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MultidimensionalapathyprofilesinAD

1

Anovelassessmentandprofilingofmultidimensionalapathyin

Alzheimer’sdisease

RatkoRadakovic12345*,JohnM.Starr35&SharonAbrahams1245

1DepartmentofPsychology,UniversityofEdinburgh,Edinburgh,UK

2AnneRowlingRegenerativeNeurologyClinic,UniversityofEdinburgh,Edinburgh,UK

3AlzheimerScotlandDementiaResearchCentre,UniversityofEdinburgh,Edinburgh,UK

4EuanMacDonaldCentreforMNDResearch,UniversityofEdinburgh,Edinburgh,UK

5CentreforCognitiveAgeingandCognitiveEpidemiology,UniversityofEdinburgh,

Edinburgh,UK

Word Count: 4203

*Correspondenceto:R.Radakovic,UniversityofEdinburgh,DepartmentofPsychology,7GeorgeSquare,Edinburgh,UK,EH89JZ

Emailaddresses:r.radakovic@ed.ac.uk,radakovic.ratko@gmail.comTel:+441316511303

MultidimensionalapathyprofilesinAD

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Abstract

Background: Apathy is a complex multidimensional syndrome, frequently reported in

Alzheimer’s disease (AD) and is associated with impaired awareness. Here we present a

psychometrically robust method to profile apathy in AD. Objectives: To determine the

validity and reliability of a multidimensional apathy measure, the Dimensional ApathyScale

(DAS),andexploretheapathysubtypeprofileanditsassociationsinAD.Methods:102

peoplewithADand55healthycontrolswererecruited.ParticipantscompletedtheDAS,

theApathyEvaluationScale(AES),GeriatricDepressionShortform(GDS-15)and

LawtonInstrumentalActivitiesofDailyLiving(LIADL).Psychometricpropertiesofthe

DASweredetermined.AD-Controlcomparisonwasperformedtoexploregroup

differencesontheDAS.LatentClassAnalysis(LCA)wasusedtoexploretheprofileof

apathyinAD.Results:TheDAShadagoodtoexcellentCronbach'sstandardizedalpha

(self-rated=0.85,informant/carer-rated=0.93),goodconvergentanddivergent

validityagainststandardapathy(AES)anddepression(GDS-15)measures.Group

comparisonshowedpeoplewithADweresignificantlyhigherforallapathysubtypes

thancontrols(p<.001),andlackinginawarenessoverallapathysubtypedeficits.LCA

showed3distinctADsubgroups,with42.2%intheExecutive-Initiationapathy,28.4%

intheGlobalapathyand29.4%intheMinimalapathygroup.Conclusions:TheDASisa

psychometricallyrobustmethodofassessingmultidimensionalapathyinAD.The

apathyprofilesinADareheterogeneous,withadditionalspecificimpairmentsrelating

toawarenessdependentonapathysubtype.

KeyWords:Apathy,Syndrome,Alzheimerdisease,Psychometrics,BehaviorRating

Scale,Awareness

MultidimensionalapathyprofilesinAD

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Introduction

Apathy,asalackofmotivation[1],isfrequentlyreportedasthemostprominent

behavioralsyndromeinAlzheimer’sdisease(AD),andisassociatedwithglobaldisease

severityandlevelofcognitiveimpairment[2,3],andhasanegativepredictiverolein

clinicalcourse[4].Furthermore,ithasbeenobservedinpredementiastages[5].Apathy

inADisalsoassociatedwithincreasedcaregiverdistressandburden[6]aswellas

functionaldecline[7]makingitanegativelyimpactfulbehavioralsymptom.Thereis

alsoapervasiveassociationbetweenincreasedapathyandanosognosia,orlackof

awarenessinAD[8].Althoughapathyrelatedanosognosiahasbeenobservedinearlier

stagesofthediseasecourse[9,10],ithasalsobeensuggestedthatthismightbedueto

progressionofneuropathology[7]withindividualslaterintheillnessshowingboth

symptoms.MograbiandMorris[11]furtherreinforcedthisandproposedthatapathy

increaseswithlackofawarenessoffailuresincognitivetasks(errormonitoring),while

emotionalreactionsinresponsetoexperiencesofillnessordeficit(emotional

reactivity),bearingsimilaritytoawareness,remainedrelativelyintact.Theyfurther

dichotomizedapathyagainstdepression,inthattheformerisassociatedwithmore

anosognosia.

However,previousresearchhasshownsomeevidencethatapathyismultidimensional

e.g..[1,12],withtheproposeddiagnosticcriteriaofapathyrecognizingthesyndromatic

natureofapathy[13,14]butwithoutathoroughmeasurementofspecificsubtypes

[15].Thishasbeenobservedindementiausingtraditionalone-dimensionalassessment

toolssuchastheNeuropsychiatricInventory(NPI)[16].Anexampleofthisisthat

peoplewithdementiawhoendorsemoreemotionallyapatheticstatementsweremore

apatheticoverall,andspecificallyshowedmoreextremeandvariablebehavioral

MultidimensionalapathyprofilesinAD

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problemssuchasinsensitivityanduncooperativeness[17].AfurtherstudybyQuaranta

etal.[18]usingtheNPIfoundtheretobedifferingapathycharacteristicsbetweenAD

andfrontotemporaldementia,wherethelatterwerereportedtomorefrequently

endorsestatementsrelatingtoalackofinitiation,decreasedemotionaloutputand

diminishedinteresttowardsfriendsorfamily.However,theNPIisatooldesignedto

assessapathyamongstotherbehavioralimpairmentsanddoesnotexamineapathy

multidimensionally.Similarly,theApathyEvaluationscale(AES)[19]isagold-standard

one-dimensionalmeasureforassessingapathybutisthoughttobecomposedof4

factors,calledcognitive,behavioral,emotionaland‘other’,whichhavebeenusedby

previousresearchtocalculatefactorialsubscorese.g.[20].However,thesefactorsare

notconsistentlyreportedinotherresearch,e.g.[21],andtheAEShasonlybeen

validatedasaone-dimensionalmeasureofapathy[15].TheScaleforAssessmentfor

NegativeSymptoms[22]isalsolesscommonlyusedmeasureofdifferenttypesof

negativesymptoms,affectiveblunting,avolition/apathyandsocial/emotional

withdrawal,whichhaveoverlapwithsomeapathysubtypes.Morerecently,LilleApathy

RatingScale(LARS)hasbeenvalidatedinagroupofmixeddementiapatients[23]but

measuresuncorroboratedfactorialsubscoresofapathy.

Ataneurobiologicallevel,aperfusionimagingstudyusingtheApathyInventory(AI)

[24],asimplemultidimensionalmeasure,observedthatcognitive,behavioraland

affectivecomponentsofapathyweremediatedbyspecificfronto-subcorticalmetabolic

circuits[25].Initiativeaspectsofapathywerenegativelyassociatedwithrightanterior

cingulatecortexperfusionwithemotionalbluntingaspectsnegativelyassociatedwith

perfusioninrightmiddleorbitofrontalgyrusinAD.Laterstructuralimagingresearch,

oncemoreusingtheAI,foundthatbothinADandProgressiveSupranuclearPalsythere

MultidimensionalapathyprofilesinAD

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wasdistinctneuroanatomicalbasisforInitiativeapathyrelatingtoanteriorcingulate

cortex,andEmotionalbluntingaspectsofapathy,relatingtostructuralchangeinsular

cortex[26].However,theAIwasfoundnotbeacomprehensiveorrobustmeasureof

multidimensionalapathy[15].

Apathyisthoughttobeassociatedwithprefrontalcortex-basalgangliacircuit

dysfunction,manifestingasdifferentsubtypesofapathy,proposedinLevyandDubois

[27,28]model.TheDimensionalApathyScale(DAS)[29]hasbeendesignedtoassess

differentapathysubtypesbyasubscale-based,quantitativemethodthathasbeen

validatedinamyotrophiclateralsclerosis[30]andParkinson’sdisease[31].TheDAS

measureslackofmotivationforplanning,attentionandorganization(Executive

apathy),indifferenceoremotionalneutrality(Emotionalapathy)andself-generationof

though(Initiationapathy).ThisDimensionalApathyframeworkrelatestodifferent

manifestationofdemotivation,takingintoaccountbothobservablebehavioral

symptomsandcognitivedeficits.Whilethereareone-dimensionalapathytoolsthat

havebeenvalidatedinAD,therearelimitedcomprehensive,validatedtoolsassessing

subtypesofapathyinthisverycommoncondition[15].

TheprimaryaimofthisstudyistovalidatetheDASinasampleofpeoplewithADand

theircarers.Furthermore,theprofileofmultidimensionalapathyinADwasexplored

boththroughgroupcomparisonandlatentprofilingofADbasedontheDAS,soasto

determinesubgroupsbasedontheprofileofscoresacrossthethreeapathysubtypes.

Finally,relevantlinksbetweentheDAS,diseaseandfunctionalvariableswillbe

explored.

MultidimensionalapathyprofilesinAD

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MaterialsandMethods

Subjects

PeoplewithADandtheircarerswererecruitedthroughJoinDementiaResearch

PlatformandbytheHealthInformationCentre(HIC)throughtheScottishDementia

ResearchInterestRegister(SDRIR),asdescribedpreviously[32].PeoplewithADwere

approachedthroughtheircarerstoparticipateinthestudy.Thiswassetupunderthe

supportoftheScottishDementiaClinicalResearchNetwork(SDCRN)in2008to

facilitatedementiaresearchbyprovidingaccesstosuitablepotentialrecruitsin

Scotland.ParticipantsontheSDRIRwerepeoplereferredbytheirclinicians,whohavea

diagnosisofdementiaorarelatedcognitivedisorderandhaveconsented(orincases

wherethepersonlackedcapacity,throughhis/herlegalrepresentative).Peoplewith

ADwerediagnosedusingtheICD-10whenjoiningtheSDRIR[32]andthoseonJoin

DementiaResearchPlatformwerediagnosedwiththeICD-10criteriaalignedwithNHS

Scotlandpractice.ExclusioncriteriaforpeoplewithADincludedthosewithClinical

DementiaRating=3(duetoseverityofdementia),severediabetes,epilepsy,

alcohol/substance-relateddisorders,severeheadinjury(thatrequiredintensivecare

hospitalization),traumaticbraininjury(inclusiveofsubarachnoidhemorrhage)and

presentorpastothersignificant,comorbidmedicalillness(suchasstroke,Parkinson’s

disease,psychiatricdiseaseetc.).AllpeoplewithADthatwererecruitedcommunity-

dwelling.

Additionally,healthycontrolswererecruitedfromtheUniversityofEdinburgh

VolunteerResearchPanel.Theywereprescreenedbeforerecruitmentwiththe

exclusioncriteriaofseverediabetes,epilepsy,alcohol/substance-relateddisorders,

severeheadinjury(thatrequiredintensivecarehospitalization),traumaticbraininjury

MultidimensionalapathyprofilesinAD

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(inclusiveofsubarachnoidhemorrhage)andpresentorpastothersignificant,comorbid

medicalillness(suchasstroke,Parkinson’sdisease,psychiatricdiseaseetc.).Controls

werenotspecificallyassessedforcognitiveimpairmentinthepresentstudy,although

wereexcludedifinformationontheUniversityofEdinburghVolunteerResearchPanel

databaseindicatedcognitiveimpairment.

ProcedureandAssessments

ThiswasapostalquestionnairestudywherecarersofpeoplewithADweresentpacks

containinginformationsheets,consentformsandquestionnairesregarding

demotivation/apathy,moodandfunctionalabilitiesofthepersonwithAD.Thecarer-

ratedpackaskedthecarerstocompletethequestionnairesbasedontheirobservations

ofthepeoplewithADandtheself-ratedpackaskedpeoplewithADtoself-ratetheir

owndemotivation/apathyandmood.Pre-paid,addressedenvelopeswereprovided.

Boththecarer-ratedandself-ratedpackscontainedtheDAS[29,30],ApathyEvaluation

Scale(AES)[19]andtheGeriatricDepressionScale-Shortform(GDS-15)[33,34]and

thecarerscompletedtheLawtonInstrumentalActivitiesofDailyLiving(LIADL)[35].

TheDASisa24-itemscalethatwasusedtomeasuremultidimensionalapathy.

Executive,EmotionalandInitiationapathywereassessedbysubscaleswhereeachitem

wasratedona4pointLikertscale,withtheminimumscoreforeachsubscalebeing0

(leastapathy)and24(mostapathy).TheDAStotalscorerangesfrom0to72.DAS

subscaleimpairmentcutoffswerecalculatedonthebasisof≥2SDabovethemeanof

thecontrolsample.Parallelself-ratedandinformant/carer-ratedversionswereused.

TheAESwasusedasan18-item,gold-standardmeasureofunidimensionalapathy

scoredona4pointLikertscale,where18indicatedleastapathyand72indicatedmost

MultidimensionalapathyprofilesinAD

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apathy.Cutoffsof>36.5fortheself-ratedand>41.5forthecarer-ratedversionswere

used[21].Furthermore,theAESiscomposedofa4factorsubstructure,Cognitive,

Behavioral,EmotionalandOtherfactors[19],wheresubfactorialscorescanbe

calculated.Parallelself-ratedandcarer-ratedversionswereused.TheGDS-15isa15-

itemscreenusedtoassessdepressionusingadichotomousscale,withscoresranging

from0(notdepressed)to15(mostdepressed).Aclinicalcut-offof>6wasusedto

indicatepresenceofdepression[36].Parallelself-ratedandcarer-ratedversionswere

used.TheLIADLisan8-itemcarer-ratedassessmentofthefunctionalindependenceof

thepersonwithAD,withtotalscoresrangingfrom0(lowfunction,dependent)to8

(highfunction,independent).

TheMiniMentalStateExam(MMSE)[37]andtheAddenbrooke’sCognitive

Examination-Revised(ACE-R)[38]asmeasuresofcognitivefunctioningwereavailable

fromtheJoinDementiaResearchPlatformandSDRIR.

EthicalapprovalwasobtainedfromtheNationalHealthService(NHS)SouthEast

ScotlandResearchEthicsCommittee01andtheSchoolPhilosophy,Psychologyand

LanguageSciences(PPLS),UniversityofEdinburghEthicalCommittee,inaccordance

withtheDeclarationofHelsinki.Informedconsentwasobtainedfromallparticipants.

Statisticalanalysis

RandSPSSstatisticsV21.0wereusedforanalysis.Independentt-testsandChisquared

testswereusedtocomparedemographicsandclinicalvariablesofthepeoplewithAD.

PsychometricpropertiesoftheDASweredeterminedthroughCronbach’sStandardized

alpha(internalconsistencyreliability)[39]andHolmcorrectedPearson’scorrelations

MultidimensionalapathyprofilesinAD

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betweenDASsubscalesandtheAES(convergentvalidity)andGDS-15(discriminant

validity).A3x3mixeddesignANOVAwasusedforcomparisonofGroup(AD

Informant/carer-ratedvsADSelf-ratedvsControlSelf-rated)andDASsubscale

(EmotionalvsExecutivevsInitiation),withposthocTukey’sHonestSignificant

Differences(Tukey’sHDS)tests.HolmcorrectedPearson’scorrelationswereusedto

examineclinicalvariableassociationwithawarenessdiscrepancyofpeoplewithADon

DASapathysubscales.Apathysubtypeawarenessdiscrepancywascalculatedthrough

subtractinginformant/carer-ratedscoresfromself-ratedscores.

Latentclassanalysis(LCA)wasusedtoinvestigateclusteringorclassifyingofpeople

withADbasedontheprofileofinformant/carer-ratedscoresontheDASsubscales

usingMclustpackageinR[40].Mclustisamodel-basedclustering,classificationand

densityestimationsoftwarethatisbasedonfiniteGaussianmixturemodelling.In

Mclust,theoptimalLCAmodelandnumberofclusters/classesareautomatically

selectedaccordingtoBayesianinformationcriterion(BIC)[41].Furthermore,the

IntegratedClassificationLikelihood(ICL)criterion[42]wasalsoappliedtosubstantiate

optimalmodelselection.Aone-wayMANOVAwasusedtoconfirmADclasses

(subgroups)selectedthroughLCAbasedonDASsubscalesdifferences.Class

subgroupingswereclassifiedbasedontheirDASscoresandthencomparedonclinical

anddemographicvariablesusingChisquaredtestsandone-wayANOVAs(Holm

corrected)withsignificantresultsfollowedupbyposthocTukey’sHDStests.

Results

315peoplewithADandtheircarerswererecruited.Therewereatotalof102AD

carersthatreturnedthesurveypack,with17.6%beingcarersforpeoplewithearly

MultidimensionalapathyprofilesinAD

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onsetAD(belowtheageof65yearsold).Themostcommoncarerrelationshiptothe

personwithADwasspouse.Ofthose,55peoplewithADreturnedtheirself-ratedpacks.

55healthycontrolswererecruited.Table1showsADandhealthycontrolgroups’

clinical,demographic,apathyanddepressioncharacteristics.

TABLE1HERE

Table1showsthattherewasnosignificantdifferencebetweenpeoplewithADand

controlsongenderandyearsofeducation.However,whiletheADgroupwas

significantlyolderthanthecontrolgroup,therewasnosignificantageassociated

correlationsbetweentheAESandGDS-15,forbothself-andcarer-ratings.Peoplewith

ADscoredsignificantlyhigherontheAESandGDS-15self-ratedmeasureswhen

comparedtocontrols.76.5%ofpeoplewithADscoredabovecut-offontheAES(carer-

rated)and52.7%ofpeoplewithADscoredabovecut-offontheGDS-15(carer-rated).

FortheN=55wherebothpeoplewithADandtheircarersreturnedthepacks,theAD

informant/carer-ratings(mean=46.6,SD=9.9)weresignificantlyhigherthanADself-

ratings(mean=38.9,SD=9.0)ontheAES(t(108)=2.049,p<.001),withnosignificant

differenceontheGDS-15.

PsychometricPropertiesoftheDAS

TheDASCronbach’sStandardizedalphavaluefortheinformant/carer-ratedversion

was0.93andtheself-ratedversionwas0.85,whichisexcellentandgood,respectively.

AtaDASsubscalelevel,Executive(informant/carer=0.89,self=0.86)andInitiation

MultidimensionalapathyprofilesinAD

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(informant/carer=0.88,self=0.84)subscalesweregood.Theinformant/carer-rated

Emotionalsubscalewasacceptable(0.73),self-ratedversionwasquestionable(0.54).

TABLE2HERE

Table2showsthatDASsubscalescorrelatedpositivelywiththeAES,withtheself-rated

ExecutiveandEmotionalcorrelatingmoderatelyandInitiationcorrelatingstronglywith

theAEScomparedtotheGDS-15.SupplementaryTable1showsintercorrelationsof

DASsubscalesandthe4subfactorialscoresoftheAES.

Alzheimer’sdiseaseapathyprofiling

GroupComparison

FIGURE1HERE

Figure1showstheADinformant/carer-rated,ADself-ratedandcontrolself-rated

groupcomparisonondifferentDASsubscales.Therewasasignificantmaineffectof

Group(F(1,489)=223.1,p<.001)andmaineffectofSubscale(F(2,489)=40.0,p<

.001).TherewasasignificantGroupandSubscaleinteraction(F(2,489)=12.8,p<

.001),whichseemedtobedrivenbythedifferencebetweenpeoplewithADand

controlsonExecutiveandInitiationapathy,moresothanEmotionalapathy,ascanbe

observedinFigure1.PosthocanalysisshowedthatpeoplewithADscoredsignificantly

higheronallsubscales,bothonself-rated(Executive:p<.001;Emotional:p<.01;

Initiation:p<.001)andinformant/carer-rated(Executive:p<.001;Emotional:p<.001;

Initiation:p<.001),whencomparedtocontrolself-ratings.ADinformant/carer-ratings

MultidimensionalapathyprofilesinAD

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werefoundtobesignificantlyhigherthanADself-ratingsinformant/carers-ratingsover

allsubscalesindicativeofamean3.4pointExecutive(p<.01),1.7pointEmotional(p<

.05)and2.9Initiation(p<.01)apathysubscalediscrepancyinawareness.

Furthermore,whenexaminingclinicalvariableassociations,theDASsubscalescores

(bothself-ratedandinformant/carer-rated)werenotsignificantlycorrelatedwith

diseaseduration.Also,nosignificantcorrelationswereobservedbetweenthe

discrepancyscoresonanyoftheDASsubscalesanddiseaseduration.

LatentClassAnalysis

FIGURE2HERE

FortheLCAofinformant/carer-ratingsforAD,comparisonofdifferentmodelsshowed

thatamodel“VVI”(diagonal,varyingvolumeandshape)supportinga3-classsolution

yieldedabestfittingmodelwithaBICvalueof-710.2.Thesecondbestmodelwas

“VVV”(ellipsoidal,varyingvolume,shape,andorientation)with2-classes,presenting

withaBICvalueof-714.9.Thiswasa4.7pointdifferencefromtheinitialmodel,which

wasconsideredsupportiveofthe3-class“VVI”model[43].TheICLcriterion

additionallysupported3-classsolution“VVI”(diagonal,varyingvolumeandshape)

modelwithaICLvalueof-721.9.Aone-wayMANOVAshowedasignificantdifference

theDASsubscales,supporting3-classsolution(F(6,194)=53.1,p<.001;Wilk'sΛ=0.1,

partialη2=.6).Figure2illustratestheDASprofilesofthedifferentclassesandTable3

showstheDAS,demographicandclinicalcharacteristicsoftheclasses.

MultidimensionalapathyprofilesinAD

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Class1wasthelargest(N=43)andwascharacterizedbydisplayingatleastoneapathy

subtype.Table3showshigherscoresontheInitiationandExecutiveapathysubscales.

Also,usingabnormalitycutoffs,58%inthisgroupwereimpairedonatleasttwoapathy

subscales,themostcommonofwhichwasExecutiveandInitiationapathy,withonly

37%displayingglobalapathyoverallDASsubscalesand5%displayingoneapathy

subscale.ThisgroupwascalledtheExecutiveandInitiationApathygroup.Class2was

marginallythesmallestgroup(N=29)but,unlikeClass1,displayeddistinctlymostwell

definedcharacteristics,withhighestmeanscoresoverallapathysubscales.

Abnormalitycutoffsshowed97%displayingglobalapathyoverallDASsubscales.This

groupwascalledtheGlobalApathygroup.Class3(N=30)wascomparativelylowerin

meanscoresonallapathysubscales,where53%showingnoapathysubscale

impairment,with30%displayingoneapathysubtypeimpairmentand17%displaying

multipleapathysubscaleimpairments,basedonabnormalitycutoffs.Thiswascalled

theMinimalApathygroup.

TABLE3HERE

Table3showsconfirmationofsubgroup(class)differencesbasedonDASsubscalesand

theAESshowingasignificantdifferencebetweentheExecutiveandInitiationapathy,

GlobalapathyandMinimalapathygroupings.Thesubgroupswerealsofoundtodiffer

significantlyondepression(GDS-15).PosthoctestsshowedthattheMinimalapathy

groupwassignificantlylessdepressedcomparedtotheExecutiveandInitiationapathy

subgroup(p<.001)andtheGlobalapathysubgroup(p<.001).Howevernosuch

differencewasfoundbetweentheExecutiveandInitiationapathysubgroupandthe

Globalapathysubgroup.Therewerenoothersignificantdifferencesonothervariables.

MultidimensionalapathyprofilesinAD

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Discussion

ThisstudyshowedthattheDASisavalidandreliableinstrumentfordetecting

multidimensionalapathyinAD,wheretheself-andinformant/carer-ratedversionshad

agoodtoexcellentinternalconsistencyreliabilityandgoodconvergentvalidityagainst

anexistentgold-standardmeasureofapathy(AES).Specifically,ExecutiveandInitiation

apathy(bothself-andinformant/carer-ratedversions)werefoundtobevalidand

reliable,whereastheself-ratedEmotionalapathywaslessso.Though,self-ratedDAS

EmotionalapathywasonlysignificantlyassociatedwiththeEmotionalsubfactorial

scoreoftheAES(SupplementaryTable1),showingaspecificlevelofconvergence

withinthesedomainsandsubscale-factorspecificvalidityfortheDASEmotionalapathy

subscale.Nevertheless,theinformant/carer-ratedDASwasfoundtobemore

psychometricallyrobust,whichislikelyduetothewell-documentedlackofawareness

ofapathyassociatedwithcognitivedeficitsinAD[8,24,44].Thisisalsoinconcordance

withmoretraditionalinstruments’relianceonexternalratings,suchastheNPI[16].

Thediscriminantvaliditywasshowntobegood,whereEmotionalapathywasnot

associatedwithdepression,whichsupportsthedistinctionbetweenthesetwo

respectiveconceptsofemotionalneutralityandemotionalitypreviouslyobserved[30,

31].

Overallinthegroupcomparison,GlobalapathywasobservedinAD,bothforself-

ratingsandinformant/carer-ratings,butatvaryingdegrees.However,thedifference

betweenpeoplewithADandcontrolsself-ratingsonExecutiveandInitiationsubscales

wasfoundtobesignificant(6.6pointsand5.8points,respectively),withEmotional

apathybeingmuchlower(2.2points)butstillsignificant.TheLCAsupportedthe

MultidimensionalapathyprofilesinAD

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presenceofdistinctprofilesofapathywithinAD,showingsubgroupsofpeoplewithAD

displayingExecutiveandInitiationapathy,GlobalapathyandMinimalapathy.The

largestofthesegroupswastheExecutiveandInitiationapathysubgroup(N=43),which

wasreinforcedbypeoplewithADandcontrolsself-ratinggroupcomparisonand

magnitudeofdifferencebetweentheExecutiveandInitiationapathysubscales.Asone

ofthemostprominentbehavioralsymptomsinAD,cognitiveimpairmentisalso

associatedwithapathy[45-47].WhilememoryimpairmentiscommoninAD,attention

[48]andexecutivedysfunction[49],suchasplanning,spatialnavigationattention[50-

52]andverbalfluency[53]arealsoparticularlynotedtobeimpairedasthedisease

progressestolaterstages,whichisparticularlyrelevanttooursamplewhichismore

impaired.However,itisimportanttodifferentiatebetweentheDASExecutiveapathy

itemsandexecutivefunctioningassessments,whereintheovert,observational

assessmentsoftheformerandtheperformance-basedassessmentofthelatter,are

unlikelytofullyoverlapbutaremorelikelytomeasuresimilarelementsrelatingto

demotivationtowardsplanning,organizationandattention.Additionally,deficitsof

emotionalprocessing,socialawareness[54]andemotionaldecision-making[55]have

alsobeenobservedinAD,butmaynotbeadefiningdeficitofthedisease.Morerecent

researchusingtheLARSshowedthatpeoplewithADshowedlessapathyinthe

“emotional”dimensionandthe“self-awareness”dimensionwhencomparedtopeople

withbehavioralvariantfrontotemporaldementia[56]andsupportsourfindingsof

EmotionalapathyasnotahallmarkofAD.WhiletheDimensionalApathyframework

attemptstoincorporateobservablebehavioralandneuropsychologicaldeficits,similar

toLevyandDubois[27,28],howapathysubtypesmapontocognitivefunctioningisyet

tobedetermined.Thiswillgiveinsightintooverlappingmechanismsofmotivationand

cognition.

MultidimensionalapathyprofilesinAD

16

Furtherexplorationshowedthatwhileawarenessoverallapathysubtypes,asassessed

throughadiscrepancyofADself-ratingandinformant/carerrating,wassignificantly

impairedinAD,ExecutiveandInitiationapathywasmostimpaired,whileEmotional

apathywaslessimpairedinmagnitude.Anosognosiaandapathyhasbeenparticularly

relatedtoexecutivedysfunction,whereADpatientsshowalackofawarenessoferrors

inthesetasks[11].Furthermore,thistypeoferrormonitoringhasbeenfoundtobe

associatedwiththeanteriorcingulate,anareaimplicitlyassociatedwithLevyand

Duboissubtypes[27,28].Inaddition,MograbiandMorrissuggestdissociationbetween

impairmentinawarenessoftheirdiseasestateandassociateddeficits,whileemotional

reactivityremainingintactinAD.Thisisconsistentwithourfindingsinthisstudy,

wherethedifferenceobservedbetweenADinformant/carer-ratingsandself-ratingson

theEmotionalapathysubscaleweresmallerthanontheothersubscales.Wealsofound

nosignificantdifferenceonthestandardizeddepressionmeasurebetweenADself-and

informant/carer-ratings,providingfurthersupportthatemotionalaspectsof

functioning,bothneutral(apathy)andnegative(depression)arenotpronetothe

awarenessdeficits.Inthescopeofpreviousresearch,amyotrophiclateralsclerosisand

Parkinson’sdisease[30,31]havenotshownapathyawarenessdeficits,whichcould

suggestthisisspecifictodementia.Furthermore,thisaddstheconstructofapathy

subtypeawarenesstotheemergingDimensionalApathyframeworkthatcanbe

measuredthroughdiscrepancyscoresbetweenself-andinformant-carerratings.

Futureresearchshouldaimtoexplorehowthisapathysubtypeawarenessdeficit

changeslongitudinallyoverthecourseofthedisease.

MultidimensionalapathyprofilesinAD

17

Furthermore,boththeExecutiveandInitiationapathyaswellastheGlobalapathy

subgroups,wereobservedtoscorehigherondepressioncomparedtotheMinimal

apathysubgroup.Duetothevariablerelationshipofapathyanddepressionreportedin

literaturethereisalackofconsensusoftheconvergenceofapathyanddepression[57-

59].Itwouldthereforebebeneficialtoexaminehowapathysubtypesanddepression

converge,aswellasdiverge,throughoutdiseaseprogressiontofurtherunderstandthe

complexrelationshipbetweenthesebehaviors.

Therearelimitationstothisstudy.Duetothenatureofthispostalquestionnairestudy,

wewerenotabletoutilizetheproposeddiagnosticcriteriaforapathy[14].However,

thereisremittoapplythesecriteriainconcordancewiththeDAStorefineapathy

diagnosis.Thediscrepancyscorebetweenself-ratedandinformant/carer-ratedDAS

scorescouldbeinterpretedasanosognosiainpeoplewithAD,itcouldalsobeduetothe

influenceofcaregiverburdenassociatedwiththisdisease,whichhasbeenshownto

associatewithapathyinAD[6].Futureresearchshouldexplorehowcaregiverburden

relatestodifferentapathysubtypes.Furthermore,self-ratingdepressionandapathy

couldaffectreliabilityofreportingduetotheseverityofdementia.However,by

includingbothself-ratedandinformant/carer-ratedscalesandinstrumentswehopeto

amelioratetheeffectsthatcouldoccurinrelationtothesetworatingmethods.Afurther

limitationisthattherewasnoformalassessmentofcognitiveimpairmentperformedon

thecontrolswithonlynotesregardingthisavailablefortheseparticipants,makingit

possiblethatsomeparticipantshavemildcognitiveimpairment.Furtherresearch

shouldlookathowcognitiveimpairmentassociateswithapathysubtypesbothin

patientpopulationsandnormativeageing,anddeterminetheapathysubtype

relationshipswithmildcognitiveimpairment.Additionally,therewerenodifferences

MultidimensionalapathyprofilesinAD

18

onmedicationstatus(cholinergicandglutaminergic)betweenapathysubgroupswithin

AD,butothermedicationwasnotfullyavailableforparticipants.However,studies

lookingatmedicationeffectsonapathyaresparseandreportmixedresults,withno

studieslookingdirectlyattheeffectonapathysubtypes[60].Finally,whilesamplesize

(ADpatient=55andCarer=102)ofthisstudycouldbecitedasalimitation,however

previousstudiesvalidatingandutilizingapathymeasurementmethodsindementiahad

similarorsmallersamplesizesthanourcurrentstudy,examplesincludetheLARS[23],

NPI[16],AES[19]andAI[24].However,useoftheDASinlargersamplesofdementia

patientswouldfurthertheunderstandingofmultidimensionalapathyindementia.

Inconclusion,theDASwasfoundtobepsychometricallyreliableandvalidfor

measurementofmultidimensionalapathyinAD.Whilebothversionswereinformative,

theinformant/carer-ratedversionseemedslightlymorepsychometricallyrobust.While

ADwascharacterizedbyaGlobalapathyoverallsubtypes,theheterogeneityofapathy

basedonsubgroupingwithinADwasobserved.AcombinationofExecutiveand

InitiationapathywasshowntobecentralinAD,whichwasfurthersupplementedbyan

apathysubtypeawarenessdeficit.Furthermore,inthescopeofprevious

multidimensionalapathyresearchinamyotrophiclateralsclerosisandParkinson’s

disease[30,31],thesefindingsaddtothecomplexitiesofapathyprofilesandindicatea

uniqueADprofile,furthertakingintoaccountapathysubtypeawarenessdifficulties.

Thiscouldproveclinicallyusefulindistinguishingitfromotherneurodegenerative

diseases,specificallyotherformsofdementia.Furtherresearchshouldinvestigatethe

degreeofthisapathysubtypeawarenessdeficitwhilealsodeterminingthecognitive

underpinningsofdifferenttypesofapathyandpursuingfurtherunderstandingoftheir

impactonfunctionalabilities,qualityoflifeandcaregiverburden.

MultidimensionalapathyprofilesinAD

19

Acknowledgments

ThisresearchwasfundedbyascholarshipfromtheAnneRowlingRegenerative

NeurologyClinic,AlzheimerScotlandDementiaResearchCentreandtheUniversityof

Edinburgh.ThisworkwassupportedbytheScottishDementiaClinicalResearch

NetworkwhoreceivedfundingfromScottishMinistersthroughtheChiefScientist

Office.Theviewsexpressedinthispublicationarethoseoftheauthorsandnot

necessarilythoseofScottishMinistersortheChiefScientistOffice.Wewouldliketo

expressourgratitudetoMrPhilipBrown(DeputyNetworkManager,Scottish

NeuroprogressiveandDementiaClinicalResearchNetwork)forhishelpwith

recruitment.Wewouldliketothanktheparticipantsandtheirfamiliesfortakingpartin

thisresearch.

ConflictofInterest/DisclosureStatement

Theauthorshavenoconflictofinteresttoreport.

References:

[1]MarinRS.(1991)Apathy:aneuropsychiatricsyndrome.JNeuropsychiatryClin

Neurosci3,243-254.

[2]vanReekumR,StussDT,OstranderL(2005)Apathy:whycare?JNeuropsychiatry

ClinNeurosci17(1),7-19.

[3]ChaseTN(2011)Apathyinneuropsychiatricdisease:diagnosis,pathophysiology

andtreatment.NeurotoxRes19,266-278.

MultidimensionalapathyprofilesinAD

20

[4]StellaF,LaksJ,GovoneJS,deMedeirosK,ForlenzaOV(2015)Associationof

neuropsychiatricsyndromeswithglobalclinicaldeteriorationinAlzheimer’sdisease

patients.IntPsychogeriatr28,779-786.

[5]ApostolovaLG,CummingsJL(2008)Neuropsychiatricmanifestationsinmild

cognitiveimpairment:asystematicreviewoftheliterature.DementGeriatrCognDisord

25,115-126.

[6]KauferDI,CummingsJL,ChristineD,BrayT,CastellonS,MastermanD,MacMillanD,

KetchelP,DeKoskyST(1998)Assessingtheimpactofneuropsychiatricsymptomsin

Alzheimer'sdisease:theNeuropsychiatricInventoryCaregiverDistressScale.JAm

GeriatrSoc46(2),210-215.

[7]StarksteinSE,JorgeR,MizrahiR,RobinsonRG(2006)Adiagnosticformulationfor

anosognosiainAlzheimer’sdisease.JNeurolNeurosurgPsychiatry77(6),719-725.

[8]StarksteinSE,BrockmanS,BruceD,PetraccaG(2010)Anosognosiaisasignificant

predictorofapathyinAlzheimer’sdisease.JNeuropsychiatryClinNeurosci22(4),378-

383.

[9]SpallettaG,GirardiP,CaltagironeC,OrfeiMD(2012)Anosognosiaand

neuropsychiatricsymptomsanddisordersinmildAlzheimerdiseaseandmildcognitive

impairment.JAlzheimersDis29,761-772.

[10]AaltenP,vanValenE,deVugtME,LousbergR,JollesJ,VerheyFR(2006)

Awarenessandbehavioralproblemsindementiapatients:aprospectivestudy.Int

Psychogeriatr18,3-17.

MultidimensionalapathyprofilesinAD

21

[11]MograbiDC,MorrisRG(2014)Ontherelationamongmood,apathy,and

anosognosiainAlzheimer'sdisease.JIntNeuropsycholSoc20(1),2-7.

[12]StarksteinSE,PetraccaG,ChemerinskiE,KremerJ(2001)Syndromicvalidityof

apathyinAlzheimer’sdisease.AmJPsychiatry158,872-877.

[13]MulinE,LeoneE,DujardinK,DelliauxM,LeentjensA,NobiliF,DessiB,TibleO,

Agüera-OrtizL,OsorioRS,YassavageJ,DachevskyD,VerheyFRJ,CruzJentoftAJ,Blanc

O,LlorcaPM,RobertPH(2011)Diagnosticcriteriaforapathyinclinicalpractice.IntJ

GeriatrPsychiatry26(2),158-165.

[14]RobertPH,OnyikeCU,LeentjensAFG,DujardinK,AaltenP,StarksteinS,Verhey

FRJ,YassavageJ,ClementJP,DrapierD,BayleF,BenoitM,BoyerP,LorcaPM,ThibautF,

GauthierS,GrossbergG,VellasB,ByrneJ(2009)Proposeddiagnosticcriteriaforapathy

inAlzheimer'sdiseaseandotherneuropsychiatricdisorders.EurPsychiatry24(2),98-

104.

[15]RadakovicR,HarleyC,AbrahamsS,StarrJM(2015)Asystematicreviewofthe

validityandreliabilityofapathyscalesinneurodegenerative.IntPsychogeriatr27,903-

923.

[16]CummingsJL,MegaM,GrayK,Rosenberg-ThompsonS,CarusiDA,GornbeinJ

(1994)TheNeuropsychiatricInventorycomprehensiveassessmentofpsychopathology

indementia.Neurology44(12),2308-2308.

MultidimensionalapathyprofilesinAD

22

[17]ChowTW,BinnsMA,CummingsJL,LamI,BlackSE,MillerBL,FreedmanM,StussD,

vanReekumR(2009)Apathysymptomprofileandbehavioralassociationsin

frontotemporaldementiavsdementiaofAlzheimertype.ArchNeurol66(7),888-893.

[18]QuarantaD,MarraC,RossiC,GainottiG,MasulloC(2012)DifferentApathyProfile

inBehavioralVariantofFrontotemporalDementiaandAlzheimer'sDisease:A

PreliminaryInvestigation.CurrentGerontologyandGeriatricsResearch

doi:10.1155/2012/719250

[19]MarinRS,BiedrzyckiRC,FirinciogullariS(1991)Reliabilityandvalidityofthe

ApathyEvaluationScale.PsychiatryRes38(2),143-162.

[20]BrodatyH,AltendorfA,WithallA,SachdevP(2010)Dopeoplebecomemore

apatheticastheygrowolder?Alongitudinalstudyinhealthyindividuals.Int

Psychogeriatr22,426-436.

[21]ClarkeDE,VanReekumR,SimardM,StreinerDL,FreedmanM,ConnD(2007)

Apathyindementia:anexaminationofthepsychometricpropertiesoftheApathy

EvaluationScale.JNeuropsychiatryClinNeuosci19,57–64.

[22]ReichmanWE,CoyneAC,AmirneniS,MolinoB,EganS.(1996)Negativesymptoms

inAlzheimer'sdisease.AmJPsychiatry153,424-426.

[23]Fernández-MatarrubiaM,Matías-GuiuJA,Moreno-RamosT,Valles-SalgadoM,

Marcos-DoladoA,García-RamosR,Matías-GuiuJ(2016).ValidationoftheLille’sApathy

RatingScaleinverymildtomoderatedementia.AmJGeriatrPsychiatry24,517-527.

MultidimensionalapathyprofilesinAD

23

[24]RobertPH,ClairetS,BenoitM,KoutaichJ,BertogliatiC,TibleO,CaciH,BorgM,

BrockerP,BedouchaP(2002)TheApathyInventory:assessmentofapathyand

awarenessinAlzheimer'sdisease,Parkinson'sdiseaseandmildcognitiveimpairment.

IntJGeriatrPsychiatry17,1099-1105.

[25]BenoitM,ClairetS,KoulibalyPM,DarcourtJ,RobertPH(2004).Brainperfusion

correlatesoftheapathyinventorydimensionsofAlzheimer'sdisease.IntJGeriatr

Psychiatry19(9),864-869.

[26]StantonBR,LeighPN,HowardRJ,BarkerGJ,BrownRG(2013)Behaviouraland

emotionalsymptomsofapathyareassociatedwithdistinctpatternsofbrainatrophyin

neurodegenerativedisorders.JNeurol260(10),2481-2490.

[27]LevyR,DuboisB(2006)Apathyandthefunctionalanatomyoftheprefrontal

cortex–basalgangliacircuits.CerebCortex16(7),916-928.

[28]LevyR(2012)Apathy:apathologyofgoal-directedbehaviour.Anewconceptof

theclinicandpathophysiologyofapathy.RevNeurol(Paris)168(8),585-597.

[29]RadakovicR,AbrahamsS(2014).Developinganewapathymeasurementscale:

DimensionalApathyScale.PsychiatryRes219(3),658-663.

[30]RadakovicR,StephensonL,ColvilleS,SwinglerR,ChandranS,AbrahamsS(2016).

MultidimensionalapathyinALS:validationoftheDimensionalApathyScale.JNeurol

NeurosurgPsychiatry87,663-669.

MultidimensionalapathyprofilesinAD

24

[31]RadakovicR,DavenportR,StarrJM,AbrahamsS(2017).Apathydimensionsin

Parkinson’sDisease.IntJGeriatrPsychiatrydoi:10.1002/gps.4697

[32]LawE,ConnellyPJ,RandallE,McNeillC,FoxHC,ParraMA,HudsonJ,WhyteLA,

JohnstoneJ,GrayS,StarrJM(2013)DoestheAddenbrooke'sCognitiveExamination-

revisedaddtotheMini-MentalStateExaminationinestablishedAlzheimerdisease?

Resultsfromanationaldementiaresearchregister.IntJGeriatrPsychiatry28,351-355.

[33]YesavageJA,SheikhJI(1986)GeriatricDepressionScale(GDS)RecentEvidence

andDevelopmentofaShorterVersion.ClinGerontol5(1-2),165-173.

[34]BrownLM,SchinkaJA(2005)Developmentandinitialvalidationofa15-item

informantversionoftheGeriatricDepressionScale.IntJGeriatrPsychiatry20(10),911-

918.

[35]LawtonMP,BrodyEM(1969)Assessmentofolderpeople:Self-maintainingand

instrumentalactivitiesofdailyliving.Gerontologist9(3),179-186.

[36]WancataJ,AlexandrowiczR,MarquartB,WeissM,FriedrichF(2006)Thecriterion

validityoftheGeriatricDepressionScale:asystematicreview.ActaPsychiatrScand

114(6),398-410.

[37]FolsteinMF,FolsteinSE,McHughPR(1975)“Mini-mentalstate”.Apractical

methodforgradingthecognitivestateofpatientsfortheclinician.JPsychiatrRes12,

189-198.

MultidimensionalapathyprofilesinAD

25

[38]MioshiE,DawsonK,MitchellJ,ArnoldR,HodgesJR(2006)TheAddenbrooke’s

cognitiveexaminationrevised(ACE-R):abriefcognitivetestbatteryfordementia

screening.IntJGeriatrPsychiatry21,1078-1085.

[39]CronbachLJ(1951)Coefficientalphaandtheinternalstructureoftests.

Psychometrika16(3),297-334.

[40]ScruccaL,FopM,MurphyTB,RafteryAE(2016)mclust5:Clustering,classification

anddensityestimationusinggaussianfinitemixturemodels.RJ8(1),289-317.

[41]SchwarzG(1978)Estimatingthedimensionofamodel.AnnStat6(2),461-464.

[42]BiernackiC,CeleuxG,GovaertG(2000)Assessingamixturemodelforclustering

withtheintegratedcompletedlikelihood.IEEETransPatternAnalMachIntell22(7),

719-725.

[43]RafteryAE(1995)Bayesianmodelselectioninsocialresearch.Sociological

methodology25,111-163.

[44]StarksteinSE(2014)AnosognosiainAlzheimer'sdisease:Diagnosis,frequency,

mechanismandclinicalcorrelates.Cortex61,64-73.

[45]RobertPH,BerrC,VolteauM,BertogliatiC,BenoitM,SarazinM,LargainS,Dubois

B(2006)Apathyinpatientswithmildcognitiveimpairmentandtheriskofdeveloping

dementiaofAlzheimer'sdisease:aone-yearfollow-upstudy.ClinNeurolNeurosurg

108(8),733-736.

MultidimensionalapathyprofilesinAD

26

[46]PalmerK,DiIulioF,VarsiAE,GianniW,SancesarioG,CaltagironeC,SpallettaG

(2010)Neuropsychiatricpredictorsofprogressionfromamnestic-mildcognitive

impairmenttoAlzheimer'sdisease:theroleofdepressionandapathy.JAlzheimers

Dis20(1),175-183.

[47]RichardE,SchmandB,EikelenboomP,YangSC,LigthartSA,MollvanCharanteEP,

vanGoolWA,Alzheimer’sDiseaseNeuroimagingInitiative(2012)Symptomsofapathy

areassociatedwithprogressionfrommildcognitiveimpairmenttoAlzheimer’sdisease

innon-depressedsubjects.DementGeriatrCognDisord33(2-3),204-209.

[48]KolanowskiAM,FickDM,YevchakMAM,HillMNL,MulhallMPM,McDowellMJA

(2012)Payattention!:Thecriticalimportanceofassessingattentioninolderadults

withdementia.JGerontolNurs38(11),23-27.

[49]PerryRJ,HodgesJR(1999)AttentionandexecutivedeficitsinAlzheimer'sdisease.

Brain122(3),383-404.

[50]McPhersonS,FairbanksL,TikenS,CummingsJL,Back-madrugaC(2002)Apathy

andexecutivefunctioninAlzheimer'sdisease.JIntNeuropsycholSoc8(3),373-381.

[51]Fernandez-GuineaS,DelgadoML,FrankA,GarcíaMR,NietoS,ZaldunbideL,Oviedo

D,RiveraP(2011)Planningabilitiesinaging,mildcognitiveimpairmentand

Alzheimer'sdiseasepatients.AlzheimersDement7(4),S243-S244.

[52]TangenGG,EngedalK,BerglandA,MogerTA,HanssonO,MengshoelAM(2015)

SpatialnavigationmeasuredbytheFloorMazeTestinpatientswithsubjective

MultidimensionalapathyprofilesinAD

27

cognitiveimpairment,mildcognitiveimpairment,andmildAlzheimer'sdisease.Int

Psychogeriatr27,1401-1409.

[53]BozeatS,GregoryCA,RalphMAL,HodgesJR(2000)Whichneuropsychiatricand

behaviouralfeaturesdistinguishfrontalandtemporalvariantsoffrontotemporal

dementiafromAlzheimer'sdisease?JNeurolNeurosurgPsychiatry69(2),178-186.

[54]KumforF,Sapey-TriompheLA,LeytonCE,BurrellJR,HodgesJR,PiguetO(2014)

DegradationofemotionprocessingabilityincorticobasalsyndromeandAlzheimer’s

disease.Brain137(11),3061-3072.

[55]BayardS,JacusJP,RaffardS,Gely-Nargeot,MC(2014)ApathyandEmotion-Based

Decision-MakinginAmnesicMildCognitiveImpairmentandAlzheimer’sDisease.Behav

Neuroldoi:10.1155/2014/231469

[56]Fernández-MatarrubiaM,Matías-GuiuJA,Cabrera-MartínMN,Moreno-RamosT,

Valles-SalgadoM,CarrerasJL,Matías-GuiuJ,(2017)Differentapathyclinicalprofileand

neuralcorrelatesinbehavioralvariantfrontotemporaldementiaandAlzheimer's

disease.IntJGeriatrPsychiatrydoi:10.1002/gps.4695

[57]LandesAM,SperrySD,StraussME,GeldmacherDS(2001)ApathyinAlzheimer's

disease.JAmGeriatrSoc49(12),1700-1707.

[58]TagarielloP,GirardiP,AmoreM(2009)Depressionandapathyindementia:same

syndromeordifferentconstructs?Acriticalreview.ArchGerontolGeriatr49(2),246-

249.

MultidimensionalapathyprofilesinAD

28

[59]MortbyME,MaerckerA,ForstmeierS(2012)Apathy:aseparatesyndromefrom

depressionindementia?Acriticalreview.AgingClinExpRes24(4),305-316.

[60]HarrisonF,AertsL,BrodatyH.(2016)Apathyindementia:systematicreviewof

recentevidenceonpharmacologicaltreatments.CurrPsychiatryRep18,103.

MultidimensionalapathyprofilesinAD

29

Table1.Demographics,apathyanddepressionscoresforAD,informant/carer-

rated(N=102),self-rated(N=55)andcontrols(N=55)

Informant/carer-

ratedAD

(N=102)

Self-rated

AD

(N=55)

Control

(N=55)

Self-rated

ADvs

controlp-

value

GenderM/F 52/50 28/27 28/27 1.000

Age(mean,SD) 78.2(8.5) 77.5(7.9) 75.0

(6.1)

0.036

YearsofEducation(mean,SD) 13.2(3.7)†† 13.3

(3.7)†

14.4

(3.2)

0.060

AES 51.7(11.5) 38.9(9.0) 28.8

(5.2)

<.001

GDS-15 7.3(4.4) 5.1(4.0) 1.9

(2.1)

<.001

LIADLScore(mean,SD) 3.0(2.2)

Ageofonset(mean,SD)years 74.6(8.2)†††

Diseaseduration(mean,SD)

years

3.9(2.4)†††

Medication(Cholinergic/

Glutaminergic/Both/None/

Unavailable%)

78.4%/4.9%/

2.9%/10.8%/

2.9%

CDR(0.5/1/2/Unavailable

%)

43.1%/39.2%/

14.7%/2.9%

MMSEscore(mean,SD) 22.0(5.3)††††

ACE-Rscore(mean,SD) 63.3(18.1)†††† Significantvaluesinbold.AD=Alzheimer’sDisease;SD=standarddeviation;AES=Apathy

EvaluationScale;GDS-15=GeriatricDepressionScale-Shortform;LIADL=LawtonInstrumental

ActivitiesofDailyLiving;CDR=ClinicalDementiaRating;MMSE=Mini-MentalStateExam;ACE-

R=Addenbrooke’sCognitiveExamination-Revised

†N=39 ††N=42

†††N=90

††††N=80

MultidimensionalapathyprofilesinAD

30

Table2.Informant/carer-ratedDASandself-ratedDASsubscalecorrelations

comparedtostandardizedapathy(AES)anddepression(GDS-15)measures

Informant/carer (N=102) AES GDS-15

DAS Executive subscale 0.80*** 0.49***

DAS Emotional subscale 0.67*** 0.30**

DAS Initiation subscale 0.86*** 0.48***

DAS Total 0.75*** 0.36***

Self (N=55) AES GDS-15

DAS Executive subscale 0.58*** 0.53***

DAS Emotional subscale 0.37* 0.13

DAS Initiation subscale 0.67*** 0.42**

DAS Total 0.75*** 0.52***

Significantvaluesinbold.DAS=DimensionalApathyScale;AES=ApathyEvaluationScale;GDS-

15=GeriatricDepressionScale-ShortForm p<.001***,p<.01**,p<.05*

MultidimensionalapathyprofilesinAD

31

Table3.ADClasscomparisononDASsubscales,descriptiveandclinicalvariables

(informant/carer-ratedN=102)

ExecutiveandInitiationApathy(Class1)

GlobalApathy(Class2)

MinimalApathy(Class3)

p-value

DASSubscale Executive(mean,SD) 17.2(3.2) 21.9(1.5) 10.6(4.4) <.001Emotional(mean,SD) 14.6(3.2) 18.9(2.6) 10.6(4.0) .002Initiation(mean,SD) 21.1(1.5) 23.8(0.4) 14.6(3.2) <.001

DescriptiveandClinical

N(male%) 43(46.5%) 29(44.8%) 30(63.3%) 1.000Onset(Early/Late) 8/35 4/25 6/24 1.000

Age(mean,SD) 78.9(8.8) 79.2(7.3) 76.2(8.9) 1.000YearsofEducation

(mean,SD)12.7(3.9)† 14.0(2.9)†† 13.5(3.7)††† 1.000

AES(mean,SD) 53.2(4.8) 63.9(4.2) 37.2(6.0) <.001GDS-15(mean,SD) 8.0(4.1) 9.4(4.0) 4.3(3.5) .007LIADLScore(mean,

SD)3.0(2.0) 1.3(1.4) 4.4(2,1) .268

Ageofonset(mean,SD)years

75.4(8.5)‡ 74.3(7.2)‡‡ 73.8(8.9)‡‡ 1.000

Diseaseduration(mean,SD)years

4.0(2.3)‡ 4.7(2.2)‡‡ 3.1(2.3)‡‡ 1.000

Medication(Cholinergic/

Glutaminergic/Both/None/Unavailable%)

79.1%/7.0%/0%/14.0%/0%

72.4%/3.4%/6.9%/13.8%/3.4%

83.3%/3.3%/3.3%/6.7%/3.3%

1.000

MMSEscore(mean,SD)

22.3(5.4)∆∆ 19.9(5.3)‡‡‡‡

24.5(3.9)∆ 1.000

ACE-Rscore(mean,SD)

64.7(17.1)∆∆∆ 56.4(17.9)‡‡‡‡

72.6(16.7)‡ 1.000

Significantvaluesinbold.AD=Alzheimer’sDisease;DAS=DimensionalApathyScale;SD=standarddeviation;AES=ApathyEvaluationScale;GDS-15=GeriatricDepressionScale-Shortform;LIADL=LawtonInstrumentalActivitiesofDailyLiving;MMSE=Mini-MentalStateExam;ACE-R=Addenbrooke’sCognitiveExamination-Revised†N=20††N=5†††N=17‡N=38‡‡N=26‡‡‡‡N=28∆N=29∆∆N=33∆∆∆N=34

MultidimensionalapathyprofilesinAD

32

Figure1.ComparisonofADinformant/carer-rated(N=55),ADself-rated(N=55)

andControlself-rated(N=55)groupsonDASsubscales

2.04.06.08.0

10.012.014.016.018.020.0

Executive Emotional Initiation

Scor

e (M

in 0

, Max

24)

DAS Subscale

AD informant/carer-rated AD self-rated Control self-rated

MultidimensionalapathyprofilesinAD

33

Figure2.AD(Informant/carer-rated;N=102)subgroupings(Classes)basedon

LCAofDASEmotional(xaxis),DASInitiation(yaxis)andDASExecutive(zaxis)

subscalescores.

MultidimensionalapathyprofilesinAD

34

SupplementaryTable1.Informant/carer-ratedDASandself-ratedDASsubscale

correlationscomparedto4factorsoftheAES

Informant/carer (N=102) AES Cognitive

Factor

AES Behavior

Factor

AES Emotional

Factor

AES Other

Factor

DAS Executive subscale 0.76*** 0.77*** 0.49*** 0.74***

DAS Emotional subscale 0.66*** 0.60*** 0.56*** 0.69***

DAS Initiation subscale 0.83*** 0.76*** 0.68*** 0.78***

Self (N=55) AES Cognitive

Factor

AES Behavior

Factor

AES Emotional

Factor

AES Other

Factor

DAS Executive subscale 0.50** 0.48** 0.24 0.53***

DAS Emotional subscale 0.30 0.23 0.46** 0.28

DAS Initiation subscale 0.56*** 0.64*** 0.38* 0.55***

Significantvaluesinbold.DAS=DimensionalApathyScale;AES=ApathyEvaluationScale;GDS-

15=GeriatricDepressionScale-ShortForm p<.001***,p<.01**,p<.05*