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Etiology,clinicalmanifestations,anddiagnosisofvasculardementia

OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate

Etiology,clinicalmanifestations,anddiagnosisofvasculardementia
Author
ClintonBWright,MD,MS

SectionEditors
StevenTDeKosky,MD,FAAN,
FACP,FANA
ScottEKasner,MD

DeputyEditor
AprilFEichler,MD,MPH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2016.|Thistopiclastupdated:Sep01,2015.
INTRODUCTIONVasculardementia(VaD)hasalonghistory.VaDwasfirstdescribedinthelate19thcentury
byBinswangerandAlzheimerwhoalsorecognizedanddescribedavarietyofunderlyingpathologicmechanisms
includingtheroleofmultipleinfarctionsandchronicischemia.Fornearly50yearsthiswasheldtobethe
predominantformofdementia.Subsequently,pathologicstudiesdemonstratedthattheamyloidplaquesand
neurofibrillarytanglesofAlzheimerdisease(AD)weremuchmorecommoninthebrainsofthedementedelderly
thanpreviouslythought[1]chronicischemicinjurywasthoughttobequiterare,andVaDwasunderstoodasthe
sequelaeofrecurrentstrokesor"multiinfarctdementia"(MID)[2].Withtheadventofsophisticatedneuroimaging
techniques,computedtomography(CT)andmagneticresonanceimaging(MRI),inthelatterpartofthetwentieth
century,thehighprevalenceofchronicvascularinjuryinthebrainwasappreciated,andinterestintheroleof
vasculardisease,includingtheroleofprogressiveischemicinjury,oncognitivedeclinereemerged.
Despitethissurgeofinterest,certainissuesimpedeprogress.Therearenopathologiccriteriaforthediagnosisof
VaD,asthereareforAD.Anumberofclinicaldiagnosticcriteriaexistbutarepoorlyvalidatedandinconsistently
applied.
Evenbasicterminologyrequiresclarification.Asanexample,thetraditionaldefinitionofdementiawasoriginally
developedinthecontextofADinwhichmemorylossoccursprominentlyandearlyoninthedisease.However,in
patientswithcognitivedeficitsultimatelyattributabletoVaD,memoryimpairmentappearssomewhatlater,and
thesepatientsmayhavesignificantcognitivedisabilitylongbeforetheymeetcriteriafordementia.
Thishasledtotheproposedconceptof"vascularcognitiveimpairment"orVCI[3,4].TheNationalInstituteof
NeurologicalDisordersandStrokeCanadianStrokeNetworkVascularCognitiveImpairmentHarmonization
Standards,recognizingthelimitationsofcurrentdiagnosticcriteriaforbothADandVaD,promulgatetheuseof
VCIas"cognitiveimpairmentthatiscausedbyorassociatedwithvascularfactors"[5].Cognitivedeficits
associatedwithvasculardiseasethatdon'tmeetcriteriafordementiaislabelled"vascularcognitiveimpairment,
nodementia"(vCIND).Thisissomewhatanalogoustothemoreacceptedterm"mildcognitiveimpairment"or
MCI,alsoknownas"cognitiveimpairment,nodementia"orCIND[6].Criteriaastowhatdeficitsqualifyas
cognitiveimpairmentareilldefined[6].UseofthetermBinswanger'sdiseasetoapplytoVaDcharacterizedby
severewhitematterdiseaseassociatedwithlongstandinghypertensionisnolongeracceptedthevolumeofthe
whitematterdamagesufficienttocauseVaDisnotknownandtherearenoaccepteddiagnosticcriteriaforthis
entity.
Atthefoundationofsomeoftheseproblemsisthefactthatcerebrovasculardiseaseisitselfaheterogeneous
disorder,withavarietyofpathophysiologicmechanismsandclinicalmanifestations.Atpresent,theentityofVaD
isbestunderstoodasaheterogeneoussyndromeratherthanadistinctdisorder,inwhichtheunderlyingcauseis
cerebrovasculardiseaseinsomeformanditsultimatemanifestationisdementia.
Thistopicwillreviewtheetiology,pathogenesis,clinicalmanifestations,anddiagnosisofvasculardementia.The
prevention,treatment,andprognosisarediscussedseparately.(See"Treatmentandpreventionofvascular
dementia".)
EPIDEMIOLOGYUsingtraditionaldefinitions,vasculardementia(VaD)isthesecondmostcommonformof
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dementiaafterAlzheimerdisease(AD)inmostclinicalseries,anditmakesup10to20percentofcasesinNorth
AmericaandEurope[7,8].Inonepathological,populationbasedstudy,cerebralmicroinfarctsaccountedforan
estimated33percentofthepopulationattributableriskfordementia[9].Therelativepreponderanceofthetwo
disordersmaybereversedinothercountries,suchasJapanandChina[10,11].
Differencesinscreeningmethodsanddiagnosticcriterialeadtovariabilityinreportedprevalenceandincidence,
butsometrendsseemconsistent.EstimatedprevalencesofVaDvaryfrom1.2to4.2percentofindividualsover
65years[12].IntheEuropeancollaborativestudyofpopulationbasedcohorts,thepooledestimateofVaD
prevalencewas1.6percentinthoseovertheageof65[7].Theprevalenceincreasedsuccessivelywithincreasing
agedecilestoabout3.6percentinmenand5.8percentinwomen,overtheageof90years.InCanada,similar
agetrendswereseenforVaDaswellastheentiregroupofvascularcognitiveimpairment(VCI)thelatter
increasedfrom2.0percentinthose65to74yearsto13.7percentinthoseover85years[13].
Ageadjustedincidentrates(IRs)areoverallestimatedat6to12casesper1000personyearsovertheageof70
years[12].InCanada,theincidenceincreasedfrom0.9per1000personyearsinthoseaged65to69yearsto
6.74inthosegreaterthan90years[14].SimilartrendswereseeninEurope[8]andtheUnitedStates[15].A
metaanalysisof23studiesfromaroundtheworld,despitemuchvariabilitybetweenstudies,showedanoverall
trendforanexponentialincreaseofincidentVaDwithage[16].
Someprevalenceandincidencedatasuggestanoverallhigherpreponderanceofthediseaseinmen[8],while
othersnotethisonlyintheyoungeragegroups[7,16],andstillothersnotenogenderdifferences[1315,17,18].
OnestudyfoundnosignificantdifferenceinIRsinblacksversuswhites[15]anotherfoundahigherincidencein
blacks[17].
RiskfactorsWhileitisexpectedthatVaDwouldshareriskfactorswithcerebrovasculardisease,theevidence
isnotcompelling.Variabledegreesofassociationand,insomestudies,noassociationshavebeenfoundfor
hypertension,diabetesandinsulinresistance,dyslipidemia,andheartdiseasewithVaDinpopulationbased
cohorts[14,17,1926].Thesedifferencesmightbepartlyexplainedbydifferencesincontrolgroupssomestudies
specificallyexcludedpatientswithcerebrovasculardiseaseand/orotherformsofdementia,whileothersdidnot.
Themetabolicsyndrome,aclusterofcardiovascularriskfactorsthatincludeobesity,hypertension,insulin
resistance,anddyslipidemia,wasweaklyassociatedwithincidentvasculardementiainthelargeHonoluluAging
study[27].Anothersimilarlysizedpopulationbasedcohortstudyfoundastrongerassociation(HR=3.7)[28].
Whenneuropsychiatrictestingwasperformedinasmallercohortofpatientswiththemetabolicsyndrome,deficits
inexecutivedysfunctionwerenoted,suggestingthatthemetabolicsyndromemaybeaprodromalstateof
vascularcognitiveimpairment[29].
Poststrokedementia
ClinicalstrokeAnumberofstudieshavedemonstratedahighincidenceofcognitiveimpairmentand
dementiaafterstrokewithratesrangingfrom6to32percentinpatientsfollowedfromthreemonthsto20years
[3044].Inonestudythatexaminedpatientswithlacunarstroke(presumablyrelatedtosmallvesselocclusive
disease),mildcognitiveimpairmentordementiawaspresentinnearlyhalf[45].Shorttermassessments(<1year)
arelikelytosignificantlyoverdiagnosepoststrokedementia[46].Inonestudythatusedacontrolgroup,stroke
wasassociatedwitha3.83relativerisk(RR)fordementiacomparedwithnonstrokehospitalizedcontrols[31].
Populationbasedstudieshavereportedsomewhatconflictingresultsregardingtheriskofdementiaafterstroke
[4750].Apooledanalysisthatincludedbothpopulationbasedandhospitalbasedcohortsfoundthat10percentof
patientswithafirststrokehadprestrokedementiaand10percentsubsequentlydevelopeddementia,whilemore
thanonethirdofpatientsdevelopeddementiaafterarecurrentstroke[51].Mildcognitiveimpairmentbeforestroke
increasesthelikelihoodofpoststrokedementia[50,52].Inanothermetaanalysis,astrokehistorywasobserved
toconferatwofoldhigherriskofdementiainpatientsyoungerthan,butnotolderthan85years[53].
Ageisnearlyuniformlyfoundtoincreasetheriskofdementiaafterstroke.Otherriskfactorscommonly,butnot
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uniformly,identifiedinthissettingincludeincreasedseverityoftheindexstroke,atrialfibrillation,thepresenceof
whitematterdiseaseandcorticalatrophy(particularlyinthetemporallobe)onimaging,multipleclinicaleventsor
lesionsonneuroimaging,hypertension,obesity,elevatedhomocysteineorhighdensitylipoproteinlevels,and
diabetesmellitus[3238,41,5461].Somestudiesindicatethatstrokeinthelefthemisphere,particularlythosewith
associatedaphasia,isariskfactor.Evidenceofpremorbidcognitiveimpairmentisalsoariskfactor,whilehigher
educationallevelfavorablymodifiestheriskforpoststrokecognitivedecline[38,50,62,63].Infact,onestudy
foundthatmildcognitiveimpairmentwasaprerequisiteforincidentdementiaafterstroke[50].Anotherlongterm
populationbasedstudyfoundthatbaselinememoryimpairmentandratesofmemorydeclineweregreaterin
patientswholaterdevelopedastrokecomparedtothosewhoremainedstrokefree[64].Moststudieshavenot
identifiedgenderasariskfactor,buttwoidentifiedahigherincidenceinfemales[31,35]andoneinmales[37].
Whilesomestudiesindicatethatmostcasesaccrueearlyafterstroke[17,65],othershavedemonstratedfairly
steadyaccrualofcasesoveryearsofannualscreeningevaluations[30,32,37].Inonecohortstudy,incidentstroke
wasassociatedwithanacutedeclineincognitivefunctionaswellasasteeperrateofcognitivedeclineand
incidentcognitiveimpairmentoverthenextsixyearsoffollowup[66]Inanothercohortstudy,recurrentstroke
wasassociatedwithgreatercognitivedeclinecomparedwithpatientswithasinglestroke[38].Moststudiesdid
notidentifycasesasADorVaDinthosethatdid,VaDratherthanADwasthediagnosisinmostcases(51to
66.7percent)[30,32,65].
DatafromtheNationalLongTermCareSurveysuggestthatpoststrokedementiaisanincreasingproblem,with
agestandardizedratesincreasingfrom0.043between1984to1990to0.080between1991to2001[67].A
concomitantdeclineinstrokecasefatalityrateswasalsoreported,whichmaycontributetotheincreasedrateof
dementia.Cognitiveimpairmentafterstrokeisalsoanimportantcontributortonursinghomeplacementand
shortenssurvival[6870].
Subclinical"silent"braininfarctionClinicallysilentbraininfarctionisalsoariskfactorforsubsequent
cognitivedecline[41,71,72].Inonestudy,nondementedpatientswithoutastrokehistorybutwithevidenceof
cerebralinfarctiononmagneticresonanceimaging(MRI)haddoubletheriskofdementiaoverfiveyearsoffollow
upcomparedwithcontrolswithnormalMRIs[73].Thepresenceofmultiplesilentinfarctionswasmorestrongly
associatedwithsubsequentcognitivedeclinethansinglelesions,andthedeclineincognitivefunctionwas
restrictedtothosewithaccrualofsilentinfarctsonfollowupimaging.Thepresenceofwhitematterchangesand
subcorticalatrophyalsowasassociatedwithriskofdementia.Aclinicopathologicstudyof72individualswithout
Alzheimerpathologyfoundasignificantcorrelationbetweenclinicallysilentthalamicandbasalganglialacunesand
clinicaldementiaratingscores[74].
ETIOLOGYANDPATHOPHYSIOLOGYAtleastthreecommonpathologicalentitiesarethoughttocontribute
substantivelytovasculardementia(VaD[75]):
Largearteryinfarctions,usuallycortical,sometimesalsoorexclusivelysubcorticalinlocation.
Smallarteryinfarctionsorlacunes,exclusivelysubcortical,inthedistributionofsmallpenetratingarteries,
affectingthebasalganglia,caudate,thalamus,andinternalcapsuleaswellasthecerebellumandbrainstem
[72,76].(See"Lacunarinfarcts".)
Chronicsubcorticalischemiaoccurringinthedistributionofsmallarteriesintheperiventricularwhitematter
andleadingtoselectivelossoftissueelementsinorderoftheirselectivevulnerabilityneuron,
oligodendrocyte,myelinatedaxon,astrocyte,andendothelialcell[77].
Thesmallarterydiseaseunderlyingbothlacunarinfarctionsandsubcorticalischemiaismostcommonlyattributed
tolipohyalinosisormicroatheromaaffectingthesmallpenetratingarteries.Theseareparticularlyprevalentinthe
elderlyandthosewithhypertensionand/ordiabetes.Sharingaprimaryvascularpathology,itisnotsurprisingthat
lacunarinfarctionsandchronicischemicchangesinthewhitemattermoreoftenoccurtogetherthanapart[78].
Otherstudieshavefoundthatthepresenceofcerebralmicrobleedsinthedeephemisphericandinfratentorial
regionsandretinopathy(bothofwhichareotherclinicalmanifestationsattributedtosmallarterydisease)are
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associatedwithvascularcognitiveimpairment[7982].GadoliniumenhancedMRIstudieshavefoundevidenceof
diffusebloodbrainbarrierdysfunctionthroughoutthewhitematteramongpatientswithlacunarinfarctionand/or
whitematterlesions,afindingnotseeninpatientswithcorticalstrokeorstrokefreecontrols[83,84].Itisnotclear
ifthisfindingispathogenicallylinkedtothediffusechronicsubcorticalischemia.Somesubcategorizethisentity
assubcorticalVaD,andthetermBinswanger'sdiseasegenerallyreferstothissubsetofVaDpatients.
Eachoftheabovefindingsiscommon.Theyarenotmutuallyexclusiveandinfact,shareunderlyingriskfactors.
AnyoneormoremaybepresentinapatientwithVaDandcontributeindependentlytocognitivedisabilities[85].
ThesealsomaybefoundinpatientswithAlzheimerdisease(AD)andinnondementedindividuals.
WhileintracerebralhemorrhageispotentiallyacontributortoVaD,itisnotgenerallydescribed,perhapsbecause
thesearelesslikelytoberecurrentevents.Subarachnoidhemorrhage,cognitiveimpairmentaftercardiacbypass
surgery,hypoxicischemicencephalopathy,andwatershedinfarctioninthesettingofprofoundhypotensionare
vasculareventsthatmaycausepermanent,devastatingcognitiveimpairment.However,thesearemore
appropriatelyconsideredundertherubricofa"staticencephalopathy"ratherthandementiabecauseofthelackof
expectedprogression.
WhilethevolumeofdamagedtissueappearstobeimportantinproducingVaD[8688],atleastonestudy
suggestedthattheabsolutenumberofinfarcts,nottheindividualoraggregateinfarctvolume,wasimportantin
producingVaD[89].Morecritical,however,istheanatomicdistributionofischemicinjury.Certainsitesinthebrain
are"strategic"forproducingdeficitsthatcause,simulate,oraddtoadementiasyndrome.Thesemaybecortical
(hippocampus,angulargyrus,gyruscinguli,frontallobe)orsubcortical(thalamus,fornix,basalforebrain,caudate,
globuspallidus,andthegenuoranteriorlimboftheinternalcapsule)[9094].Damagetothethalamus,in
particular,appearstobeanimportantdeterminantofcognitiveimpairment[94,95].Becauseoftheprominentand
disablingcognitiveeffectsofevenasinglestrokeintheseareas,thesepatientsareoftenlabeledashaving
"strategicinfarctdementia,"althoughinsuchcasesthecoursemaybestaticratherthanprogressive[96].
Thepotentialcausesofcerebralinfarcts,bothlargeandsmall,arenumerous[6].(See"Overviewoftheevaluation
ofstroke".)Twoentities,cerebralamyloidangiopathyandCADASIL,requirespecificdiscussioninthiscontext.
RELATEDCONDITIONS
CerebralamyloidangiopathyCerebralamyloidangiopathy(CAA)isadisordercausedbyaccumulationof
amyloidincerebralvessels,anditleadstomultiplelobarhemorrhages,microbleeds,orinfarctions.CAAis
prevalentinthosewithAD,anddementiaintheseindividualshasbeentraditionallyascribedtoAD.However,
extensiveCAAcanalsocauseischemicwhitematterdamage,acomplicationthatispresumablyrelatedtodiffuse
narrowingofpenetratingcorticalvesselsbyamyloiddeposits[97,98].
ThesepatientscanpresentwithVaD.PopulationbasedautopsyseriessuggestthatCAAisassociatedwith
cognitiveimpairmentevenaftercontrollingforageandADpathology[99101].Inoneseries,corticalmicrobleeds
suggestiveofCAAwereidentifiedbymagneticresonanceimaging(MRI)in65percentofpatientswithvascular
dementia[102].Otherstudiesfoundacorrelationbetweenthepresenceandnumberoflobarmicrobleedswith
cognitiveimpairment[103,104].(See"Cerebralamyloidangiopathy".)
CadasilCerebralautosomaldominantarteriopathy(CADASIL)isadisordercausedbymutationsinthe
NOTCH3geneonchromosome19thatproducessubcorticalinfarctsandleukoencephalopathy.Patientsdevelopa
subcorticalVaDsyndromeinthefifthtoseventhdecades.Othercommonfeaturesincludemigrainewithauraand
psychiatricsymptoms.Pathologyrevealsextensivelacunarinfarctionsandwhitematterischemiafromocclusion
ofvesselsbydiseasespecificgranularmaterial.Thesimultaneousprevalenceofmigraine,theabsenceof
traditionalatheroscleroticriskfactors,andahistoryofmultipleaffectedfamilymemberssuggestthisdiagnosis[6].
Thistopicisdiscussedindetailseparately.(See"Cerebralautosomaldominantarteriopathywithsubcortical
infarctsandleukoencephalopathy(CADASIL)".)
MixeddementiaMixeddementia,orADwithcerebrovasculardisease,referstothecooccurrenceofADand
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VaDpathologyandisincreasinglyrecognizedasaconditionrequiringindependentconsideration.Itisoftendifficult
todistinguishADandVaDletalonedeterminewhichisetiologicallymostimportantwhenbothpathologiesare
present.AboutonethirdofpatientsdiagnosedwithVaDwillhaveADpathologyatautopsy[105].Usingthe
relativelyloosedefinitionsofpathologiccriteriaforADandVaD,patientswithclinicaldementiaareinfactmore
likelytohavecombinedpathologyratherthaneitherADorVaDinisolation[86].(See"Epidemiology,pathology,
andpathogenesisofAlzheimerdisease",sectionon'Cerebrovasculardisease'.)
CLINICALFEATURESGiventhediversepathologies,itisnotsurprisingthattheclinicalmanifestationsof
vasculardementia(VaD)arediverse.Cliniciansandinvestigatorshavelongrecognizedtwoclinicalpatternsone
inwhichthepredominantpathologyandclinicalfeaturesarecorticalandoneinwhichtheyaresubcortical[106].
Whileinthemselvesheterogeneous,thesetwopatternsnonethelesshavedistinctfeatures.
CorticalsyndromeInprimarilycorticalVaD,cognitivefeaturesarespecifictotheareasaffected[106]:
Medialfrontal:executivedysfunction,abulia,orapathy.Bilateralmedialfrontallobeinfarctionmaycause
akineticmutism.
Leftparietal:aphasia,apraxia,oragnosia.
Rightparietal:hemineglect(anosognosia,asomatognosia),confusion,agitation,visuospatialand
constructionaldifficulty.
Medialtemporal:anterogradeamnesia.
Corticalbranchocclusionsareoftencausedbyembolismfromtheheartorlargearteriesandmaypresentwith
clinicalstroke.However,whenthesuperiordivisionofthemiddlecerebralarteryisnotinvolved,hemiparesismay
notbeanobvioussignalthatstrokehasoccurred.Onsetmayappearmoreinsidiousasaresult,anditisnot
uncommonforthepatienttoimproveagainbeforethenextevent.Thecourseisthusoftenperceivedasfluctuating
orstepwise.Asfewasonethirdofpatientswithmultiinfarctdementia(MID)experiencebothanabruptonsetand
stepwisedeterioration[107].
SubcorticalsyndromeInsubcorticalpathology,bothlacunarinfarctionsandchronicischemiaaffectthedeep
cerebralnucleiandwhitematterpathways.Theseoftendisruptfrontallobeandothercorticocorticocircuits,
producingdeficitsattributabletoremotebrainareas[96,106,108,109].Characteristicfeaturesinclude:

Focalmotorsigns
Earlypresenceofgaitdisturbance(marcheapetitpasormagnetic,apraxicgaitorParkinsoniangait)
Historyofunsteadinessandfrequent,unprovokedfalls
Earlyurinaryfrequency,urgency,andotherurinarysymptomsnotexplainedbyurologicdisease
Pseudobulbarpalsy
Personalityandmoodchanges,abulia,apathy,depression,emotionalincontinence[110]
Cognitivedisordercharacterizedbyrelativelymildmemorydeficit,psychomotorretardation,andabnormal
executivefunction[111]

ThecourseofsubcorticalVaDmaybegradualorstepwiseandeithersloworfastindecline.
DIAGNOSISTheinitialapproachtoapatientwithevidenceofcognitivedeclineispresentedelsewhere.(See
"Evaluationofcognitiveimpairmentanddementia".)Thespecificapproachinpatientswithsuspectedvascular
dementia(VaD)ispresentedhere.
NeuroimagingWhilenotessentialintheevaluationofallpatientswithdementia,neuroimagingshouldbe
performedinpatientswithsuspectedVaDbyvirtueofstrokehistory,vascularriskfactors,abnormalneurologic
examination,oracourseorsymptomcomplexatypicalforAD.MRIissignificantlymoresensitivethanCT
however,ifsufficientevidenceofvascularpathologyisseenonCT,anMRImaynotbenecessary.MRIwillshow
thefundamentalhallmarksofVaDincludingcorticalandsubcorticalinfarctionsaswellasthepresenceof
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subcorticalischemicchangesorleukoaraiosis.However,radiographiccriteriaalonehavebeenshowntobe
inadequateatdifferentiatingbetweenpoststrokepatientswithandwithoutdementia[112].
WhitematterlesionsCerebralwhitematterlesions(WML)orleukoaraiosisonbrainMRIisanonspecific
radiologicfinding.Thesechangesaresomewhatubiquitousinthenormalaswellasthedementedelderly
population.RadiologicWMLdonotdefineasingleneuropathologyandareassociatedwithnonvascularpathology
includinginfections,demyelination,neoplasia,andmetabolicdisorders,makingclinicalcorrelationimportant.
Inelderlypatientswithvascularriskfactorsand/orvasculardementia(VaD),WMLarebelievedtoberelatedto
cerebralhypoperfusionorischemia[113].Inthissetting,pathologicalstudiesshowrarefactionofthewhitematter
(areductioninaxonalandmyelindensity)andperivasculargliosisratherthanfrankinfarction[72,114116].A
postmortemstudyofcerebralmolecularpathologyinelderlypatientsfoundthatmolecularmarkersofahypoxic
response,arteriolarsclerosis,andcerebralamyloidangiopathywereincreasedinWMLcomparedwiththenormal
whitematterintheseindividuals[117].Furtherevidencethattheselesionshaveavascularorigincomesfrom
anotherhistopathologicstudy,whichfoundthattheselesionsconsistentlydemonstratereducedCD31staining,a
markerofendothelialvascularintegrity[118].Also,intheFraminghamoffspringstudy,WMLwereassociatedwith
higherplasmalevelsofasymmetricaldimethylarginine(ADMA),aninhibitorofendothelialnitricoxidesynthaseand
amarkerofendothelialdysfunction[119].
ThepresenceofWMLissignificantlyassociatedwithageandhypertension[113,120130].TheburdenofWML
increasesovertimeage,hypertension,andsmokingareriskfactorsforlesionprogression[127,131136].WML
aremorecommoninpatientswithischemicstrokeandareassociatedwiththeincidenceofbothsilentandclinical
infarctions[121,132,137,138].Chronickidneydisease,metabolicsyndrome,microvascularretinopathy,coronary
plaqueburden,elevatedhomocysteine,lowervitaminB12levels,andCreactiveproteinlevels(andother
inflammatorybiomarkers)arealsoassociatedwithWML[139149].ThevolumeofWMLhasalsobeencorrelated
withplasmaAbeta40levels[150,151].
StudiesinsiblingsandtwinssuggestageneticbasisfortheaccumulationofWML[152,153].Thesemayreflect,
inpart,ageneticriskforcerebrovasculardisease[153155].Whilesomestudieshavereportedassociations
betweencertaingeneticlociandWML[156164],a2009metaanalysisofthelargestavailablestudiesconcluded
thatnogeneticpolymorphismhasyetshownconvincingevidenceforanassociationwithWML[165].
StudieshavenotconsistentlyshownarelationshipbetweentheextentofWMLandthepresenceofdementia
[87,166,167].Thereareseveralpotentialreasonsforthisincluding:
TraditionaldefinitionsofdementiamaybeaninsensitivemeasureofcognitivechangeinVaD.WMLappear
tomoreconsistentlyaffectsubsetsofcognition,inparticulartestsofexecutivecontrolandothercognitive
domainsassociatedwithfrontallobesystems,suchasprocessingspeed[87,168171].Supportingthisisa
studyin70olderadultsthatfoundthatWMLspecificallypredictedexecutiveimpairmentsandslowed
processingspeed,notperformanceonmemoryandnamingtasks[172].ThefactthatWMLaremorereliably
associatedwithincreasedriskofcognitivedeclineandincidentdementia,ratherthanprevalentdementia,is
alsoconsistentwiththishypothesis[56,73,108,173178].
MethodsquantifyingWMLseverityareinconsistentandoftensubjective.Ratingscalesbasedonvisual
assessmentdonotcorrelatewellwithcomputerizedvolumetricassessments[179].Nonetheless,volumetric
changesdoindicatethatthegreaterbrainvolumeaffectedbysuchchanges,thegreatertheriskof
concurrentorfuturecognitivedecline[87,176,178,180].Somestudiessuggestthattheremaybeathreshold
effectforlesionvolumeinproducingcognitiveimpairment[87,181,182].TheseverityofWMLhasalsobeen
correlatedwithdeficitsingaitandmotorfunction,clinicalfeaturesofsubcorticalvasculardementia[178,183
185].
TheanatomicdistributionofWMLmaybemoreimportantthanthetotalvolume[186,187].Evidencefrom
several,butnotallstudiesindicatesthatcognitiveimpairmentisbetterassociatedwithperiventricularrather
thansubcorticalWML[108,126,137,172,175,188,189].Thisobservationsuggeststhatdisruptionof
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periventricularlongassociationfibersconnectingdistantcorticalregionscausesgreatercognitiveimpairment
thandisruptionofsubcorticalassociationarcuatefibers[175,190].Thespecificimportanceofpathologyin
thislocationtocognitivedeclineissupportedbytheobservationthatperiventricularbutnotnonperiventricular
WMLareassociatedwithlowercorticalcholinergicactivityasmeasuredonpositronemissiontomography
[191].
However,thelocalizationofhyperintensitiesintheperiventricularversussubcorticalwhitematteris,inmany
cases,anartifactofviewingimagesofthebrainintheaxialplane.Onanatomicmapping,periventricularand
deepwhitematterhyperintensitiesarehighlycorrelatedwitheachotherandprogressivelylargertotalwhite
matterhyperintensityvolumesareassociatedwithsmoothextensionfromperiventriculartosubcorticalareas
[192].
ProgressionofWMLmaycorrelatebetterwithVaDthanasinglemeasureofWMLvolume.Increasingwhite
matterlesionburdenonserialMRIscanshasbeenassociatedwithacceleratedcognitivedeclineinseveral
studies[131,133,135,178,193196].ProgressionofWMLismorelikely,however,inpatientswithahigher
baselinelesionload.
DiagnosticcriteriaAnumberofclinicalcriteriahavebeenpublishedforthediagnosisofVaD.Theearliestof
these,theHachinskiIschemicScore(HIS)(table1)isstillusedtodayandwasestablishedtodistinguishmulti
infarctdementia(MID)fromADratherthanasindependentdiagnosticcriteriaforVaD.TheHISitemshighlight
clinicalfeaturesspecifictoVaD,suchasstepwisedeterioration,fluctuatingcourse,hypertension,historyof
stroke,andfocalneurologicsymptoms[197].DatafrompathologicallyverifiedcasesshowthatanHIS7hasa
sensitivityandspecificityofabout90percentforVaDandgoodinterraterreliability[197].However,differentiating
VaDfrommixeddementiaisadifficultproblemwithalltheavailablecriteria.ThisisnolesstrueoftheHIS,in
whichthespecificityinseparatingeitherVaDorADfrommixeddementiahasbeenfoundtobe17.2and29.4
percent,respectively[197].
ThereareagrowingnumberofindependentdiagnosticcriteriaforVaD:
NationalInstituteforNeurologicalDisordersandStrokeAssociationInternationalepourlaRechercheet
l'EnseignementenNeurosciences(NINDSAIREN)(table2)
DiagnosticandStatisticalManualofMentalDisorders(mostrecentedition,DSM5,releasedin2013)(table
3)[198]
StateofCaliforniaAlzheimer'sDiseaseDiagnosticandTreatmentCenters(ADDTC)
InternationalClassificationofDiseases,tenthedition(ICD10)
AmericanHeartAssociation(AHA)StatementonVascularContributionstoCognitiveImpairmentand
Dementia[199]
Thecriteriavaryby:

Howdementiaisdefined
WhattypesofCVDareincluded
Whatotherdisordersmustbespecificallyexcluded
Whetherfocalexaminationfindingsarerequired
Whetherthepresenceofvasculardiseasemustbecorroboratedbyneuroimaging
Whetheratemporalrelationshipbetweenstrokeeventandcognitivedeclineisrequired

WhiletheNINDSAIRENandtheADDTCcriteriarequirethepresenceofamemorydisorder,thecurrentAHA
criteriahaveremovedthisrequirement,insteadpermittingadeclineinanytwocognitivedomains.Thisisin
keepingwithDSM5criteriafordementiaandrevisedNationalInstituteonAgingAlzheimersAssociation
diagnosticguidelinesforAlzheimerdisease[200].Mostcriteriarelyonneuroimagingconfirmationof
cerebrovascularlesionsand/orahistoryofclinicalstrokeandrequireatemporalassociationbutnotananatomic
associationbetweencognitive/functionaldeclineandstrokeevent.
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Anumberofstudieshaveshownthatthedifferentcriteriadonotidentifythesamepatients,leadingtovariationsin
publishedprevalenceandincidenceestimatesaswellastreatmenteffects[197,201206].Asanexample,inthe
assessmentof167patientswithprobabledementia,thenumberofcasesdiagnosedwithVaDwere:DSMIV=
45,ADDTC=23,NINDSAIREN=12,andICD10=21[201].OnlyfivecasesmetcriteriaforVaDusingallfour
diagnostictools.
Overall,theHIS(table1)andDSMIV(table4)criteriaappearthemostliberalintheidentificationofVaDandthe
NINDSAIRENthemostconservative.Inaddition,datasuggestinterraterreliability(kappa=0.44to0.61)isonly
moderateforthesecriteria[202].ItisnotyetclearhowtherevisedDSM5criteria(table3)releasedin2013will
performandcomparewithothercriteria.Ofnote,vasculardementiaisnowreferredtoasmajorvascular
neurocognitivedisorderinDSM5[198].
Becauseofitsmoredistinctiveandperhapsmoreuniformclinicalprofile,forwhichtheabovecriteriamaybe
insensitive,separatecriteriaforsubcorticalVaDhavebeenproposed.Thisrequiresneuroimagingevidenceof
subcorticalvascularpathologyandatypicalneuropsychiatricprofile[91].
Whilenecessaryforresearchstudies,clinicalcriteriathatdistinguishVaDfromADormixeddementiaseemless
clinicallyimperative.Intheevaluationofpatientswithdementia,itmaybemoreimportanttoidentifyapotential
contributionfromvascularpathologyratherthantospecificallydiagnoseVaD.TheHISiswellsuitedforthis
purpose.
NeuropsychologicaltestingFormalneuropsychologicaltestingquantitatesthedegreeofcognitiveimpairment
andthedomainsinvolvedinordertoprovideabaselinemeasurementtofollowthecourseofdiseaseandresponse
totreatment.
TestingcanalsohelpdetectcognitivepatternssuggestiveofcertaindisorderssuchasVaD,AD,LewyBody
disease,andfrontotemporaldementia.OnereviewfoundthatpatientswithVaDhavesimilardeficitscompared
withADpatients(ontestsoflanguage,construction,andmemoryregistration)butaresignificantlylessimpaired
ontestsofrecognitionmemoryandaremoreimpairedonmeasuresofexecutivefunctioning[207].
Executivefunctioningistheabilitytoconceptualizeallfacetsofanactivityandtranslatethatintoappropriateand
effectivebehaviortestsofthisdomainmightincludetrailmakingandthedigitsymboltest,aswellasbedside
taskssuchastheLuria"fistedgepalm"testandtheGoNoGotaskincludedintheFrontalAssessmentBattery
[208,209].DeficitsinthisareaarecommontoalldementiasbutaredistinctiveinVaD,inthatmeasurabledeficits
oftenoccurpriortothediagnosisofdementia,correlatebestwithneuroimagingfindings,andcausemostofthe
earlyimpairmentspriortothedevelopmentofseverememoryloss[210].Thesetenetshavenotbeenwell
validatedwithclinicalneuropathologicstudies.However,onesmallautopsyseriesfoundthatpredominant
executivedysfunctionwaspresentinfourofsixpatientswithcognitiveimpairmentattributedtocerebrovascular
disease,withasensitivityof67percentandaspecificityof86percent[211].
Whenattemptingtodistinguishstaticcognitivedeficitsafterastrokefromaprogressivedementiasyndrome,
serialneuropsychologicaltesting,usuallyannually,isofteninvaluable.Deficitsdetectedonneuropsychological
testscanfrequentlybehelpfulclinicallyandguidedecisionsregardingindependentliving,safetyrestrictions,and
thelike.
TestingforunderlyingvascularpathologyWhencerebralinfarctionoccursorisidentifiedonneuroimaging,
evaluationtodefineaspecificstrokesubtypeoretiologyshouldbeinitiated.(See"Overviewoftheevaluationof
stroke".)Ataminimum,atypicalpatientwithVaDshouldhavecarotidDopplerultrasoundorothercarotidimaging
ifstrokesinthatterritoryhaveoccurred.Workupforcardiogenicemboliusuallyincludesanechocardiogramand
oftenaholtermonitor.Patientsshouldbescreenedforusualriskfactorsincludingsmoking,hypertension,
diabetes,andhyperlipidemia.Thesearerecommendedonthebasisthatsuchtestingleadstoeffective
preventativestrategiesforrecurrentstroke,butthisapproachhasnotbeenshowntoimproveprognosisinpatients
withoratriskforVaDperse.

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SpecifictestingforthemoreunusualcausesofstrokeandVaDshouldbeguidedbyspecificcircumstancesthat
makethesedisorderssuspect(anunusualsituation).ForpatientswithahistorysuggestiveofCADASIL,a
commerciallyavailablegenetictestisavailable.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)
BeyondtheBasicstopic(see"Patientinformation:Dementia(includingAlzheimerdisease)(Beyondthe
Basics)")
SUMMARYANDRECOMMENDATIONSWhileconsiderableuncertaintycontinuestosurroundvascular
dementia(VaD),thefollowingsummarizescurrentunderstandingandofferssomepragmaticsuggestionsfor
evaluation.
ThepresentationofcognitiveimpairmentinVaDmaybequitedistinctfromAlzheimerdisease(AD),
especiallyearlyinthediseasecourse,withprominentdeficitsinexecutivedysfunctioncausingsignificant
disability,evenwhilememoryimpairmentisquitemildandbeforethepatientreachescriteriafordementia.
(See'Clinicalfeatures'above.)
Neuropsychologicaltestingcanbehelpfultobetterprofilethenatureandseverityofthecognitivedeficitsand
chartdiseasecourseinVaD.(See'Neuropsychologicaltesting'above.)
ThereisconsiderableoverlapbetweenADandVaDwithregardtocomorbidityaswellassharedriskfactors
andevenpathogenesis.Thecombinationofpathologiesmaybemorecommonthaneitherinisolation.(See
'Mixeddementia'above.)
TherearenouniformdiagnosticcriteriaforVaD.Evidenceofprominentexecutivedysfunction,astroke
history,vascularriskfactors,andahighHachinskiIschemicScore(table1)shouldsuggesteitherthe
diagnosisofVaDorADwithcerebrovasculardiseaseandpromptaneuroimagingstudy.(See'Diagnosis'
above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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GRAPHICS
Hachinskiischemicscore
Feature

Value

Abruptonset

Stepwisedeterioration

Fluctuatingcourse

Nocturnalconfusion

Preservationofpersonality

Depression

Somaticcomplaints

Emotionalincontinence

Hypertension

Historyofstroke

Associatedatherosclerosis

Focalneurologicsymptoms

Focalneurologicsigns

Ahighscore(7)suggestsvasculardementia,whilealowscore(4)suggestsAlzheimer
disease.
Graphic81210Version4.0

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NINDSAIRENcriteriaforprobablevasculardementia
Thecriteriafortheclinicaldiagnosisofprobablevasculardementia
includeallofthefollowing:
Dementia
Definedbycognitivedeclinefromapreviouslyhigherleveloffunctioningandmanifestedby
impairmentofmemoryandoftwoormorecognitivedomains(orientation,attention,language,
visuospatialfunctions,executivefunctions,motorcontrol,andpraxis),preferablyestablishedby
clinicalexaminationanddocumentedbyneuropsychologicaltestingdeficitsshouldbesevere
enoughtointerferewithactivitiesofdailylivingnotduetophysicaleffectsofstrokealone.
Exclusioncriteria:Caseswithdisturbanceofconsciousness,delirium,psychosis,severe
aphasia,ormajorsensorimotorimpairmentprecludingneuropsychologicaltesting.Alsoexcluded
aresystemicdisordersorotherbraindiseases(suchasAD)thatinandofthemselvescould
accountfordeficitsinmemoryandcognition.
Cerebrovasculardisease
Definedbythepresenceoffocalsignsonneurologicexamination,suchashemiparesis,lower
facialweakness,Babinskisign,sensorydeficit,hemianopia,anddysarthriaconsistentwith
stroke(withorwithouthistoryofstroke),andevidenceofrelevantCVDbybrainimaging(CTor
MRI)includingmultiplelargevesselinfarctsorasinglestrategicallyplacedinfarct(angulargyrus,
thalamus,basalforebrain,orPCAorACAterritories),aswellasmultiplebasalgangliaandwhite
matterlacunes,orextensiveperiventricularwhitematterlesions,orcombinationsthereof.
Arelationshipbetweentheabovetwodisorders
Manifestedorinferredbythepresenceofoneormoreofthefollowing:
(a)Onsetofdementiawithinthreemonthsfollowingarecognizedstroke
(b)Abruptdeteriorationincognitivefunctionsorfluctuating,stepwiseprogressionofcognitive
deficits.
AD:AlzheimerdiseaseCVD:cerebrovasculardiseaseCT:computedtomographyMRI:magnetic
resonanceimaging.
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DSM5criteriaformajorvascularneurocognitivedisorder
A.Evidenceofsignificantcognitivedeclinefromapreviouslevelofperformanceinoneormore
cognitivedomains:
Learningandmemory.
Language.
Executivefunction.
Complexattention.
Perceptualmotor.
Socialcognition.
B.Thecognitivedeficitsinterferewithindependenceineverydayactivities.Ataminimum,
assistanceshouldberequiredwithcomplexinstrumentalactivitiesofdailyliving,suchaspaying
billsormanagingmedications.
C.Thecognitivedeficitsdonotoccurexclusivelyinthecontextofadelirium.
D.Thecognitivedeficitsarenotbetterexplainedbyanothermentaldisorder(eg,majordepressive
disorder,schizophrenia).
E.Theclinicalfeaturesareconsistentwithavascularetiology,assuggestedbyeitherofthe
following:
Onsetofthecognitivedeficitsistemporallyrelatedtooneormorecerebrovascularevents.
Evidencefordeclineisprominentincomplexattention(includingprocessingspeed)andfrontal
executivefunction.
F.Thereisevidenceofthepresenceofcerebrovasculardiseasefromhistory,physicalexamination,
and/orneuroimagingconsideredsufficienttoaccountfortheneurocognitivedeficits.
G.Thedeficitsarenotbetterexplainedbyanotherbraindiseaseorsystemicdisorder.
DSM:diagnosticandstatisticalmanual.
AmericanPsychiatricAssociation.DiagnosticandStatisticalManualofMentalDisorders,FifthEdition
(DSM5),AmericanPsychiatricAssociation,Arlington,VA2013.
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DSMIVcriteriafordementia
1.Memoryimpairment
2.Atleastoneofthefollowing:
Aphasia
Apraxia
Agnosia
Disturbanceinexecutivefunctioning

3.Thedisturbancein1and2significantlyinterfereswithwork,socialactivities,orrelationships
4.Disturbancedoesnotoccurexclusivelyduringdelirium

Additionalcriteriafordementiatype:
DementiaoftheAlzheimertype:
Gradualonsetandcontinuingcognitivedecline
Notcausedbyidentifiablemedical,psychiatric,orneurologiccondition
Vasculardementia:
Focalneurologicalsignsorlaboratoryevidenceofcerebrovascularcondition
Dementiaduetoothermedicalconditions:
Evidencefromhistory,physicalexam,orlaboratoryfindingsofaspecificmedicalcondition
causingcognitivedeficits(HIVdisease,headtrauma,Parkinsondisease,Huntington'schorea,
Pick'sdisease,CreutzfeldJacob)
AdaptedfromAmericanPsychiatricAssociationDiagnosticandStatisticalManual,4thed,APAPress,
WashingtonDC,1994.
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ContributorDisclosures
ClintonBWright,MD,MSNothingtodisclose.StevenTDeKosky,MD,FAAN,FACP,FANAConsultant:
NovartisPharmaceuticalsRochePharmaceuticalsAcumenPharmaceuticalsBiogenCognitionTherapeutics
[Healthcareconsultations].ScottEKasner,MDGrant/Research/ClinicalTrialSupport:WLGoreandAssociates
[Stroke(PFOclosure)]Acorda[Stroke(dalfampridine)]AstraZeneca[Stroke(ticagrelor)]Bayer[Stroke
(rivaroxaban)].Consultant/AdvisoryBoards:Bayer[Stroke]BMS[Stroke]Novartis[Stroke]Merck[Stroke]
DaiichiSankyo[Stroke]BoehringerIngelheim[Stroke].AprilFEichler,MD,MPHEquityOwnership/Stock
Options:Johnson&Johnson[Dementia(galantamine),Epilepsy(topiramate)].
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovided
tosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDate
standardsofevidence.
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