Myelin Integrity Predicts Activities of Daily Living in Alzheimer’s DiseaseJessica Man, Tanja Su, Katie Lehman1, Steve Correia1, Stephen Salloway1, Sean Deoni2

1Department of Psychiatry and Human Behavior, Brown Medical School, 2Department of Engineering, Brown University

Hypothesis

Objectives

Background

• Toexaminethemyelinintegrityofcerebralwhitematteranditsrelationshiptoactivitiesofdailyliving(ADLs)inpatientswithAlzheimer’sDisease.

Alzheimer’s Disease (AD)• Debilitatingneurodegenerativediseasecharacterizedbyprogressivedeclineinmemoryandothercognitivedomainsleadingtoimpairmentineverydayfunctioning1.

• Characterizedpathologicallyingreymatter(GM)byextraneuronalamyloid-beta42(Aß42)plaquesandintranueronalhyperphosporylatedtauneurofibrillarytangles2.Whitematter(WM)pathologyincludesaxonloss,gliosis,andreducedmyelinintegrity3.

• Aß42istoxictooligodendrocytes3providingapossiblemechanismformyelinloss.MousemodelsofADshowearlymyelinchanges4.

• CouldmyelinlossbeanearlymarkerofAD?Myelin Imaging• Multi-componentDrivenEquilibriumSinglePulseObservationofT1andT2(mcDESPOT)isanewMRItechniqueformeasuringmyelinintegrity(myelinwatercontent)incerebralwhitematter5.ReportedhereistheT1componentofmcDESPOT.

• HigherT1valuesarelinkedtoincreasedmyelinwatercontent(decreasedmyelinintegrity).

Disability Assessment for Dementia (DAD)• Informant-basedinterview-formatassessmentofinstrumentalandbasicalActivitiesofDailyLiving(ADLs)inpatientswithAD1.

• MeasuresactualADLsperformance,notestimatedcapacity,overprevious2weeksin3aspectedforeachactivity:initiation,planning&organization,effectiveness.Higherscoresindicatebetterperformance.

• PriorstudieslinkimpairmentinfrontalbrainsystemstodeclineinexecutiveandADLsfunctioning6.

• Myelinintegritywoulddecreaseacrossthespectrumofcognitivelynormalelderlytomoderate-to-severeAD,asevidencebydecliningT1values.

• InpatientswithpresumedADpathology,functionalstatus(i.e.,DADscore)wouldberelatedtodecreasedmyelinintegrityinanteriorwhitematterregions,butnotposteriorregions.

Participants&Procedures

• 16patients,maleandfemale,withnormalcognitivestatus,MCI,mildAD,andmoderate-to-severeAD.

• ParticipantsunderwentMRIwithmcDESPOTandcompletedabatteryofneuropsychologicaltests,includingLetter-NumberSequencingandStroopColor-WordtomeasureexecutivefunctionsandtheDAD.

Figure 1:ROIsin (A)genuofCC,(B)spleniumofCC,(C)anteriorWM,and(D)posteriorWM.

ImageAnalysis

Regions of Interest (ROIs)• SquareROIsplacedinspleniumandgenuofcorpuscallosumandbilaterallyinanteriorandposteriorWMoncoronalT1maps.

• 5x5or3x3voxelROIsononesliceofspleniumandgenu;3x3voxelROIson3contiguousslicesofanteriorandposteriorWM (SeeFigure1).

Summary of ROIs for Statistical Analysis• FoursummarywhitematterregionvariableswerecalculatedshowingthemeanT1valuesforthecombinedROIsineachregionasfollows:genu,splenium,andanteriorandposteriorWM(left-rightcombined).

Results

Demographics• ExploratorygroupcomparisonsusingANOVAshowednosignificanteffectofage(p=0.082)oreducation(p=0.264).Genderwasnotstatisticallyanalyzedduetosmallgroupsize(SeeTable1).

Table 1:Demographics(mean+SD)Control MCI MildAD M-to-SAD(n=4) (n=5) (n=3) (n=4)

Age 72.0+5.6 73.4+9.1 81.3+2.1 83.0+5.0

Education 14.0+2.3 15.2+4.6 10.0+3.5 12.0+3.3

Female 4 2 3 2

Male 0 3 0 2

Table 2:DADandCognitiveTests(mean+SD)Control MCI MildAD M-to-SAD(n=4) (n=5) (n=3) (n=4)

DAD 39.8+0.5 37.6+2.3 28.7+5.8 19.0+1.2

MMSE 28.5+2.4 26.4+3.8 15.0+7.2 13.8+5.5

EXEC* 0.25+0.6 -1.03+0.9 -2.06+0.9 -2.04+0.7

*EXECreferstomeandemographicallycorrectedzscoresforL-NSeqandStroopColor-Word.

DAD and Cognitive Tests• ANOVAshowedmaineffectsofDAD,MMSE,andEXEC(allp>0.005)(SeeTable2).

Table 3:T1values(ms)byregion(mean+SD)Control MCI MildAD M-to-SAD(n=4) (n=5) (n=3) (n=4)

Genu 1010.8+14.7 1101.3+186. 1018.1+21.1 1196.2+238.

Ant.WM 1154.7+3.24 1169.5+63.4 1196.3+56.2 1228.3+68.9

Splenium 1055.5+45.0 1017.9+31.3 1049.2+48.8 1095.1+65.4

Post.WM 1286.8+11.3 1212.9+19.8 1290.0+38.7 1306.6+63.1

Myelin Integrity (T1 values)• ANOVAshowedmaineffectofposteriorWM(p=0.012)(SeeTable3).

Figure 2:BivariatecorrelationsbetweenDADscores&T1valuesof (A)genuofCC,(B)spleniumofCC,(C)anteriorWM,and(D)posteriorWM.Scatterplotisnotcorrectedforage.

Table 4:PartialcorrelationbetweenregionalT1valuesandDADcontrollingforage

r p

Genu -0.434 0.18

Ant.WM -0.208 0.54

Splenium -0.676 0.02

Post.WM -0.676 0.02

Patientgroupsonly.

Correlations• DADcorrelatedsignificantlywithspleniumofCCandposteriorWM,butnotwithgenuofCCandanteriorWM(SeeTable3).

• Whenexecutivemeasureswereincludedasanadditionalcontrolvariableinpartialcorrelation,theassociationbetweenDADandposteriorWMremainedsignificant(p=0.046),butitsassociationwithspleniumbecamenon-significant(p=0.059).

• TheseresultsprovideevidenceofanassociationbetweenposteriormyelinintegrityinADandADLs.

• Thisevidenceextendsourpreviousfindingofanassociationbetweenmyelinintegrityandcognitiveimpairmentinthesamesample(datanotshown).

• ThisresultsuggeststhattheposteriorprogressionofADpathologyalterstheassociationbetweenage-relatedanteriorWMchangesandfunctionalcapacity6.Thatis,itraisesthepossibilitythatposteriormyelindegradationimpactstheupstreamassociationbetweenfrontalcircuitsandADLs.

• Ourresultstentativelysuggestthattheassociationbetweenposteriormyelin(asmeasuredbyT1values)andfunction(DAD)inpatientswithpresumedADpathologyisnotfullyaccountedforbyexecutivefunction.

• Thesepreliminaryresultsarelimitedbythesmallsamplesizeandtheheterogeneityofclinicaldementiaseverity.

• AnalysesarecurrentlyunderwaytodeterminewhetherdecreasedmyelinintegritycontributestoADLsfailurebeyondotherneuroimagingmarkersofdiseaseseveritysuchascorticalthicknessandhippocampalvolume.

Discussion

[1]Gauthier,S.,Gelinas,I.,&GauthierL.International Psychogeriatrics9,163-5.(1997).[2]Pauwels,E.,Volterrani,D.,Mariani,G.Drug News Perspective22,151-60.(2009).[3]Sjobeck,M.,Haglund,M.,Englund,E.Internal Journal of Geriatric Psychiatry20,919-26. (2005).[4]Desai,M.etal.Glia57,54-65.(2009).[5]Deoni,S.etal.Magnetic Resonance in Medicine60,1372-87.(2008).[6]Cahn-Weiner,D.,Boyle,P.,Malloy,P.Applied Neuropsychology9,187-91.(2002).

References

ThisstudyissupportedbytheAlzheimer’sAssociation(NIRG-09-131008)andProvidence,RI’sDepartmentofVeteran’sAffairs.