Physical Activity Predicts Population-Level Age-Related Differences in Frontal White Matter

This is a sel -a chi ed e sion o an o iginal a icle. This e sion may di e om he o iginal in pagina ion and ypog aphic de ails. Au ho (s): Ti le: Yea : Ve sion: Copy igh : Righ s: Righ s u l: Please ci e he o iginal e sion: CC BY 4.0 h ps://c ea i ecommons.o g/licenses/by/4.0/ Physical Ac i i y P edic s Popula ion-Le el Age-Rela ed Di e ences in F on al Whi e Ma e © 2018 he Au ho (s) Published e sion S ömme , Juho; Da is, Simon W.; Henson, Richa d N.; Tyle , Lo aine K.; Conso ium, Camb idge Cen e o Ageing and Neu oscience; Campbell, Ka en L. S ömme , J., Da is, S. W., Henson, R. N., Tyle , L. K., Conso ium, C. C. F. A. A. N., & Campbell, K. L. (2020). Physical Ac i i y P edic s Popula ion-Le el Age-Rela ed Di e ences in F on al Whi e Ma e . Jou nals o Ge on ology Se ies A: Biological Sciences and Medical Sciences, 75(2), 236- 243. h ps://doi.o g/10.1093/ge ona/gly220 2020 © The Au ho (s) 2018. Published by Ox o d Uni e si y P ess on behal o The Ge on ological Socie y o Ame ica. 236 Jou nals o Ge on ology: Biological Sciences ci e as: J Ge on ol A Biol Sci Med Sci, 2020, Vol. 75, No. 2, 236–243 doi:10.1093/ge ona/gly220 Ad ance Access publica ion Oc obe 4, 2018 This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/4.0/), which pe mi s un es ic ed euse, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. O iginal A icle Physical Ac i i y P edic s Popula ion-Le el Age-Rela ed Di e ences in F on al Whi e Ma e Juho M. S ömme , PhD,1, Simon W. Da is, PhD,2 Richa d N. Henson, PhD,3 Lo aine K.Tyle , PhD,4 Cam-CAN,3,4 and Ka en L.Campbell, PhD5 1Depa men o Psychology, Uni e si y o Jy äskylä, Finland. 2Depa men o Neu ology, Duke Uni e si y School o Medicine, Du ham, No h Ca olina. 3Medical Resea ch Council Cogni ion and B ain Sciences Uni and 4Depa men o Psychology, Uni e si y o Camb idge, UK. 5Depa men o Psychology, B ock Uni e si y, S Ca ha ines, On a io, Canada. Add ess co espondence o: Juho M.S ömme , PhD, Depa men o Psychology, Uni e si y o Jy äskylä, PO Box 35, Jy äskylä FI-40014, Finland. E-mail: [email p o ec ed] Recei ed: Ap il 30, 2018; Edi o ial Decision Da e: Sep embe 17, 2018 Decision Edi o : Rozalyn Ande son, PhD Abs ac Physical ac i i y has posi i e e ec s on b ain heal h and cogni i e unc ion h oughou he li e span. Thus a , ew s udies ha e examined he e ec s o physical ac i i y on whi e ma e mic os uc u e and psychomo o speed wi hin he same, popula ion-based sample (c i ical i conclusions a e o ex end o he wide popula ion). He e, using di usion enso imaging and a simple eac ion ime ask wi hin a ela i ely la ge popula ion-de i ed sample (N=399; 18–87yea s) om he Camb idge Cen e o Ageing and Neu oscience (Cam-CAN), we demons a e ha physical ac i i y media es he e ec o age on whi e ma e in eg i y, measu ed wi h ac ional aniso opy. Highe sel - epo ed daily physical ac i i y was associa ed wi h g ea e p ese a ion o whi e ma e in se e al on al ac s, including he genu o co pus callosum, uncina e asciculus, ex e nal capsule, and an e io limb o he in e nal capsule. We also show ha he age- ela ed slowing is media ed by whi e ma e in eg i y in he genu. Ou indings con ibu e o a g owing body o wo k, sugges ing ha a physically ac i e li es yle may p o ec agains age- ela ed s uc u al disconnec ion and slowing. Keywo ds: B ain aging, Exe cise, Cogni i e decline Aging is associa ed wi h p o ound changes in b ain s uc u e, including g ay ma e a ophy and al e a ions in he in eg i y o whi e ma e (WM). Mic os uc u al changes in he in acellula and ex acellula componen s o WM occu h oughou he aging b ain, bu end o be mo e p onounced in on al associa i e ac s (1,2). These age- ela ed changes a e hough o be d i en la gely by changes in myelin, wi h axon ibe s being ela i ely una ec ed by age (3). F ac ional aniso opy (FA), an index o mic os uc u al WM in eg i y ha is sensi i e o changes in ce eb al myelin le els, as indexed by pos mo em his ology (4), declines p og essi ely wi h age in heal hy adul s, especially in hose WM ac s ha ma u e la e in li e, such as an e io pa s o co pus callosum (5). This loss o myelin in eg i y is conside ed one o he key mech- anisms unde lying no mal age- ela ed a iabili y in cogni i e pe - o mance (1,6), o en su passing g ay ma e olume es ima es in he abili y o accoun o age- ela ed cogni i e decline (7). Inc eased WM in eg i y is o en posi i ely co ela ed wi h be e pe o mance ac oss a numbe o cogni i e domains and, in some ci cums ances, WM in eg i y media es age- ela ed slowing o cogni i e p ocessing (8–12). In ac , a subs an ial po ion o he age- ela ed a iance in cogni i e p ocessing speed has been shown o be a ibu able o dec eases in on al WM in eg i y (3,13). The ole o WM s uc- u es like he genu o co pus callosum in media ing he e ec o age on cogni i e p ocessing speed has now been eplica ed many imes (2,12), and his ela ionship appea s o be speci ic o p ocessing speed and execu i e unc ioning, a he han o he aspec s o cog- ni ion (eg, language, mo o unc ioning) (10). Thus, main enance o WM s uc u al connec i i y appea s o be pa icula ly c i ical o he p e en ion o gene al age- ela ed slowing. Howe e , despi e he ubiqui y and cogni i e ele ance o hese pa e ns o change in ce e- b al WM, he speci ic media o s explaining hese e ec s—beyond ch onological age i sel —a e unclea . Al hough se e al li es yle ac o s p obably con ibu e o he main enance o WM in eg i y wi h age, one o he mos obus Downloaded om h ps://academic.oup.com/biomedge on ology/a icle-abs ac /75/2/236/5114653 by Uni e si y o Jy askyla use on 02 Feb ua y 2020 p edic o s o WM heal h appea s o be physical ac i i y. High ca - dio espi a o y i ness and engagemen in physical ac i i y ha e been shown o ha e p o ec i e e ec s o WM in eg i y (14–16) and cogni i e pe o mance (17–19) in heal hy olde adul s. E idence om p ospec i e s udies also indica es ha physical ac i i y con- side ably educes he isk o demen ia and Alzheime ’s disease (20). In e es ingly, Bu zynska and colleagues (21) showed ha no only engagemen in physical ac i i y, bu also a oiding seden a y be- ha io , is impo an o p ese ing WM mic os uc u al in eg i y la e in li e, possibly ia di e en pa hways. Seden a y li es yle is mo e likely o be associa ed wi h obesi y and poo ae obic i - ness, and is a leading cause o disease and disabili y (22), which, in u n, a e shown o be associa ed wi h lowe WM in eg i y (23). Longi udinal da a om ae obic exe cise in e en ion p og ams in olde adul s show ha he selec i e inc eases in i ness associa ed wi h ae obic exe cise, bu no low-in ensi y con ol in e en ions, p edic inc eases in WM in eg i y in he p e on al and empo al ce eb um (24) and inc eases WM olume in he an e io co pus callosum (25). As no ed ea lie , hese b ain egions a e pa icula ly ulne able o he de imen al e ec s o age. Toge he , hese s udies emphasize he po en ial bene i s o physical ac i i y in p e en ing age- ela ed WMloss. Al hough se e al s udies sugges a link be ween exe cise and di e ences in WM in eg i y wi h age (24,26), i emains o be seen whe he his ela ionship holds wi hin a la ge, popula ion-based li e span sample. Popula ion-based samples a e c i ical i ou con- clusions a e o ex end beyond ela i ely selec (and po en ially biased) samples o esea ch olun ee s o he popula ion in gene al. Mo eo e , ew s udies, i any, ha e examined he ela ionship be- ween b ain heal h and pa icipan s’ epo s o e e yday ac i i ies and ou ines (encompassing such ac i i ies as cleaning he house and mode o anspo a ion/dis ance o wo k), which a guably o e a mo e ecologically alid coun e poin o s anda d in e en ion s ud- ies (27). In his s udy, we examined he ela ionship be ween age, sel - epo ed physical ac i i y, WM mic os uc u e, and p ocessing speed wi hin a la ge, popula ion-based sample om he Camb idge Cen e o Ageing and Neu oscience (Cam-CAN) (28). Pa icipan s (N = 399) comple ed a physical ac i i y ques ionnai e (29) and se ies o cogni i e es s, including simple eac ion ime (RT) ask in hei homes, be o e unde going a se ies o s uc u al and unc ional MRI scans, which included di usion enso imaging (28). Di usion enso imaging was used o es ima e FA wi hin 21 majo ac s om he John Hopkins Uni e si y (JHU) Whi e Ma e A las and ela ed o physical ac i i y and p ocessing speed sepa a ely in a se ies o media ion models. Ou i s objec i e was o de e mine whe he physical ac i - i y media es age- ela ed decline in WM wi hin pa icula ac s and whe he hese a e he ac s ha a e mos suscep ible o age- ela ed decline. To his end, sepa a e media ion models we e un o each ac , es ing whe he he ela ionship be ween age and FA was media ed by daily physical ac i i y. Ou second objec i e was o examine whe he pe o mance on he simple RT ask is associa ed wi h WM in eg i y and whe he he age- ela ed decline in his measu e is media ed by WM in eg i y. Only hose ac s ha showed a signi ican media ion e ec o physical ac i i y in he i s model (co ec ed o mul iple compa isons) we e included in o he second se o models es ing he associa ion be ween age, FA, and RT. Thus, ou planned analyses will help o elucida e a possible explana ion o age- ela ed declines in WM heal h and p o ide e idence o he ole o his measu e in p edic ing declines in p ocessingspeed. Me hods Pa icipan s A heal hy, popula ion-based sample o 708 pa icipan s (age ange 18–88yea s) was collec ed as pa o he Cam-CAN ( o a de ailed desc ip ion o he s udy, see e . (28)). The e hical app o al o he s udy was ob ained om he Camb idgeshi e 2 (now Eas o England—Camb idge Cen al) Resea ch E hics Commi ee. Pa icipan s ga e w i en in o med consen . Exclusion c i e ia included poo ision (below 20/50 on Snellen es (30)), poo hea ing ( ailing o hea 35 dB a 1,000 Hz in ei he ea ), low Mini–Men al S a us Examina ion (24 o lowe (31)), sel - epo ed subs ance abuse (assessed by he D ug Abuse Sc eening Tes [DAST-20 (32)]), poo English knowledge (non-na i e o nonbilingual English speake ), cu en psychia ic diso de , o neu ological disease. In addi ion, people wi h con aindica ions o MRI o MEG we e excluded. Handedness was assessed using Edinbu gh Handedness In en o y (33). O he ini ial 708, 646 pa icipan s had alid T1, T2, and di usion enso imaging/di usion ku osis imaging da a. We also excluded pa icipan s who did no comple e he RT ask (n=75) and hose wi h ou lying FA alues u he han h ee imes in e qua ile ange abo e o below he age decile mean (n=25; o al emaining N=399, 221 emales, age ange 18–87yea s). The sample cha ac- e is ics a e desc ibed in Table1. Table1. Pa icipan Demog aphic In o ma ion by Age Decile Age Decile 1 2 3 4 5 6 7 N (pe cen age o he o al 399) 28 (7) 72 (18) 70 (17) 59 (15) 67 (17) 60 (15) 43 (11) Age ange (y) 18–27 28–37 38–47 48–57 58–67 68–77 78–87 Sex (male/ emale) 10/18 35/37 33/37 26/33 29/38 25/35 20/23 Highes educa ion Uni e si y 19 64 54 40 40 29 15 A’ le els 6 4 8 10 15 13 13 GCSE g ade 3 4 8 8 9 10 7 None o e 16 0 0 0 1 3 8 8 MMSE 29.18 (1.0) 29.49 (1.0) 28.94 (1.2) 29.05 (1.3) 28.93 (1.3) 28.57 (1.5) 28.02 (1.4) Simple RTmean (s) 0.34 (0.04) 0.34 (0.04) 0.35 (0.06) 0.36 (0.06) 0.38 (0.06) 0.40 (0.08) 0.41 (0.07) PAEE 43 (13) 46 (16) 52 (16) 47 (17) 38 (15) 34 (16) 25 (13) No e: MMSE=Mini–Men al S a us Examina ion; PAEE=physical ac i i y ene gy expendi u e (kJ/d/kg); simple RTmean=mean RT on he simple RT ask. Values in pa en heses a e SD. Jou nals o Ge on ology: BIOLOGICAL SCIENCES, 2020, Vol. 75, No. 2 237 Downloaded om h ps://academic.oup.com/biomedge on ology/a icle-abs ac /75/2/236/5114653 by Uni e si y o Jy askyla use on 02 Feb ua y 2020 Imaging P ep ocessing and Region-wise Analysis The MRI da a we e collec ed om a Siemens 3T TIM TRIO (Siemens, E langen, Ge many). To es ima e WM in eg i y, di usion- weigh ed images we e acqui ed wi h a wice- e ocused spin echo sequence, wi h 30 di usion g adien di ec ions each o b alues o 1,000 and 2,000s/mm2, and h ee images acqui ed using a b alue o 0 (echo ime=104ms, epe i ion ime=9.1s, oxel size=2×2× 2mm3, ield o iew=192× 192 mm2, 66 axial slices, GRAPPA accele a ion ac o =2). All p ep ocessing was comple ed using a combina ion o unc- ions om FSL e sion 4.1.8 (be , eddy, d i i , and TBSS) and cus- om MATLAB sc ip s. The di usion da a we e p ep ocessed o eddy cu en s and subjec mo ion using an a ine egis a ion model. A e emo al o nonb ain issue, a nonlinea di usion enso model was i o he di usionweigh edimage olumes. Nonlinea i ing o he di usion enso p o ides a mo e accu a e noise modeling han s and- a d linea model i ing and enables a ious cons ain s on he di - usion enso , such as posi i e de ini eness. The enso ’s eigensys em was used o compu e he FA a each oxel; FA maps we e spa ially no malized in o a s anda d s e eo ac ic space using ac -based spa- ial s a is ics (34). Images we e hen smoo hed wi h a 6mm ull wid h a hal maximum Gaussian ke nel o add ess possible esidual e o s and in e indi idual a iabili y and o ensu e he no mali y equi e- men s o pa ame ic s a is ics we e me and hen masked wi h a bina- ized e sion o each pa icipan ’s FA map, such ha oxels below an FA h eshold o 0.35 we e no conside ed o u he analysis. Nex , he mean FA alues o e 21 bila e ally symme ical ac egiono in e es s(ROIs) om he JHU Whi e Ma e A las (h p:// cm m.med.jhmi.edu/) we e ex ac ed o subsequen analysis: genu o co pus callosum, body o co pus callosum, splenium o co pus callosum, column and body o o nix, o nix (c es), ce eb al ped- uncle, an e io limb o in e nal capsule, pos e io limb o in e nal capsule, e olen icula pa o in e nal capsule, an e io co ona adia a, supe io co ona adia e, pos e io co ona adia e, pos e - io halamic adia ion, sagi al s a um, ex e nal capsule, cingu- la e gy us, hippocampus, supe io longi udinal asciculus, supe io on o-occipi al asciculus, uncina e asciculus, and ape um. Physical Ac i i y Ques ionnai e In o ma ion abou physical ac i i y ene gy expendi u e (PAEE) was ga he ed as pa o a la ge sel -comple ed ques ionnai e, which asked abou educa ion, aining, a el, hobbies, and social ac i i- ies. The ques ions abou physical ac i i y we e based on i ems om he Eu opean P ospec i e In es iga ion in o Cance S udy–No olk Physical Ac i i y Ques ionnai e (EPIC-EPAQ2) (29). The ull ques- ionnai e is p o ided in Supplemen a y Ma e ial. Indi idual o al PAEE pe day (kJ/d/kg) was calcula ed om sel - epo ed ac i i ies in o me abolic equi alen s (35,36), based on he s anda d de ini ion o 1 MET as 3.5ml O2/min/kg (o 71 J/min/kg) based on he es ing me abolic a e (37). In addi ion, PAEE was di ided in o sub ypes in ela ion o he na u e o he ac i i y o in es iga e hei con ibu ion o o al PAEE and age- ela ed di e ences in i . Wo k PAEE includes all ac i i ies pe o med a wo k; Home PAEE includes home- and housewo k- ela ed ac i i ies; Leisu e PAEE includes all olun a y leisu e ac i i y and exe cise; and Commu e PAEE includes commu - ing o wo k and o he a el. Response TimeTask In he simple RT ask, pa icipan s we e sea ed behind a com- pu e sc een and es ed hei igh hand on a esponse box wi h ou bu ons (one o each inge ). On he sc een, hey iewed an image o a hand wi h blank ci cles abo e each inge . Pa icipan s we e ins uc ed o p ess wi h he index inge as quickly as pos- sible whene e he ci cle abo e he index inge in he image u ned black. On p essing he bu on, o a e maximum 3 seconds, he ci cle became blank again, and he a iable in e ial in e al began. The in e ial in e al a ied pseudo andomly wi h posi- i ely skewed dis ibu ion, minimum 1.8 seconds, mean 3.7 sec- onds, median 3.9 seconds, and maximum 6.8 seconds. The ask included 50 ials, and mean RT was calcula ed o co ec ials a e applying a 3 SD im o he da a. S a is ical Analysis Pea son’s co ela ion coe icien s (pa ialling ou gende and educa- ion) we e compu ed o examine he ela ionship be ween age and o al PAEE. Fo he PAEE sub ypes (which we e skewed in hei dis ibu ions), Spea man’s ank co ela ion coe icien s we e com- pu ed (pa ialling ou gende and educa ion) o examine age- ela ed changes in he ypes o ac i i y con ibu ing o o alPAEE. To es whe he physical ac i i y helps o p edic he e ec s o age- ela ed WM decline, we an a se ies o media ion analyses, in which a hi d media o a iable ully o pa ially accoun s o he ela ionship be ween an independen p edic o and dependen ou - come a iables (38). In each analysis, he independen ac o was age, he dependen ac o was one o he 21 WM ac s (ie, mean FA wi hin a ac ), and he media o was he amoun o physical ac i i y (Figu e2D). Fo hose acks ha showed a signi ican medi- a ion e ec , we wen on o es he cogni i e signi icance o ha e ec by examining he ela ionship be ween WM in hose ac s and age- ela ed slowing (Figu e2). To his end, we an ano he se o media ion analyses using age as he independen ac o , simple RT as he dependen ac o and mean FA wi hin each o he p e i- ously iden i ied ac s as he media o (Figu e2E). Di ec e ec s o age on FA and RT we e also included in hese eg essions. S a is ical signi icance o media ion analyses is ypically signi ied by a signi i- can a enua ion o he ela ionship (β alue) be ween p edic o and ou come a iables, deno ed he e by a 95% con idence in e al (CI) o s anda dized eg ession coe icien ha does no c oss ze o. All signi icance es s we e wo ailed, and alse disco e y a e (39) a 0.05 was applied o p o ec agains amilywise Type Ie o . Resul s Aging and Physical Ac i i y To al PAEE, con olled o gende and educa ion, showed a g ad- ual decline wi h age, =−.37, p d < .001 (Figu e1A). This is also shown in he esul s o he media ion models as pa h a, ha is, he di ec nega i e e ec o age on o al PAEE (Table2). Wo k- ela ed ac i i y ( ho = −.52, p d < .001) and commu ing- ela ed ac i i y ( ho=−.46, p d < .001) showed mode a e nega i e co ela ions wi h inc easing age, bu home- ela ed ac i i y showed a e y weak co el- a ion ( ho=−.099, p d =.06) and leisu e ime ac i i y no co ela ion ( ho=−.09, p d =.09) wi h age (Figu e1B). To conclude, leisu e- and home- ela ed ac i i ies seem o emain s able ac oss he li e span, whe eas wo k- and commu ing- ela ed ac i i ies decline and p ob- ably con ibu e o he decline in o al PAEE. Aging and WM In eg i y The di ec e ec o age on FA was nega i e in all o he analyzed ac s, excep he pos e io limb o in e nal capsule, which showed 238 Jou nals o Ge on ology: BIOLOGICAL SCIENCES, 2020, Vol. 75, No. 2 Downloaded om h ps://academic.oup.com/biomedge on ology/a icle-abs ac /75/2/236/5114653 by Uni e si y o Jy askyla use on 02 Feb ua y 2020 a small age- ela ed inc ease in FA (Table2, pa h c). The e ec o age on FA was ela i ely la ge (s anda dized β’s < −0.5) in he genu and body o he co pus callosum, o nix, an e io co ona adia a, pos- e io halamic adia ion, sagi al s a um, and ape um (Figu e2A and C). Physical Ac i i y and WM In eg i y The i s media ion analyses es ed whe he o al PAEE media ed he age–FA ela ionships. Fou ac s showed a media ion e ec ha su i ed alse disco e y a e co ec ion: genu o co pus callosum, an e io limb o in e nal capsule, ex e nal capsule, and uncina e as- ciculus (Table2, pa h ab, Figu e2A and C). The media ion e ec s o PAEE on hese WM ac s a e posi i e (Table2, pa h ab), sugges ing ha highe physical ac i i y is associa ed wi h less age- ela ed WM degene a ion (see Figu e2A). (These e ec s emain equal when con- olling o gende and educa ion, al hough gende has a di ec e ec on FA in an e io limb o in e nal capsule [B=−0.426, SE=0.096, 95% CI = −0.616 o −0.237]. These analyses we e also un wi h body mass index as a co a ia e o in es iga e he associa ion be ween body mass index and PAEE. The e we e no associa ions be ween body mass index and PAEE, al hough body mass index has a ma - ginal di ec e ec on ex e nal capsule [ß=−0.100, SE=0.051, 95% CI = −0.200 o −0.001].) No media ion e ec s we e ound when di e en PAEE ypes we e used as media o ins ead o o al PAEE. WM In eg i y and Speed o P ocessing The second media ion analyses es ed whe he FA (in he ac s ela ed o exe cise) media ed he ela ionship be ween age and p o- cessing speed. As expec ed, age was associa ed wi h slowe espond- ing on he simple RT ask, B=0.362, CI=0.273 o 0.452, SE=0.047 (Table3, pa h c). C i ically, mean FA in he genu o co pus callosum signi ican ly media ed he e ec o age on RT (ab=0.150, CI=0.045 o 0.251, SE=0.050; Table3, pa h ab, Figu e2B), sugges ing ha p ese a ion o WM in he genu o co pus callosum is associa ed wi h less age- ela ed slowing (Figu e2B). None o he o he ac s showed signi ican media ion o main e ec s (Table3, pa h ab and c). (These e ec s emain equal when con olling o gende and edu- ca ion, al hough gende has a di ec e ec on FA in an e io limb o in e nal capsule [B=−0.426, SE=0.096, 95% CI=−0.616 o −0.237].) Discussion This s udy had wo majo aims. Fi s , we examined whe he phys- ical ac i i y media es he e ec s o age on WM in eg i y. In line wi h p e ious wo k, we ound highe physical ac i i y o ha e posi i e e ec s ha may p o ec agains he damaging e ec s o age on FA in an e io WM ac s, namely he genu o co pus callosum, uncina e asciculus, an e io limb o in e nal capsule, and ex e nal capsule. The second aim o his s udy was o examine whe he WM in eg i y wi hin he ac s ha bene i om physical ac i i y media es age- ela ed slowing o p ocessing speed. O he ou ac s es ed, only he genu o he co pus callosum media ed a signi ican po ion o he a iance be ween age and RT on a simple mo o  ask. This is he i s s udy, o ou knowledge, o show a ela ionship be ween sel - epo ed e e yday ac i i ies and FA in a popula ion- de i ed sample. Al hough ou esul s ely on a c oss-sec ional sam- ple, and hus canno ela e physical ac i i y o a es o longi udinal change, hese esul s sugges ha hose who a e mo e physically ac i e in hei day- o-day li es also ha e mo e you h-like pa e ns o WM mic os uc u e. This is consis en wi h p e ious s udies ocusing on heal hy olde indi iduals, which ha e linked highe sel - epo ed physical ac i i y o highe WM olume (40) and lesse WM a ophy (15). Objec i ely measu ed ca dio espi a o y i ness has also been shown o be associa ed wi h FA in he cingulum (23) and la ge po ion o he co pus callosum (14) in olde adul s. A ecen s udy wi h wo la ge samples o olde adul s demons a ed ha WM ac s be ween p e on al egions and medial empo al lobe a e pa icula ly associa ed wi h ca dio espi a o y i ness and ha hese associa ions media e spa ial wo king memo y pe o mance (41). In ou sample, which co e s he whole adul age ange om 18 o 87yea s, highe e e yday physical ac i i y was associa ed wi h less age- ela ed loss o WM in se e al adjacen an e io ac s. Simila ly, a ecen s udy showed ha highe ca dio espi a o y i ness, assessed wi h he max- imum olume o oxygen up ake (peak VO2), is ela ed o highe FA in se e al WM ac s in olde adul s (42). Thei s udy ound egional speci ici y in he sensi i i y o ca dio espi a o y i ness, including genu o co pus callosum as one o he esponsi e egions. As wi h he cu en esul s, hey showed ha no all WM ac s ha decline wi h age a e associa ed wi h ca dio espi a o y i ness. O e all, physical ac i i y declined wi h inc easing age. This appea s o be due la gely o a dec ease in ac i i y ela ed o wo k and commu ing, whe eas home- and leisu e- ela ed ac i i ies emained ela i ely s able ac oss he age span. These esul s a e in line wi h a ecen e iew concluding ha in childhood, habi ua ion o ac i e li es yle, like ac i e a el o ou doo play, a e impo an Figu e1. (A) The e ec o age on o al physical ac i i y ene gy expendi u e (PAEE). (B) The e ec o age on PAEE sub ypes o home-, wo k-, leisu e-, and commu ing- ela ed ac i i ies. Jou nals o Ge on ology: BIOLOGICAL SCIENCES, 2020, Vol. 75, No. 2 239 Downloaded om h ps://academic.oup.com/biomedge on ology/a icle-abs ac /75/2/236/5114653 by Uni e si y o Jy askyla use on 02 Feb ua y 2020 con ibu o s o o al daily physical ac i i y, whe eas in adul hood, li e e en s ha e he g ea es in luence on physical ac i i y beha io (43). In he p esen da a, a d op in wo k- ela ed ac i i y a ound Table2. Media ion Models Tes ing he Media ion o he Rela ionship Be ween Age and Whi e Ma e In eg i y (F ac ional Aniso opy) in Genu o Co pus Callosum, An e io Limb o In e nal Capsule, Ex e nal Capsule, and Uncina e Fasciculus by Physical Ac i i y Ene gy Expendi u e Whi e Ma e T ac Pa h a (Age → PAEE) Pa h b (PAEE → FA) Pa h ab (Media ion E ec ) Pa h c′ (Residual Age → FA) Pa h c (Age → FA) B (95% CI) B SE p B (95% CI) B SE p B (95% CI) B SE B (95% CI) B SE p B (95% CI) B SE p Genu o co pus callosum −0.382 (−0.474 o −0.291) 0.046 8.24 <.001 0.092 (0.019 o 0.164) 0.037 2.50 .017 −0.035 (−0.066 o −0.006)* 0.015 −0.696 (−0.768 o −0.623) 0.037 18.89 <.001 −0.731 (−0.798 o −0.664) 0.034 21.34 <.001 An e io limb o in e nal capsule −0.382 (−0.474 o −0.291) 0.046 8.24 <.001 0.118 (0.014 o 0.221) 0.053 2.23 .033 −0.045 (−0.093 o −0.004)* 0.023 −0.173 (−0.277 o −0.070) 0.053 3.29 .001 −0.218 (−0.315 o −0.122) 0.049 4.46 <.001 Ex e nal capsule −0.382 (−0.474 o −0.291) 0.046 8.24 <.001 0.102 (0.005 o 0.200) 0.050 2.07 .049 −0.040 (−0.083 o −0.003)* 0.020 −0.365 (−0.463 o −0.268) 0.050 7.82 <.001 −0.404 (−0.495 o −0.314) 0.046 8.81 <.001 Uncina e asciculus −0.382 (−0.474 o −0.291) 0.046 8.24 <.001 0.141 (0.037 o 0.245) 0.053 2.66 .011 −0.054 (−0.100 o −0.013)* 0.022 −0.138 (−0.242 o −0.034) 0.053 2.61 .012 −0.192 (−0.289 o −0.096) 0.049 3.91 <.001 No es: B=s anda dized eg ession coe icien ; CI=con idence in e al; FA= ac ional aniso opy; PAEE=Physical Ac i i y Ene gy Expendi u e. *Signi ican media ion e ec s ( o all e ec s, signi icance is deno ed by a 95% CI ha does no c oss ze o; alse disco e y a e co ec ed p alue < .05). Figu e 2. (A) The ela ionship be ween whi e ma e in eg i y ( ac ional aniso opy [FA]) and age (s eepe line) and age con olled o PAEE (gen lie line) in genu o co pus callosum (GCC), ex e nal capsule (EC), an e io limb o in e nal capsule (ALIC), and uncina ed asciculus (UNC). FA dec eases g adually wi h age wi hin all o he analyzed whi e ma e ac s: GCC: = –. 731, p < .001; EC: = –. 404, p < .001; ALIC: = –. 218, p < .001; UNC: = –. 192, p < .001. The de imen al e ec o age on FA is diminished in all o he analyzed ac s when PAEE is pa ialled ou om age: GCC: = –. 688, p < .001; EC: = –. 348, p < .001; ALIC: = –. 163, p = .001; UNC: = –. 130, p = .009. The esul s indica e a posi i e ela ionship be ween highe physical ac i i y and age- ela ed di e ences in whi e ma e mic os uc u e. (B) The ela ionship be ween eac ion ime and age (s eepe line) and age con olled o whi e ma e in eg i y (FA) in genu o co pus callosum (gen lie line). Reac ion imes become g adually slowe wi h age: = .362, p < .001. The e ec o age on eac ion ime is diminished when FA in genu o he co pus callosum is pa ialled ou om age: = .156, p = .002. The esul s indica e a posi i e ela ionship be ween whi e ma e in eg i y in an e io co pus callosum and age- ela ed di e ences in eac ion ime pe o mance. (C) Whi e ma e ac ROIs om JHU FA a las. T ac s which su i e he i s s age o media ion analysis (genu, an e io limb o he in e nal capsule, and he ex e nal capsule) a e ende ed in (le o igh ) supe io axial, sagi al, and oblique iews. (D) Schema ic ep esen a ion o he media ion pa hs. PAEE media es he e ec o age on FA in genu o co pus callosum. (E) FA in genu o co pus callosum media es he e ec o age on eac ion ime. Full colo e sion is a ailable wi hin he online issue. 240 Jou nals o Ge on ology: BIOLOGICAL SCIENCES, 2020, Vol. 75, No. 2 Downloaded om h ps://academic.oup.com/biomedge on ology/a icle-abs ac /75/2/236/5114653 by Uni e si y o Jy askyla use on 02 Feb ua y 2020 60 yea s o age coincides wi h he mean e i emen age in ou sample. Thus, i may be ha people whose e e yday ac i i y is highly dependen on he ac i i ies associa ed wi h wo k show he g ea es d op in he o al ac i i y compa ed wi h hose wi h an ac i e li es yle ou side o wo king li e. Thus, i seems pa icula ly impo an o p o- mo e physical leisu e ac i i ies among e i ed olde adul s, possibly wi h he help o socie al ac ions. Age- ela ed slowing o cogni i e p ocessing has been p oposed o unde lie age- ela ed declines wi hin a ious domains o cogni ion (44). In he p esen s udy, simple RT slowed g adually wi h inc eas- ing age, which is a common inding among a ious ypes o age- ela ed e ec s on speed o p ocessing (45). Age- ela ed slowing in RT was media ed by FA in he genu o co pus callosum, bu no in he o he ac s ha ela ed o physical ac i i y. These indings a e in line wi h an ea lie s udy sugges ing ha WM de e io a ion in he an e - io pa o he co pus callosum may con ibu e o gene al age- ela ed slowing (2), hough o he s udies ha e also ela ed he splenium o co pus callosum and an e io limb o in e nal capsule (46) and mo e global WM s uc u e (12,47) o pe cep ual-mo o speed. A ecen s udy also showed ha lowe whole b ain FA is linked o ine icien b ain esponse o cogni i e demands o locomo ion (48). We acknowledge ha ou esul s do no speak o causali y because media ion analyses based on c oss-sec ional da a do no ine i ably ep esen causal ela ionships be ween age, physical ac i - i y, WM in eg i y, and RT. Ne e heless, we assume ha age, an inde- penden ac o in bo h o he media ion models, canno be changed by he in luence o o he ac o s and, u he mo e, ha psychomo o speed (RT) is a esul o ne ous sys em unc ioning (WM in eg i y), a he han he o he way ound (49). Howe e , he causal in e ac ion be ween li es yle ac o s (eg, physical ac i i y) and b ain s uc u e emains unclea : I is well known ha en i onmen and beha io , including physical ac i i y, can cause plas ic changes in he b ain, bu a he same ime, changes in b ain s uc u e and unc ion a e known o in luence beha io (ie, willingness owa d ac ion demanding phys- ical ac i i y). Fu he mo e, he s eng h o such in e ences, based on sel - epo ed ques ionnai e da a, a e necessa ily limi ed. Al hough he eliabili y o such ques ionnai es is high (50), hei absolu e alidi y is mode a e a bes . Thus, obse a ions in la ge samples such as ou s mus be alida ed wi h mo e ime-in ensi e ascula measu es, such as VO2 up ake and neu oimaging measu es o ce eb al pe usion. In addi ion, i is impo an o no e ha he Cam-CAN sample ep esen s he popula ion in he Uni ed Kingdom, and hus hese esul s may no gene alize o a non-Caucasian popula ion. To conclude, we ound ha sel - epo ed le els o physical ac i - i y media ed age- ela ed WM loss in a numbe o an e io ac s. Al hough bea ing in mind he limi a ions o c oss-sec ional da a and a media ion-based app oach, ou indings complemen he e idence om p e ious wo k sugges ing ha a physically ac i e li es yle may ha e p o ec i e bene i s agains age- ela ed s uc u al disconnec ion and cogni i e decline. The indings o his s udy u he suppo pub- lic heal h ecommenda ions abou he bene i s o leading a physically ac i e li es yle ac oss he li e span, including olde adul s. Supplemen a y Ma e ial Supplemen a y da a is a ailable a The Jou nals o Ge on ology, Se ies A: Biological Sciences and Medical Sciences online. Funding This wo k was suppo ed by he Bio echnology and Biological Sciences Resea ch Council (g an numbe BB/H008217/1). Table3. Media ion Models Tes ing he Media ion Be ween Age and Simple Reac ion Time, by Co ela ion o he Whi e Ma e In eg i y (F ac ional Aniso opy) in Genu o Co pus Callosum, An e io Limb o In e nal Capsule, Ex e nal Capsule, and Uncina e Fasciculus Whi e Ma e T ac Pa h a (Age → FA) Pa h b (FA → RT) Pa h ab (Media ion E ec ) Pa h c′ (Residual Age → RT) Pa h c (Age → RT) B (95% CI) B SE p B (95% CI) B SE p B (95% CI) B SE B (95% CI) B SE p B (95% CI) B SE p Genu o co pus callosum −0.731 (−0.798 o −0.664) 0.034 21.00 <.001 −0.205 (−0.343 o −0.067) 0.070 2.92 .004 0.150 (0.045 o 0.251)* 0.050 0.213 (0.079 o 0.346) 0.068 3.44 .001 0.362 (0.273 o 0.452) 0.046 7.92 <.001 An e io limb o in e nal capsule −0.218 (−0.315 o −0.122) 0.049 4.46 <.001 −0.084 (−0.196 o 0.029) 0.067 1.46 .166 0.018 (−0.006 o 0.051) 0.014 0.344 (0.252 o 0.437) 0.047 7.30 <.001 0.362 (0.273 o 0.452) 0.046 7.92 <.001 Ex e nal capsule −0.404 (−0.504 o −0.305) 0.051 8.00 <.001 −0.039 (−0.150 o 0.072) 0.053 0.69 .525 0.016 (−0.023 o 0.061) 0.022 0.347 (0.247 o 0.447) 0.051 6.80 <.001 0.362 (0.273 o 0.452) 0.046 7.92 <.001 Uncina e asciculus −0.192 (−0.290 o −0.095) 0.050 3.87 <.001 −0.013 (−0.101 o 0.075) 0.045 0.30 .768 0.003 (−0.014 o 0.020) 0.009 0.360 (0.269 o 0.451) 0.046 7.75 <.001 0.362 (0.273 o 0.452) 0.046 7.92 <.001 No es: B=s anda dized eg ession coe icien ; CI=con idence in e al; FA= ac ional aniso opy; RT=Reac ion Time. *Signi ican media ion e ec s ( o all e ec s, signi icance is deno ed by a 95% CI ha does no c oss ze o; alse disco e y a e co ec ed p alue < .05). Jou nals o Ge on ology: BIOLOGICAL SCIENCES, 2020, Vol. 75, No. 2 241 Downloaded om h ps://academic.oup.com/biomedge on ology/a icle-abs ac /75/2/236/5114653 by Uni e si y o Jy askyla use on 02 Feb ua y 2020 Acknowledgmen s We a e g a e ul o he Cam-CAN esponden s and hei p ima y ca e eams in Camb idge o hei pa icipa ion in his s udy. We also hank colleagues a he MRC Cogni ion and B ain Sciences Uni MEG and MRI acili ies o hei assis ance. The Cam-CAN co po a e au ho consis s o he p ojec p in- cipal pe sonnel: Lo aine K Tyle , Ca ol B ayne, Edwa d T.Bullmo e, And ew C.Calde , Rhod i Cusack, Tim Dalgleish, John Duncan, Richa d N.Henson, Fiona E. Ma hews, William D. Ma slen-Wilson, James B. Rowe, Me edi h A.Sha o; esea ch associa es: Ka en Campbell, Te esa Cheung, Simon Da is, Linda Gee ligs, Rogie Kie i , Anna McCa ey, Abdu Mus a a, Da en P ice, Da id Samu, Jason R.Taylo , Ma hias T ede , Kamen Ts e ano , Janna an Belle, Ni in Williams; esea ch assis an s: Lau en Ba es, Tina Eme y, Sha on E zinçlioglu, And ew Gadie, So ia Ge base, S animi a Geo gie a, Clai e Hanley, Be h Pa kin, Da id T oy; a ilia ed pe sonnel: Tibo Aue , Ma a Co eia, Lu Gao, Emma G een, Ra ael Hen iques; esea ch in e iewe s: Jodie Allen, Gillian Ame y, Liana Amun s, Anne Ba c o , Amanda Cas le, Che yl Dias, Jona han Dow ick, Melissa Fai , Hayley Fishe , Anna Goulding, Ada sh G ewal, Geo Hale, And ew Hil on, F ances Johnson, Pa icia Johns on, Thea Ka anagh-Williamson, Magdalena Kwasniewska, Alison McMinn, Kim No man, Jessica Pen ose, Fiona Roby, Diane Rowland, John Sa gean , Maggie Squi e, Be h S e ens, Aldab a S odda , Che yl S one, T acy Thompson, Ozlem Yazlik; and adminis a i e s a : Dan Ba nes, Ma ie Dixon, Jaya Hillman, Joanne Mi chell, Lau a Villis. The p incipal pe sonnel, including Lo aine K.Tyle , o he Cam-CAN p ojec designed he s udy. Simon W.Da is and Juho M.S ömme analyzed he da a. The in e p e a ion o da a was pe o med by Juho M.S ömme , Ka en Campbell, and Simon W.Da is. The manusc ip was p epa ed by Juho M.S ömme and e ised by all he coau ho s o his s udy. All o he au ho s app o e he inal e sion o he manusc ip o be published. Con lic o In e es The au ho s decla e ha he esea ch was conduc ed in he absence o any comme cial o inancial ela ionships ha could be cons ued as a po en ial con lic o in e es . Re e ences 1. Madden DJ, Benne IJ, Bu zynska A, Po e GG, Chen NK, Song AW. Di usion enso imaging o ce eb al whi e ma e in eg i y in cogni- i e aging. Biochim Biophys Ac a. 2012;1822:386–400. doi:10.1016/j. bbadis.2011.08.003 2. Salami A, E iksson J, Nilsson LG, Nybe g L. Age- ela ed whi e ma e mic os uc u al di e ences pa ly media e age- ela ed decline in p o- cessing speed bu no cogni ion. 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