Participant characteristics associated with the effects of a physical and cognitive training program on executive functions

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/ Pa icipan cha ac e is ics associa ed wi h he e ec s o a physical and cogni i e aining p og am on execu i e unc ions © 2022 Ti kkonen, Tö mäkangas, Kulmala, Hänninen, Neely and Sipilä. Published e sion Ti kkonen, Anna; Tö mäkangas, Timo; Kulmala, Jenni; Hänninen, Tuomo; Neely, Anna S igsdo e ; Sipilä, Sa ianna Ti kkonen, A., Tö mäkangas, T., Kulmala, J., Hänninen, T., Neely, A. S., & Sipilä, S. (2022). Pa icipan cha ac e is ics associa ed wi h he e ec s o a physical and cogni i e aining p og am on execu i e unc ions. F on ie s in Aging Neu oscience, 14, A icle 1038673. h ps://doi.o g/10.3389/ nagi.2022.1038673 2022 nagi-14-1038673 Oc obe 19, 2022 Time: 15:6 # 1 TYPE B ie Resea ch Repo PUBLISHED 25 Oc obe 2022 DOI 10.3389/ nagi.2022.1038673 OPEN ACCESS EDITED BY Rubem C. A. Guedes, Fede al Uni e si y o Pe nambuco, B azil REVIEWED BY Kenju Shimomu a, Fukushima Medical Uni e si y, Japan Na alia Sha ashkina, Pi ogo Russian Na ional Resea ch Medical Uni e si y, Russia *CORRESPONDENCE Anna Ti kkonen [email p o ec ed] SPECIALTY SECTION This a icle was submi ed o Neu ocogni i e Aging and Beha io , a sec ion o he jou nal F on ie s in Aging Neu oscience RECEIVED 07 Sep embe 2022 ACCEPTED 06 Oc obe 2022 PUBLISHED 25 Oc obe 2022 CITATION Ti kkonen A, Tö mäkangas T, Kulmala J, Hänninen T, Neely AS and Sipilä S (2022) Pa icipan cha ac e is ics associa ed wi h he e ec s o a physical and cogni i e aining p og am on execu i e unc ions. F on . Aging Neu osci. 14:1038673. doi: 10.3389/ nagi.2022.1038673 COPYRIGHT © 2022 Ti kkonen, Tö mäkangas, Kulmala, Hänninen, Neely and Sipilä. 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 (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) and he copy igh owne (s) a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms. Pa icipan cha ac e is ics associa ed wi h he e ec s o a physical and cogni i e aining p og am on execu i e unc ions Anna Ti kkonen1*, Timo Tö mäkangas1, Jenni Kulmala2,3,4, Tuomo Hänninen5, Anna S igsdo e Neely6,7 and Sa ianna Sipilä1 1Ge on ology Resea ch Cen e , Facul y o Spo and Heal h Sciences, Uni e si y o Jy äskylä, Jy äskylä, Finland, 2Facul y o Social Sciences (Heal h Sciences) and Ge on ology Resea ch Cen e, Tampe e Uni e si y, Tampe e, Finland, 3Di ision o Clinical Ge ia ics, Cen e o Alzheime Resea ch, Depa men o Neu obiology, Ca e Sciences, and Socie y (NVS), Ka olinska Ins i u e , S ockholm, Sweden, 4Popula ion Heal h Uni , Finnish Ins i u e o Heal h and Wel a e, Helsinki, Finland, 5Neu oCen e , Depa men o Neu ology, Kuopio Uni e si y Hospi al, Kuopio, Finland, 6Depa men o Social and Psychological S udies, Ka ls ad Uni e si y, Ka ls ad, Sweden, 7Enginee ing Psychology, Luleå Uni e si y o Technology, Luleå, Sweden Backg ound: Physical and cogni i e in e en ions ha e been shown o induce posi i e e ec s on olde adul s’ execu i e unc ioning. Howe e , since pa icipan s wi h di e en backg ound cha ac e is ics may espond di e en ly o such in e en ions, we in es iga ed whe he aining e ec s on execu i e unc ions we e associa ed wi h sex, aining compliance, and age. We also in es iga ed i change in global cogni ion was associa ed wi h physical and cogni i e aining in e en ion-induced changes in execu i e unc ions. Me hods: Explo a o y da a om a andomized con olled ial we e analyzed. Pa icipan s we e 70–85-yea -old men and women who ecei ed a 12- mon h physical (PT) o physical and cogni i e aining (PTCT) in e en ion. Measu emen s o execu i e unc ions ela ed o inhibi ion (S oop), se shi ing (T ail Making Tes B) and upda ing (Ve bal Fluency) we e pe o med a baseline and 12 mon hs. Da a we e analyzed using a longi udinal linea pa h model o he wo measu emen s occasion. Resul s: S oop imp o ed signi ican ly mo e in women and pa icipan s in he low compliance subg oup who ecei ed PTCT han in coun e pa s in he PT subg oup (di e ence –8.758, p= 0.001 and di e ence – 8.405, p= 0.010, espec i ely). In addi ion, TMT B imp o ed a e he in e en ion in he low compliance PTCT subg oup and wo sened in he co esponding PT subg oup (di e ence –15.034, p= 0.032). No o he signi ican associa ions we e obse ed. F on ie s in Aging Neu oscience 01 on ie sin.o g nagi-14-1038673 Oc obe 19, 2022 Time: 15:6 # 2 Ti kkonen e al. 10.3389/ nagi.2022.1038673 Conclusion: Execu i e unc ions in women and in he pa icipan s, who only occasionally engaged in aining showed g ea e imp o emen a e he PTCT han PT in e en ion. Howe e , he addi ional ex a bene i gained om he PTCT in e en ion was uniquely exp essed in each execu i e unc ion measu ed in his s udy. KEYWORDS olde adul s, execu i e unc ions, aining esponse, physical aining, physical and cogni i e aining In oduc ion Execu i e unc ions a e high-o de cogni i e unc ions ha enables independen , app op ia e and sel -se ing beha io (Ha ada e al.,2013). I is gene ally ag eed ha execu i e unc ions a e consis o h ee sub-domains, inhibi ion, se shi ing and upda ing ha a e uni ed bu show also di e si y and se e as a base, o example, o p oblem sol ing, easoning and planning (Miyake e al.,2000;Diamond,2013). Execu i e unc ions has been shown o be p one age- ela ed decline (Ha ada e al.,2013), howe e his decline can be a enua ed wi h aining (Diamond,2013). Physical and cogni i e in e en ions ha e been shown o induce posi i e e ec s on olde adul s’ execu i e unc ioning (Ten B inke e al.,2020;Sipilä e al.,2021;Han e al.,2022). Howe e , pa icipan s wi h di e en baseline cha ac e is ics may espond di e en ly o di e en aining in e en ions. To de elop op imized in e en ions and guidelines o execu i e unc ioning among olde people, he ac o s ha may in luence aining esponses need o be iden i ied. The esul s o PASSWORD, ou ea lie andomized con olled s udy (Sipilä e al.,2021), showed ha a 12-mon h mul icomponen physical aining p og am combined wi h compu e -based cogni i e aining imp o ed execu i e unc ions ela ed o inhibi ion mo e compa ed o physical aining alone among olde adul s who did no mee physical ac i i y guidelines a baseline. Howe e , no signi ican in e en ion-induced changes be ween he s udy g oups we e obse ed in o he domains o execu i e unc ions namely se shi ing o upda ing. P e ious esea ch indings sugges ha he aining esponse o physical and cogni i e aining (PTCT) in e en ions a e depended on sex, aining equency and age, al hough o he p e ious s udies a e somewha inconsis en . Fo example, me a-analysis by Ba ha e al. (2017) ound ha women execu i e unc ioning gained g ea e bene i om physical aining in e en ions compa ed o men. Howe e , ecen andomized con olled ial (Roig-Coll e al.,2020) did no ound sex di e ences in exe cise e icacy a e combined PTCT. Addi ionally, p e ious me a-analysis has sugges ed ha high equency o combined PTCT (5 imes a week o mo e) is ine icien o execu i e unc ions (Zhu e al.,2016). Physical aining, in u n, has been sugges ed o be mos bene icial o execu i e unc ions when aining equency is a he equen (3–5 imes a week) in me a-analysis by Ka e al. (2014). Mo eo e , p e ious me a-analyses ha e been shown ha , among olde adul s, olde age was associa ed wi h g ea e posi i e in e en ion induced change in execu i e unc ions a e combined PTCT (Zhu e al.,2016;Han e al.,2022). Conce ning he physical aining i migh be ha age does no ha e a simila ole (Ka e al.,2014). Finally, be e global cogni ion has been show o co ela e wi h be e pe o mance in execu i e unc ions (Shao e al.,2020). In his hypo hesis-gene a ing analysis, we in es iga ed whe he he aining esponses obse ed in di e en domains o execu i e unc ioning, inhibi ion, se shi ing and upda ing we e dependen on sex, aining compliance o age. We u he in es iga ed i change in global cogni ion was associa ed wi h in e en ion-induced change in execu i e unc ions sub- domains. Me hods S udy design This s udy u ilized da a om ou ea lie assesso -blinded andomized con olled ial.1The s udy design and he esul s ha e been published p e iously (Sipilä e al.,2018,2021). E hical app o al o he s udy was ob ained om he E hical Commi ee o Cen al Finland Heal h Ca e Dis ic (14/12/2016, e : 11/2016). All pa icipan s ga e a w i en consen be o e he baseline measu emen s. Pa icipan s Pa icipan s we e 70–85-yea -old communi y-dwelling men and women li ing in Jy äskylä, Finland and we e andomly 1h p://www.is c n.com/ISRCTN52388040 F on ie s in Aging Neu oscience 02 on ie sin.o g nagi-14-1038673 Oc obe 19, 2022 Time: 15:6 # 3 Ti kkonen e al. 10.3389/ nagi.2022.1038673 ex ac ed om Finland’s Popula ion In o ma ion Sys em adminis e ed by he Popula ion Regis e Cen e . The inclusion c i e ia we e willingness o pa icipa e, no mee ing physical ac i i y guidelines (less han 150 min o mode a e ac i i y/week and no egula esis ance aining), abili y o walk 500 me e s wi hou assis ance, and a Mini-Men al S a e Examina ion (MMSE) sco e ≥24. The exclusion c i e ia we e a se e e ch onic condi ion and/o medica ion a ec ing cogni i e and/o physical pe o mance, any con aindica ion o walking o physical aining o walking es s, dep essi e mood (GDS- 15 >5 poin s and no ha ing he sel - epo ed o physician and p ima y in es iga o -assessed esou ces o commi o he s udy), isk-le el use o alcohol (>7 uni s pe week o women and 14 o men), o any o he con aindica ions o physical aining o ano he membe o he household pa icipa ing in he PASSWORD-s udy. A e exclusions, 314 pa icipan s we e ec ui ed o he s udy. Randomiza ion and blinding Pa icipan s we e andomized in a 1:1 a io and s a i ied by age (70–74, 75–79, 80–85) and sex in o he PTCT (n= 155) o Physical T aining alone (PT) (n= 159) g oups. In e en ions The in e en ions ha e been desc ibed p e iously (Sipilä e al.,2021). In b ie , bo h g oups ecei ed a 12-mon h mul icomponen p og essi e physical aining in e en ion which was designed on he basis o physical ac i i y guidelines and ea lie s udies (Sih onen e al.,2004;Po egijs e al., 2008;Fielding e al.,2011). The PT in e en ion included wo supe ised aining sessions a week, one o esis ance and balance exe cises and he o he o walking and dynamic balance exe cises. Resis ance and balance exe cises included sho wa m-up, balance exe cises and s eng hening esis ance exe cises o lowe limbs, unk, and uppe body. Walking and dynamic balance sessions included 10-min wa m-up and dynamic balance aining, ollowing 10–20 min con inuously walk wi h a ge in ensi y o somewha ha d o ha d. Supe ised esis ance aining session ook place in senio gyms equipped wi h machines u ilizing ai p essu e echnology.2Supe ised walking and dynamic balance aining sessions ook place ou doo s excep du ing win e mon hs indoo spo s hall. In addi ion, pa icipan s ecei ed a p og essi e home exe cise p og am which was ins uc ed o pe o m 2–3 imes a week. Home exe cise p og am included s eng h exe cises o lowe limbs, balance exe cises and s e ching. The PTCT g oup ecei ed also 12-mon h p og essi e compu e -based cogni i e 2h p://www.hu . i/en aining in e en ion a ge ed a imp o ing execu i e unc ions. Pa icipan s we e ins uc ed o pe o m cogni i e aining 3–4 imes a week. Measu emen s Execu i e unc ions we e assessed a baseline, 6 and 12 mon hs. O he ou comes we e assessed a baseline and 12 mon hs. This s udy u ilized da a om he baseline and 12 mon hs measu emen s o all ou comes. Execu i e unc ions Inhibi ion was assessed wi h he Colo -Wo d S oop es . In his es pa icipan s we e eques ed o name colo s in incong uen and cong uen condi ions. Finally, he ime di e ence be ween wo condi ions was calcula ed and used as he ou come (G a e al.,1995). Se shi ing was assessed wi h he T ail Making Tes Pa B. This es equi es pa icipan s o al e na ely combine numbe s and le e s as quickly as possible (Rei an,1958). Upda ing was assessed wi h he Ve bal Fluency Tes . This es equi es pa icipan s o name as many wo ds beginning wi h P, A o S as hey can in h ee sepa a e 1-min ials (Koi is o e al.,1992). The o al sco e is he summed numbe o he named wo ds. Pa icipan cha ac e is ics Subg oup analyses on age, sex, global cogni ion, and aining compliance we e p e-speci ied o walking speed, he main ou come, o PASSWORD (Sipilä e al.,2021). Pa icipan sex and age we e d awn om Finland’s Popula ion In o ma ion Sys em adminis e ed by he Popula ion Regis e Cen e . Global cogni ion was assessed a baseline and a e he in e en ions wi h he Conso ium o Es ablish a Regis y o Alzheime ’s Disease (CERAD) (Chandle e al.,2005;Paajanen e al.,2010). Compliance was based on pa icipa ion in supe ised aining sessions. The high-compliance PT subg oup pa icipa ed in a leas 50% and he low-compliance PT subg oup in less han 50% o he supe ised PT sessions. The high-compliance PTCT subg oup pa icipa ed in a leas 50% o he supe ised PT sessions and pe o med Cogni i e aining (CT) a leas wice a week. The low compliance PTCT subg oup pa icipa ed in less han 50% o he supe ised PT sessions and/o pe o med CT less han wice a week. The mean compliance o each p og am (walking and dynamic balance sessions: 59% in he PT g oup and 62% in he PTCT g oup. Resis ance and balance sessions: 72% in PT g oup and 77% in PTCT g oup. Cogni i e aining: on a e age 1.9 imes a week) has been published p e iously (Sipilä e al.,2021). Desc ip i e a iables Body heigh and weigh we e measu ed a baseline, and BMI was calcula ed. Educa ion, cu en physical ac i i y, smoking F on ie s in Aging Neu oscience 03 on ie sin.o g nagi-14-1038673 Oc obe 19, 2022 Time: 15:6 # 4 Ti kkonen e al. 10.3389/ nagi.2022.1038673 s a us, and sel - a ed heal h we e sel - epo ed. Educa ion was ca ego ized as low (p ima y school o less) medium (middle school, olk high school, oca ional school, o seconda y school) o high (high school o uni e si y). Cu en physical ac i i y was assessed wi h a se en-poin scale (Hi ensalo e al.,2000) and e- ca ego ized as high (ca ego ies 5–7) medium (ca ego ies 3 and 4) o low (ca ego ies 1 and 2). Smoking s a us was ca ego ized as ne e smoke s (ne e smoke /less han 100 imes), o me smoke s (ne e smoked egula ly bu smoked o e 100 imes) o cu en smoke (cu en smoke , egula ly o occasionally). Sel - a ed heal h was epo ed as e y good/good o a e age/poo . S a is ical analyses As desc ip i e s a ics we epo he means and s anda d de ia ions o con inuous a iables and equencies and pe cen ages o ca ego ical a iables sepa a ely o PT and PTCT g oups. To iden i y po en ial ou lie s o he ou come a iables o he main analyses, he ou come dis ibu ions we e inspec ed g aphically using uni a ia e his og ams and quan ile plo s and bi a ia e sca e plo s. Skew and ku osis we e conside ed as summa y s a is ics o dis ibu ion shape. While he plo s, skew, and ku osis (absolu e alue less han uni y) indica ed accep able shape o dis ibu ion o all a iables. Fo he analyses, he ou comes we e eg essed wi hin measu emen wa es in a wo-g oup linea pa h model accoun ing o longi udinal co ela ion in he ou come a iables. Using cus om con as s, we compu ed he di e ences in he eg ession coe icien s om he measu emen wa es as he e ec s o ime, and he di e ence in hese ime e ec s be ween g oups was compu ed as he in e ac ion e ec . Ou comes we e es ed o g oup-in e ac ion o e ime using an in e ac ion con as in a linea model o he wo longi udinal measu emen s. The model s uc u e was se simila o he linea mixed model in o de o accoun o wi hin-pe son co ela ion, bu i also pe mi ed mo e gene al ou come a iance s uc u e speci ica ion and lexible handling o missing da a wi h he maximum likelihood app oach based on he missing-a - andom (MAR) assump ion. Fo con inuous exposu e a iables (age and Ce ad) he model included a wi hin-subjec pa o he epea ed measu emen s o each subjec , and a be ween-subjec s pa con as ing he PTCT and PT g oups based on eg ession coe icien di e ences. A simila model was used o bina y exposu e a iables (sex and aining compliance), bu now he con as was based on di e ences in expec ed ma ginal means. We epo g oup means o each a ailable measu emen wa e and g oup-by- ime in e ac ions as p ima y signi icance es s. As u he subg oup con as s, we also compa ed i he backg ound ac o s and desc ip i e a iables di e ed be ween PTCT and PT g oups among men and women and high and low compliance g oups. This analysis was ca ied ou in SPSS o windows, e sion 26. The speci ic con as s used o all compa isons a e shown in he model and con as speci ica ion sec ion o he supplemen a y documen . The pa h model analyses we e conduc ed in Mplus, e sion 7.4 (Mu hen and Mu hén,2017). Resul s Pa icipan s’ mean age was in PT g oup was 74.4 and in PTCT g oup 74.5 yea s, app oxima ely 60% o pa icipan s we e women in bo h g oups, 25% in PT g oup and 18% in PTCT g oup had he high le el o educa ion (Table 1). Ou p e ious s udy, sugges ha PTCT g oup imp o ed signi ican ly mo e hei pe o mance in S oop han PT g oup (Sipilä e al.,2021). This subg oup analysis shows ha women, and he low-compliance g oups in PTCT imp o ed S oop pe o mance signi ican ly mo e han in he co esponding PT subg oups (di e ence -8.758, p= 0.001 and di e ence - 8.405, p= 0.010, espec i ely) (Table 2). In men and he high-compliance subg oups, no signi ican di e ences be ween TABLE 1 Pa icipan ’s cha ac e is ics. PTCT (n= 155) PT (n= 159) Age (yea s) 74.4 ±3.9 74.5 ±3.8 BMI 28.0 ±4.9 27.9 ±4.5 MMSE 27.9 ±1.4 27.4 ±1.5 CERAD 79.5 ±8 79.0 ±8.2 SEX, no (%) Feman 96 (62) 92 (58) Man 59 (38) 67 (42) Educa ion, no (%) Low 23 (15) 25 (16) Medium 94 (61) 106 (67) High 38 (25) 28 (18) Cu en physical ac i i y, no (%) Low 56 (36) 70 (44) Medium 80 (52) 68 (43) High 19 (12) 21 (13) Smoking s a us, no (%) Ne e 94 (61) 97 (61) Fo me 52 (34) 57 (36) Cu en 9 (6) 5 (3) Sel - a ed heal h, no (%) Ve y good/good 73 (47) 68 (43) A e age/poo 82 (53) 91 (57) Means and s anda d de ia ions. F equencies and pe cen ages. PTCT, Physical and cogni i e aining; PT, Physical aining; BMI, Body Mass Index; MMSE, Mini-Men al S a e Examina ion; CERAD, Conso ium o Es ablish a Regis y o Alzheime ’s Disease. F on ie s in Aging Neu oscience 04 on ie sin.o g nagi-14-1038673 Oc obe 19, 2022 Time: 15:6 # 5 Ti kkonen e al. 10.3389/ nagi.2022.1038673 TABLE 2 Means wi h 95% con idence in e als and uns anda dized eg ession coe icien s (B) wi h 95% con idence in e als o subg oup analysis o he S oop ou comes. S oopaPTCT PT PTCT-PT 95% CI 95% CI 95% CI Subg oup NMean Lowe Uppe NMean Lowe Uppe Di e ence Lowe Uppe P- alue O e all 155 BL 45.1 41.9 48.4 159 48.1 43.7 52.6 –6.766 –11.111 –2.421 0.002 FU 34.0 31.2 36.8 43.8 40.5 47.1 Men 59 BL 42.5 38.0 47.1 67 50.8 42.5 59.2 –3.575 –10.942 3.793 0.342 FU 34.6 29.8 39.4 46.5 40.8 52.2 Women 96 BL 46.7 42.3 51.2 95 46.2 41.6 50.8 –8.758 –13.873 –3.643 0.001 FU 33.6 30.2 37.0 41.8 38.0 45.7 Low compliance 95 BL 46.2 42.1 50.2 55 48.2 42.5 53.9 –8.405 –14.780 –2.031 0.010 FU 35.1 31.5 38.7 45.5 39.9 51.1 High compliance 60 BL 43.5 38.1 48.9 103 48.3 42.2 54.4 –5.966 –12.736 0.804 0.084 FU 32.3 28.0 36.6 43.0 39.0 47.1 B Lowe Uppe B Lowe Uppe Di e ence Lowe Uppe P- alue Age 155 BL 0.860 0.026 1.695 159 1.037 –0.126 2.200 0.654 –0.482 1.790 0.259 FU 1.368 0.686 2.049 0.890 0.032 1.749 CERADb141 BL –0.538 –0.939 –0.136 147 –0.691 –1.141 –0.241 –0.090 –0.655 0.474 0.754 FU –0.514 –0.810 –0.218 –0.577 –0.902 –0.252 aLowe ime indica es be e pe o mance, bComp ises e bal luency, modi ied Bos on naming es , wo d lis s cons uc ional p axis, wo d lis ecall and wo d lis ecogni ion disc iminabili y ( o al sum sco e ange 0–100). B, uns anda dized eg ession coe icien ; CI, con idence in e al; PTCT, physical and cogni i e aining; PT, physical aining; CERAD, Conso ium o Es ablish a Regis y o Alzheime ’s Disease. Men s. Women, p= 0.257, T aining less s. mo e han 50% (PT only), p= 0.596, T aining less s. mo e han 50% (PT and CT), p= 0.607. he PT and PTCT in e en ions we e obse ed. Age o global cogni ion we e no signi ican ly associa ed wi h he in e en ions-induced changes in S oop pe o mance. Pos -in e en ion TMT B pe o mance imp o ed signi ican ly in he low compliance PTCT subg oup and wo sened, i.e., was below he baseline le el, in he low compliance PT subg oup (di e ence -15.034, p= 0.032) (Table 3). No signi ican di e ences in he change in TMT B change we e obse ed among men, women, o he high- compliance subg oups. Mo eo e , no signi ican associa ions o age o global cogni ion wi h change in TMT B by in e en ion ype we e obse ed. No signi ican di e ences in change in Ve bal Fluency we e obse ed be ween he s udy subg oups (Table 4) and none o he pa icipan cha ac e is ics we e signi ican ly associa ed wi h change in Ve bal Fluency by in e en ion ype. Discussion In his hypo hesis-gene a ing analysis, we in es iga ed whe he he aining esponses o di e en sub-domains o execu i e unc ioning we e dependen on age, sex, aining compliance o change in global cogni ion. Ou ea lie s udy sugges ed ha he 1-yea PTCT in e en ion p o ided addi ional bene i o inhibi ion compa ed o physical aining alone (Sipilä e al.,2021). The p esen subg oup analyses sugges s ha he bene i ound o inhibi ion may be d i en by women sex and/o low compliance, de ined as pa icipa ion in less han hal o he aining. Howe e , we ound no s a is ically signi ican in e ac ions be ween he sex subg oups and high- and low-compliance subg oups. The se shi ing esul s showed ha he pa icipan s in he low-compliance subg oup bene i ed mo e om he PTCT han om physical aining alone. We ound ha women who ecei ed he PTCT showed a signi ican ly g ea e imp o emen in hei pos -in e en ion inhibi ion pe o mance han hose who ecei ed physical aining alone. Women who ecei ed PTCT imp o ed hei pe o mance in S oop by 28% whe eas women who ecei ed physical aining alone imp o ed hei pe o mance by 9%. The co esponding changes among men indica ed a simila bu lowe , s a is ically non-signi ican e ec . Men ecei ing PTCT imp o ed hei pe o mance in S oop by 19% and men ecei ing physical aining by 9%. The mechanism unde lying he lowe mean esponse a e among men emains unclea . I may be ha ac i a ion o he neu al ci cui s and/o molecula mechanisms (G issom and Reyes,2019) u ilized by he women o sol e he challenges p esen ed by ou cogni i e aining con ibu ed o hei supe io pe o mance in inhibi ion. Addi ionally, women end o expe ience less decline o e ime in execu i e unc ions compa ed o men (McCa ey e al.,2016) and i migh be ha he e o e hey we e mo e esponsi e o F on ie s in Aging Neu oscience 05 on ie sin.o g nagi-14-1038673 Oc obe 19, 2022 Time: 15:6 # 6 Ti kkonen e al. 10.3389/ nagi.2022.1038673 TABLE 3 Means wi h 95% con idence in e als and uns anda dized eg ession coe icien s (B) wi h 95% con idence in e als o subg oup analysis o he TMT-B ou comes. TMT-BaPTCT PT PTCT-PT 95% CI 95% CI 95% CI Subg oup NMean Lowe Uppe NMean Lowe Uppe Di e ence Lowe Uppe P- alue O e all BL 155 130.7 120.8 140.6 158 132.2 123.7 140.8 –5.349 –13.620 2.922 0.205 FU 119.3 108.6 129.9 126.1 117.7 134.6 Men BL 59 134.4 120.3 148.4 67 143.1 127.4 158.7 –13.486 –27.924 0.952 0.067 FU 117.2 104.7 129.7 139.4 123.0 155.8 Women BL 96 128.5 115.1 141.9 91 124.3 115.3 133.3 –0.494 –10.190 9.202 0.920 FU 119.9 104.8 135.0 116.2 108.6 123.7 Low compliance BL 95 137.4 123.2 151.6 54 125.8 112.8 138.7 –15.034 –28.769 –1.299 0.032 FU 127.9 112.0 143.8 131.3 115.2 147.4 High compliance BL 60 120.2 108.6 131.8 103 135.9 124.8 147.1 –1.775 –13.150 9.599 0.760 FU 106.7 95.5 117.8 124.2 114.3 134.1 B Lowe Uppe B Lowe Uppe Di e ence Lowe Uppe P- alue Age BL 155 5.358 2.941 7.774 158 3.741 1.537 5.945 –1.574 –3.747 0.599 0.156 FU 4.470 1.802 7.138 4.427 2.276 6.578 CERADbBL 141 –1.317 –2.148 –0.486 147 –2.939 –3.788 –2.089 0.268 –0.826 1.362 0.631 FU –1.136 –1.968 –0.303 –3.026 –3.830 –2.222 aLowe ime indica es be e pe o mance, bComp ises o e bal luency, modi ied Bos on naming es , wo d lis s, cons uc ional p axis, wo d lis ecall and wo d lis ecogni ion disc iminabili y ( o al sum sco e ange 0–100). B, uns anda dized eg ession coe icien ; CI, con idence in e al; PTCT, physical and cogni i e aining; PT, physical aining; CERAD, Conso ium o Es ablish a Regis y o Alzheime ’s Disease. Men s. Women, p= 0.143, T aining less s. mo e han 50% (PT only), p= 0.001, T aining less s. mo e han 50% (PT and CT), p= 0.145. cogni i e aining compa ed o men. I is no ewo hy ha he women ecei ing he PTCT only gained addi ional bene i in inhibi ion. This migh be due o ou cogni i e aining p og am, which likely os e s goal main enance, a key equi emen o which is inhibi ion. Hence, he g ea es imp o emen induced by cogni i e aining was ound in he S oop ask (Sipilä e al., 2021). We ound ha he addi ional bene i o he PTCT on inhibi ion and se - shi ing compa ed o physical aining alone was mos ly obse ed in he low-compliance subg oups. In he low-compliance subg oup ecei ing PTCT, inhibi ion and se shi ing imp o ed by 24 and 7%, espec i ely, as compa ed o he 6% imp o emen in inhibi ion and he 4% educ ion in se shi ing in he low-compliance subg oup ecei ing physical aining alone. Ou esul s showed ha di e en sub-domains o execu i e unc ions esponded di e en ly o he wo in e en ions, i.e., o he in e en ion combining PTCT and he in e en ion comp ising physical aining alone. I seems ha combining PTCT is bene icial enhancing he inhibi ion o in o ma ion o e load. We ound ha low-le el PTCT bene i ed inhibi ion signi ican ly mo e han low-le el physical aining alone. A simila end was obse ed among pa icipan s whose aining was on a high le el, al hough he di e ence be ween he subg oups was no s a is ically signi ican . Se shi ing, in u n bene i ed om low le el PTCT, whe eas a low le el o physical aining alone was no su icien o main ain o imp o e pe o mance o his ask. We he e o e sugges ha he p ocess unde lying he aining esponse in se shi ing di e s om ha unde lying inhibi ion, and hence u he in es iga ion is needed o cla i y hese mechanisms. Ou addi ional subg oup analyses showed (see Supplemen a y ma e ial) some selec ion bias o compliance and sex. Fo example, 70% o he men who ecei ed PTCT we e in he low-compliance subg oup and 30% in he high-compliance subg oup, whe eas only 27% o he men ecei ing physical aining alone we e in he low- and 73% in he high-compliance subg oup. A simila end was obse ed among women. In addi ion, 70% o he pa icipan s who ecei ed PTCT and we e in he high-compliance subg oup we e women and only 30% we e men. In he physical aining g oup, he co esponding pe cen ages we e 52 and 48%. Ou analyses showed ha he aining esponses in execu i e unc ioning we e no dependen on age o change in global cogni ion. To ou knowledge, his is he i s s udy o in es iga e whe he hese backg ound ac o s a e associa ed wi h he g ea e bene icial e ec o he PTCT on execu i e unc ions compa ed o physical aining alone. The e o e, mo e esea ch is needed o in es iga e he associa ions o di e en backg ound ac o s wi h F on ie s in Aging Neu oscience 06 on ie sin.o g nagi-14-1038673 Oc obe 19, 2022 Time: 15:6 # 7 Ti kkonen e al. 10.3389/ nagi.2022.1038673 TABLE 4 Means wi h 95% con idence in e als and uns anda dized eg ession coe icien s (B) wi h 95% con idence in e als o subg oup analysis o he e bal luency ou comes. Ve bal luencyaPTCT PT PTCT-PT 95% CI 95% CI 95% CI Subg oup NMean Lowe Uppe NMean Lowe Uppe Di e ence Lowe Uppe P- alue O e all BL 155 42.3 40.3 44.4 159 40.9 38.9 42.9 0.291 –1.753 2.335 0.780 FU 46.0 43.7 48.3 44.3 42.2 46.4 Men BL 59 39.5 36.0 43.0 67 35.7 32.7 38.7 –0.937 –4.116 2.241 0.563 FU 41.4 37.6 45.1 38.6 35.4 41.7 Women BL 96 44.1 41.6 46.6 92 44.7 42.3 47.1 0.894 –1.725 3.514 0.503 FU 48.8 46.1 51.5 48.5 46.0 50.9 Low compliance BL 95 41.2 38.8 43.9 55 40.9 37.8 44.0 –0.436 –3.551 2.676 0.784 FU 44.2 41.4 47.0 44.3 40.9 47.7 High compliance BL 60 44.1 40.9 47.3 103 40.9 38.2 43.5 1.424 –1.284 4.133 0.303 FU 48.9 45.1 52.7 44.2 41.6 46.9 B Lowe Uppe B Lowe Uppe Di e ence Lowe Uppe P- alue Age BL 155 0.141 –0.392 0.675 159 –0.449 –0.975 0.078 –0.173 –0.705 0.360 0.525 FU –0.099 –0.689 0.492 –0.516 –1.066 0.035 CERADbBL 141 0.539 0.328 0.749 147 0.409 0.207 0.611 –0.075 –0.350 0.200 0.593 FU 0.510 0.296 0.724 0.455 0.252 0.659 aHighe numbe o named wo ds indica es be e pe o mance. bComp ises o e bal luency, modi ied Bos on naming es , wo d lis s, cons uc ional p axis, wo d lis ecall and wo d lis ecogni ion disc iminabili y ( o al sum sco e ange 0–100). B, uns anda dized eg ession coe icien ; CI, con idence in e al; PTCT, physical and cogni i e aining; PT, physical aining. Men s. Women, p= 0.383, p= 0.863, T aining less s. mo e han 50% (PT and CT), p= 0.377. in e en ion-induced imp o emen s in execu i e unc ions and de e mine whe he speci ic subg oups gain addi ional bene i om he PTCT compa ed o physical aining alone. The s eng hs o his s udy include he ep esen a i e sample o communi y-dwelling olde adul s who did no mee he physical ac i i y guidelines. We used measu es app op ia e o assessing olde adul ’s execu i e unc ions and global cogni ion. In addi ion, he ac ha he cogni i e measu emen s we e conduc ed by same esea ch assis an a bo h ime poin s is likely o enhance he eliabili y o ou esul s. This s udy also has i s limi a ions. The main limi a ion o his s udy is i s hypo hesis- gene a ing, explo a o y design, which makes i impossible o apply he powe calcula ions o he PASSWORD-s udy o he subg oup analysis. Mo eo e , ou esul s canno be gene alized o o he age g oups o pe sons wi h an ac i e li es yle, ad e se medical condi ions, o impai ed cogni i e unc ions. In conclusion, PTCT imp o ed olde adul s’ execu i e unc ions, especially among he women and he pa icipan s who only occasionally complied wi h he aining egimen. Howe e , he addi ional bene i om PTCT was uniquely exp essed in each o he execu i e unc ions in es iga ed in his s udy. In o ma ion p o ided by his s udy is o alue when de eloping e ec i e in e en ions o p omo e execu i e unc ions in olde adul s. Da a a ailabili y s a emen The da ase s used du ing he cu en s udy a e a ailable om he co esponding au ho on easonable eques . E hics s a emen The s udies in ol ing human pa icipan s we e e iewed and app o ed by he E hical Commi ee o Cen al Finland Heal h Ca e Dis ic . The pa ien s/pa icipan s p o ided hei w i en in o med consen o pa icipa e in his s udy. Au ho con ibu ions AT, TT, and SS: acquisi ion, analysis, in e p e a ion o da a, and d a ing o he manusc ip . TT: s a is ical analyses. All au ho s: c i ical e ision o he manusc ip , concep , and design. Funding This PASSWORD s udy was unded by he Academy o Finland (G an no. 296843 o SS). SS was also suppo ed by F on ie s in Aging Neu oscience 07 on ie sin.o g nagi-14-1038673 Oc obe 19, 2022 Time: 15:6 # 8 Ti kkonen e al. 10.3389/ nagi.2022.1038673 unding om he Eu opean Union’s Ho izon 2020 Resea ch and Inno a ion P og am unde he Ma ie Skłodowska- Cu ie g an ag eemen (G an no. 675003). TT was an Academy o Finland Pos doc o al Resea che (G an no. 286536) du ing he implemen a ion o his s udy. JK was suppo ed by unding om he Minis y o Educa ion and Cul u e. 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 . Publishe ’s no e All claims exp essed in his a icle a e solely hose o he au ho s and do no necessa ily ep esen hose o hei a ilia ed o ganiza ions, o hose o he publishe , he edi o s and he e iewe s. Any p oduc ha may be e alua ed in his a icle, o claim ha may be made by i s manu ac u e , is no gua an eed o endo sed by he publishe . Supplemen a y ma e ial The Supplemen a y Ma e ial o his a icle can be ound online a : h ps://www. on ie sin.o g/a icles/10.3389/ nagi.2022.1038673/ ull#supplemen a y-ma e ial Re e ences Ba ha, C. K., Da is, J. C., Falck, R. S., Nagama su, L. S., and Liu-Amb ose, T. (2017). Sex di e ences in exe cise e icacy o imp o e cogni ion: A sys ema ic e iew and me a-analysis o andomized con olled ials in olde humans. F on . Neu oendoc inol. 46:71–85. doi: 10.1016/j.y ne.2017.04.002 Chandle , M. J., Lac i z, L. H., Hynan, L. S., Ba na d, H. D., Allen, G., Deschne , M., e al. (2005). A o al sco e o he CERAD neu opsychological ba e y. 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