Enhancement of Visuospatial Working Memory by the Differential Outcomes Procedure in Mild Cognitive Impairment and Alzheimer’s Disease

nagi-10-00364 No embe 13, 2018 Time: 12:36 # 1 ORIGINAL RESEARCH published: 13 No embe 2018 doi: 10.3389/ nagi.2018.00364 Edi ed by: Changiz Geula, No hwes e n Uni e si y, Uni ed S a es Re iewed by: Elizabe a Blagoja Mukae o a-Ladinska, Uni e si y o Leices e , Uni ed Kingdom Jessica Pe e , Uni e si ä Be n, Swi ze land *Co espondence: Ana B. Vi as [email p o ec ed] Angeles F. Es é ez [email p o ec ed] Recei ed: 16 Janua y 2018 Accep ed: 23 Oc obe 2018 Published: 13 No embe 2018 Ci a ion: Vi as AB, Ypsilan i A, Ladas AI, Koun i F, Tsolaki M and Es é ez AF (2018) Enhancemen o Visuospa ial Wo king Memo y by he Di e en ial Ou comes P ocedu e in Mild Cogni i e Impai men and Alzheime ’s Disease. F on . Aging Neu osci. 10:364. doi: 10.3389/ nagi.2018.00364 Enhancemen o Visuospa ial Wo king Memo y by he Di e en ial Ou comes P ocedu e in Mild Cogni i e Impai men and Alzheime ’s Disease Ana B. Vi as1*, An onia Ypsilan i2, A is ea I. Ladas1, Fo eini Koun i3, Magda Tsolaki3,4 and Angeles F. Es é ez5,6* 1Depa men o Psychology, CITY College, In e na ional Facul y o he Uni e si y o She ield, Thessaloniki, G eece, 2Depa men o Psychology, Sociology and Poli ics, She ield Hallam Uni e si y, She ield, Uni ed Kingdom, 3G eek Associa ion o Alzheime ’s Disease and Rela ed Diso de s, Thessaloniki, G eece, 4Depa men o Neu ology, A is o le Uni e si y o Thessaloniki, Thessaloniki, G eece, 5Depa amen o de Psicología, Uni e sidad de Alme ía, Alme ía, Spain, 6CERNEP Resea ch Cen e , Uni e sidad de Alme ía, Alme ía, Spain In he p esen s udy we in es iga ed he e icacy o he di e en ial ou comes p ocedu e (DOP) o imp o e isuospa ial wo king memo y in pa ien s wi h Alzheime ’s disease and mild cogni i e impai men (MCI). The DOP associa es co ec esponses o he o-be- emembe s imulus wi h unique ou comes. Ele en pa ien s diagnosed wi h Alzheime ’s disease, 11 pa icipan s wi h MCI, and 17 heal hy ma ched con ols pe o med a spa ial delayed memo y ask unde he DOP and a con ol condi ion (non-di e en ial ou comes –NOP-). We ound ha pe o mance ( e minal accu acy) was signi ican ly be e in he DOP condi ion ela i e o he NOP condi ion in all h ee g oups o pa icipan s. AD pa ien s pe o med wo se, and ook longe o bene i om he DOP. In line wi h p e ious animal and human esea ch, we p opose ha he DOP ac i a es b ain s uc u es and cogni i e mechanisms ha a e less a ec ed by heal hy and pa hological aging, op imizing in his way he unc ion o he cogni i e sys em. Keywo ds: di e en ial ou comes p ocedu e, spa ial ecogni ion memo y, mild cogni i e impai men , Alzheime ’s disease, cogni i e in e en ion INTRODUCTION Acco ding o he WHO, 47.5 million o people li ed wi h demen ia in 2015 and his numbe is expec ed o inc ease by 59%(75.6 millions) un il 2030 (WHO, 2015). Demen ia o Alzheime ype (AD) is he mos common ype as i ep esen s abou 60–80% o he cases (OECD/EU, 2016). Wo ldwide and Eu opean ini ia i es ha e been pu o wa d in an a emp o amelio a e he nega i e impac o his age- ela ed neu odegene a i e disease, and one o he key ac ions is p omo ing be e and ea lie diagnosis (OECD/EU, 2016). The clinical cons uc o mild cogni i e impai men (MCI) appea ed some decades ago, and has been de ined as a s age in be ween heal hy aging and ea ly demen ia (Pe e sen, 2016). I is ecognized ha he e a e wo main ypes o MCI, amnes ic and non-amnes ic (Pe e sen, 2016). Tha is, indi iduals who p esen only memo y impai men s and hose who exhibi o he cogni i e de ici s han memo y. E idence also sugges s ha amnes ic MCI F on ie s in Aging Neu oscience | www. on ie sin.o g 1No embe 2018 | Volume 10 | A icle 364 nagi-10-00364 No embe 13, 2018 Time: 12:36 # 2 Vi as e al. DOP: Cogni i e In e en ion in MCI and AD (aMCI) is mos likely o p og ess o demen ia o Alzheime ’s ype, bu he o he ype migh also p og ess o demen ia (Pe e sen e al., 1999;A náiz and Almk is , 2003). Since he e is cu en ly no accep ed pha macological ea men o MCI (Pe e sen e al., 2014), and simila ly no e ec i e pha macological ea men o AD (Mangialasche e al., 2010), in he las yea s he e has been an inc easing in e es in he po en ial bene i s o cogni i e aining in e en ions (CCT), which a e ela i ely inexpensi e and po en ially scalable (see Bamidis e al., 2014 o a e iew). A ecen me a-analysis s udy (Hill e al., 2017) included 17 (686 pa icipan s) and 12 (389 pa icipan s) andomized con olled ials on he e icacy o CCT in MCI and demen ia pa ien s, espec i ely. The s udy epo ed mode a e and signi ican e ec sizes o he e icacy o CCT in imp o ing global cogni ion, memo y, wo king memo y and a en ion in indi iduals wi h MCI. Howe e , he e was no e idence in a o o he hypo hesis ha CCT can bene i indi iduals al eady diagnosed wi h demen ia. Also, he e we e non-signi ican e ec s o bene i s in execu i e unc ions and p ocessing speed in MCI. A di e en app oach o enhance cogni i e pe o mance is o ac i a e p ocesses ha a e less a ec ed by aging and demen ia by applying, o example, basic p inciples o lea ning and ein o cemen ha we e disco e ed ea ly on in animals (e.g., T apold, 1970;T apold and O e mie , 1972), ins ead o aining speci ic cogni i e skills ha migh be al eady impai ed, and hus di icul o eco e . Following his a ional, Es é ez e al. (2001, 2003, 2007) i s employed he di e en ial ou comes p ocedu e (DOP) in humans o imp o e pe o mance in condi ional disc imina i e lea ning asks, in which a co ec choice esponse o a speci ic s imulus-s imulus associa ion is ein o ced wi h a pa icula ou come. One ypical example o an e e yday ask o senio ci izens ha equi es his ype o lea ning is disc imina ing p esc ip ion pills associa ed o di e en heal h condi ions (e.g., yellow pill o hype ension and whi e pill o choles e ol). Du ing he aining wi h he DOP, he pa icipan would be p esen ed wi h one o six names o heal h condi ions ollowed by six di e en pills (ma ching- o-sample ask). When he adul s co ec ly choose he pill ha ma ches a pa icula condi ion, hey always ecei e a speci ic ou come (e.g., he p aise “good job” o hype ension-yellow pill) in he DOP, (see Molina e al., 2015); whe eas in he non-di e en ial ou comes p ocedu e (NOP), ha is a ypical condi ion o posi i e ein o cemen in his example, he e is no a p e-de e mined and speci ic link be ween a pa icula ou come ( he ein o ce ) and he co ec esponse o a pa icula condi ion-pill associa ion ( he s imulus). This appa en ly e y simple manipula ion o a anging he ou comes in a ask, so ha a single and unique ou come is consis en ly associa ed wi h a pa icula pa ing o s imuli o be lea ned, has shown o signi ican ly lessen memo y decline in heal hy and pa hological aging. Thus, in López-C espo e al.’s (2009) s udy (see also Sa age e al., 1999 o simila esul s in a s), olde adul s had be e memo y accu acy o aces when speci ic ou comes we e used. Ac ually, memo y pe o mance in he g oup o olde adul s did no dec ease wi h a longe memo y delay (5 s. 30 s delay) only in he DOP condi ion. In a la e s udy, Plaza e al. (2012) also demons a ed he bene i s o he di e en ial ou comes aining in imp o ing memo y o aces in a g oup o 8 pa ien s wi h demen ia o he Alzheime ype. Using he same ask employed by López-C espo e al. (2009),Plaza e al. (2012) epo ed be e pe o mance in he DOP condi ion only in he g oup o demen ia pa ien s and no in he g oup o ma ched heal hy con ols. Tha is, he DOP was e ec i e in d as ically dec easing impai men s o ace ecogni ion in demen ia pa ien s when sho memo y delays we e employed. A p esen , and o ou knowledge, he main (and only) heo e ical amewo k p oposed o explain he e ec s obse ed wi h he DOP is he wo-memo y sys ems model, which is based on wo k conduc ed by Sa age and colleagues in a s ( .g., Sa age and Langlais, 1995;Sa age and Pa sons, 1997; Sa age, 2001). Acco ding o his model, he unique associa ion, in he DOP, be ween a pa icula disc imina i e s imulus and a speci ic ou come c ea es an implici ewa d expec ancy ha is ac i a ed wi h he p esen a ion o he s imulus, he so- called by Sa age and colleagues p ospec i e memo y sys em. This au oma ically ac i a ed expec ancy ep esen a ion guides and acili a es beha io al choices, and consequen ly lea ning and pe o mance. We would like o no ice hough ha he de ini ion o p ospec i e memo y in his heo y di e s om he one used in he cogni i e li e a u e wi h human, whe e p ospec i e memo y e e s o u u e plans and ac ions which a e associa ed wi h execu i e unc ions. On he o he hand, and acco ding o his model, lea ning unde non-di e en ial ou comes condi ions depends on main aining ac i a ed he ep esen a ion o he disc imina i e s imulus o e he delay in he e ospec i e memo y sys em. A he neu al le el, p ospec i e and e ospec i e memo y ha e been associa ed wi h dis inc neu o ansmi e s and b ain ne wo ks (Sa age e al., 2004, 2007; Rami ez and Sa age, 2007;Sa age and Ramos, 2009), which a e also di e en ially a ec ed by heal hy and pa hological aging (Ma o ana e al., 2009;Sch oe e e al., 2009). Al hough, we do no know ye he exac p ocesses and b ain a eas unde lying he DOP e ec s in humans, e idence om animal esea ch wi h a s s ongly sugges s ha unlike he NOP, he o me does no equi es he ac i a ion o he hippocampus and he choline gic neu o ansmi e sys em (e.g.,Sa age and Pa sons, 1997;Sa age e al., 2004). Thus, he e ec i eness o he DOP in p e ious s udies wi h heal hy olde adul s as well as demen ia pa ien s could be due o his p ocedu e ac i a ing p ocesses and b ain s uc u es ha a e less a ec ed by heal hy and pa hological aging. To sum up, e idence so a sugges s ha he DOP can be e ec i e in imp o ing memo y o aces in heal hy olde adul s and in pa ien s wi h AD. In he p esen s udy, we u he es his hypo hesis by in es iga ing he e ec i eness o he DOP in imp o ing spa ial wo king memo y in a g oup o indi iduals wi h MCI, a g oup o pa ien s wi h AD and a g oup o ma ched heal hy con ols. Neu opsychological esea ch on AD has mos ly in es iga ed e bal media ed memo y (episodic memo y and seman ic memo y), which has long been conside ed as he mos cha ac e is ic and ea lies cogni i e sign o he disease. Compa a i ely, e y li le a en ion has been paid o isuospa ial memo y, while mo e ecen e idence sugges s ha spa ial memo y de ici s a e p esen in ea ly s ages o AD and may ac ually cons i u e ea ly p edic o s o he disease F on ie s in Aging Neu oscience | www. on ie sin.o g 2No embe 2018 | Volume 10 | A icle 364 nagi-10-00364 No embe 13, 2018 Time: 12:36 # 3 Vi as e al. DOP: Cogni i e In e en ion in MCI and AD (see Iachini e al., 2009, o a e iew). Fu he mo e, isuospa ial abili ies play a undamen al ole in e e yday ac i i ies. Fo ins ance, being able o ind a ou e and na iga e a new en i onmen is essen ial o main ain independen li ing. Based on p e ious s udies wi h he DOP (e.g., Plaza e al., 2012), we expec ha spa ial wo king memo y will be signi ican ly imp o ed in he g oup o AD pa ien s when unique ou comes a e associa ed wi h each a ge spa ial loca ion. Also, since aMCI has a pa hology cha ac e is ic o ea ly AD (Mo is e al., 2001), we expec ha spa ial wo king memo y will be also imp o ed in his g oup o pa icipan s. MATERIALS AND METHODS Pa icipan s Ele en pa ien s wi h Alzheime disease (AD g oup), 11 pa ien s wi h mild cogni i e impai men (MCI g oup) and 17 heal hy con ols (HC g oup) pa icipa ed in he s udy. Nine o he MCI pa icipan s we e diagnosed wi h mul i-domain amnes ic MCI (aMCImd) and he emaining wo wi h single domain aMCI. Pa ien s we e ec ui ed om he G eek Associa ion o Alzheime ’s Disease and Rela ed Diso de s (Alzheime ’s Hellas) in Thessaloniki, and diagnosed by a neu ologis . Diagnosis o demen ia was made acco ding o he c i e ia o NINCDS-ADRDA (McKhann e al., 1984). AD pa ien s we e ca ego ized in he mode a e s age and had a ela i ely low MMSE sco e indica ing mode a e cogni i e de e io a ion (mean MMSE = 14.63). Diagnosis o MCI was made acco ding o he c i e ia o Pe e sen (2004) and Winblad e al. (2004), and included neu ological and neu oimaging examina ion, neu opsychological/neu opsychia ic assessmen , medical/social his o y, and blood es s. Sco es o he G eek e sion o Mon eal Cogni i e Assessmen (MoCA; Koun i e al., 2007) a e epo ed in addi ion o he sco es o he Mini-Men al S a e Examina ion (MMSE; Fols ein e al., 1975) only o MCI pa ien s and con ol pa icipan s (see Table 1), since his ins umen was de eloped o assis in he de ec ion o MCI (Nas eddine e al., 2005). None heless, all he pa ien s comple ed bo h sc eening ools; MoCA was adminis e ed a e MMSE, wi h 1 mon h apa . The g oup o MCI pa icipan s had ela i ely low MoCA and MMSE mean sco es, since se e al pa icipan s we e mo e cogni i ely impai ed al hough did no classi y o he diagnosis o demen ia and me Pe e sen’s c i e ia o MCI. The e m la e MCI has ecen ly been coined in he li e a u e o e e o a sub ype o MCI, which shows a g ea e cogni i e impai men and is mo e likely o p og ess o AD (Aisen e al., 2010). Cogni i ely heal hy olde adul s (ma ched o gende , age, and educa ion) we e ec ui ed om Senio s Day Ca e cen es in Neapoli, Thessaloniki. The exclusion c i e ia o heal hy olde adul s included; (i) any men al heal h condi ion ha could a ec pe o mance on he ask (e.g., dep ession, anxie y, s oke, and insomnia), (ii) in ake o psycho opic d ugs such as an i-dep essan s and anxioly ics; and (iii) a sco e in he MMSE below 24 (Foun oulakis e al., 2000). The s udy was app o ed by he Uni e si y o She ield E hics Commi ee. S imuli and Ma e ials The ask was designed and un by E-p ime 2.0 (Psychology So wa e Tools, 2012). The e we e wo di e en e sions o he asks, so ha each pa icipan pe o med he ask unde di e en ial and non-di e en ial ou comes condi ions, wi h a pe iod o 2 weeks apa . The o de o he ou come condi ions, and he e sion-ou come mapping was coun e balanced ac oss pa icipan s. The wo e sions di e ed only in he geome ical shape ha ma ked a ge and non- a ge loca ions. In one e sion, he shape consis ed o a 2.5 ×2.5 cm whi e squa e, whe eas in he o he e sion, he shape was a 5 ×2.5 cm lime ec angle. The s imuli we e p esen ed on a black backg ound on a ouch sc een (12.100 TFT LCD WXGA moni o ). The shapes could appea in one o eigh posi ions a anged in a 3 ×3 imagina y ec angle equidis an om he bo de s. The ou comes consis ed o wo se s o ou pic u es o landscapes ha we e p esen ed a he cen e o he sc een along wi h he ph ase “You may win . . .” ollowed by he name o a ein o ce . Each ph ase (e.g., “You may win an umb ella”) appea ed always wi h he same pic u e o landscape. The ein o ce s we e e e yday objec s (e.g., umb ella, mug, key ing, a bel , e c.) ha we e a led o a he end o he expe imen . P ocedu e Each pa icipan was assessed indi idually in a quie oom. A he beginning o he i s session, each pa icipan was andomly assigned o one o he wo ou comes condi ions (DOP o NOP). Then, he esea che explained he ask o ally while a sample ial was shown on he sc een, and pa icipan s un a p ac ice block o 4 ials. In he DOP condi ion, each a ge loca ion was always pai ed wi h a speci ic ou come (e.g., co ec esponses o he shape appea ing on he igh uppe co ne o he sc een we e always ollowed by he same landscape pic u e-ph ase). In he NOP condi ion, a landscape pic u e- ph ase ( he ou come) was andomly p esen ed a e co ec esponses o a ge loca ions. Tha is, in his condi ion each a ge loca ion was equally o en pai ed wi h each o he ou landscape pic u es-ph ases. In each e sion o he ask, al hough TABLE 1 | Demog aphic a iables and mean sco es ob ained on he Mini-men al S a e Examina ion (MMSE) and he Mon eal Cogni i e Assessmen (MOCA) by pa icipan s in he s udy (s anda d de ia ions in pa en hesis). AD g oup MCI g oup HC g oup n11 11 17 Sex (% Female) 60 75 70 Age (yea s) p- alue 72.4 (5.30) 0.067 70 (10.9) 0.542 67.5 (7.5) Yea s o educa ion p- alue 7.4 (2.06) 0.314 7.9 (2.4) 0.506 8.5 (2.5) MMSE p- alue 14.6 (2.87) <0.001 23.6 (0.90) <0.001 28.4 (1.42) MOCA p- alue 19.1 (0.90) <0.001 25.1 (1.43) P- alues a e o compa isons be ween each g oup (AD and MCI) and he con ol g oup. Compa isons we e pe o med wi h independen samples S uden ’s - es s. F on ie s in Aging Neu oscience | www. on ie sin.o g 3No embe 2018 | Volume 10 | A icle 364 nagi-10-00364 No embe 13, 2018 Time: 12:36 # 4 Vi as e al. DOP: Cogni i e In e en ion in MCI and AD FIGURE 1 | S imuli sequence ( om le o igh ) used in he expe imen . he shape could be p esen ed in all eigh possible loca ions ac oss he ials, ou loca ions we e ne e used as a ge s, and so esponses o any o hese non- a ge loca ions we e ne e ein o ced. Each ial sequence (see Figu e 1) s a ed wi h a cen al ixa ion poin (+) o 500 ms. Then a shape was p esen ed sequen ially in ou loca ions (one a ge and h ee non- a ge loca ions andomly selec ed o each ial) du ing 750 ms each ime. Righ a e he las shape disappea ed om he sc een, a black sc een was p esen ed o 2 o 15 s depending on he delay condi ion. Finally, he p obe display appea ed on sc een un il he pa icipan made a espond. The p obe display consis ed o wo shapes ( wo whi e squa es in one e sion, and wo lime ec angles in he o he e sion o he ask): one p esen ed a he a ge , p e iously ma ked, loca ion and he o he a a dis ac o loca ion. In hal o he ials he dis ac o was a non- a ge loca ion. In he o he hal , i was one o he h ee a ge loca ions ha we e no ma ked du ing he ou -loca ions sequence. Pa icipan s we e asked o selec he ele an shape ( ial-and-e o p ocedu e) by ouching i on he sc een wi h no ime limi . I pa icipan s selec ed co ec ly he ele an shape, he ein o ce (landscape pic u e and ph ase) was hen p esen ed o 3 s. Inco ec esponses we e ollowed by a blank sc een ha las ed also o 3 s. The ask consis ed o h ee expe imen al blocks o 16 ials each. S a is ical Analysis Pe cen ages o co ec esponses o each pa icipan we e submi ed o a mixed ANOVA wi h G oup (AD, MCI, and HC) as he be ween-subjec ac o and Ou comes (DOP and NOP) and Delay (2 and 15 s) as he wi hin-subjec ac o s. Bon e oni pos hoc es was used o pos hoc compa isons when app op ia e. La ency da a did no show any signi ican e ec and he e o e only accu acy da a a e epo ed. S a is ical analyses we e pe o med using SPSS 22.0 and he s a is ical signi icance le el was se a p≤0.05. RESULTS Resul s om he accu acy da a (see Figu e 2) analysis showed signi ican main e ec s o Delay [F(1,36) = 11.56, p= 0.002, η2 p= 0.243] and G oup [F(2,36) = 13.40, p<0.001, η2 p= 0.427]. Tha is, pa icipan s o e all we e mo e accu a e in he sho han in he long delay (67% s. 61% accu acy o he 2- and 15-s delays, espec i ely). Bon e oni pos hoc pai -wise compa isons showed also signi ican di e ences be ween he AD g oup (49%) and he MCI and HC g oups (71% and 73%, espec i ely; ps<0.001). Tha is, heal hy con ol and MCI pa ien s we e bo h mo e accu a e han AD pa ien s. Finally, a signi ican e ec o Ou comes was obse ed [F(1,36) = 22.23, p<0.001, η2 p= 0.382] indica ing ha pa icipan s pe o med he ask be e in he DOP han in he NOP condi ion (71% s. 58% accu acy, espec i ely). No o he e ec s, no hei in e ac ion, eached s a is ical signi icance (ps>0.05). Al hough pa icipan s in he h ee g oups appea ed o show a be e spa ial delayed ecogni ion memo y in he DOP han in he NOP condi ion (58% s. 40%, 77% s. 65%, and 76% s. 70% accu acy o he AD, MCI and HC g oups in he DOP and NOP condi ions, espec i ely), i is wo h no ing ha o e all AD pa ien s’ pe o mance was a chance in he DOP condi ion (Chi-squa e = 2.56, d = 1; p= 0.110). Thus, i appea ed ha AD pa ien s needed mo e aining wi h he p ocedu e in o de o obse e imp o emen s in pe o mance. To es his ad hoc hypo hesis, we g ouped he da a om hese pa icipan s in h ee blocks o six een ials each (see Figu e 3) and conduc ed a epea ed measu es ANOVA wi h Ou comes (DOP and NOP), Delay (2 and 15 s) and Block o ials (B1, B2, and B3) as he wi hin-subjec ac o s. Resul s showed a signi ican main e ec o Ou comes [F(1,10) = 15.78, p= 0.003, η2 p= 0.612], and a signi ican Ou comes ×Block in e ac ion [F(2,20) = 4.56, p= 0.023, η2 p= 0.313]. The analysis o he in e ac ion e ealed ha accu acy linea ly inc eased wi h blocks o ials only in he DOP condi ion [F(2,20) = 4.16, p= 0.031, η2 p= 0.294] (52, 59, and 65% accu acy in blocks 1, 2, and 3, espec i ely), and ha pe o mance was abo e chance in he las wo blocks o ials al hough his e ec was ma ginal in Block 2 (Chi-squa e = 3.2, d = 1; p= 0.072 o Block 2 and Chi-squa e = 9.0, d = 1; p= 0.003 o Block 3). Howe e , in he NOP condi ion pe o mance ne e eached abo e chance le els. DISCUSSION In he p esen s udy we in es iga ed i he DOP, an easy- o- implemen echnique, would be e ec i e in imp o ing spa ial wo king memo y in people wi h MCI and AD. Thus, pa icipan s in bo h g oups and in a hi d g oup o ma ched heal hy con ols we e asked o emembe a cued loca ion a e a delay o 2 o 15 s. In he DOP condi ion, each a ge loca ion was pai ed wi h a unique ou come; whe eas in he NOP condi ion we p esen ed ou comes in a andomized ashion. The esul s showed ha pe o mance was signi ican ly imp o ed unde he DOP in all h ee g oups. S ill, he g oup o pa ien s wi h AD pe o med signi ican ly wo se han he o he wo g oups, F on ie s in Aging Neu oscience | www. on ie sin.o g 4No embe 2018 | Volume 10 | A icle 364 nagi-10-00364 No embe 13, 2018 Time: 12:36 # 5 Vi as e al. DOP: Cogni i e In e en ion in MCI and AD FIGURE 2 | Mean pe cen age o co ec esponses as a unc ion o G oup (AD, MCI, and HC), Ou comes (DOP and NOP), and Delay (2 and 15 s). E o ba s ep esen he s anda d e o o he mean. which had compa able o e all pe o mance. When we conduc ed u he analyses in he g oup o pa ien s wi h AD, we ound ha e en ually pa ien s lea ned how o do he ask. Tha is, hey pe o med signi ican ly abo e chance in he las block o ials bu only unde he DOP. These indings eplica e and ex end he p e ious inding o a bene icial e ec o his p ocedu e in imp o ing memo y o aces in heal hy olde adul s (López- C espo e al., 2009), and pa ien s wi h AD (Plaza e al., 2012). I is wo h no ing ha he g oup o AD pa ien s examined in Plaza e al. (2012) di e s om he one examined in his p esen s udy in e ms o se e i y o cogni i e impai men s. Tha is, pa ien s in Plaza e al. (2012) we e classi ied as mild AD; whe eas in his s udy hey we e ca ego ized as mode a e AD. Consequen ly, he p esen indings also ex end he posi i e e ec s o he DOP o AD pa ien s wi h mo e ad anced cogni i e de e io a ion. This s udy also shows o he i s ime ha indi iduals wi h aMCI (mul i- o single domain), which is conside ed a s age in be ween heal hy aging and demen ia, exhibi imp o ed spa ial wo king memo y wi h he DOP. One limi a ion o he cu en s udy was ha we did no include and compa e o he sub ypes o MCI such as non-amnes ic MCI o he mo e ecen diagnos ic di e en ia ion be ween ea ly and la e MCI (Aisen e al., 2010). Thus u u e s udies may in es iga e o he sub ypes, since likelihood o p og ess o AD changes as a unc ion o MCI sub-diagnos ic ca ego y (Pe e sen e al., 1999;A náiz and Almk is , 2003;Alexopoulos e al., 2006). As expec ed in he con ol condi ion (NOP), he pe o mance o AD pa ien s was signi ican ly wo se, ela i e o he g oup o MCI and HC, and a chance le el. This inding is in ag eemen wi h e idence sugges ing ha spa ial memo y de ici s a e signi ican in AD (see Iachini e al., 2009, o a e iew). Howe e , he pe o mance o he MCI pa icipan s did no FIGURE 3 | Mean pe cen age o AD pa ien s’ co ec esponses as a unc ion o Ou comes (DOP and NOP), Block o ials (B1, B2, and B3), and Delay (2 and 15 s). E o ba s ep esen he s anda d e o o he mean. signi ican ly di e om he HC pa icipan s in he con ol (NOP) condi ion. This inding does no seem o suppo he hypo hesis ha spa ial memo y de ici s may cons i u e an ea ly ma ke o AD (Iachini e al., 2009). Gi en ha we employed an expe imen al ask apping on speci ic p ocesses, namely delayed isuospa ial ecogni ion o loca ions, u u e s udies should u he in es iga e spa ial memo y in aMCI. Al hough i has been known o decades now ha di e en ial ou comes ha pai uniquely wi h a cue-s imulus imp o e disc imina i e lea ning in animals, li le is known abou he neu ocogni i e mechanisms behind he DO e ec in humans. As discussed ea lie on, wo k conduc ed wi h animals sugges s ha F on ie s in Aging Neu oscience | www. on ie sin.o g 5No embe 2018 | Volume 10 | A icle 364 nagi-10-00364 No embe 13, 2018 Time: 12:36 # 6 Vi as e al. DOP: Cogni i e In e en ion in MCI and AD di e en ypes o memo y p ocesses a e ac i a ed when lea ning unde di e en ial ou comes as compa ed o non-di e en ial ou comes (Sa age, 2001). Tha is, i has been ound ha unde NOP condi ions he HC is ac i a ed, one o he i s b ain s uc u es a ec ed in AD and MCI (Didic e al., 2013). This b ain s uc u e, howe e , has no been associa ed o pe o mance unde he DOP. Thus, al hough his s udy does no o e s di ec e idence ela ing his hypo hesis, based on he a o emen ioned s udies and he wo memo y sys em model, we p opose ha he bene icial e ec s o he DOP obse ed in all h ee g oups esul om he ac i a ion o neu al sys ems and cogni i e p ocesses ha a e less a ec ed by heal hy and pa hological aging. Fu u e s udies should es his hypo hesis by addi ionally in es iga ing how b ain ese e and neu oplas ici y in MCI and AD (F e e e al., 2015), may acili a e he u iliza ion o speci ic neu al ne wo ks unde di e en ial and non-di e en ial ou comes condi ions. In e es ingly, in one o he ew s udies wi h humans in es iga ing b ain ac i a ion in he DOP, Mok e al. (2009) ound non-modali y speci ic ac i a ion o he pos e io pa ie al co ex (including he pos e io cingula e co ex) in he DOP condi ion, and p oposed ha his ac i a ion could be esponsible o he ansi ion om e ospec i e memo y o p ospec i e memo y ( ewa d expec ancy) p ocessing. Since his a ea seems o be a ec ed bo h in AD and MCI, bu o a g ea e ex end in AD (Sch oe e e al., 2009), his could explain ou inding o a la e e ec o he DOP in he AD pa ien s g oup. We would like o conclude highligh ing ha he p esen esul s demons a e, o he i s ime, ha he way in which he ou comes a e associa ed o he o-be- emembe s imulus may g ea ly a ec delayed spa ial ecogni ion memo y in MCI and AD pa ien s. The inexpensi e and easy o implemen p ocedu e o applying di e en ial ou comes ollowing co ec esponses, helped pa icipan s o be e pe o m he ask. This inding could ha e signi ican implica ions o he e e yday li e o pa ien s wi h AD, and olde adul s wi h MCI, since spa ial skills a e c ucial o main ain independency (e.g., ind he ou e back home). Since he p esen s udy employed a ypical expe imen al-cogni i e ask, u u e s udies may in es iga e he e ec i eness o he DOP in aining spa ial skills using mo e ecological con ex s and asks. AUTHOR CONTRIBUTIONS AV con ibu ed o he o iginal idea, design o he s udy, da a analysis, and d a ed he manusc ip . AE con ibu ed o he o iginal idea, design o he s udy, da a analysis, and w i ing. AY ec ui ed and es ed he heal hy con ols and MCI pa icipan s, con ibu ed o da a analysis and w i ing. AL es ed Alzheime ’s disease pa ien s and con ibu ed o he w i ing. FK and MT we e esponsible o ec ui men and es ing o AD and MCI pa ien s, o hei diagnosis and neu opsychological assessmen , and app o ed he inal e sion o be submi ed. FUNDING This s udy was suppo ed by he Spanish Minis y o Economy and Compe i i eness (PSI2015-65248-P), co- unded by ERDF (FEDER) unds. REFERENCES Aisen, P. S., Pe e sen, R. C., Donohue, M. C., Gams , A., Raman, R., Thomas, R. G., e al. (2010). Clinical Co e o he Alzheime ’s disease neu oimaging ini ia i e: p og ess and plans. Alzheime s Demen . 6, 239–246. doi: 10.1016/j.jalz.2010.03. 006 Alexopoulos, P., G imme , T., Pe neczky, R., Domes, G., and Ku z, A. (2006). P og ession o demen ia in clinical sub ypes o mild cogni i e impai men . Demen . Ge ia . Cogn. Diso d. 22, 27–34. doi: 10.1159/000093101 A náiz, E., and Almk is , O. (2003). Neu opsychological ea u es o mild cogni i e impai men and p eclinical Alzheime ’s disease. Ac a Neu ol. Scand. 107, 34–41. doi: 10.1034/j.1600-0404.107.s179.7.x Bamidis, P. D., Vi as, A. B., S yliadis, C., F an zidis, C., Klados, M., Schlee, W., e al. (2014). A e iew o physical and cogni i e in e en ions in aging. Neu osci. Biobeha . 44, 206–220. doi: 10.1016/j.neubio e .2014.03.019 Didic, M., Felician, O., Ba beau, E. J., Mancini, J., La ge -Flo ence, C., T amoni, E., e al. (2013). Impai ed isual ecogni ion memo y p edic s Alzheime ’s disease in amnes ic mild cogni i e impai men . Demen . Ge ia . Cogn. Diso d. 35, 291–299. doi: 10.1159/000347203 Es é ez, A. F., Fuen es, L. J., Ma i-Be a, P., González, C., and Ál a ez, D. (2001). The di e en ial ou comes e ec as a use ul ool o imp o e condi ional disc imina ion lea ning in child en. Lea n. Mo i . 32, 48–64. doi: 10.1006/lmo . 2000.1060 Es é ez, A. F., Fuen es, L. J., O e mie , J. B., and González, C. (2003). Di e en ial ou comes e ec in child en and adul s wi h down synd ome. Am. J. Men . Re a d. 108, 108–116. doi: 10.1352/0895-8017(2003)108<0108:DOEICA>2.0. CO;2 Es é ez, A. F., Vi as, A. B., Alonso, D., Ma í-Be a, P., Fuen es, L. J., and O e mie , J. B. (2007). Enhancing challenged s uden s’ ecogni ion o ma hema ical ela ions h ough di e en ial ou comes aining. Q. J. Exp. Psychol. 60, 571–580. doi: 10.1080/17470210600820039 Fols ein, M. F., Fols ein, S. E., and McHugh, P. R. (1975). Mini-men al s a e (MMSE). J. Psychia . Res. 12, 189–198. doi: 10.1016/0022-3956(75)90026-6 Foun oulakis, K. N., Tsolaki, M., Chan zi, H., and Kazis, A. (2000). Mini Men al S a e Examina ion (MMSE): a alida ion s udy in G eece. Am. J. Alzheime s Dis. O he Demen . 15, 342–345. doi: 10.1177/153331750001500604 F e e , T., Gaud eau, P., Schumann-Ba d, P., Billa d, J. M., and Popa-Wagne , A. (2015). Mechanisms unde lying he neu op o ec i e e ec o b ain ese e agains la e li e dep ession. J. Neu al T ansm. 122, 55–61. doi: 10.1007/s00702- 013-1154-2 Hill, N. T., Mowszowski, L., Naismi h, S. L., Chadwick, V. L., Valenzuela, M., and Lampi , A. (2017). Compu e ized cogni i e aining in olde adul s wi h mild cogni i e impai men o demen ia: a sys ema ic e iew and me a-analysis. Am. J. Psychia y 174, 329–340. doi: 10.1176/appi.ajp.2016.160 30360 Iachini, T., Ia a one, A., Senese, V. P., Ruo olo, F., and Ruggie o, G. (2009). Visuospa ial memo y in heal hy elde ly, AD and MCI: a e iew. Cu . Aging Sci. 2, 43–59. doi: 10.2174/1874609810902010043 Koun i, F., Tsolaki, M., Ele he iou, M., Agogia ou, C., Ka agiozi, K., Bakoglidou, E., e al. (2007). “Adminis a ion o Mon eal Cogni i e Assessmen (MoCA) es in G eek elde ly pa ien s wi h mild cogni i e impai men and pa ien s wi h demen ia,” in P oceedings o he 9 h Eu opean Con e ence on Psychological Assessmen , and 2nd In e na ional Con e ence o he Psychological Socie y o No he n G eece, A hens, 155–156. López-C espo, G., Plaza, V., Fuen es, L. J., and Es é ez, A. F. (2009). Imp o emen o age- ela ed memo y de ici s by di e en ial ou comes. In . Psychoge ia . 21, 503–510. doi: 10.1017/s1041610209008576 F on ie s in Aging Neu oscience | www. on ie sin.o g 6No embe 2018 | Volume 10 | A icle 364 nagi-10-00364 No embe 13, 2018 Time: 12:36 # 7 Vi as e al. DOP: Cogni i e In e en ion in MCI and AD Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P., and Ki ipel o, M. (2010). Alzheime ’s disease: clinical ials and d ug de elopmen . Lance Neu ol. 9, 702–716. doi: 10.1016/S1474-4422(10)70119-8 Ma o ana, A., Mo i, F., Esposi o, Z., Kusayanagi, H., Mon eleone, F., Codeca, C., e al. (2009). Dopamine modula es choline gic co ical exci abili y in Alzheime ’s disease pa ien s. Neu opsychopha macology 34, 2323–2328. doi: 10.1038/npp.2009.60 McKhann, G., D achman, D., Fols ein, M., Ka zman, R., P ice, D., and S adlan, E. M. (1984). Clinical diagnosis o Alzheime ’s disease Repo o he NINCDS- ADRDA Wo k G oup∗unde he auspices o depa men o heal h and human se ices ask o ce on Alzheime ’s disease. Neu ology 34, 939–939. doi: 10.1212/ WNL.34.7.939 Mok, L. W., Thomas, K. M., Lungu, O. V., and O e mie , J. B. (2009). Neu al co ela es o cue-unique ou come expec a ions unde di e en ial ou comes aining: an MRI s udy. B ain Res. 1265, 111–127. doi: 10.1016/j.b ain es.2008. 12.072 Molina, M., Plaza, V., Fuen es, L. J., and Es é ez, A. F. (2015). The di e en ial ou comes p ocedu e enhances adhe ence o ea men : a simula ed s udy wi h heal hy adul s. F on . Psychol. 6:1780. doi: 10.3389/ psyg.2015.01780 Mo is, J. C., S o and , M., Mille , J. P., McKeel, D. W., P ice, J. L., Rubin, E. H., e al. (2001). Mild cogni i e impai men ep esen s ea ly-s age Alzheime disease. A ch. Neu ol. 58, 397–405. doi: 10.1001/a chneu .58.3.397 Nas eddine, Z. S., Phillips, N. A., Bedi ian, V., Cha bonneau, S., Whi ehead, V., Collin, I., e al. (2005). The Mon eal Cogni i e Assessmen , MoCA: a b ie sc eening ool o mild cogni i e impai men . Am. J. Ge ia . Soc. 53, 695–699. doi: 10.1111/j.1532-5415.2005.53221.x OECD/EU (2016). Heal h a a Glance: Eu ope 2016: S a e o Heal h in he EU Cycle. Pa is: OECD Publishing. doi: 10.1787/9789264265592-en Pe e sen, R. C. (2004). Mild cogni i e impai men as a diagnos ic en i y. J. In e n. Med. 256, 183–194. doi: 10.1111/j.1365-2796.2004.01388.x Pe e sen, R. C. (2016). Mild cogni i e impai men . Con inuum 22, 404–418. doi: 10.1212/CON.0000000000000313 Pe e sen, R. C., Ca acciolo, B., B ayne, C., Gau hie , S., Jelic, V., and F a iglioni, L. (2014). Mild cogni i e impai men . J. In e n. Med. 275, 214–228. doi: 10.1111/ joim.12190 Pe e sen, R. C., Smi h, G. E., Wa ing, S. C., I nik, R. J., Tangalos, E. G., and Kokmen, E. (1999). Mild cogni i e impai men : clinical cha ac e iza ion and ou come. A ch. Neu ol. 56:303. doi: 10.1001/a chneu .56.3.303 Plaza, V., López-C espo, G., An únez, C., Fuen es, L. J., and Es é ez, A. F. (2012). Imp o ing delayed ace ecogni ion in Alzheime ’s disease by di e en ial ou comes. Neu opsychology 26, 483–489. doi: 10.1037/a0028485 Psychology So wa e Tools (2012). E-p ime (Compu e So wa e). Pi sbu gh, PA: Au ho . Rami ez, D. R., and Sa age, L. M. (2007). Di e en ial in ol emen o he basola e al amygdala, o bi o on al co ex, and nucleus accumbens co e in he acquisi ion and use o ewa d expec ancies. Beha . Neu osci. 121:896. doi: 10.1037/0735- 7044.121.5.896 Sa age, L. M. (2001). In sea ch o he neu obiological unde pinnings o he di e en ial ou comes e ec . In eg . Physiol. Beha . Sci. 36, 182–195. doi: 10. 1007/BF02734092 Sa age, L. M., Buzze i, R. A., and Rami ez, D. R. (2004). The e ec s o hippocampal lesions on lea ning, memo y, and ewa d expec ancies. Neu obiol. Lea n. Mem. 82, 109–119. doi: 10.1016/j.nlm.2004.05.002 Sa age, L. M., Koch, A., and Rami ez, D. (2007). Amygdala inac i a ion by muscimol, bu no ERK/MAPK inhibi ion, impai s he use o ewa d expec ancies du ing sho - e m memo y. Eu . J. Neu osci. 26, 3645–3651. doi: 10.1111/j.1460-9568.2007.05959.x Sa age, L. M., and Langlais, P. J. (1995). Di e en ial ou comes a enua e memo y impai men s on ma ching- o-posi ion ollowing py i hiamine- induced de iciency in a s. Psychobiology 23, 153–160. Sa age, L. M., and Pa sons, J. (1997). The e ec s o delay in e al, in e ial in e al, amnes ic d ugs, and di e en ial ou comes on ma ching- o-posi ion in a s. Psychobiology 25, 303–312. Sa age, L. M., Pi kin, S. R., and Ca e i, J. M. (1999). Memo y enhancemen in aged a s: he di e en ial ou comes e ec . De . Psychobiol. 35, 318–327. doi: 10.1002/(SICI)1098-2302(199912)35:4<318::AID-DEV6>3.0.CO;2-8 Sa age, L. M., and Ramos, R. L. (2009). Rewa d expec a ion al e s lea ning and memo y: he impac o he amygdala on appe i i e-d i en beha io s. Beha . B ain Res. 198, 1–12. doi: 10.1016/j.bb .2008.10.028 Sch oe e , M. L., S ein, T., Maslowski, N., and Neumann, J. (2009). Neu al co ela es o Alzheime ’s disease and mild cogni i e impai men : a sys ema ic and quan i a i e me a-analysis in ol ing 1351 pa ien s. Neu oimage 47, 1196– 1206. doi: 10.1016/j.neu oimage.2009.05.037 T apold, M. A. (1970). A e expec ancies based upon di e en posi i e ein o cing e en s disc iminably di e en ? Lea n. Mo i . 1, 129–140. doi: 10.1016/0023- 9690(70)90079-2 T apold, M. A., and O e mie , J. B. (1972). “The second lea ning p ocess in ins umen al lea ning,” in Classical Condi ioning II: Cu en Theo y and Resea ch, ed. W. F. P okasy (New Yo k, NY: Apple on-Cen u y), 427–452. WHO (2015). Demen ia, Fac Shee . A ailable a : h p://www. alida ion-e a. com/index.php/ /cou an / ecommanda ions/109-e a-eu opean- alida ions- assozia ion/cu en /news lash/234-who-demen ia- ac -shee -ma ch-2015 Winblad, B., Palme , K., Ki ipel o, M., Jelic, V., F a iglioni, L., Wahlund, L. O., e al. (2004). Mild cogni i e impai men –beyond con o e sies, owa ds a consensus: epo o he In e na ional Wo king G oup on Mild Cogni i e Impai men . J. In e n. Med. 256, 240–246. doi: 10.1111/j.1365-2796.2004. 01380.x Con lic o In e es S a emen : 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 . Copy igh © 2018 Vi as, Ypsilan i, Ladas, Koun i, Tsolaki and Es é ez. 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. F on ie s in Aging Neu oscience | www. on ie sin.o g 7No embe 2018 | Volume 10 | A icle 364