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
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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
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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.
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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,
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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
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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.
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Con lic o In e es S a emen : The au ho s decla e ha he esea ch was
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