A substrate-free activity-based protein profiling screen ...
A novel assessment and profiling of …...both through group comparison and latent profiling of AD...
Transcript of A novel assessment and profiling of …...both through group comparison and latent profiling of AD...
MultidimensionalapathyprofilesinAD
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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:[email protected],[email protected]:+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
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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
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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
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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.
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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*