re-covery. Many patients with poststrokevascular cognitive impairment will ex-perience improvements in cognition, oreven resolution of cognitive deficits,during the stroke recovery process.Cognitive rehabilitation may includetraining for compensatory strategies orcognitive skills training.41

Randomized controlled trials of cho-linesterase inhibitors show that theyhave a modest benefit in patients withvascular dementia, including in mixedvascular and AD dementia.4 The AHA/ASA and Canadian Best Practice Rec-ommendations for Stroke Care recom-mend consideration of cholinesteraseinhibitor therapy with intermediate-level evidence.4,41 The 2012 CanadianConsensus Conference on the Di-agnosis and Treatment of Dementiarecommends that cholinesterase in-hibitor therapy should be consideredin patients with AD with concomi-tant cerebrovascular disease, withintermediate-level evidence, but thatthere is insufficient evidence to rec-ommend cholinesterase inhibitortherapy for patients with pure vascu-lar dementia.42 Donepezil andgalantamine are the best-studied cho-linesterase inhibitors.4 The benefits ofmemantine are not well established.4

This author frequently uses acetylcho-linesterase inhibitors in patients withprogressive probable or possible vas-cular dementia, particularly when acontribution from comorbid AD can-not be excluded.

Perhaps the most important part ofmanagement of vascular cognitive im-pairment is the identification of thecausative cerebrovascular processesand initiation of secondary preventionstrategies to prevent their progressionor recurrence. A list of causes of vas-cular cognitive impairment is shown in

Table 6-2. Many vascular diseases canbe prevented or their progressioncan be slowed by existing therapiesproven effective by randomized con-trolled trials. With adequate controlof vascular risk factors, it may bepossible to reduce the rate of progres-sion of vascular cognitive impair-ment or even arrest any progression,as long as comorbid neurodegener-ative pathologies are not also presentand symptomatic. For patients withpoststroke vascular cognitive impair-ment, stroke recurrence is a strongrisk factor for cognitive worsening oronset of new dementia.

For patients with ischemic stroke,diagnosis of the causes and manage-ment of risk factors should be doneaccording to ischemic stroke second-ary prevention guidelines from theAHA/ASA.43 For patients with intrace-rebral hemorrhage, diagnosis and man-agement of risk factors should be doneaccording to intracerebral hemorrhageguidelines.44 Hypertension is the stron-gest risk factor for stroke overall andfor each main stroke type individually,and therefore warrants careful atten-tion to achieve adequate blood pres-sure control.

The management of patients withnonstroke vascular cognitive impair-ment, which is predominantly causedby cerebral small vessel disease, is lesscertain and lacks evidence from ran-domized trials. The most commoncause of cerebral small vessel diseaseis arteriolosclerosis due to aging andvascular risk factors such as hyperten-sion and diabetes mellitus. However,cerebral amyloid angiopathy is an im-portant alternative cause in a minorityof patients.45 This author suggeststhat patients with arteriosclerotic cere-bral small vessel disease should havemeasurement of blood pressure, anECG to assess for atrial fibrillation,

KEY POINTSh Acetylcholinesterase

inhibitors have amodest beneficialeffect in vascularcognitive impairment.

h The most importantcomponent of vascularcognitive impairmentmanagement isidentifying andtreating the underlyingcerebrovascularprocesses that lead tobrain injury.

h Patients with vascularcognitive impairmentwith stroke should betreated according tosecondary preventionguidelines for stroke.



measurement of serum lipid profile,and measurement of either fastingblood glucose or glycosylated hemo-globin A1c to assess for diabetes mel-litus. More intensive investigationsfor proximal sources of embolism,such as echocardiography, prolongedcardiac rhythm monitoring for atrialfibrillation, and noninvasive carotid im-aging for carotid-territory infarcts,should be considered in patients withinfarcts that could be of embolic ori-gin, such as cortical infarcts, but maynot be necessary in patients with onlysmall subcortical infarcts likely causedby intrinsic small vessel disease.

There are no proven therapies forprevention of cognitive decline in pa-tients with cerebral small vessel dis-ease.45 Secondary prevention shouldfocus on addressing the vascular riskfactors identified in the diagnosticworkup. It is reasonable to start aspirinin patients with silent brain infarcts,and this treatment may also be con-sidered in patients with extensive, con-fluent white matter hyperintensities.When considering indications forstatin therapy, it is not proven whethercerebral small vessel disease should beconsidered an atherosclerotic diseaseequivalent; therefore, the use of statinsmay be considered on a case-by-casebasis in individual patients, particularlywhen there is hypercholesterolemia.White matter hyperintensity progres-sion has been evaluated as a secondaryend point in several randomized con-trolled trials. Progression is probablyslowed by good blood pressure con-trol46 but was not slowed by intensiveglucose management (to glycosylatedhemoglobin A1c level of less than6.0%),47 with mixed results for twotrials of statin therapy.48 A single trial ofhomocysteine-lowering vitamin therapyshowed less MRI white matter hyper-intensity progression in the treatment

arm, but only in patients with severehyperintensities at baseline.49 A limita-tion of all of these trials is that thesample sizes were not large enough tolink slowing of white matter hyperin-tensity progression with reduction inclinical end points such as cognitivedecline or stroke.

PREVENTION OF VASCULARCOGNITIVE IMPAIRMENTImproved population control of vas-cular risk factors is one of the mostpromising approaches to dementiaprevention. Stroke and cardiovascularmortality has been declining for sev-eral decades, probably partly relatedto better control of vascular risk fac-tors as well as better acute manage-ment. There is emerging evidencethat the age-standardized incidenceof dementia is declining, but thedegree to which this declining inci-dence can be attributed to bettervascular risk factor control is un-known.50 The Finnish Geriatric Inter-vention Study to Prevent CognitiveImpairment and Disability (FINGER)study randomly assigned participantsto a vascular risk factor control reg-imen as part of a multidomain ap-proach to dementia prevention andfound that the multidomain interven-tion, which also included diet, exer-cise, and cognitive training, preventeddecline in cognitive test scores.51

CONCLUSIONVascular cognitive impairment is the sec-ond most common cause of dementiaand is a frequent contributor to mixeddementia. All patients with cognitiveimpairment should be assessed forcontributing vascular causes. The di-agnostic approach should be based onidentifying cognitive impairment,identifying vascular disease, includingclinically hard-to-recognize cerebral

KEY POINTh Careful control of

vascular risk factorsmay be an importantcomponent ofdementia prevention.




small vessel disease on neuroimaging,and then using clinical judgment todetermine whether the two are related.Vascular cognitive impairment shouldbe classified into poststroke and non-stroke forms. The most importantaspect of vascular cognitive impairmentmanagement is to diagnose the causesand risk factors for the underlyingcerebrovascular diseases and then ini-tiate secondary prevention targetedagainst those diseases.

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Vascular Cognitive Impairment ￼￼Continuum 2016

Vascular Cognitive Impairment Continuum 2016