) Distinguishingnormalfrompathologicalaging(suchasAlzheimer?sDisease)isamajorscientificgoal.The projectsinthisapplicationseektoutilizelongitudinaldesign,neuroimagingtechniques,andcarefullyselected candidategenes(singlenucleotidepolymorphisms;?SNPs)tohelpuncoverbiologicalmechanismsinindividual differencesinbrainandcognitiveaging.Thiswithin-personapproachisnecessarytotrackhowanindividual (ofanyage)agesacrosstime,andtoselectivelyinvestigatetheroleofspecificrisk/protectivefactorswhile holdingothervariablesconstant(within-persondesign).HereweleveragedatacollectedfromR00NIAaward on190individualsaged20-94yearstobeginWave2follow-upinYear1andWave3inYear4ofthe proposedproject.Thiswillallowforthreewavesofdataspanning6.5yearsinafive-yearstudy,providing crucialinformationaboutindividualdifferencesinbrainandcognitiveaging.Specifically,thisprojectaimsto capitalizeontheknownbiologicaleffectsofSNPsinthedopaminergicsystem(COMTval158andDRD2C/T) andintheregulationofneuroplasticity(BDNFval66met).Agingisaccompaniedbystarkdiminutiontothe dopamineneuronsandthosemajorbrainregionstheyoriginatefromandinnervate.However,thebrainis surprisinglyplastictothesechanges,andamajorfactorinregulatingneuroplasticityisbrain-derivedgrowth factor.Thefirstspecificaimoftheprojectistoinvestigatewithin-personchangeinpersonswithorwithout predispositiontoreducedavailabilityofdopamineinthesynapsesinfrontal-parietalandfronto-striatalbrain regions.WewillexaminechangeinabilitytomodulatethiscircuitryinfunctionalMRIstudiesofcognitive challengeoverthecourseofthreefollow-uppoints.Wewillfurtherexaminethebrainstructuralchanges (degradationofwhitematterconnectivity,corticalthinning)thatmaymediatethischangeinneuralfunction,as wellascognitivedeclineorpreservationthatresultsfromthesechanges.Thesecondspecificaimwillsimilarly examinewithin-personchangesinmodulationofbrainactivationtodifficultyinpersonswithorwithout predispositiontoreducedavailabilityofneuroplasticityfactors,particularlyinlimbiccircuitryandthechangesto brainstructurethatmaymediatethesefunctionalchangesandpredictcognitiveoutcome.
Our thirdaim utilizes aninnovativeneuroimagingtechnique,NODDI(neuriteorientationdispersionanddensityimaging),toimage withmorespecificitythanpreviouslypossibletheneuriteswhichformsynapticunits.Wewillintroducethisin Wave2,withfollow-upinWave3tomeasurechangeindendrite/synapticdensity,anothermarkerof neuroplasticity.Wewillthenfurtherassociatelevelandchangeindendriticdensityinindividualsbasedon geneticriskforreducedBDNFlevelsandatriskforAlzheimer?sDiseasebyexaminingneuritedensityin amyloidpositivevsamyloidnegativeindividuals,aswellasthosewithAPOEe4positivity.Understanding biologicalmechanismsthatguideindividualstowardnormalorpathologicalaging,likeAlzheimer?sDisease, willhelpidentifywhommayrespondbesttofutureinterventionstoincreaseresiliencetoaging?seffects.
Betterunderstandingofthemechanismsthatsteeranindividualovertimetowardnormalagingoramore pathologicalagingtrajectory,suchasAlzheimer?sDiseaseisanimportantpublichealthgoal.Thisproposal seekstofollowacohortofindividualsagedacrosstheadultlifespanfor6.5yearstoinvestigatethe dopaminergic-andneuroplasticity-driveninfluencesofwithin-personchangeincognitiveandbrainaging.This projectalsoinvestigatesbetaamyloiddepositionandgeneticrisksfordevelopingAlzheimer?sDisease.
