Peripheral Arterial Disease and Cognitive Function

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cognitiveconsequencesofhypertension(10 3 12).However, thegroupsexaminedhereinhaveneverbeendirectlycom- paredwithrespecttocognitiveperformance.Anteriorstroke patientswerechosenascontrolsbecausepriorresearchsug- geststhatmilderformsofcardiovasculardiseasemayhavea particularlypotentimpactoncognitivefunctionsthatare associatedwithadequatefunctioningofanteriorbrainregions (32).Itwashypothesizedthatacontinuumofcognitiveim- pairmentwouldbenotedinrelationtoincreasinglysevere manifestationsofcardiovasculardisease-hypertension,PAD, andstroke.Fourth,asnotedpreviouslybyPhillips(23),itisof interesttoexaminethepotentialinfluenceofmedicallyas- sessedcardiovascularriskfactors,measuredascontinuous variables,oncognitiveperformancewithinPADpatients. Priorworkhasutilizeddichotomousmeasuresofsuch variables. MATERIALSANDMETHODS Subjects PADpatients Thirty-eightoldercommunity-dwelling,stroke-freeadultswithPADwere recruitedfromongoingPADresearchprotocolsforparticipationinthisstudy. AllpatientswereclassifiedashavingFontainestageIIPADbythefollowing criteria:(a)apositiveRosequestionnaireforintermittentclaudication(33); (b)intermittentclaudicationelicitedduringascreeningtreadmilltest;and(c) anABIatrest 0.97,andanABI 0.85oneminuteafterthegraded treadmilltestusedtoassessclaudication(34,35).ThemeanABIwas0.67 (SD 0.48).Patientsinthelargerprotocolswererecruitedfromthevascular surgeryclinicsattheUniversityofMarylandSchoolofMedicineandthe BaltimoreVeteransAffairsMedicalCenter(B-VAMC),andviaadvertise- mentsfromthecommunity.Studyexclusionswerelegpainwhileatrest, recentperipheralrevascularizationsurgeryforPAD( 3months),recent myocardialinfarction( 6months),stroke,dementia,neurologicaldisease, coronaryarterybypasssurgery,carotidendarterectomy,symptomaticangina duringexercisetreadmilltesting,poorlycontrolledhypertension( \x2 180/100 mmHg),poorlycontrolleddiabetes(fastingbloodglucose \x2 200mg/dl), severedyslipidemia,renalorhepaticdisease,psychiatricdisorder,andheavy alcoholuse. StrokePatients Twenty-sixischemicstrokepatientswererecruitedfromalargerprotocol investigatingtheimpactofaerobicexerciseinterventiononrecoveryof function.Patientswererandomizedaboutequallytotheactivetreatmentand controlarmsofthisstudy.However,allparticipantsengagedinthepresent biomedicalassessmentsandneuropsychologicaltestingbeforebeginningthe exerciseprotocol.Thesepatientshadbeenrecruitedbyreferralsfromlocal physicians,exercisephysiologists,newspaperadvertisement,andbothinpa- tientandoutpatientscreeningsatthelocalUniversity,VeteransAffairs,and rehabilitationhospitals.Allpatientshadstrokeaffectingtheanteriorcircula- tionandreflectinginvolvementofthecarotidterritory(58%right-sided infarction;42%left-sidedinfarction).Studyexclusionswere 6months post-stroke,dementia,otherneurologicaldiseaseaffectinggaitfunction, receptiveorglobalaphasia,diagnosedMajorDepression,poorlycontrolled diabetes,unstablecardiacdisease,clinicallyapparentPAD(FontaineClassII orgreater),activecancer,pulmonaryorrenalfailure,severeorthopedic conditions,uncontrolledhypertension( \x2 / 160/100mmHg),chronicob- structivepulmonarydisease,renalorhepaticdisease,andheavyalcoholuse. HypertensivesandNormotensives Twentyhypertensiveand23normotensivepatientswereparticipatingina largerprotocolexaminingtherelationofhypertensiontocognitiveperfor- manceandbrainstructureandfunction.Thesestroke-freeparticipantswere recruitedfromtheB-VAMC,theGeriatricsResearchEducationandClinical Center,andbyadvertisementinthelocalcommunity.Hypertensivesmet criteriaformild-to-moderateessentialhypertension(36):systolicbloodpres- sure(SBP) 140to180mmHgand/ordiastolicbloodpressure(DBP) 90to 105mmHguponclinicalassessmentorbypriorphysiciandiagnosis.Nor- motensiveshadSBP 140mmHgandDBP 90mmHg.Exclusionary criteriaforbothhypertensivesandnormotensivesincludedhistoryorclinical evidenceofcardiovasculardisease(otherthanhypertensionamongthehy- pertensivegroup),clinicallyapparentPAD(FontaineClassIIorgreater), diabetes,othermajormedicaldisease(eg,renal,hepatic,pulmonary),neuro- logicaldisease,stroke,dementia,psychiatricdisorder,heavyalcoholuse,or medicationsaffectingcentralnervoussystemfunction.Participantstaking antihypertensivemedicationshadbeenweanedforatleasttwoweeksbefore cognitivetesting. SamplecharacteristicsforallgroupsaredepictedinTable1.Allpartic- ipantsprovidedinformedconsentinaccordancewiththeguidelinesofthe UniversityofMaryland,Baltimore 9 sInstitutionalReviewBoard. Methods Allparticipantsfirstreceivedacomprehensivemedicalevaluationinclud- inghistory,physicalexamination,bloodchemistries,clinicalassessmentof bloodpressure,agradedexercisetreadmilltest,andanoralglucosetolerance test.Bloodpressure,lipids,andglucosewereassessedwhilepatientswere takingtheirroutinemedications.Totalplasmacholesterolandglucoselevels weredeterminedenzymatically.Onaseparateday,participantscompleteda neuropsychologicaltestbattery.Testswereselectedforpreviouslydemon- stratedsensitivitytovasculardiseasesincludinghypertension,PAD,and/or stroke(32),andtobrieflyassessthefollowingdomainsofcognitivefunction: attention,workingmemory,verbalandnonverballearningandmemory, executivefunctions,visuospatialskills,motorspeed,andmanualdexterity. Languagefunctionswerenotassessedbecausedeficitsonthesetestsarenot typicallyassociatedwithvasculardiseasediagnosesbeforestroke(32). Attentionandworkingmemorywereassessedbystandardadministration oftheDigitsForwardandDigitsBackwardportionsoftheWechslerAdult IntelligenceScale 3 Revised(37),respectively.Verbalmemory(immediate S.R.WALDSTEINetal. 758PsychosomaticMedicine65:757 3 763(2003) and30minutesdelayedrecall)wasexaminedbyrecallofconnecteddiscourse usingtheLogicalMemorysubscaleoftheWechslerMemoryScale 3 Revised (WMS-R)(38).Nonverbalmemory(immediateand30minutesdelayed recall)wasevaluatedbyrecallofgeometricfiguresusingtheVisualRepro- ductionssubscaleoftheWMS-R(38).TrailMakingTestPartsAandB(39) andtheStroopColor-WordTest(40)assessedperceptuo-motorspeedand executivefunctions(eg,mentalflexibility,responseinhibition).PartAofthe TrailMakingTestrequiresparticipantstodrawalineconnectingrandomly arrayed,consecutivelynumberedcirclesasquicklyaspossible.InPartB, participantsdrawalineconnectingconsecutivelynumberedandlettered circlesasquicklyaspossiblebyalternatingbetweennumbersandletters(ie, 1-A-2-B-3).TheStroopColor-WordTestrequiresparticipantstoreadaloud, asquicklyaspossible,fromthreepages.ForPage1,theparticipantreadsalist ofcolornames(ie,red,green,blue).ForPage2thecolorsofinks(ie,red, green,blue)arenamed.Page3(theinterferencepage)requiresnamingthe coloroftheinkinwhichcolornamesareprintedinincongruentcolors(ie,red printedinblue).TheinterferencescorewascomputedasperGolden 9 scriteria (40).MotorspeedandmanualdexteritywereexaminedwiththeGrooved PegboardTest(41)inwhichparticipantsinsert25pegs,asquicklyas possible,intoslottedholesthatareangledindifferentdirectionsonapeg- board,firstwiththedominantandthenthenondominanthand.Visuospatial abilitywasevaluatedwiththeJudgmentofLineOrientationtest(42).This testrequiressubjectstoassesstheconfigurationoflinesdrawnatdifferent angles.ParticipantsalsocompletedtheBeckDepressionInventory(BDI)(43) toassessdepressivesymptomatology. GroovedPegboard 3 DominantandNondominanthanddataaremissing for3and13strokepatients,respectively;thesepatientswereunableto completethetestduetotheirhemiparesis.GroovedPegboardandBDIdata aremissingfor8and9PADpatients,respectively,duetolateinclusionof thesetestsintheprotocol.PADandstrokepatientscompletedthesplit-half versionoftheJudgmentofLineOrientationtest.Scoresweredoubledfor analysisforcomparabilitywiththehypertensiveandnormotensivegroups. RESULTS Aseriesofone-way(diagnosticgroup)analysesofvari- ance(ANOVAs)orchi-squareanalysesrevealedthatthe groupswerecomparablewithrespecttoeducation,gender, andtotalcholesterollevels(Table1).However,thegroups differedsignificantlywithrespecttoage,SBP,DBP,glucose levels,smokinghistory,andBDIscores(p 9 s 0.05).More specifically,PADpatientsandhypertensivesweresignifi- cantlyolderthannormotensivesandstrokepatients(whoalso differedfromnormotensives)(p 9 s 0.05).BDIscoreswere significantlyhigherinPADandstrokepatientsthaninhyper- tensivesandnormotensives(p 9 s 0.05).Normotensiveshad lowerSBPandDBPthanallothergroups( p 0.05),and hypertensiveshadhigherSBPthanstrokepatients,andhigher DBPthanPADpatients(p 9 s 0.05).PADpatientshadhigher glucoselevelsthanallothergroups(p 9 s 0.05),andthegreat- estproportionofcurrentsmokers. One-wayANCOVAs(ageandeducationascovariates) wereusedtocontrasttheneuropsychologicalperformanceof thePAD,stroke,hypertensive,andnormotensivegroups. Educationwasretainedasacovariatedespitetheabsence ofsignificantgroupdifferencesinthisvariablegivenits potentinfluenceoncognitivefunctionandthepronounced correlationwiththemajorityofcognitivetests(upto r 0.46)inthepresentinvestigation.TheBonferronicor- rectionwasusedtocontrolforTypeIerror(significance levelsetat p 0.004).Tukey 9 sHonestlySignificantDiffer- ence(HSD)wasusedtocomputepost-hocanalysisof groupdifferences.Results(seeTable2)revealedsignifi- cantgroupdifferencesonVisualReproductions-Immedi- ateRecall( p 0.00001)andDelayedRecall( p .003); GroovedPegboard-DominantHandandNondominant Hands(p 9 s 0.00001);TrailMakingA( p 0.00001)and TrailMakingB( p 0.00001);andDigitsBackward ( p 0.002).Tukey 9 sHSDtestsrevealedthatPADpatients TABLE1.Samplecharacteristics Characteristic Normotensive(n 23)Hypertensive(n 20)PAD(n 38)**Stroke(n 26) Mean(SD)or%Mean(SD)or%Mean(SD)or%Mean(SD)or% Ageyears*66.3(5.8)70.0(5.7)69.8(7.0)62.3(8.1) Educationyears14.1(2.4)14.2(2.2)12.7(2.9)12.9(3.0) Gender%male70%75%74%77% BeckDepressionscores*3.7(3.3)4.8(4.5)8.0(8.0)8.4(7.0) Smokers%current*0%5%51%23% %ever39%63%35%42% %never61%32%14%35% SBP,mmHg*121.0(11.8)150.6(16.7)146.1(23.0)143.5(19.1) DBP,mmHg*71.1(7.4)80.9(7.3)75.2(10.4)78.5(11.3) Fastingglucose,mg/dl*92.4(7.7)104.7(20.3)126.0(50.3)99.6(8.1) Totalcholesterol,mg/dl193.3(38.1)186.9(27.1)180.8(33.1)175.8(32.7) Diabetes0%0%39%39% Coronaryarterydisease0%0%16%19% Myocardialinfarction0%0%14%12% Chronicobstructive pulmonarydisease0%0%14%0% Hypertension0%100%63%84% Revascularization 3 319% 3 Coronaryarterydisease historyoftreatedangina,myocardialinfarction,orangioplasty. *p .05. **n 29forBDIscores. PERIPHERALARTERIALDISEASEANDCOGNITION 759 PsychosomaticMedicine65:757 3 763(2003) performedsignificantlymorepoorlythanhypertensives andnormotensives,butbetterthanstrokepatientsonVisual Reproductions 3 ImmediateRecall,bothGroovedPegboard tests,bothTrailMakingtests, 1 andDigitsBackward (p 9 s 0.05);theyalsoperformedworsethannormotensives onVisualReproductions-DelayedRecall( p 0.05),and betterthanstrokepatientsonVisualReproductions-De- layedRecall( p 0.05).Inaddition,hypertensivesscored significantlymorepoorlythannormotensivesonVisual Reproductions-ImmediateandDelayedRecall,andthe GroovedPegboardtests(p 9 s 0.05).Testswithskewed scoredistributions(GroovedPegboard,TrailMakingAand B)werealsoanalyzedfollowingnormalizationwithalog transformation.Resultswerecomparableusingtransformed andrawscores.Theseanalyseswerealsorepeatedwith depressionscoresasanadditionalcovariateusingthesub- sampleofPADpatients( N 29)whohadBDIscoresavail- able.Thisyieldedcomparableresults. 2 Next,toexaminepotentialbiomedicalpredictorsofneuro- psychologicalperformancewithinPADpatientsonly,Pearson orpoint-biserialcorrelationswerefirstcomputedbetween diagnosticvariables(ie,historyofdiabetes,myocardialinfarc- tion,coronaryarterydisease,chronicobstructivepulmonary disease,hypertension,revascularizationsurgery,smokinghis- tory),medicallyassessedcardiovascularriskfactors(ie,ABI, SBP,DBP,fastingplasmacholesterolandglucose),andthe neuropsychologicaltestsfoundtodifferbetweenPADpa- tientsandtheothergroups.Ageandeducation,whichare potentinfluencesoncognitivefunction,werepartialed.Only thosevariablesdisplayingsignificantpartialcorrelationswith cognitivemeasureswereretainedforsubsequentmultiple regressionanalyses:DBP,plasmaglucoselevels,smoking history. Toassessthemultivariaterelationofselectcardiovascular riskfactors(DBP,glucose,smokinghistory)tocognitive function(aftercontrollingforage,education,anddepression scores)withinPADpatients,aseriesofhierarchicalmultiple regressionanalyseswerecomputedinwhicheachofthese variableswasforcedintotheequation.Thefollowingbiomed- icalvariablesindependentlypredictedpoorerperformanceon threeoftheseventests.ForVisualReproductions-Delayed Recall,plasmaglucoselevels(r 2 0.15, p 0.02);forGrooved Pegboard-DominantHand,DBP(r 2 0.19, p .003);andfor GroovedPegboard-NondominantHand,DBP(r 2 0.16, p 0.03). Finally,consistentwithpriorresearch(23,27),weesti- matedthedegreeofimpairmentexhibitedbythevascular diseasegroupsbycomputingtheproportionofparticipants ineachgroupwhoscoredatorbelowthe5thpercentileof performancedisplayedbythehealthynormotensivegroup. Thesechi-squareanalyseswereconductedonlyforthetests showntodifferamongthediagnosticgroups.Asdepicted 1 AnalysisofthedifferencescorebetweenTrailMakingAandByielded acomparablepatternofsignificantfindingsthussuggestingthatmental flexibilitywasaffectedratherthanjustresponsespeed. 2 Aftercovaryingage,education,anddepressionscores,theFandpvalues associatedwiththeteststhatpreviouslydifferedsignificantlyamongthe groups(aftercovaryingjustageandeducation)wereasfollows:Visual Reproductions 3 ImmediateRecall(F 12.01, p 0.00001);VisualReproduc- tions 3 DelayedRecall(F 5.81, p .001);GroovedPegboard 3 Dominant Hand(F 13.2, p 0.00001);GroovedPegboard 3 NondominantHand (F 15.4, p 0.00001);TrailMakingA(F 10.67, p 0.00001);TrailMaking B(F 10.15; p 0.00001);DigitsBackward(F 5.84, p .001).Allother resultsremainednonsignificant. TABLE2.NeuropsychologicalPerformancebyDiagnosticGroup Test Normotensive (n 23) Hypertensive (n 20) PAD (n 38) Stroke (n 26) ! FP Mean(SD)Mean(SD)Mean(SD)Mean(SD) LogicalMemory 4 ImmediateRecall26.0(7.1)24.9(6.0)20.1(7.5)22.1(5.7)2.46.07 LogicalMemory 4 DelayedRecall20.7(9.0)20.0(7.0)14.3(7.3)17.3(6.6)2.69.05 VisualReproductions 4 ImmediateRecall a,b,c,d,e,f 34.1(5.5)31.4(5.7)29.2(7.1)24.4(6.0)11.76.00001 VisualReproductions 4 DelayedRecall a,b,f 25.6(8.3)22.6(8.6)22.4(10.2)17.7(8.8)4.85.003 DigitSpanForward7.8(2.2)8.1(1.7)7.0(2.5)6.5(2.7)2.39.07 DigitSpanBackward b,c,d,e,f 7.3(2.5)7.4(2.1)6.1(2.6)4.9(2.0)5.41.002 TrailMakingA(sec)* b,c,d,e,f 31.1(10.0)33.4(10.8)48.9(23.9)61.3(25.7)12.58.00001 TrailMakingB(sec)* b,c,d,e,f 88.3(36.3)93.2(42.9)151.6(90.8)182.1(82.1)10.44.00001 StroopColor-WordTest \x3 3.39(5.69) \x3 4.94(6.41) \x3 5.70(6.56) \x3 4.55(7.51)0.54.65 GroovedPegboard 4 DominantHand(sec)* a,b,c,d,e,f 75.6(8.5)89.0(14.3)106.0(41.4)119.4(35.5)14.86.00001 GroovedPegboard 4 NondominantHand(sec)* a,b,c,d,e,f 79.0(8.5)100.1(21.4)118.2(43.1)164.0(50.3)18.67.00001 JudgmentofLineOrientation24.3(4.3)24.8(3.6)21.7(5.9)20.4(5.4)2.0.05 *Higherscoresindicatepoorerperformance a Hypertensives Normotensives; b PAD Normotensives; c Stroke Normotensives; d PAD Hypertensives; e Stroke Hypertensives; f Stroke PAD n 30fortheGroovedPegboardtests; ! n 23forGroovedPegboard 4 DominantHand;n 13forGroovedPegboard 4 NondominantHand. S.R.WALDSTEINetal. 760PsychosomaticMedicine65:757 3 763(2003) inTable3,aclearprogressionofimpairmentisapparentin theperformanceofthehypertensive,PAD,andstroke groups. DISCUSSION ResultsofthepresentinvestigationindicatethatstageII PADpatientsperformedmorepoorlythanhealthynormoten- sivesandmild-to-moderateessentialhypertensives,butbetter thananteriorischemicstrokepatients,onvarioustestsof nonverbalmemory,concentration,perceptuo-motorspeed, manualdexterity,andexecutivefunction(ie,mentalflexibil- ity).Inaddition,hypertensivesdisplayedpoorerperformance thannormotensivesontestsofnonverbalmemoryandmanual dexterity.Groupdifferenceswerenotnotedonothertestsof basicattention,verbalmemory,visuospatialability,andex- ecutivefunction(ie,responseinhibition).Theseresultswere independentofage,education,anddepressionscores.Overall, thesefindingssuggestthatcognitiveperformancemaybe- comeprogressivelyimpairedwithincreasinglyseveremani- festationsofcardiovasculardisease.Thisconclusionisfurther supportedbythefindingthatincreasingproportionsofpa- tientsinthehypertensive,PAD,andstrokegroupsexhibited impairedperformance( / 5thpercentileofnormotensive controls). Theseresultsarelargelyconsistentwithandextendon priorresearch.Inthisregard,bothseverePADpatients(stage IVamputees)andaspectrumofPADpatients(mildtomod- erateclaudicantsandamputees)havepreviouslybeenshown toexhibitcomprisedcognitiveperformanceontestsofatten- tion,perceptuo-motorspeed,executivefunctions,visualmem- ory,andvisuospatialfunction(21 3 23).Inoneinvestigation, theperformanceofPADpatientswaspoorerthanthatof healthynormalcontrols,butlargelysimilartothatofathero- thromboticstrokepatients(23).Thepresentfindingsextend thisworktopatientswithmilderPAD(intermittentclaudica- tion),andindicatethatthesepatientsalsodisplayfairlypro- nouncedcognitivedifficulties.UnlikePhillips(23),wefound thatPADpatientsgenerallyperformedbetterthanstrokepa- tients.Thismayreflectthefactthatourcohorthadsomewhat lessseverePAD.Asinthepresentinvestigation,pronounced cognitivedeficitsamongstrokepatientshavebeennotedpre- viously(30,31),ashastheperformancedifferentialbetween hypertensivesandnormotensives(10 3 12). Phillips(23)previouslynotedthatanindexofPVDsever- ityandhistoryofischemicheartdiseasepredictedpoorer cognitiveperformancewithintheirPVDpatients.However, theseinvestigatorsexaminedpatientswithabroaderspectrum ofPVDandagreaterproportionofheartdiseasethaninthe presentsample.Here,ourindexofPADseverity,theABI,and historyofcoronaryarterydiseaseormyocardialinfarctiondid notcorrelatewithcognitiveperformanceinourgroupofPAD patients.ThelackofassociationbetweenABI(presumablyan indirectindexofseverityofatherosclerosis)andcognition maybeduetoourselectionofpatientswithFontaineStageII diseaseandexclusionofpatientswithmoreseverePAD.In contrast,thepresentfindingsindicatedthathigherDBPand plasmaglucoselevelswereassociatedwithpoorerperfor- manceonselecttestsofmotorspeed,manualdexterity,and delayedvisualmemorywithinPADpatients. ThemechanismswherebyPADisassociatedwithcogni- tivedysfunctionremainunknown(44).However,severaldi- rectandindirectmechanismsarebiologicallyplausible.First, asnotedearlier,riskfactorsforatherosclerosisaregenerally thesameforallarterialsystems(2)andincludedyslipidemia, diabetes,hypertension,andsmoking.Asnotedabove,both bloodpressureandglucoselevelswereshowntoimpact within-groupvariabilityinperformanceamongPADpatients. Furthermore,thesefactorshavebeenassociatedwithstruc- turalabnormalitiesinthebrainonmagneticresonanceimag- ingreflectingmicrovasculardisease,indexesofmacrovascu- lardisease,brainatrophy,anddiminishedcerebralperfusion (forreviewssee10,11,44).Next,atherosclerosisinthecarotid arteries,whichisoftencomorbidwithPAD(4,5),hasbeen relatedtodecreasedcognitiveperformance(7 3 9)perhapsby indirectlyreducingcerebralperfusion.Atherosclerosisofthe largeintracerebralarteriesmayhavesimilareffects.Inaddi- tion,generalizedatherosclerosismayberelatedtocognitive dysfunctionviaincreasedmicroemboli.We,andothers,hy- pothesizethatitisthesestructuralchangesinthebrain,and theintracerebralandcervicocerebralarteriesthatmarkthe gradualemergenceofcerebrovasculardiseaseandthatac- countforthediminishedperformanceofPADpatients.How- ever,fewstudieshaveexaminedthebrainsofPADpatients. Inthisregard,PADhasbeenassociatedwithwhitematter lowattenuation(hypodenselesions)andatrophyonbrain computerizedtomography(45).Inaddition,meanABIswere TABLE3.Estimateofclinicalimpairment:proportionofhypertensives,PAD,andstrokepatientsscoringatorbelowthe5thpercentileofthe healthynormotensivecontrolgroup TestHypertensive(n 20)PAD(n 38)Stroke(n 26) % VisualReproductions 4 ImmediateRecall , ! 152648 VisualReproductions 4 DelayedRecall5812 DigitSpanBackward*, 01627 TrailMakingA*, 53236 TrailMakingB 153556 GroovedPegboard 4 DominantHand , ! 505387 GroovedPegboard 4 NondominantHand4067100 *Hypertensives PAD; Hypertensives Stroke; ! PAD Stroke;( p .05). PERIPHERALARTERIALDISEASEANDCOGNITION 761 PsychosomaticMedicine65:757 3 763(2003) foundtobesignificantlylowerinpatientswithwhitematter lesionsonmagneticresonanceimagingintheRotterdam Study(46).ThepresenceofPADwasalsoassociatedwith increasedriskofwhitematterlesions.Thesefindingsare consistentwiththefactthatPADisariskfactorforstroke(6). However,todate,neuroimaginghasnotbeenexaminedin conjunctionwithneuropsychologicaltestinginPADpatients. Asnotedpreviously(23,47),itispossiblethatthosePAD patientswhodisplaythemostpronouncedcognitivedeficits andsilentbraindiseaseareatgreatestriskforfuturestrokeor vasculardementia.Itwillbeimportant,infuturework,to assessbrainmorphology(usingMRI)andthestatusofthe intracerebralandcervicocerebralarteries(usingcarotidultra- soundormagneticresonanceangiography)inconjunction withneuropsychologicaltestinginordertoevaluatethebrain mechanismsthatunderliethecognitivedysfunctionnotedin thesepatients. Phillipsandcolleagueshavepreviouslydiscussedpotential clinicalimplicationsofcognitivedeficitsamongPADpatients (23,47).Theseinvestigatorspointoutthat,foramputees,the presenceofcognitivedeficitsmayaffectrehabilitationefforts withprostheticdevices.Moregenerally,cognitivedifficulties mayaffecttheabilityofPADpatientstoeffectivelyfollow complicatedtreatmentregimens.Phillips(47)hasalsofound thatdiminishedvisuospatialfunction,attentionandmemory predictedpoorereverydayfunctioningamongPVDpatientsat one-yearfollow-up.Itisthuscriticaltofurtherassessthe impactofcognitivedeficitsonactivitiesofdailylivingand functionalstatusamongPADpatients. Severalstudylimitationswarrantcomment.First,subjects underwentextensivemedicalevaluationbeforeentryintotheir respectiveparentstudies,andpersonswithpoorlycontrolled medicalcomorbiditiesweregenerallyexcluded.Thus,the presentresultsmightnotgeneralizetothelargerpatientpop- ulations.Second,hypertensivesubjectsweretaperedofftheir standardantihypertensivemedicationsbeforecognitivetest- ing,whereasPADandstrokepatientswerestudiedontheir routinemedications(forethicalreasons).Itisthereforepos- siblethatmedicationusemayhavecontributed,inpart,tothe impairedcognitivefunctioninthePADandstrokepatients. Third,itisimportanttonotethatourneuropsychological batteryprovidedonlyabriefsamplingofselectcognitive functions.Thespecifictestsusedalsohavecertainlimitations. Forexample,DigitsForwardisaverygrossmeasureof attention.Inaddition,itislikelythatupperextremityparesis deleteriouslyaffectedstrokepatients 9 performanceoftests requiringmotorresponding(eg,TrailMakingTest,Grooved Pegboard,VisualReproductions).Fourth,anteriorstrokepa- tientswhoarenonaphasicandwhoarewillingandableto participateinanexerciseinterventionstudymaynotberep- resentativeofthelargerpopulationofanteriorstrokepatients. Becausetheyarelikelytobemorehighlyfunctioning,the performancedifferentialbetweenthesestrokepatientsandthe otherthreegroupsisprobablyunderestimated.Fifth,itwould havebeenusefultomeasuretheABIinallofourgroupsto furtherdocumenttheirdifferentiallevelsofseveritywith respecttovasculardisease. Wesuggestthatfutureresearchinthisareaattendto severalconsiderations.Itwouldbeusefultofurthercharac- terizetheperformanceofPADpatientsusingmoreextensive neuropsychologicaltestbatteries.Itwouldalsobehelpfulto examinewhetherPADpatientsofincreasinglevelsofseverity (stagesI 3 IV)displaydifferencesinthedegreeofcognitive difficulties.Useofneuroimagingprocedures(eg,MRI,carotid ultrasound)inconjunctionwithcognitivetestingwillbeim- portantinelucidatingthebiologicalmechanismsunderlying thecognitiveimpairmentsassociatedwithPAD.Finally,fu- tureworkshouldevaluatewhetherthediminishedcognitive performanceofPADpatientsnegativelyaffectstheirquality oflife,activitiesofdailyliving,andabilitytocomplywith medicalregimens. Insum,theresultsofthepresentinvestigationreveala spectrumofcognitivedifficultiesamongstageIIPADpa- tients.Anexaminationoftheproportionsofimpairedpatients displayedinTable3suggeststhatthesedifficultiesrangefrom mildtosevere.Thefindingsalsosuggesttheexistenceofa continuumofcognitiveimpairmentinpatientswithincreas- inglyseverecardiovasculardisease(ie,hypertension,PAD, stroke).Theseresultshighlighttheneedtoenhanceeffortsin cardiovasculardiseasepreventionandinterventiontoreduce cerebrovascularriskandpotentiallyimprovecognitivefunc- tionandqualityoflife.Furthermore,considerationofcogni- tivedeficitsmaybecriticalinplanningmedicalregimensand rehabilitationeffortsforPADpatients. ThisworkwassupportedbytheDepartmentofVeteransAffairs BaltimoreGeriatricResearchEducationandClinicalCenter;the UniversityofMarylandClaudeD.PepperOlderAmericansInde- pendenceCenter(NIAP60AG12583);NIHgrantsR29AG15112, R01AG16685,R29AG14487-01,K01AG00657,andK24AG00930; aVAMeritGrant;BristolMyersSquibbMedicalImaging,Inc.;and theGeriatricsandGerontologyEducationandResearchProgramof theUniversityofMaryland,Baltimore. 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