Gray Matter Volume and Cognitive Performance During ...

In terms of brain anatomy, normal aging is associated with structural changes, on account of extensive gray matter (GM) atrophy (Raz et al., ... Articles AurelPopa-Wagner UniversityofMedicineandPharmacyofCraiova,Romania Jean-FrancoisDemonet CentreHospitalierUniversitaireVaudois(CHUV),Switzerland VincentKoppelmans TheUniversityofUtah,UnitedStates Theeditorandreviewers'affiliationsarethelatestprovidedontheirLoopresearchprofilesandmaynotreflecttheirsituationatthetimeofreview. Abstract Introduction MaterialsandMethods Results Discussion Conclusion AuthorContributions Funding ConflictofInterestStatement Acknowledgments Footnotes References SuggestaResearchTopic> DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex totalviews ViewArticleImpact SuggestaResearchTopic> SHAREON OpenSupplementalData ORIGINALRESEARCHarticle Front.AgingNeurosci.,03August2018 |https://doi.org/10.3389/fnagi.2018.00235 GrayMatterVolumeandCognitivePerformanceDuringNormalAging.AVoxel-BasedMorphometryStudy StephenRamanoël1*,ElenaHoyau2,LouiseKauffmann2,3,FélixRenard4,CédricPichat2,NaïlaBoudiaf2,AlexandreKrainik4,5,AssiaJaillard4andMonicaBaciu2 1INSERM/CNRS,InstitutVision,SorbonneUniversity,PierreandMarieCurieUniversities(UPMC)Paris06,Paris,France 2CNRSLPNCUMR5105,UniversityofGrenobleAlpes,Grenoble,France 3CNRS,GrenobleINP,GIPSA-lab,UniversityofGrenobleAlpes,Grenoble,France 4UMSIRMaGeGrenobleHospital,UniversityofGrenobleAlpes,Grenoble,France 5GrenobleInstituteofNeuroscience,UniversityofGrenobleAlpes,Grenoble,France Normalagingischaracterizedbydeclineincognitivefunctioninginconjunctionwithextensivegraymatter(GM)atrophy.AfirstaimofthisstudywastodetermineGMvolumedifferencesrelatedtoagingbycomparingtwogroupsofparticipants,middle-agedgroup(MAG,meanage41years,N=16)andolderadults(OG,meanage71years,N=14)whounderwentanmagneticresonanceimages(MRI)voxel-basedmorphometry(VBM)evaluation.TheVBManalysesincludedtwooptimizedpipelines,forthecortexandforthecerebellum.Participantswerealsoevaluatedonawiderangeofcognitivetestsassessingbothdomain-generalandlanguage-specificprocesses,inordertoexaminehowGMvolumedifferencesbetweenOGandMAGrelatetocognitiveperformance.OurresultsshowsmallerbilateralGMvolumeintheOGrelativetotheMAG,inseveralcerebralandrightcerebellarregionsinvolvedinlanguageandexecutivefunctions.Importantly,ourresultsalsorevealedsmallerGMvolumeintherightcerebelluminOGrelativetoMAG,supportingtheideaofacomplexcognitiveroleforthisstructure.Thisstudyprovidesabroadpictureofcerebral,butalsocerebellarandcognitivechangesassociatedwithnormalaging. Introduction Normalagingisassociatedwithvariousbehavioral,cognitiveandcerebralchangesthataffectmultiplefunctionssuchasattention(Geerligsetal.,2014),workingmemory(Nybergetal.,2012),processingspeed(Seidleretal.,2010)andcognitivecontrol(Coppinetal.,2006;Salthouse,2010;Marchandetal.,2011).Thedegreeofcognitivedeclineisnotidenticalforallcognitiveprocesses,i.e.,somefunctionsundergomoreseverechangethanothers.Forexample,whileexecutivefunctionsaretypicallythefirsttoshowimpairmentduringnormalaging,languageabilitiesremainrelativelyintact(MeyerandFedermeier,2010),orevenimproveintermsofvocabulary,semanticsandspeechprocessing(Kavéetal.,2009;VerhaegenandPoncelet,2013;citedinBaciuetal.,2016).Cognitiveabilitiescanbegenerallyclassifiedasdomain-general(e.g.,executivefunctioning)anddomain-specificfunctions(e.g.,languageabilities;Fedorenko,2014;Karmiloff-Smith,2015;Karmiloff-Smithetal.,2016).Alargebodyofevidenceindicatesthatagingmodifiesthecerebralrepresentationofdomain-generalanddomain-specificcognitiveprocessesintermsoffunctionalreorganization.Forinstance,severalstudieshavereportedincreasedinvolvementofanteriorfrontalareas,relativetoposterioroccipitalandmedialtemporalareasduringtasksinvolvingbothdomain-generalanddomain-specificcognitiveprocessesassociatedwithaging(Gutchessetal.,2005;Davisetal.,2008;seeWingfieldandGrossman,2006;MorcomandJohnson,2015;Helderetal.,2016),suggestingsupplementalrecruitmentofexecutiveareastoperformagiventask.Themodulationofcerebralactivitybyperformanceisanotherimportantagingeffect.Aging,however,isnotauniformprocess,oldadultsvaryinthedegreeoftheircognitiveabilities’decline.Forexample,Wierengaetal.(2008)showedthat,inadditiontothepredominantleft-hemisphericactivationclassicallyelicitedduringwordretrieval,olderadultstendtoexhibitsupplementaryrighthemisphericactivationthatismodulatedbytheirperformance:thehighertheperformance,thehighertheactivationinrightinferiorfrontalcortex.Otherstudiesalsopointtoadissociationbetweenhigh-andlow-performingolderadults,withthelatterexhibitinglesshemisphericasymmetryreductionthantheformer(Cabezaetal.,2002). Intermsofbrainanatomy,normalagingisassociatedwithstructuralchanges,onaccountofextensivegraymatter(GM)atrophy(Razetal.,2005;Driscolletal.,2009).Itisworthnotingthat,asisthecasewithcognitivefunctions,thespatiallocalizationanddegreeofatrophyarenothomogeneousacrossthebraininolderadults(forareviewseeFjelletal.,2014).ThefrontalandtemporallobesexhibitthehighestdegreeofGMatrophy.Substantialchangeshavealsobeenobservedintheparietallobe,whereastheoccipitallobeappearstoremainrelativelyintact.RecentfindingshavealsoreportedGMvolumereductioninthecerebellum(Goodetal.,2001;Alexanderetal.,2006;Abeetal.,2008)includinganumberofcerebellarregionsthataremainlyinvolvedincognitiveratherthanmotorfunctions(Buckner,2013). Inordertononinvasivelyassessthestructuralcerebralchangesassociatedwithnormalaginginvivo,voxel-basedmorphometry(VBM)hasnowbecomearoutinemethodintheneuroimagingcommunity.TheVBMmethodenablesanautomated,quantitativeandobjectiveevaluationofthetissuevolume(GMvolume)acrossthebrain(Kurthetal.,2015).Cross-sectionalandlongitudinalstudieshavedemonstratedclearrelationshipsbetweencognitivedeclineandtheatrophyofspecificbrainregions.Forexample,reducedperformanceinepisodicmemory(EM)innormalolderadultsiscorrelatedwithreducedvolumeoftheentorhinalcortexofthemedialtemporallobe(Jessenetal.,2006).Similarly,executivedeficitsinnormalagingareassociatedwithgreateratrophyofprefrontalregions(RazandRodrigue,2006).However,onlyalimitednumberoflongitudinalstudieshaveevaluatedthelinkbetweencognitioningeneralandGM(Nybergetal.,2010;Lovdenetal.,2013;Pudasetal.,2013;Gorbachetal.,2017;Leongetal.,2017)andonlyafewwerelanguage-specific(Shaftoetal.,2010). Inthepresentstudy,weevaluatedtheeffectofage(oldergroup,OGrelativetomiddle-agedgroup,MAG)onGMvolume,usingawholebrainvoxel-relatedGManalysis,inconjunctionwithacognitive-scoreevaluation.Tothisend,wefocusedonhowGMvolumediffersbetweenMAGandOGindomain-specificregionsinvolvedinlanguageandsemanticmemorybutalsointhedomain-generalregionsinvolvedintransversalcognitiveprocessesandexecutivefunctions(i.e.,thehigh-levelcognitiveabilitiesnecessaryforsuccessfuladaptivebehaviortocopewithcomplexsituations).Moreover,giventhefactthatcerebellaratrophyoccurswithage(Goodetal.,2001;Alexanderetal.,2006;Abeetal.,2008)andasmoreandmorestudieshaveemphasizedtheimportantroleofthisstructureforcognition(seeforexampleSokolovetal.,2017)wealsoincludedaspecificpipelineforcerebellumanalyses.Incomparisonwithstandardpipelinesforwholebrainanalyses,thepresentoneallowedustoimprovetheaccuracyofinter-subjectalignmentduringnormalizationstepandremovalofsupra-tentorialGMwhichcouldbiasfinalresults.Wecarriedoutawhole-brainanalysisandspecificcerebellaranalysistoevaluateGMdifferencesbetweenmiddle-agedandolderadultsrelativetomiddle-agedadults,weexpectedoldadultstoexhibitsmallerGMvolumeincerebralandcerebellarregionsinvolvedinbothdomain-generalandspecificprocesses,suchasfrontalareasinvolvedinlanguageprocessesandexecutivefunctioning.Furthermore,weexpectedthisreducedGMvolumetobeassociatedwithdifferencesinperformanceincognitivetestsevaluatingtherespectiveprocesses. MaterialsandMethods Participants Amongthe31healthyparticipantsinitiallyincluded,weretained30whoweredividedintotwoagegroups:aMAG(N=16;11males;meanage±standarddeviation(SD):40.8±8.6years;range30–57years,andanoldergroup(OG,N=14;10males;meanage±SD:70.5±6.6years;range59–84).Theexcludedparticipantwas84yearsoldandshowedaberrant(superiorto2*SDOG)GM(543cm3)andcerebrospinalfluid(CSF)volume(706cm3)valuesrelativetothemeanCSFandGMvolumesoftheOG(CSF;mean=389cm3;SD:107cm3;GM:mean=664cm3;SD:57cm3).AllparticipantswerenativeFrenchspeakers;hadahighlevelofeducation(mean±SDMAG:4±0;OG:3.85±0.36;low-performingOG(lOG):3.85±0.36;high-performingOG(hOG):3.85±0.36)asmeasuredbythePoitrenaudquestionnaire(Kalafatetal.,2003).Therewasnodifferenceineducationlevelbetweengroups(MAGvs.OGandlOGvs.hOG).Participantswereright-handed(EdinburghHandednessInventory;Oldfield,1971);hadnormalorcorrected-to-normalvision;andreportednohistoryofneurologicaldisorderorsensorimotordysfunctions.Theotherinclusioncriteriaweretheabsenceofgeneralcognitive(MiniMentalStateExamination,MMSE;Folsteinetal.,1975)orEM(“5words”test;Duboisetal.,2002)deficits,aswellastheabsenceofanxietyanddepression(HospitalAnxietyandDepressionscale,HAD;ZigmondandSnaith,1983).Participantsgavetheirwritteninformedconsenttoparticipateinthestudywhichwasapprovedbythelocalethicscommittee(CPPN°:2014-A00569-38;ComitédeprotectiondespersonnesSudEst(SouthEastPeople’sProtectionCommittee)).ThedemographicandinclusioncriteriaarereportedinTable1. TABLE1 Table1.Demographicinformationandinclusioncriteriaforallparticipants. CognitiveAssessment Severalcognitivetestswereadministeredtoevaluatethecognitivelevelofeachparticipantintermsofdomain-generalanddomain-specificprocesses.Thedomain-generalevaluationsincludedshort-termmemory(DigitSpanMemorytest;Weschler,2008);processingspeedandmentalflexibility(TrailMakingTestpartB,TMT-B;Tombaugh,2004);visualscanningandmotorprocesses(TrailMakingTestpartA;TMT-A;Tombaugh,2004);andaglobalevaluationofexecutivefunctionsandfrontalefficiency(FrontalAssessmentBattery,FAB;DartinetandMartinaud,2005).Domain-specificevaluationsconcernedmainlylanguageandsemanticmemoryandincludedassessmentsofvocabularyandverbalintelligence(Mill-Hillvocabularyscale;Deltour,1993);lexicalretrievalandgeneration(picturenaming,PN;DO-80,Metz-Lutzetal.,1991);semanticprocessing(PyramidandPalmTreetest,PPT;HowardandPatterson,1992)andtheVerbalAutomatismstest(Beauregard,1971),whichwasusedtodeterminelevelsofoverlearnedsemanticinformation.Asthistestissensitivetoaging,olderadultsgenerallyperformbetterthanyoungerparticipants.Finally,wetestedwordfluencyusingacategoricalfluencytest(Cardebatetal.,1990),whichassessesthefollowing:integrityoflexico-semanticprocesses;strategicprocessesforsearchingandretrieval;andtheintegrityofphoneticandarticulatoryprocesses.CognitivescoresandsignificantdifferencesbetweengroupsarereportedinTable2.Basedonthesescores,theOGwasthensubdividedintohOGandlOGsubgroups(see“Results”section,Table3). TABLE2 Table2.Mean(Mean_MAG;Mean_OG)andstandarddeviation(SD_MAG;SD_OG)ofscoresobtainedoncognitivetestsineachgroupandstatisticalvalues(F,p)fortheinter-groupcomparisons. TABLE3 Table3.Cerebralregionsexhibitinganeffectofageonthegraymatter(GM)bycomparing(a)middle-aged(MAG)>older(OG)adults;and(b)older(OG)>middle-aged(MAG)adultsusingtwo-samplet-tests. MRIAcquisition Magneticresonanceimages(MRI)wereacquiredusingawhole-body3TAchievaPhilipsscanner(PhilipsMedicalSystems,Netherlands)witha32-channelheadcoilattheMRIfacilityIRMaGeinFrance.WeacquiredaT1-weightedhigh-resolutionthree-dimensionalanatomicalvolume,byusinga3DModifiedDrivenEquilibriumFourierTransform(MDEFT)sequence(numberofslices=160,echotime(TE)=3.98ms,repetitiontime(TR)=25ms,flipangle=15°,fieldofview(FOV)=256×240×160mm,acquisitionresolution0.94×0.96×1.00mm,acquisitionmatrix272×249,reconstructionmatrix288×288,resolutionreconstruction0.89×0.83×1).Noneoftheparticipantsexhibitedabnormalitiesinbrainstructures. DataProcessing CognitiveScores TheeffectofageoncognitivescoreswasdeterminedbyperformingaMANOVAanalysisontheperformanceobtainedforeachtestinMAGandinOGcontrolledforgenderandsocio-educationaleffect(see“Results”section,Table2).CognitivescoreswerenormalizedbasedonthemeanandSDconsideringallparticipants.InordertoevaluatehowcognitiveperformancevariesamongolderadultsandclassifyOGparticipantsinthehOGandlOG,wefirstevaluatedthenormaldistribution(Kolmogorov-Smirnov)ofthescoresforeachtest.Wecontrolledforoutliersbyexaminingthatscoresdidnotexceedthreetimestheinterquartileinterval. MRIData WholeBrainAnalyses DataprocessingwasperformedusingSPM12release6685(WellcomeDepartmentofImagingNeuroscience,London,UK1)implementedinMATLAB7(MathworksInc.,Natick,MA,USA).WeprocessedthedataviaDiffeomorphicAnatomicalRegistration,usingtheExponentialLiealgebraalgorithm(DARTEL,AshburnerandFriston,2005;Ashburner,2007)forthesegmentationandnormalizationsteps.TheDARTELsegmentationproceduremakesuseofanumberoftissueprobabilitymapsincludingGM,whitematter(WM),CSF,softtissue,skullandnon-brainregionsoftheimage.Aftersegmentation,weperformedavisualinspectionandaqualitycheckofthedata,byapplyingthemodules“displayonesliceforallimages”and“checksamplehomogeneityusingcovariance”implementedintheVBM12toolbox2.Next,theGM,WMandCSFtissueclassesobtainedduringthesegmentationstep,wereusedtocreateacustomtemplatebasedonoursample.Foreachparticipant,flow-fieldswerecomputedduringtemplatecreationtoprovidethetransformationmatrixfromeachnativeimagetothetemplate.Finally,imagesobtainedinthepreviousstepwerenormalizedtotheMNIspace(voxelsizeof1mmisotropic),modulatedandsmoothedusingan8-mmfullwidthathalfmaximum(FWHM)Gaussiankernel.Importantlyforsubsequentstatisticalanalyses,thetotalintracranialvolume(TICV)wascomputedfromtheGM,WMandCSFmodulatedimages.Morphologicalanalyseswereperformedwiththegenerallinearmodel(Fristonetal.,1995)withSPM12implementedinMATLAB7.WeperformedawholebrainanalysisusingtheGMimagesinatwo-samplet-testtocompareGMvolumebetweenMAGandOG.Weusedanabsoluteimplicitmaskwitharecommendedthresholdvaluefixedatp>0.2forGMvoxelanalyses(Callaertetal.,2014).Inaddition,inordertopreventpotentialbiasrelatedtobrainsizeandgenderdifferencesbetweengroups,theTICVandgenderwereincludedinthestatisticalmodel,ascovariatesofnointerest.DifferencesinGMvolumewereconsideredsignificantiftheyexceededavoxel-wisethresholdofp<0.05family-wiseerror(FWE)corrected,withaminimumclusterextentof20voxels.Finally,weconvertedtheMNIcoordinatesofvoxelswithmaximalstatisticalsignificancesintoTalairach(TalairachandTournoux,1988)coordinates,byusingtheMNi2TALfunctionMatthewBrett3tofacilitatecomparisonswithotherstudies. CerebellumAnalyses Basedonresultsreportedbypreviousstudiesshowingtheroleofthecerebelluminseveralcognitivedomains(Buckner,2013)andtodealwiththepooralignmentperformanceforcerebellarstructuresduringspatialprocessingstepsofthewhole-brainanalysis,weperformedaspecificcerebellumGMvoxelbasedanalysisusingtheSPMtoolboxSUIT(Diedrichsen,2006;Diedrichsenetal.,2009;SpatiallyUnbiasedAtlasTemplate4).Thiscerebellar-specificpipelinealsoallowedustobetterremovesupra-tentorialGMwhichcouldbiasfinalresults.First,foreachparticipant,theanatomicalscansweremanuallyreorientedinordertosetthemtotheorigin(0,0,0;anteriorcommissure).Next,theIsolatefunctionofSUITwasusedtoobtainsegmentationmapsofthecerebellum.Then,GMisolatedmapswerecorrectedtoexcludeimageswiththeGMlocatedoutsidethecerebellum.Finally,theimageswerenormalizedtotheSUITspaceusingthenewDARTELflowfieldsobtainedfromtheSUITtoolbox,modulatedandsmoothed,usinga6mmFWHMGaussiankernel. Results CognitiveScores AgingEffect AsshowninTable2,andrelativetotheOG,theMAGwerefasterforTMT-A(visualscanningandprocessingspeed;F(1,30)=−9.5p=0.005)andPPT(semanticprocessing;F(1,30)=−51.834,p<0.05).TheOGalsoproducedmorewordsthantheMAGforcategoricalfluency(F(1,30)=6.624,p=0.016).ForTMT-B(mentalflexibility)theOGhadlowerscoresthantheMAG(TMT-B,F(1,30)=23.737,p<0.05).WedidnotobserveddifferencebetweenMAGandOGontheFAB(globalfrontalfunctioning;F(1,30)=2.494,p=0.126)andonthePN(F(1,30)=0.814,p=0.375).Asexpected,theOGhadhigherscoresforverbalautomatisms(F(1,30)=10.975,p=0.003)thantheMAG.Thecognitive-testresultssuggestthatagingismainlyassociatedwithlowerperformancesfordomain-generalprocesses—and,toalesserextent,fordomain-specificprocesses. MRIMorphologicalResults WholeBrain Thewholebrainvoxel-basedGManalysesandcomparisonsbetweengroupsrevealedsignificantlysmallerGMvolumeforOGcomparedtoMAGinfrontal,parietal,temporalandoccipitalregions,aswellasofthecerebellum(Table3andFigure1).Morespecifically,weobservedbilateralGMdecreasedofthemiddle(BA10)andinferior(BA45,47)frontalgyri,insula,supramarginal(BA40),superioroccipital(BA18),cerebellum,aswellasoftherightangular(BA39),superiortemporal(BA41),leftpostero-superiortemporal(BA22)andpost-central(BA3,2,1)gyri. FIGURE1 Figure1.Cerebralregions(wholebrainanalysis)showingthesignificantdifferencesbetweengroups(olderadultsvs.middle-agedadults)onthegraymatter(GM)volume(inmm3)of(A)thefrontalcortex;(B)thetemporalandparietalcortices;and(C)theoccipitalcortexandcerebellum.Thesignificancethresholdforclustersandindividualvoxellevelwasdefinedasp<0.05family-wiseerror(FWE),correctedformultiplecomparisons(T>5.77),withextentthresholddefinedas20voxels(voxelsize=1mm3). Cerebellum Thecerebellumvoxel-wiseGManalysisusingtheSUITtoolbox(Diedrichsen,2006;Diedrichsenetal.,2009)revealedasignificantcluster(340mm3)intherightcerebellarhemisphere(p<0.05FWEcorrected)reflectingdecreasedGMvolumeintheOG.ThelocationofthisregioncorrespondstothelobulecrusIoftherightcerebellarhemisphere(Figure2).Thisresultwasdisplayedonatwo-dimensionalcerebellumtemplateimplementedintheSUITtoolbox(DiedrichsenandZotow,2015).Figure3showsacomparisonofthetwospatialprocessingpipelinesused. FIGURE2 Figure2.Cerebellumregion(cerebellaranalysis)showingsignificantdifferencesbetweengroups(olderadultsvs.middle-agedadults)ontheGM(inmm3),andrepresentedonatwo-dimensionaltemplatewithlobulesindicatedbyromannumeralsfromItoXwithaprependedHandVforthehemisphericandvernalcompartment,respectively.Onthisimage,thelargestlobuleHVIIisdividedintoCrusI,CrusII(bothcorrespondingtoHVIIa)andHVIIb.Statisticalsignificancethresholdfortheclusterlevelwassetatp<0.05FWEcorrectedformultiplecomparisons.Wereportedonlyonesignificantcluster(T=4.99)belongingtotheCrusIoftherightcerebellum,withextentthresholddefinedas20voxels(voxelsize=1mm3). FIGURE3 Figure3.Visualcomparisonofco-registrationduringspatialprocessingusing(A)theSPM-DARTELpipeline;and(B)theSUIT-DARTELpipeline. Discussion Thepresentstudyaimedtoassess:(1)howagingimpactsGMvolume;inrelationto;(2)howagingimpactsperformanceintasksinvolvingbothdomain-general(i.e.,executivefunctioning)anddomain-specificfunctions(i.e.,languageandsemanticmemory). Theolderadultsincludedinthisstudyexhibited:(a)decreasedperformanceontestsreflectingexecutivefunctioning,frontalefficiencyandprocessingspeed;and(b)difficultyinretrievingandgeneratingwordsandperformingsemanticprocessing.Olderadultsalsoshowedagreaterfrequencyofverbalautomatisms.Thesefindingsareconsistentwithpreviousstudies(Bhereretal.,2004;Zelazoetal.,2004;Huizingaetal.,2006;ColletteandSalmon,2014;Baciuetal.,2016;Boudiafetal.,2016;Hoyauetal.,2017)showingagenerallylowercognitiveperformanceinthecourseofnormalaging. Atthecerebrallevel,VBManalysescomparingtheOGtotheMAGrevealedthatagingwasalsoassociatedwithsignificantlysmallerbilateralGMvolumeinfrontal,temporal,parietalandoccipitalregions.SmallerGMvolumeinthefrontallobeconcernedfirstthemiddlefrontalgyrus,withagreaterextentintherighthemisphere.Thisregionisknowntobeinvolvedincognitivecontrolandtoplayakeyroleinreorientingattentionaccordingtothetaskdemands(Rossietal.,2009;Japeeetal.,2015).Thispatternisconsistentwithanumberofstudiesreportingchangesinthecapacitytoswitchbetweentasksortodisregarddistractorsinolderparticipants(Rajahetal.,2008,2010).GMvolumedifferencesalsoconcernedthebilateralinferiorfrontalgyrus,aswellastheleftsuperiortemporalgyrus.Theseregionsareinvolvedinmotorplanningandarticulation,andinexecutiveprocessingrelatedtoaccessingphonologicalrepresentations(Hickok,2009).Finally,significantlysmallerGMvolumeofthebilateralinsula,involvedinwordretrievalandgeneration(Abeletal.,2009)wasobservedinOGascomparedtoMAG,withanextensiveclusterinthelefthemisphere.Interestingly,theOGinthepresentstudyexhibitedlowercognitiveperformanceforanumberoflanguagetestsreflectinglexicalretrievalandgenerationandsemanticprocessing,andrecruitingexecutivefunctionssuchasswitching,inhibitionandstrategicsearchabilities,aswellasworkingmemoryprocesses(Troyeretal.,1997;BryanandLuszcz,2000).Togetherwithbehavioralresults,thesmallerGMvolumeoffrontalareasinagingobservedherethereforeappearstobeconsistentwithpreviousstudiessuggestingarelationshipbetweenexecutivedeclineandGMvolumeofthefrontallobe(Goodetal.,2001;Tisserandetal.,2004;Lemaitreetal.,2012;Manardetal.,2016). Theage-relatedsmallerGMvolumeobservedinourstudyalsopertainedtoregionsthatarepartofalargerfronto-parietalnetworkinvolvedinattentionalprocesses,includingtherightsupramarginalandangulargyri.Theseregionsareinvolvedinattentionprocessesrelatedtoexecutivefunctions(Seghier,2012)andthecontrolofattentionalshiftsinspace(Chenetal.,2012)andexerttop-downattention-switchingcontrolsignalstovisualareas(Rossietal.,2009).Thisnetwork,includingnotablytheleftfrontalcortexasahub,inrelationtothedorsalattentionalnetwork(DAN)andthedefault-mode-network(DMN),havebeenalsoreportedtoplayakeyroletomaintainthememoryperformanceinnormalandpathologicalaging(Franzmeieretal.,2017a,b).Finally,diminishedGMvolumeofthebilateralsuperioroccipitalgyriandtransversetemporalgyrus(primaryauditorycortex)wasalsoobservedintheOG.Thisresultisconsistentwithapreviousfindingthatreportedglobalthinningofthecerebralcortex,includingthecerebralregionsdedicatedtoperceptualprocessingwithage(Salatetal.,2004).Tosumup,ourfindingsofage-relatedsmallerGMvolumeinfrontal,temporalandoccipitalcorticalareasconsistentwithpreviousresults,whichsuggestthatdecreasedGMvolumeoftheseareasisassociatedwithdiminishedexecutiveefficiency(Tisserandetal.,2004).AlthoughpreviousstructuralandfunctionalstudiesoncognitiveandGMchangesinnormalagingmostlyfocusedonthecerebralcortex,thepresentstudyalsoaddressedGMchangesinthecerebellum,byusingaspecificanalysispipelineoptimizedforthisstructure.VBManalysesinthecerebellumrevealedsignificantlysmallerGMvolumeintheOGintherightlobuleHVIIa,includingthecrusIandcrusIIregions(x=−36;y=12;z=4;t-value=7.13).Overthepastdecades,evidencehasindicatedthatcerebellarfunctioningextendsbeyondthescopeofclassicalsensorimotorcontrolandisrelatedtodomainssuchasattention,language,executivefunctionandsocialcognition.Inarecentopinionarticle,Sokolovetal.(2017)assertthatcerebellarcomputations—basedonoftheirextensivereciprocalconnectionswiththefrontal,parietalandtemporalassociativecortices—areuniversalacrosssensorimotorandassociativeprocesses,alongwithtwokeyphenomena,predictionanderror-basedlearning.Recentresultsshowthatthemosthumancerebellummapsarerelatedtocerebralassociationnetworks.Furthermore,KellyandStrick(2003)foundthatlargeregionsnearcrusIandcrusIIexhibitconnectionswithprefrontalcortexarea46(whichisinvolvedinexecutiveprocesses)innon-humanprimates.Importantly,thiscorticalcircuitbetweenthecerebellumandprefrontalcortexoverlapswithregionsdedicatedtomotorcontrol(Buckner,2013).AnotherstudyrevealedthatlobuleHVIIa,includingcrusI,isconnectedtoalargeassociationnetworkinvolvedinexecutivecontrol(Habasetal.,2009).Thecerebellumisalsosignificantlyinvolvedinlanguage,socialcognitionandcognitioningeneral(Buckner,2013).RightcrusIatrophyinolderadultsmayberelatedtotheirlowersemanticcognitivescores,giventhatthisregionisconnectedtotheleftcerebralregionsthatarethoughttobeinvolvedinthesemanticdemandsoftaskprocessing(Petersenetal.,1989;Stoodley,2012).Overall,thesmallerGMvolumeinthecerebellumobservedintheOGextendspreviousfindingsonGMatrophyinnormalagingrelatedtocognitiveabilities(Lemaîtreetal.,2005;Razetal.,2005;Driscolletal.,2009)andparticularlytoexecutivefunctions. ThepresentVBMstudyhasanumberoflimitations.Inparticular,asthisanalysisisexclusivelycross-sectionalitprovidesnoinformationconcerningcausalityandtemporalchanges.ThisissueremainsparticularlyrelevantforgainingagreaterunderstandingoftheconcurrentchangesincognitivescoresandGMvolumeastheyrelatetocognitiveperformance.Indeed,onecriticalquestionremainsregardingtheextenttowhichsmallerGMvolumeinolderrelativetomiddle-agedparticipantalsovariesaccordingtocognitiveperformance.ItisforexamplepossiblethatolderadultswithhighercognitiveperformanceexhibitlessGMvolumereductionthanthosewithlowercognitiveperformance.Forexample,arecentstudyadoptedacross-sectionalapproachtostructuralMRItoinvestigatedifferencesinGMvolumeinrelationtocognitiveperformance(Nissimetal.,2017).Usingalongitudinalapproach,anotherstudy(Tisserandetal.,2004)carriedouta3-yearcomparisonofGMdensitybetweena“stable”anda“decliner”group.ThesestudiessuggestedalinkbetweenGMvolumeofthefrontallobeandcognitiveperformance,suggestingthatGMvolumeinthisregionmightbeapredictorofcognitivefunctioninginolderadults.Whenitcomestonormalorpathologicalaging,cerebralreserve(Katzman,1993;Satz,1993)andcognitivereserve(Stern,2002,2009)arekeyconceptsthatneedtobetakenintoconsideration.Cerebralreservedesignatestheamountofcerebraldeteriorationthatcanbetoleratedbeforeacriticalthresholdisreachedwhoseclinicalorfunctionalconsequencesareinevitable,whereascognitivereservereferstotheabilitytousetheavailablecerebralreservetoperformataskflexiblyandefficiently.Withrespecttothisconceptualframework,severalresearchesonanimalandhumanspositthebeneficroleforsuccessfulagingofarichenvironmentandagreatereducationtomaintaincognitiveperformancerelativelywellinfaceofage-relatedbrainmodificationsandpathology(Freretetal.,2015;Franzmeieretal.,2017a,b;Gelfoetal.,2018).However,duetotherelativelysmallsampleofolderparticipant,furtheranalysescomparingGMvolumebetweenlow-andhighperformerscouldnotbeperformedinthepresentstudy.Moreover,oursamplesizeremainstooweektodiscernsubtleGMdifferencesoradistinctpatternofresultsdependingonthesexoftheparticipants(Weineretal.,2017).Furtherstudiesincludingalargersamplewouldthusallowtopreciselytestthesehypotheses.Furtherresearch,includingthecollectionofgenetic,structuralandfunctionalbrainconnectivityinformation,isalsoneededontheindividualtrajectoriesofthebrainstructureinnormalaging,andinrelationtocognitivescores.Suchresearchwouldhelptomakethedistinctionbetweentransitionalphasesandnormalcognitiveandbrainagingpatternsinpathologicalsettings. Conclusion ThepresentVBMstudyaimedtoassesstheeffectofagingonGMandtointerpretresultsinrelationtothecognitiveperformance.Overall,thisstudyprovidedabroadpictureondomain-generalcognitivefunctioning,butalsolanguage-specificprocessesinnormalaging,aswellastheassociatedanatomicaldifferencesinthewholebrain,includingthecerebellum.AdecreaseofGMvolumewasobservedinseveralregionsinoldercomparedtomiddle-agedadults,interpretedinrelationtolowercognitivescoresintestsassessingeitherdomaingeneralorspecificprocesses.TheseresultsreplicateandfurthersupportpreviousfindingssuggestingageneraldeclineincognitiveprocessesassociatedwithsmallerGMvolumeinthecourseofnormalaging.Moreover,theseresultsemphasizetheimportanceoftakingintoaccountthecerebellumstructurewhenstudyingchangesassociatedwithnormalaging,whichclearlyextendbeyondthecerebralcortex.Thesefindingsopenupnewperspectivesforthedevelopmentandapplicationofinnovativetrainingmethodsandprogramsthataimtopromotesuccessfulnormalaging. AuthorContributions MBandNB:conceivedthestudy.NB,CP,AKandAJ:dataacquisition.SR,EHandFR:dataprocessing.SR,EH,MBandLK:manuscriptwriting. Funding ThisresearchwasfundedbyARC2“QualitédeVie&Vieillissement”RégionRhôneAlpes,FranceandbyInstitutUniversitairedeFrance(IUF).TheGrenobleMRIfacilityIRMaGewaspartlyfundedbytheFrenchprogram“Investissementd’Avenir”runbythe“AgenceNationalepourlaRecherche”:Grant“Infrastructured’AvenirenBiologieSanté”(ANR-11-INBS-0006). ConflictofInterestStatement Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest. Acknowledgments Wethanktheparticipantsofthisstudyfortheirvaluablecontributions.WethanktheGrenobleMRIIRMaGEunitforenablingustoperformtheMRIacquisitions. 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Editedby:AurelPopa-Wagner,DepartmentofNeurology,UniversityHospitalEssen,Germany Reviewedby:VincentKoppelmans,UniversityofUtah,UnitedStatesJean-FrancoisDemonet,InstitutNationaldelaSantéetdelaRechercheMédicale(INSERM),France Copyright©2018Ramanoël,Hoyau,Kauffmann,Renard,Pichat,Boudiaf,Krainik,JaillardandBaciu.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).Theuse,distributionorreproductioninotherforumsispermitted,providedtheoriginalauthor(s)andthecopyrightowner(s)arecreditedandthattheoriginalpublicationinthisjournaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionorreproductionispermittedwhichdoesnotcomplywiththeseterms. *Correspondence:StephenRamanoël,[email protected] COMMENTARY ORIGINALARTICLE Peoplealsolookedat SuggestaResearchTopic>