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