The Quick Dementia Rating System - Center for Biomedical ...bradd/Harvard_Dementia... · CDR-SB,...
Transcript of The Quick Dementia Rating System - Center for Biomedical ...bradd/Harvard_Dementia... · CDR-SB,...
TheQuickDementiaRatingSystem
JamesE.Galvin,MD,MPHProfessorofNeurology
Director,ComprehensiveCenterforBrainHealthCharlesE.SchmidtCollegeofMedicine
Disclosures• ResearchSupport
• NationalInstitutesofHealth• 7R01AG040211-06• R01AG057681-01A1• R01AG056531-01A1• U01NS100610-01• R01AG056610-01• R01AG054425-01A1• R01NS088040-01
• FloridaDepartmentofHealth• MichaelJFoxFoundation• LewyBodyDementiaAssociation• MangurianFoundation• AlbertCharitableTrust• LangbertFoundation• AnonymousFoundation
• ClinicalTrials• Amgen• Biogen• Novartis• AlzheimerPreventionInitiative
• Consultant• Biogen,Axovant,Roche,Eisai,Lilly,Bracket,Medavante
• RoyaltiesandLicenseAgreements• Roche,Lilly,Biogen,Quintiles,Roobrik,ContinuumClinical,Langland
IownnostocksorequitiesinanyPharmaceuticalorBiotechnologyCompanies
Acknowledgements• GalvinLab
• MagdalenaTolea,PhD• StephanieChrisphonte,MD• KeriGreenfield,MSN,ANP,GNP• MarciaWalker,MSN,FNP• NiurkaShkolnik,LCSW• AmieRosenfeld,DPT• StephaniePetrovitch,MD• IrisCohen,MSW• OlenaMahneva,PhD• KattySaravia,MS,CCMA• MaryLouRiccio,MEd• ClaudiaMoore,CCRC• MarianMirsky,RT
• FloridaAtlanticUniversity• ElanBarenholtz,PhD• ZhongweiLi,PhD• BehnazGhoraani,PhD• JuYoungPark,PhD• LilahBesser,PhD• LisaWiese,PhD
• NewYorkUniversity• AbBrody,PhD• ElsFieremans,PhD• TimothyShepherd,MD,PhD• TracyButler,MD• RicardoOsorio,MD
• WashingtonUniversity• AnneFagan,PhD
• UniversityofCalifornia-Davis• DavidJohnson,PhD
• PennStateUniversity• MarieBoltz,PhD
• MtSinaiIcahnSchoolofMedicine• AlisonGoate,PhD
• IndustryPartners• MagQuLtdInc.• Biocrates• DiamiRBiosciences
ChallengesandOpportunitiesinEarlyDetectionofMCIandADChallenges • Disagreementonbestmethods• Noagreementonvalueofscreening
• Currentmedicationsaresymptomatic
• Clinicaltrialshavefailedtomeetoutcomes
• “Hungup”onamyloidhypothesis• Biomarkersareinvasiveandexpensive
Opportunities• Mostpeoplewanttoknow• Medicationsmayreducesymptomburdenandslowprogression
• Opportunitytoparticipateinclinicaltrials
• Patientcapableofcontributingtomedical,financialandsocialdecisionmakingprocess
• Longtermplanning
DesiredAttributesofabriefscale• Predictiveofearlydementia• Inexpensive• Highfacevalidity• Reliable,SensitiveandSpecific• Brief• Easytoadministerandscore• Sociallyacceptable• Culturallysensitive• Biologicalrelevant
TheAD8
TOTAL AD8 SCORE
Daily problems with thinking and/or memory
Difficulty remembering appointments
Difficulty handling complicated financial affairs (e.g. balancing checkbook, income taxes, paying bills)
Forgets correct month or year
Trouble learning how to use a tool, appliance or gadget (e.g. VCR, computer, microwave, remote control)
Repeats questions, stories or statements
Reduced interest in hobbies/activities
Problems with judgment (e.g. falls for scams, bad financial decisions, buys gifts inappropriate for recipients)
N/A, Don’t know
NO, No change
YES, A change
Remember, “Yes, a change” indicates that you think there has been a change in the last several years cause by cognitive (thinking and memory) problems
Galvin JE et al, Neurology, 2005
• Reportcognitivelossincomparisonwithpatient’spremorbidfunction
• Reportinterferencewithusualdailyactivities
• Consistentchange,evenwhenpatient’sbrieftestperformanceis“normal”,maydetectearliestsymptomaticstagesofdementia
• Lessbiasedbyrace,culture,educationorSES
• Dependentonareliable,observantinformant
Interview(eitherinformantorpatient)• 2-3minutestocomplete• In-person,phone,orweb
Variable AD8<2 AD8>2 PDemographicsAge,years 75.3(7.2) 75.5(7.5) nsApoE,%ε4 30.1 48.7 .003
DementiaRatingsCDR-SB,range0-18 0.06(0.19) 2.8(2.5) <0.001AD8,range0-8 0.3(0.5) 5.0(2.1) <0.001MMSE,range30-0 28.5(1.5) 25.8(4.6) <0.001
BiomarkerStudiesPiBAmyloid,units 0.12(.23) 0.45(.42) <0.001CSFAb42,pg/ml 590.7(266.2) 435.6(209.6) <0.001CSFtau,pg/ml 303.6(171.2) 500.5(261.3) <0.001CSFp-tau181,pg/ml 52.2(23.9) 76.7(39.9) <0.001
TheAD8 • Worksacrosscultures/languages
GalvinJEetal.,JAMANeurol2007;64:725-730;GalvinJEetal.,Brain2010;133:3290-300Tempo
ralvolum
eAD8dementiastatus
50000
52000
54000
56000
58000
60000
Nodementia Dementia
P=0.009
MeanAD8score(±SD) CDR N Informant Patient 0 149 0.64(1.19) 1.01(1.52) 0.5 102 3.49(2.32) 2.80(2.19)
Cohen’sd 1.66 0.98
1. MEMORYANDRECALL□0 Noobviousmemorylossorslightinconsistentforgetfulnessthatdoesnot
interferewitheverydayfunction
□0.5Consistentmildforgetfulnessorpartialrecollectionofeventsthatmayinterferewithperformingeveryday activities;repeatsquestions/statements,misplacesitems,forgetsappointments
□1 Mildtomoderatememoryloss;morenoticeableforrecentevents;interfereswithperformingeverydayactivities
□2 Moderatetoseverememoryloss;onlyhighlylearnedinformationremembered;newinformationrapidlyforgotten
□3 Severememoryloss,almostimpossibletorecallnewinformation;long-termmemorymaybeaffected
1. MOOD□0 Nochangesinmood,interestormotivationlevel
□0.5Occasionalsadness,depression,anxiety,nervousnessorlossofinterest/motivation
□1 Dailymildissueswithsadness,depression,anxiety,nervousnessorlossofinterest/motivation
□2 Moderateissueswithsadness,depression,anxiety,nervousnessorlossofinterest/motivation
□3 Severeissueswithsadness,depression,anxiety,nervousnessorlossofinterest/motivation
1. ATTENTIONANDCONCENTRATION□0 Normalattention,concentrationandinteractionwithhis/herenvironment
andsurroundings
□0.5Mildproblemswithattention,concentration,andinteractionwithenvironmentandsurroundings,mayappeardrowsyduringday
□1 Moderateproblemswithattentionandconcentration,mayhavestaringspellsorspendtimewitheyesclosed, increaseddaytimesleepiness
□2 Significantportionofthedayisspentsleeping,notpayingattentiontoenvironment,whenhavingaconversationmaysaythingsthatareillogicalornotconsistentwithtopic
□3 Limitedtonoabilitytopayattentiontoexternalenvironmentorsurroundings
PropertiesofQDRSPropertiesofQDRSbyCognitiveStatusandDementiaEtiology Controls MCI AD LBD VaD FTD p-value Age,y 70.1(7.6) 76.2(8.9) 79.8(7.5) 78.4(7.7) 77.2(6.2) 72.7(8.2) .001 Education,y 16.7(2.4) 15.9(3.0) 15.2(2.9) 14.5(3.6) 14.8(3.4) 16.8(3.3) .28 CDR 0.2(0.3) 1.9(1.6) 1.0(0.6) 1.5(0.9) 1.7(0.9) 0.8(0.8) <.001 CDR-SB 0.03(0.1) 0.4(0.3) 5.7(3.3) 8.8(5.2) 9.3(6.3) 5.2(4.7) <.001 MMSE 28.7(1.6) 26.1(3.3) 19.6(5.5) 18.2(7.7) 19.7(6.0) 23.6(1.4) .005 FunctionalActivitiesQuestionnaire 0.0(0.0) 3.6(4.2) 10.5(8.5) 17.1(10.1) 16.6(13.9) 8.1(9.9) .001 NeuropsychiatricInventory 0.9(1.6) 5.6(4.7) 7.7(5.7) 11.6(5.7) 11.4(5.6) 10.5(9.1) .002 QDRSTotal 0.3(0.5) 3.5(2.7) 7.2(5.1) 11.7(6.9) 11.6(7.8) 7.4(6.3) <.001 QDRSCognitiveSubscale 0.2(0.3) 1.5(0.9) 3.1(1.9) 4.5.(2.6) 2.8(2.3) 2.7(2.4) .005 QDRSBehavioralSubscale 0.2(0.3) 2.0(2.0) 4.2(3.5) 7.5(4.9) 8.8(5.9) 5.4(4.8) <.001 Key:AD=Alzheimer’sDisease;LBD=LewyBodyDementia;VaD=VascularDementia;FTD=FrontotemporalDegeneration;CDR=ClinicalDementiaRating;CDR-SB=CDRSumofBoxes;MMSE=MiniMentalStateExam;
Normal 0-1Mild cognitive impairment 2-5Mild dementia 6-12Moderate dementia 13-20Severe dementia 20-30
CorrelationBetweenQDRSandCDRIntraclassCorrelationCoefficientsbetweenQDRSandCDRQDRSDomain CDRDomain ICC(95%CI) p-valueMemoryandRecall Memory .715(.63-.78) <.001Orientation Orientation .751(.67-.81) <.001DecisionMakingandProblemSolving JudgmentandProblemSolving .853(.81-.89) <.001ActivitiesOutsidetheHome CommunityAffairs .899(.87-.92) <.001FunctionatHomeandHobbyActivities HomeandHobbies .830(.78-.87) <.001ToiletingandPersonalHygiene PersonalCare .908(.88-.93) <.001QDRSDerivedSumofBoxes CDRSumofBoxes .924(.90-.94) <.001QDRSDerivedGlobalScore CDRGlobalScore .902(.87-.93) <.001• TheQDRSishighlycorrelatedwiththelongerCDRinterviewacrossall6domains,theCDRsumofboxesandthe
globalCDRscore.• ThesefindingssupportthattheQDRSaccuratelycapturestheinformationcollectedduringtheCDRbutdoesso
withouttheneedforatrainedclinician.• Thissignificantcutsdownthetimerequiredforclinicalevaluationandstaging.
CorrelationbetweenQDRSandGoldStandardEvaluationMeasure Mean(SD) R p-value CovarianceCDR-SB 5.2(4.4) .820 <.001 20.4CDR 0.9(0.7) .801 <.001 3.2GDS 4.0(1.0) .699 <.001 4.0FAQ 9.9(9.5) .830 <.001 46.3UPDRS 12.5(18.3) .462 <.001 40.4MMSE 21.8(6.4) -.599 <.001 -21.0AnimalNaming 11.3(6.1) -.485 <.001 -15.4BNT 9.3(4.2) -.329 <.001 -7.1HTLV–Total 12.4(5.6) -.454 <.001 -12.9HTLV–Delay 1.6(2.4) -.299 <.001 -3.7L-NSequence 3.6(1.4) -.353 <.001 -2.3TrailsA 68.8(46.6) .369 <.001 75.8TrailsB 141.4(44.2) .275 .002 43.6HADS–Anxiety 5.9(3.5) .121 .09 2.0HADS–Depression 6.1(3.8) .239 .001 4.4AD8–Patientversion 2.7(1.9) .207 .004 1.9NPI 7.9(5.9) .561 <.001 19.7MFQ 1.8(1.2) .554 <.001 4.0Epworth 7.3(4.8) .363 <.001 10.3Alertness 7.0(2.0) -.511 <.001 -6.1CaregiverBurden 17.1(10.2) .315 <.001 18.9CaregiverDepression 2.2(2.7) .163 .08 2.0
QDRSVersionsandClinicalVariablesStrengthofAssociationbetweenQDRSversionsandClinicalVariables
InfQDRS PtQDRS CDR-SB CDR
Age .217(.002) .106(.15) .311(<.001) .306(<.001)
Education -.077(.29) -.099(.19) -.138(.06) -.160(.03)
FunctionalActivitiesQuestionnaire .847(<.001) .732(<.001) .838(<.001) .805(<.001)
NeuropsychiatricInventory .522(<.001) .326(<.001) .411(<.001) .356(<.001)
HealthyUtilitiesIndex-3 -.793(<.001) -.655(<.001) -.677(<.001) -.625(<.001)
CaregiverBurden .389(<.001) .254(.001) .310(<.001) .311(<.001)
CaregiverDepression .230(.002) .121(.11) .202(.006) .176(.02)
Internalconsistency(Cronbachalpha):InformantQDRS:0.939PatientQDRS:0.922
QDRSVersionsandCognitiveVariablesStrengthofAssociationbetweenQDRSversionsandCognitiveVariables InfQDRS PtQDRS CDR-SB CDRMoCAtotal -.640(<.001) -.507(<.001) -.834(<.001) -.784(<.001)NumberSpanForward -.316(<.001) -.232(.002) -.339(<.001) -.325(<.001)NumberSpanBackward -.408(<.001) -.284(<.001) -.469(<.001) -.462(<.001)HVLT-Immediate -.521(<.001) -.415(<.001) -.691(<.001) -.642(<.001)HVLT–Delay -.395(<.001) -.305(<.001) -.460(<.001) -.404(<.001)HVLT-Cued -.454(<.001) -.420(<.001) -.622(<.001) -.522(<.001)TrailmakingA .511(<.001) .361(<.001) .673(<.001) .639(<.001)TrailmakingB .370(<.001) .261(<.001) .554(<.001) .446(<.001)Number-SymbolCoding -.538(<.001) -.449(<.001) -.700(<.001) -.606(<.001)AnimalFluency -.581(<.001) -.459(<.001) -.680(<.001) -.636(<.001)LetterFluency -.459(<.001) -.423(<.001) -.518(<.001) -.460(<.001)MINT -.309(<.001) -.279(<.001) -.548(<.001) -.484(<.001)NoisePareidolia -.439(<.001) -.299(<.001) -.558(<.001) -.557(<.001)King-Devick .456(.003) .335(.03) .474(.002) .538(<.001)HADS-Anxiety .095(.20) .176(.02) -.004(.96) .046(.54)HADS-Depression .305(<.001) .387(<.001) .141(.06) .122(.10)AD8 .278(<.001) .426(<.001) .199(.007) .180(.01)
QDRStoCDRReliabilityConstructreliability(ICC)betweenQDRSversionsandCDR InfQDRS–PtQDRS InfQDRS–CDR PtQDRS-CDRMemory .756 .754 .499Orientation .783 .787 .699Decisionmaking .750 .728 .742Activitiesoutsidehome .803 .862 .780Activitiesinsidehome .822 .861 .759Personalhygiene .918 .887 .855Behavior .716 ----- ----Language .839 ---- ----Mood .729 ---- ----Attention .749 ---- ----TotalQDRS .887 ---- ----QDRS-derivedCDR-SB .889 .909 .831QDRS-derivedCDR .770 .826 .740
WisconsinRegistryforAlzheimerPrevention(WRAP)
• Longitudinalobservationalcohortstudyenrichedwithpersonswithaparentalhistory(PH)ofprobableAlzheimer'sdisease(AD)dementiahasenrolled1561peopleatameanbaselineageof54years
• Participantsreturnforasecondvisit4yearsafterbaseline,andsubsequentvisitsoccurevery2years• Eighty-onepercent(1270)ofparticipantsremainactiveinthestudyatacurrentmeanageof64and9yearsoffollow-up
• Seriallyassessedcognition,self-reportedmedicalandlifestylehistories(e.g.,diet,physicalandcognitiveactivity,sleep,andmood),laboratorytests,genetics,molecularimaging,structuralimaging,andcerebrospinalfluid
• PHofprobableADisassociatedwith46%apolipoproteinE(APOE)ε4positivity,morethantwicetherateof22%amongpersonswithoutPH
• Subclinicalorworsecognitivedeclinerelativetointernalnormativedatahasbeenobservedin17.6%ofthecohort
• Twenty-eightpercentexhibitamyloidand/ortaupositivity• Biomarkerelevations,butnotAPOEorPHstatus,areassociatedwithcognitivedecline.
• Agreementstatistics(concordance=88.9%)supporteduseoftheQDRSasaninitialinformantreportandmodifyingcenterprotocoltoadministerCDRsonlywhenQDRS>0reducedCDRassessmentsby79.8%.
QDRSinWRAPSampleQDRSIntheWisconsinRegistryforAlzheimerPrevention
AllSubjects(N=59)
TrueNegatives(N=46)
TruePositives(N=5)
FalseNegatives(N=5)
FalsePositives(N=3)
Age,mean(SD) 64.9(5.4) 64.3(5.6) 68.8(3.1) 63.6(4.7) 68.67(0.6) Gender,percentfemale 55.9% 65.2% 20% 20% 33.3% APOEε4,percentpositive 45.8% 43.5% 60% 40% 66.7% FamilyHistory,percentpositive 66.1% 63% 60% 100% 66.7% CDR-global,mean 0.085(0.2) 0 0.5 0.5 0 QDRS-global,mean 0.068(0.2) 0 0.5 0 0.5 CDR-SumofBoxes,mean(SD) 0.25(0.6) 0.044(0.1) 1.5(1.3) 0.9(0.6) 0.17(0.3) QDRS-SumofBoxes,mean(SD) 0.20(0.4) 0.044(0.1) 1.4(0.4) 0.3(0.3) 0.5(0) ComorbidConditions,mean(SD) 1.07(1.1) .98(1.0) 1.4(0.9) 1.0(1.7) 2.0(1.0) WRATReadingStandardScore,mean(SD) 105.8(9.6) 105.4(9.9) 112.0(9.0) 106.8(6.9) 101.3(8.7) TrailsBrawscoresec,mean(SD) 60.05(21.3) 56.3(18.4) 65.5(38.1) 74.4(23.4) 85.67(14.0) LogicalMemoryImmediate,mean(SD) 28.4(6.4) 29.3(6.0) 27.6(9.8) 24.4(4.5) 23.3(6.3) LogicalMemoryDelayed,mean(SD) 25.6(7.1) 26.8(6.6) 23.0(11.8) 21.0(4.2) 20.0(4.6) RAVLTTotalLearningTrials1-5,mean(SD) 49.4(9.8) 51.2(9.7) 43.4(5.4) 45.0(10.8) 39.0(5.0) RAVLTLongDelay,mean(SD) 9.7(3.5) 10.2(3.5) 9.4(1.5) 8.4(4.0) 5.7(3.5) MMSE,mean(SD) 29.4(0.8) 29.4(0.9) 29.6(0.5) 29.4(0.5) 29.7(0.6) CES-D,mean(SD) 5.2(5.5) 4.8(5.4) 7.8(3.4) 7.0(8.2) 5.3(4.0)
QDRSandMRIQDRSandMRIBiomarkersintheWRAPSample Graymatter Whitematter Accumbens Hippocampus ThalamusMemory -0.078 -0.084 -0.065 -0.029 -0.097Orientation -0.156 -0.047 -0.138 -0.106 -0.088DecisionMaking -0.125 -0.089 -0.137 -0.042 -0.086Activities -0.160 -0.071 -0.167 -0.108 -0.126Function -0.097 -0.045 -0.033 -0.199 -0.276PersonalHygiene -0.111 -0.059 0.060 0.083 -0.030Behavior 0.003 0.073 0.011 0.036 0.004Language -0.015 -0.005 -0.195 -0.056 -0.087Mood -0.151 -0.118 -0.100 -0.037 -0.104Attention -0.097 -0.023 -0.071 -0.114 -0.036Cognitivesubscore -0.127 -0.080 -0.185 -0.079 -0.129Behavioralsubscore -0.164 -0.073 -0.099 -0.098 -0.151TotalQDRS -0.165 -0.085 -0.153 -0.101 -0.159
QDRSandPIBImagingQDRSandPiBPETBiomarkersintheWRAPSample PiBIndex MedialFrontal PostCingulate Precuneus MidTemporalMemory -.061 -.068 -.055 -.038 -.051Orientation .075 .048 .054 .109 .106DecisionMaking .226 .202 .163 .197 .222Activities .115 .099 .068 .098 .142Function .065 .045 .036 .072 .098PersonalHygiene -.044 -.056 -.022 -.058 -.059Behavior .070 .048 .084 .093 .045Language .050 .036 .023 .049 .066Mood -.131 -.112 -.131 -.110 -.141Attention -.040 -.031 -.040 -.010 -.029Cognitivesubscore .095 .071 .060 .103 .112Behavioralsubscore -.018 -.022 -.030 -.004 -.013TotalQDRS .04 .025 .014 .057 .052
CSFBiomarkersQDRSandCSFBiomarkersintheWRAPSample Aβ42 Aβ42/40 Tau p-Tau Aβ42/Tau Aβ42/pTauMemory -.02 -.104 -.050 -.024 .013 -.025Orientation -.198 .186 -.183 -.175 .007 -.028DecisionMaking -.210 .092 .111 .093 -.228 -.229Activities -.144 .120 .068 .059 -.203 -.193Function -.184 .107 -.005 .036 -.164 -.191PersonalHygiene .015 -.038 -.063 -.061 .038 .036Behavior -.065 -.075 .018 .069 -.109 -.132Language -.135 .206 -.024 -.054 -.113 -.109Mood .061 .012 -.032 -.021 .017 .028Attention -.018 -.115 .023 .056 -.066 -.091Cognitivesubscore -.190 .118 -.045 -.048 -.113 -.139Behavioralsubscore -.068 .006 .001 .035 .115 -.127TotalQDRS -.138 .069 -.022 -.003 -.128 -.148
QDRSDetectsPreclinicalADQDRS=0-1 QDRS>1 P-value
Aβ42 729.9(191.9) 618.5(205.9) .001
Aβ42/Aβ40 2.9(1.6) 3.3(2.3) .15
T-Tau 310.9(117.6) 327.5(109.9) .39
P-Tau 46.7(14.7) 49.9(14.8) .18
Aβ42/Tau 2.7(1.0) 1.9(0.6) <.001
Aβ42/p-Tau 17.2(6.5) 12.6(6.4) <.001
PiBIndex 1.1(0.2) 1.1(0.2) .67
GreyMattervolume(L) .65(.06) .63(.06) <.001
Hippocampalvolume(mm3) 3831.6(438.3) 3626.9(475.1) .001
Summary• TheQDRSishighlycorrelatedwithGoldStandardmeasuresofdementiastaging,neuropsychologicaltesting,andADbiomarkers.
• BothInformantandPatientversionsoftheQDRSarevalidandreliable• QDRSdomainsmostcloselyassociatedwithPiBimagingweredecisionmaking,activitiesoutsidethehome,andmood.
• QDRSdomainsofmemoryandattentionwasassociatedwithAβ42/40• QDRSdomainsoforientation,decisionmaking,language,activitiesoutsidethehome,andhomefunctioningwereassociatedwithAβ42,Aβ42/40ratioandtheratioofAβ42totauspecies.
• OnlyOrientationandDecisionmakingwereassociatedwithTauspecies• QDRSscoreswereassociatedwithADbiomarkers(CSF,PiBPET,andMRI)suggestingthatincreasedQDRSscores(particularlythecognitivesubscore)maydetectcontrolindividualswhoarelikelytohavepreclinicalAD
• CansubstituteQDRSforCDRforrapidscreeningfortrialeligibility