) 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.

Public Health Relevance

Betterunderstandingofthemechanismsthatsteeranindividualovertimetowardnormalagingoramore pathologicalagingtrajectory,suchasAlzheimer?sDiseaseisanimportantpublichealthgoal.Thisproposal seekstofollowacohortofindividualsagedacrosstheadultlifespanfor6.5yearstoinvestigatethe dopaminergic-andneuroplasticity-driveninfluencesofwithin-personchangeincognitiveandbrainaging.This projectalsoinvestigatesbetaamyloiddepositionandgeneticrisksfordevelopingAlzheimer?sDisease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG056535-02
Application #
9532715
Study Section
Cognition and Perception Study Section (CP)
Program Officer
Wagster, Molly V
Project Start
2017-08-01
Project End
2022-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas-Dallas
Department
Other Health Professions
Type
Sch Allied Health Professions
DUNS #
800188161
City
Richardson
State
TX
Country
United States
Zip Code
75080
Foster, Chris M; Kennedy, Kristen M; Horn, Marci M et al. (2018) Both hyper- and hypo-activation to cognitive challenge are associated with increased beta-amyloid deposition in healthy aging: A nonlinear effect. Neuroimage 166:285-292
Kennedy, Kristen M; Foster, Chris M; Rodrigue, Karen M (2018) Increasing beta-amyloid deposition in cognitively healthy aging predicts nonlinear change in BOLD modulation to difficulty. Neuroimage 183:142-149
Horn, Marci M; Kennedy, Kristen M; Rodrigue, Karen M (2018) Association between subjective memory assessment and associative memory performance: Role of ad risk factors. Psychol Aging 33:109-118
Kennedy, Kristen M; Boylan, Maria A; Rieck, Jenny R et al. (2017) Dynamic range in BOLD modulation: lifespan aging trajectories and association with performance. Neurobiol Aging 60:153-163
Foster, Chris M; Kennedy, Kristen M; Rodrigue, Karen M (2017) Differential Aging Trajectories of Modulation of Activation to Cognitive Challenge in APOE ?4 Groups: Reduced Modulation Predicts Poorer Cognitive Performance. J Neurosci 37:6894-6901