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Biological Psychology
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The impo ance o age in he sea ch o ERP bioma ke s o aMCI
Susana Cid-Fe nández
⁎
, Mónica Lindín, Fe nando Díaz
Labo a o io de Neu ociencia Cogni i a, Depa amen o de Psicoloxía Clínica e Psicobioloxía, Uni e sidade de San iago de Compos ela, Galicia, Spain
ARTICLE INFO
Keywo ds:
Amnes ic mild cogni i e impai men (aMCI)
Aging
N2
P3
Go/NoGo
E en - ela ed po en ials (ERPs)
ABSTRACT
Alzheime ’s Disease (AD) has become a majo heal h issue in ecen decades, and he e is now g owing in e es in
amnes ic mild cogni i e impai men (aMCI), an in e media e s age be ween heal hy aging and demen ia, usually
AD. E en - ela ed b ain po en ial (ERP) s udies ha e some imes ailed o de ec di e ences be ween aMCI and
con ol pa icipan s in he Go-P3 (o P3b, ela ed o a ge classi ica ion p ocesses in a a ie y o asks) and
NoGo-P3 ( ela ed o esponse inhibi ion p ocesses, mainly in Go/NoGo asks) ERP componen s. The aim o he
p esen s udy was o e alua e whe he he age ac o , which is no usually aken in o accoun in ERP s udies,
modula es g oup di e ences in hese componen s. Wi h his aim, we di ided wo g oups o olun ee pa ici-
pan s, 34 subjec s wi h aMCI (51–87 yea s) and 31 con ols (52–86 yea s), in o wo age subg oups: 69 yea s o
less and 70 yea s o mo e. We eco ded b ain ac i i y while he pa icipan s pe o med a dis ac ion-a en ion
audi o y- isual (AV) ask. Task pe o mance was poo e in he olde han in he younge g oup, and aMCI
pa icipan s p oduced ewe co ec esponses han he ma ched con ols; bu no in e ac ions o he age and
g oup ac o s on pe o mance we e ound. On he o he hand, Go-P3 and NoGo-N2 la encies we e longe in aMCI
pa icipan s han in con ols only in he younge subg oup. Thus, he younge aMCI pa icipan s ca ego ized he
Go s imuli in wo king memo y and p ocessed he NoGo s imuli (which equi ed esponse inhibi ion) slowe han
he co esponding con ols. Finally, he combina ion o he numbe o hi s, Go-P3 la ency and NoGo-N2 la ency
yielded accep able sensi i i y and speci ici y sco es (0.70 and 0.92, espec i ely) as ega ds dis inguishing aMCI
pa icipan s aged 69 yea s o less om he age-ma ched con ols. The indings indica e age should be aken in o
accoun in he sea ch o aMCI bioma ke s.
1. In oduc ion
The wo ld’s popula ion is aging, owing o dec eased bi h a es and
inc eased li e expec ancy (Pa k & Reu e -Lo enz, 2009). The ac-
cele a ed inc ease in aging is accompanied by an inc ease in he p e-
alence o neu odegene a i e diseases.
Alzheime ’s Disease (AD) is he mos common o m o demen ia and
is becoming inc easingly mo e p e alen (And easen & Blennow, 2005;
Bennys, Rondouin, Bena a , Gabelle, & Touchon, 2011), a g ea cos o
a ec ed indi iduals and hei amilies and o socie y as a whole (Pa k &
Reu e -Lo enz, 2009). The p e alence and incidence a es o AD in-
c eases exponen ially wi h age, wi h he mos no able ise om 70 yea s
on, as he la e-onse o m o AD accoun s o mo e o he 95% o a -
ec ed (Rei z, B ayne, & Mayeux, 2011).
Howe e , mos AD pa ien s expe ience some memo y decline be o e
eaching he clinical h eshold o he diagnosis o AD (Pe e sen e al.,
2001). The s a e in which he e is g ea e memo y loss han expec ed
o no mal aging, bu which does no a ec daily li ing and does no
mee he c i e ia o AD, is e med amnes ic Mild Cogni i e Impai men
(aMCI; Pe e sen e al., 2001,2009). Indi iduals wi h aMCI show an
inc eased isk o de eloping AD ela i e o heal hy aging: longi udinal
s udies ha e e ealed ha aMCI pa ien s ha e an 80% chance o de-
eloping AD wi hin 6 yea s o diagnosis (Pe e sen e al., 2001,2009,
1999). The p e alence o MCI a p esen is di icul o calcula e, as i
depends on he p ecise diagnos ic c i e ia (Wa d, A ighi, Michels, &
Ceda baum, 2012). Despi e his, as AD inc eases doubles e e y 5 yea s
a e age 65 (Jones, B uns, & Pe e sen, 2017), i is wo hy o e alua e
adul s wi h aMCI om se e al yea s be o e ha age.
Cha ac e iza ion o aMCI is impo an o enable co ec diagnosis
and p ognosis, hus inc easing he p obabili y o clinical in e en ion
be o e b ain damage becomes i e e sible (B edesen, 2014). The sea ch
o aMCI ma ke s has he e o e ecei ed a g ea deal o a en ion in he
las wo decades. Use ul bioma ke s should be able o de ec he neu-
opa hology and mus be alida ed in neu opa hologically con i med
cases. In addi ion, bioma ke s should also be p ecise, eliable, non-in-
asi e, simple o ob ain and inexpensi e (Thies, T uschke, Mo ison-
Bogo ad, & Hodes, 1998). Al hough se e al aMCI bioma ke s ha e been
p oposed (Albe e al., 2011), hey a e expensi e (e.g. unc ional
h ps://doi.o g/10.1016/j.biopsycho.2019.01.015
Recei ed 14 No embe 2018; Recei ed in e ised o m 24 Janua y 2019; Accep ed 25 Janua y 2019
⁎
Co esponding au ho .
E-mail add ess: [email p o ec ed] (S. Cid-Fe nández).
Biological Psychology 142 (2019) 108–115
A ailable online 02 Feb ua y 2019
0301-0511/ © 2019 Else ie B.V. All igh s ese ed.
T
magne ic esonance imaging) and/o in asi e (e.g. posi on emission
omog aphy, ce eb ospinal luid measu es) and ha e ei he no been
alida ed (Jack e al., 2011) o show limi ed sensi i i y and speci ici y
(DeKosky & Ma ek, 2003;Rei z & Mayeux, 2014;Rei z e al., 2011).
The e en - ela ed b ain po en ials (ERP) echnique is a sui able ool
o use in he sea ch o bioma ke s, as i is non-in asi e and ela i ely
inexpensi e, and has al eady shown o be use ul in he sea ch o bio-
ma ke s o aMCI and AD (e.g. Cespón, Galdo-Ál a ez, & Díaz, 2013;
Cespón, Galdo-Ál a ez, & Díaz, 2015;Cespón, Galdo-Ál a ez, Pe ei o,
& Díaz, 2015;Co ea-Ja aba, Lindín, & Díaz, 2018;Lindín, Co ea,
Zu ón, & Díaz, 2013; o e iews, see Jackson & Snyde , 2008;Vecchio
& Mää ä, 2011).
In p e ious s udies in ol ing he sea ch o bioma ke s o aMCI, we
used he ERP echnique o eco d he b ain ac i i y o pa icipan s while
hey pe o med a dis ac ion-a en ion audi o y- isual (AV) ask (Cid-
Fe nández, Lindín, & Díaz, 2017;Cid-Fe nández, Lindín, & Díaz, 2017;
Cid-Fe nández, Lindín, & Díaz, 2014;Lindín e al., 2013). In his ask,
pa icipan s a e p esen ed wi h pai s o audi o y- isual s imuli, and
hey a e asked o a end o he isual s imuli (making a Go/NoGo ask)
and o igno e he audi o y s imuli (consis ing o a passi e oddball ask
wi h h ee s imuli: s anda d, de ian and no el). The ollowing ERP
componen s associa ed wi h he p ocessing o isual s imuli (p eceded
by s anda d audi o y s imuli) we e iden i ied and e alua ed: (1) N2b
(Go-N2) and P3b (Go-P3), in esponse o Go isual s imuli, and (2)
NoGo-N2 and NoGo-P3, in esponse o NoGo isual s imuli. The Go-N2
and NoGo-N2 ampli udes we e smalle in aMCI han in con ol pa i-
cipan s, indica ing de ici s in he e alua ion o a ge s imuli in wo king
memo y (WM) and in esponse inhibi ion p ocesses, espec i ely, in
pa icipan s wi h aMCI. No di e ences we e obse ed be ween he
g oups in ela ion o he Go- and NoGo-P3 componen s, o in Go- and
NoGo-N2 la encies (Cid-Fe nández e al., 2014b,2017a;Muda e al.,
2016).
Go-P3 (o P3b) is a widely s udied ERP componen , ypically max-
imal a pa ie al elec odes in young adul s, wi h la encies o
300–700 ms a e s imulus p esen a ion. The s imuli ha elici his ERP
componen a e a ended s imuli ha equi e a esponse, e.g. he a ge
s imuli o an oddball ask, o he Go s imuli o a Go/NoGo ask. Go-P3 is
ypically in e p e ed as a co ela e o con ex upda ing (when a a ge
s imulus is p esen ed) o o s imulus classi ica ion in wo king memo y
(Coles & Rugg, 1996;Donchin & Coles, 1988;Ku as, I agui, & Hillya d,
1994). Mos s udies using an oddball ask ha e epo ed longe P3b
la encies in aMCI pa ien s han in heal hy con ols (e. g. Bennys, Po e ,
Touchon, & Rondouin, 2007;Lai, Lin, Liou, & Liu, 2010;Li e al., 2010;
Papadaniil e al., 2016;Papaliagkas, Kimiskidis, Tsolaki, &
Anogianakis, 2008;Pa a, Ascencio, U quina, Manes, & Ibáñez, 2012),
al hough o he s udies did no obse e any di e ences (Papaliagkas,
Kimiskidis, Tsolaki, & Anogianakis, 2011). Rega ding he P3b ampli-
ude, mos s udies did no e eal di e ences be ween g oups (e. g.
Bennys e al., 2007;Golob, I imaji i, & S a , 2007;Lai e al., 2010;
Papadaniil e al., 2016;Papaliagkas e al., 2008,2011), al hough in
some s udies his pa ame e was signi ican ly smalle in aMCI pa ien s
han in heal hy con ols (Li e al., 2010;Pa a e al., 2012).
On he o he hand, he NoGo-P3 componen peaks a ound he
300–500 la ency window a cen al elec odes a e p esen a ion o a
NoGo s imulus ha equi es a p epo en esponse o be wi hheld. This
has been in e p e ed as an index o esponse inhibi ion p ocesses
(Boku a, Yamaguchi, & Kobayashi, 2001;Jackson, Jackson, & Robe s,
1999;Naka a, Sakamo o, Inui, Hoshiyama, & Kakigi, 2009). S udies
e alua ing he NoGo-P3 pa ame e s ha e gene ally no ound any di -
e ences be ween MCI pa icipan s and con ols (2017a,Cid-Fe nández,
Lindín, & Díaz, 2014;Muda e al., 2016). Howe e , López Zunini e al.
(2016) obse ed smalle NoGo-P3 ampli udes in aMCI han in con ol
pa icipan s, in e p e ing his esul as an indica o o impai ed mo o
esponse inhibi ion p ocesses in aMCI.
In wo p e ious ERP s udies ca ied ou in ou labo a o y, di e -
ences be ween aMCI pa icipan s and heal hy con ols we e obse ed,
bu only when he sample was spli in o di e en age g oups. Lindín
e al. (2013) used he AV ask and analyzed he misma ch nega i i y
(MMN), a componen ela ed o au oma ic and p e-a en i e p ocessing
o s imuli (Nää änen, Paa ilainen, Rinne, & Alho, 2007). The MMN
ampli ude was smalle in he aMCI han in he con ol pa icipan s, bu
only in he g oup aged 50–64 yea s and no in olde pa icipan s (Lindín
e al., 2013). In addi ion, in a S oop ask s udy, Ramos-Goicoa, Galdo-
Ál a ez, Díaz, and Zu ón, (2016) obse ed longe P3b la ency in aMCI
han in heal hy pa icipan s, bu only in he younge subg oup (64 yea s
old o less). Al oge he hese esul s show ha some impo an e ec s
(and po en ial aMCI bioma ke s) may be masked when he age ac o is
no aken in o accoun in he analyses. Indeed, Ramos-Goicoa e al.
(2016) sugges ed ha he age ac o may ha e some in luence in he
mixed esul s ound in he li e a u e ega ding P3b la ency.
In line wi h his obse a ion, he age anges o he men ioned s u-
dies di e conside ably: while he pa icipan s o he s udy ha ob-
se ed g oup di e ences in P3b la ency a e he younges (younge
subg oups age ange = 51–64 yea s old; Ramos-Goicoa e al., 2016)
hose o s udies ha did no ind such di e ences we e qui e (Muda
e al., 2016; age ange = 54–86 yea s old; aMCI mean age = 68.5 yea s
old; con ol mean age = 65.4 yea s old) o much (López Zunini e al.,
2016; aMCI mean age = 75.6 yea s old; con ol mean age = 72.4 yea s
old) olde . On he o he hand, only he s udy ha used he eldes
sample was able o obse e di e ences ega ding P3b ampli ude, as his
pa ame e was la ge in he con ol han in he aMCI g oup (López
Zunini e al., 2016).
In he p esen s udy, we used he AV ask o e alua e (1) possible
di e ences be ween con ol (heal hy) pa icipan s and aMCI pa ici-
pan s in ask pe o mance ( eac ion ime -RT- and numbe o co ec
esponses), in he Go-N2 and -P3 ERP componen s (in esponse o isual
s imuli ha equi ed a esponse), and in he NoGo-N2 and -P3 ERP
componen s (in esponse o isual s imuli ha equi ed o wi hhold a
p epo en esponse); and (2) whe he hese di e ences a e modula ed
by age. Fo his pu pose, wo age subg oups we e es ablished o s a-
is ical compa ison: pa icipan s aged 69 yea s o less and pa icipan s
70 yea s o mo e. We es ed whe he he Age ac o in e ac s wi h he
G oup ac o (aMCI s con ols), o cla i y whe he impo an g oup
e ec s on he pa ame e s o he a o emen ioned ERP componen s may
be o e looked.
Acco ding o p e ious epo s, we expec ed o ind di e ences be-
ween g oups in he beha iou al measu es, wi h poo e pe o mance in
he aMCI han in he con ol pa icipan s (longe RT and ewe co ec
esponses). By con as , we did no expec o ind any gene al g oup
di e ences in he Go- and NoGo-P3 la encies, and only expec ed o ind
longe Go-P3 la encies in he aMCI han in he con ol pa icipan s in
he younge subg oups, in acco dance wi h Ramos-Goicoa e al. (2016).
In addi ion, we did no expec o ind g oup di e ences o he Go-P3
ampli ude, in he global sample o in ei he o he age subg oups. Fi-
nally, we we e also expec ing o ind some age-dependen di e ences
be ween g oups o he Go-N2 (o N2b) and NoGo-N2 la encies, as (1)
in p e ious s udies using he A-V ask we ailed o obse e any g oup
di e ences ega ding hese pa ame e s, and (2) i seems ha he e a e
signi ican changes in he N200 subcomponen s in MCI adul s com-
pa ed o heal hy adul s ac oss s udies, despi e some con adic ions
be ween esul s ( o a e iew see Howe, 2014).
2. Ma e ials and me hods
2.1. Pa icipan s
Six y- i e olun ee s we e ec ui ed om P ima y Ca e Heal h
Cen e s in San iago de Compos ela, Galicia (Spain), a e being e e ed
o ou esea ch g oup by hei gene al p ac i ione s (GPs). The pa i-
cipan s had no his o y o clinical s oke, auma ic b ain inju y, mo o -
senso y de ici s o alcohol o d ug abuse/dependence, and hey we e
no diagnosed wi h any signi ican medical o psychia ic illnesses.
S. Cid-Fe nández e al. Biological Psychology 142 (2019) 108–115
109
Each pa icipan hen unde wen he ollowing neu opsychological
es s: 1) he Spanish e sion o he Mini-Men al S a e Examina ion
(MMSE; Lobo e al., 1999); 2) he Spanish e sion o he Cali o nian
Ve bal Lea ning Tes (CVLT; Benede Ál a ez & Alexand e, 1998),
which assesses sho -delay ee ecall, sho -delay ecall wi h seman ic
cues, and long-delay ee ecall; 3) he Spanish e sion o he Cam-
b idge Cogni i e Examina ion (CAMCOG-R), which assesses de e io a-
ion in speci ic domains, such as language, a en ion-calcula ion, p axis,
pe cep ion and execu i e unc ioning (Huppe e al., 1996); and (4) he
Spanish e sion o he Law on-B ody Ins umen al Ac i i ies o Daily
Li ing (IADL) scale (Ve ga a e al., 2012).
Pa icipan s we e classi ied in o wo g oups: Con ol (31 subjec s,
aged be ween 52 and 86 yea s, wi h no mal cogni i e unc ioning) and
aMCI (34 subjec s aged be ween 51 and 87 yea s). The aMCI pa ici-
pan s me he gene al c i e ia o MCI ou lined by Albe e al. (2011)
and he c i e ia o aMCI p oposed by Pe e sen (2004). Thus, all aMCI
pa icipan s ul illed he ollowing c i e ia: 1) memo y complain s
co obo a ed by an in o man ; 2) pe o mance o less han 1.5 SDs
below age no ms in he CVLT; 3) no signi ican impac on ac i i ies o
daily li ing; and 4) no demen ia. Fo a mo e ex ensi e desc ip ion o he
global samples, see Juncos-Rabadán, Facal, Lojo-Seoane, and Pe ei o
(2013). The aMCI and con ol pa icipan s we e ma ched acco ding o
age and le el o educa ion.
In o de o e alua e whe he he age ac o modula es he di e -
ences be ween he g oups, wo subg oups we e es ablished in each
g oup: 69 yea s o less and 70 yea s o mo e. In each age subg oup,
aMCI and con ol pa icipan s we e also ma ched acco ding o age and
le el o educa ion. The demog aphic and neu opsychological measu es
o he pa icipan s a e summa ized in Table 1, oge he wi h he di -
e ences be ween g oups, calcula ed by he co esponding analysis.
To con ol o he e ec s o dep ession, olun ee s wi h sco es o
mo e han 10 in dep ession sc eening (Ge ia ic Dep ession Scale;
Yesa age e al., 1983) we e no included in he s udy. All pa icipan s
had no mal audi ion and no mal o co ec ed- o-no mal ision. All
we e igh -handed, as assessed by he Edinbu gh in en o y (Old ield,
1971). Righ a e he neu opsychological e alua ion, pa icipan s un-
de wen he psychophysiological e alua ion.
In addi ion, all pa icipan s ga e hei w i en in o med consen
p io o aking pa in he s udy. The esea ch p ojec was app o ed by
he Galician Clinical Resea ch E hics Commi ee (Xun a de Galicia,
Spain). The s udy was pe o med in acco dance wi h he e hical s an-
da ds es ablished in he 1964 Decla a ion o Helsinki (Lynöe, Sandlund,
Dahlq is , & Jacobsson, 1991).
2.2. P ocedu e
The dis ac ion-a en ion audi o y- isual ask was adap ed om
Esce a, Alho, Winkle , and Nää änen, (1998). Pa icipan s we e p e-
sen ed wi h 500 pai s o audi o y- isual (A-V) s imuli. Each pai o
s imuli consis ed o a isual s imulus (200 ms du a ion) p eceded by an
audi o y s imulus (150 ms du a ion), sepa a ed by an in e al o 300 ms
(SOA). Each pai o s imuli was sepa a ed by an in e al o 2 s. Pa i-
cipan s we e asked o a end o he isual s imuli and o igno e he
audi o y s imuli. They should espond p essing one bu on wi h one
hand i he isual s imulus was a le e , ano he bu on wi h he o he
hand i i was a numbe (33% each; Go s imuli), and wi hhold hei
esponses i i was a iangle (34%; NoGo s imuli). The ask p ocedu e is
u he explained in Cid-Fe nández e al. (2017b; see Fig. 1; and
2017b).
2.3. EEG eco ding
The EEG was eco ded ia 49 elec odes placed in an elas ic cap
(Easycap, GmbH), acco ding o he In e na ional 10-10 Sys em. All
elec odes we e e e enced o an elec ode a ached o he ip o he
nose, and an elec ode posi ioned a Fpz se ed as g ound. The ho -
izon al elec ooculog am (EOG) was eco ded ia wo elec odes placed
a he ou e can hi o bo h eyes, whe eas he e ical EOG was eco ded
ia wo elec odes placed sup a and in ao bi ally o he igh eye. The
EEG was con inuously digi ized a a a e o 500 Hz (bandpass
0.01–100 Hz), and he elec ode impedance was main ained below 10 k
Ω.
Once he signal was s o ed, i was passed h ough a digi al
0.1–30 Hz (24 dB/oc a e slope) bandpass il e , and ocula a e ac s
we e co ec ed using he G a on, Coles & Donchin me hod (G a on,
Coles, & Donchin, 1983).
Wi h he aim o e alua ing he ERP componen s o in e es (Go-N2,
NoGo-N2, Go-P3 and NoGo-P3 componen s), he EEG was segmen ed
by ex ac ion o audi o y s imulus-locked epochs o 1450 ms (150 ms
p e-audi o y s imulus). The epochs composed by he s anda d audi o y-
a ge isual pai s wi h co ec esponses we e e alua ed. All epochs
we e co ec ed o he mean ol age o he i s 150 ms o each epoch,
and segmen s exceeding ± 100 μV we e au oma ically ejec ed. The
epochs we e hen a e aged sepa a ely o he Go and NoGo ials (Go
and NoGo condi ions, espec i ely), and a minimum o 38 a e ac - ee
epochs we e a e aged o each condi ion.
Table 1
Mean alues and s anda d de ia ions (in pa en heses) o he demog aphical and neu opsychological measu es conside ed.
C aMCI p ≤
*
C ≤ 69 y.o. aMCI ≤ 69 y.o. p ≤
*
C ≥ 70 y.o. aMCI ≥ 70 y.o. p ≤
*
N = 31 N = 34 N = 13 N = 17 N = 18 N = 17
Age 69.6 (9.5) 69.9 (9.1) .896 60.1 (5.8) 62.7 (5.6) .228 76.4 (4.0) 77.1 (5.4) .675
Yea s o educa ion 9.1 (5.0) 9.1 (4.5) .984 9.8 (5.5) 9.7 (4.5) .947 8.6 (4.6) 8.5 (4.5) .987
Sex (Women/Men) 22/9 19/15 9/4 8/9 13/5 11/6
MMSE 28.0 (1.8) 25.7 (2.5) .001 28.6 (1.2) 26.3 (2.0) .001 27.6 (2.1) 25.0 (2.8) .004
CVLT (sho -delay ee ecall) 8.9 (3.1) 3.7 (1.9) .001 11.2 (2.5) 4.7 (1.4) .001 7.2 (2.3) 2.6 (1.7) .001
CVLT (sho -delay cued ecall) 10.4 (3.2) 5.5 (2.2) .001 12.6 (1.9) 6.4 (1.7) .001 8.9 (3.1) 4.5 (2.4) .001
CVLT (long-delay ee ecall) 9.8 (3.5) 4.1 (3.1) .001 12.5 (2.9) 5.3 (2.7) .001 8.2 (3.0) 2.9 (3.0) .001
CVLT (long-delay cued ecall) 10.6 (3.3) 5.7 (2.7) .001 12.5 (2.1) 6.5 (1.9) .001 9.2 (3.4) 5.0 (3.2) .001
CAMCOG-R (O ien a ion) 9.4 (0.9) 9.1 (1.0) .146 9.9 (0.4) 9.4 (0.7) .056 9.1 (1.1) 8.7 (1.2) .303
CAMCOG-R (Language) 24.9 (2.1) 24.3 (2.9) .293 25.8 (2.1) 24.7 (2.4) .219 24.3 (1.9) 23.8 (3.3) .579
CAMCOG-R (A en ion and Calcula ion) 7.4 (1.5) 6.4 (2.3) .036 7.6 (1.6) 6.6 (2.3) .177 7.2 (1.4) 6.1 (2.3) .097
CAMCOG-R (P axis) 10.9 (1.3) 9.9 (2.6) .058 11.1 (1.3) 9.8 (2.7) .136 10.7 (1.3) 9.9 (2.5) .250
CAMCOG-R (Pe cep ion) 6.3 (1.5) 6.2 (1.5) .888 6.5 (1.7) 6.5 (1.4) .987 6.1 (1.4) 5.9 (1.6) .737
CAMCOG-R (Execu i e unc ion) 15.9 (5.2) 14.6 (4.1) .249 18.6 (6.0) 15.5 (3.9) .092 13.9 (3.6) 13.7 (4.2) .823
C: con ol g oup; aMCI: amnes ic MCI g oup; y.o.: yea s old; MMSE: Mini-Men al S a e Examina ion; CVLT: Cali o nia Ve bal Lea ning Tes ; CAMCOG-R: Camb idge
Cogni i e Examina ion.
* ANOVA (G oup), signi ica ion le el < 0.05.
S. Cid-Fe nández e al. Biological Psychology 142 (2019) 108–115
110
2.4. Da a analysis
Reac ion imes (RTs, be ween he onse o he isual s imulus and
p essing he key) o co ec esponses and he numbe o co ec e-
sponses (Hi s) we e e alua ed in he Go condi ion.
The Go-N2 (in he 250–430 ms in e al) and he Go-P3 (in he
450–750 ms in e al) componen s (a e he Go isual s imulus), and
he NoGo-N2 (in he 200–360 ms in e al) and he NoGo-P3 (in he
400–650 ms in e al) componen s (a e he NoGo isual s imulus)
we e also e alua ed. The peak ampli udes (in mic o ol s) and la encies
(in milliseconds) o he Go- and NoGo-N2 and -P3 componen s we e
e alua ed a he midline elec ode whe e he ampli ude was maximal
(Pz o Go-P3, Cz o Go-N2, NoGo-N2 and NoGo-P3).
2.5. S a is ical analysis
Two- ac o analysis o a iance (ANOVA), wi h he be ween-subjec
ac o s G oup ( wo le els: Con ol, aMCI) and Age ( wo le els: 69 o less
yea s old and 70 o mo e yea s old), was applied o he RTs, Hi s and
ampli udes and la encies o he Go-N2 and -P3 and he NoGo-N2 and
-P3 componen s. Whene e he ANOVAs e ealed signi ican e ec s due
o he ac o s o hei in e ac ions, pos hoc compa isons o he mean
alues (adjus ed o Bon e oni co ec ion) we e conduc ed. Di e ences
we e conside ed signi ican a p ≤ 0.05.
Finally, ecei e ope a ing cha ac e is ic (ROC) cu es we e con-
s uc ed o hose ERP and beha io al pa ame e s in which he G oup
ac o exe ed a signi ican main e ec o in e ac ion. These pa ame e s
Fig. 1. G and-a e age e en - ela ed b ain po en ial wa e o ms o he age subg oups in he con ol (blue/ligh g ey line) and aMCI (o ange/da k g ey line) g oups,
o each condi ion (Go: uppe panel; NoGo: lowe panel) (Fo in e p e a ion o he e e ences o colou in his igu e legend, he eade is e e ed o he web e sion
o his a icle).
S. Cid-Fe nández e al. Biological Psychology 142 (2019) 108–115
111
we e also combined by cons uc ing a bina y logis ic eg ession model,
wi h he pa ame e s included as he explana o y a iables (co a ia es)
and he g oup o in e es as he dependen a iable. The p edic ed
p obabili ies we e sa ed as a new a iable and ROC cu es we e
compu ed. An a ea unde he cu e (AUC) o 1.0 co esponds o a
pe ec p edic ion, whe eas a alue o 0.5 indica es a useless model.
3. Resul s
The RTs, numbe o hi s, and ampli udes and la encies o he Go-
and NoGo-N2, and Go- and NoGo-P3 componen s a e summa ized in
Table 2, and he ERP wa e o ms e alua ed a e depic ed in Fig. 1.
3.1. Beha iou al measu es
The wo ac o ANOVA (G oup x Age) applied o he RTs e ealed a
signi ican e ec o he Age ac o (F (1, 59) = 4.2, p = .045), as his
pa ame e was signi ican ly longe in he olde (70 o mo e yea s old)
han in he younge (69 o less yea s old) pa icipan s (see Table 2).
The e we e no o he signi ican e ec s o in e ac ions ega ding he
RTs.
The wo ac o ANOVA (G oup x Age) applied o he numbe o hi s
also e ealed a signi ican e ec o he Age ac o (F (1, 59) = 8.6,
p = .005), as his pa ame e was signi ican ly smalle in he olde han
in he younge pa icipan s (see Table 2). In addi ion, a ma ginally
signi ican e ec o he G oup ac o was obse ed (F (1, 59) = 3.4,
p = .07), as his pa ame e was smalle in he aMCI han in he Con ol
g oup (see Table 2). No signi ican in e ac ion o he ac o s was ob-
se ed.
3.2. ERP componen s
3.2.1. Go-N2 and NoGo-N2
The wo- ac o ANOVAs (G oup × Age) did no show any sig-
ni ican main e ec s o in e ac ions o he ac o s o he Go-N2 am-
pli ude and la ency o he NoGo-N2 ampli ude a he Cz elec ode lo-
ca ion.
The wo- ac o ANOVA (G oup × Age) applied o he NoGo-N2
la ency a Cz showed a signi ican e ec o he G oup ×Age in e ac ion
(F (1, 50) = 6.1, p = .017), as his pa ame e was signi ican ly longe
(p = .004) in he aMCI han in he con ol pa icipan s, bu only in he
younge subg oup (69 o less yea s old), and signi ican ly longe
(p = .039) in he elde con ols (70 o mo e yea s old) han in he
younge con ols (69 o less yea s old; see Fig. 1).
3.2.2. Go-P3 and NoGo-P3
The wo ac o ANOVAs (G oup × Age) applied o he Go-P3 am-
pli ude a Pz, did no show any signi ican main e ec s o in e ac ions.
The wo ac o ANOVA (G oup × Age) applied o he Go-P3 la ency
a Pz e ealed a signi ican e ec o he G oup ×Age in e ac ion (F (1,
54) = 4.5, p = .039), as his pa ame e was signi ican ly longe in he
aMCI han in he con ol pa icipan s, bu only in he younge subg oup
(≤ 69 yea s old; p = .049; see Fig. 1).
The wo ac o ANOVAs (G oup × Age) applied o he NoGo-P3
ampli ude and la ency a Cz did no show any signi ican main e ec s o
in e ac ions o he ac o s.
3.3. ROC cu es
The numbe o hi s disc imina ed g oups (aMCI e sus con ols) wi h
sensi i i y and speci ici y sco es o 0.59 and 0.62, espec i ely
(AUC = .68). In addi ion, he Go-P3 la ency (a Pz) showed sensi i i y
and speci ici y sco es o 0.65 and 0.66, espec i ely, o dis inguishing
con ol and aMCI pa icipan s aged ≤ 69 yea s (AUC = 0.71). Fo he
same compa ison (con ol e sus aMCI in he younge subg oup), he
NoGo-N2 la ency (a Cz) showed sensi i i y and speci ici y sco es o
0.60 and 0.67, espec i ely.
The numbe o hi s and Go-P3 la ency a Pz we e hen combined
wi h he aim o dis inguishing aMCI pa icipan s aged ≤ 69 yea s om
hei con ol coun e pa s, yielding a sensi i i y sco e o 0.82 and a
speci ici y sco e o 0.75 (AUC = 0.79). Fo he same compa ison, he
combina ion o NoGo-N2 la ency (a Cz) and Go-P3 la ency (a Pz)
yielded sensi i i y and speci ici y sco es o 0.70 and 0.67, espec i ely,
while he combina ion o NoGo-N2 la ency a Cz and he numbe o hi s
yielded sensi i i y and speci ici y sco es o 0.80 and 0.75, espec i ely.
Finally, he h ee pa ame e s (numbe o hi s, NoGo-N2 la ency a
Cz and Go-P3 la ency a Pz) we e combined wi h he aim o dis in-
guishing aMCI om con ol pa icipan s o 69 yea s-old o less, ob-
aining a sensi i i y sco e o 0.70 and a speci ici y sco e o 0.92.
4. Discussion
The RT was signi ican ly longe and he numbe o hi s signi ican ly
lowe in he olde (≥ 70 yea s old) han in he younge (≤ 69 yea s
old) pa icipan s. In addi ion, he numbe o hi s was lowe in he aMCI
han in he Con ol g oup (al hough his e ec was only ma ginally
signi ican ). The Go-P3 (o P3b) and he NoGo-N2 la encies we e sig-
ni ican ly longe in he aMCI han in he con ol pa icipan s, bu only
in he younge subg oup (≤ 69 yea s old). In addi ion, he NoGo-N2
la ency was signi ican ly longe in he olde han in he younge pa -
icipan s, bu only in he con ol g oup.
I is gene ally ag eed ha olde adul s eac mo e slowly han
younge adul s, as demons a ed in a a ie y o cogni i e asks (Glisky,
2007;Sal house, 2000). In ac , he slowe RT in he olde han in he
younge pa icipan s suppo s p e ious indings ob ained wi h he AV
ask in heal hy subjec s (Cid-Fe nández, Lindín, & Díaz, 2016) and wi h
o he asks in heal hy subjec s (Lucci e al., 2013) and subjec s wi h
aMCI (Ramos-Goicoa e al., 2016). Howe e , he di e ences be ween
g oups in his pa ame e a e no always s a is ically signi ican (e.g.
Cid-Fe nández e al., 2014b;Co ea-Ja aba, Cid-Fe nández, Lindín, &
Díaz, 2016).
Mo eo e , he olde pa icipan s p o ided ewe co ec esponses
han he younge pa icipan s. Al hough a simila endency was ob-
se ed in p e ious s udies using he AV ask, he di e ences was no
ound o be s a is ically signi ican (Cid-Fe nández e al., 2014b,2016).
The disc epancy in he esul s o he di e en s udies may be due o he
di e en age cu -o used he e (69/70 yea s old in he p esen s udy;
64/65 yea s old in he p e ious s udies). Besides, i seems ha he
gene al inc ease in RTs ac oss aging s udies is usually associa ed wi h
li le o no dec ease in accu acy (Ra cli , Thapa , & McKoon, 2010). In
addi ion, he con ol pa icipan s p o ided a g ea e numbe o co ec
Table 2
Numbe o co ec esponses (Hi s) and eac ion imes (RT, om he isual
s imulus onse o he bu on p ess), and ampli udes (in mic o ol s) and la-
encies (in milliseconds, om he isual s imulus onse ) o P3b and NoGo-P3
componen s o each age g oup.
YOUNGER (≤ 69 yea s old) OLDER (≥ 70 yea s old)
CONTROL aMCI CONTROL aMCI
Hi s 224.2 (5.2) 215.5 (19.3) 210.1 (21.0) 200.3 (25.7)
RT 605.5 (86.7) 640.6 (64.4) 660.5 (107.3) 679.6 (96.2)
N2b Amp (Cz) −10.3 (7.0) −6.4 (4.6) −6.7 (9.2) −5.2 (4.8)
N2b La (Cz) 583.5 (49.1) 625.8 (33.2) 620.3 (60.8) 630.4 (65.7)
NoGo-N2 Amp (Cz) −8.0 (6.2) −4.1 (3.4) −4.7 (7.2) −3.6 (3.0)
NoGo-N2 La (Cz) 536.2 (22.7) 578.4 (51.4) 598.5 (58.9) 570.0 (64.2)
P3b Amp (Pz) 4.6 (7.4) 7.4 (5.9) 8.4 (9.1) 6.4 (5.7)
P3b La (Pz) 528.5 (80.4) 597.4 (87.9) 588.1 (111.1) 547.3 (108.1)
NoGo-P3 Amp (Cz) 10.8 (4.9) 11.0 (4.9) 10.4 (7.2) 11.0 (7.6)
NoGo-P3 La (Cz) 477.0 (74.4) 504.4 (53.5) 521.9 (77.2) 501.4 (97.2)
RT: eac ion ime; Amp: ampli ude; La : la ency.
S. Cid-Fe nández e al. Biological Psychology 142 (2019) 108–115
112
esponses han he aMCI pa icipan s, al hough he di e ence was only
ma ginally signi ican (0.07). This is consis en wi h he indings o a
p e ious s udy using he AV ask (Cid-Fe nández e al., 2014a), whe e
his esul was signi ican .
Rega ding he ERP pa ame e s, he aMCI pa icipan s showed
longe Go-P3 and NoGo-N2 la encies han con ol pa icipan s, bu only
hose in he younge subg oup. This may indica e ha he aMCI pa -
icipan s aged 69 yea s o less old ca ego ized he Go s imuli in he
wo king memo y mo e slowly and we e slowe ega ding ea ly e-
sponse inhibi ion p ocessing han hei con ol coun e pa s. Howe e ,
his di e ence was no obse ed in he pa icipan s aged 70 yea s o
mo e. The la ency alues show ha he e iden (and signi ican ) di -
e ence be ween he younge aMCI and con ol pa icipan s disappea s
in he olde subg oups (see Table 2 and Fig. 1).
These esul s may be able o explain a leas in pa he con a-
dic o y esul s epo ed in o he s udies ega ding Go/NoGo asks pe -
o med by aMCI pa icipan s. On one hand, López Zunini e al. (2016)
did no ind any g oup di e ences be ween aMCI and con ol pa ici-
pan s in he la encies o he NoGo-N2 and Go and NoGo-P3 ERP com-
ponen s. The mean ages o hei pa icipan s (con ol, mean age = 72.4
y-o; aMCI, mean age = 75.6 y-o) esemble he mean ages o ou elde ly
subg oup, so i is easonable ha hey we e no able o cap u e di -
e ences in la encies be ween con ol and aMCI pa icipan s as hose
obse ed in he p esen s udy in he younge age subg oup.
On he o he hand, Muda e al. (2016) ound g oup di e ences in
N2 la ency (globally, including bo h Go- and NoGo-N2), as his pa a-
me e was longe in he aMCI han in he con ol g oup. The mean ages
o hei g oups (con ol, mean age = 65.4 y-o; aMCI, mean age = 68.5
y-o) a e much mo e alike ou younge subg oup, so i is possible ha
hey we e able o cap u e his global e ec due o he age o hei
sample (younge han in López Zunini e al., 2016). Howe e , hey did
no ind di e ences in Go-P3 la ency as hose epo ed in his s udy, bu
his migh be explained by he di e en age ange o he aMCI adul s, as
in Muda e al. (2016) i was sligh ly highe han in ou s udy (ou
s udy = 51 yea s-old onwa ds, hei s udy = 57 yea s-old onwa ds).
The p esen esul s may e lec a decline in aMCI ha becomes
e iden ea ly in aging (slowe Go-P3 la ency and slowe NoGo-N2 la-
ency in younge aMCI ela i e o younge heal hy adul s), and in-
iguingly disappea s in la e aging s ages (absence o di e ences in Go-
P3 and NoGo-N2 la encies be ween olde aMCI ela i e o olde heal hy
adul s). Al hough we a e no able o in e he cause o his pa e n om
his s udy, i migh e lec a hypo he ical compensa o y mechanism ha
would allow he aMCI pa ien s o p ese e hei speed o s imulus ca-
ego iza ion a e an ea ly decline. Al e na i ely, his esul migh in-
dica e ha hose adul s diagnosed wi h aMCI a an ea lie age may
show la ge impai men s han hose diagnosed la e in aging. Any o
hese hypo heses should be es ed in u u e s udies.
Ramos-Goicoa e al. (2016) also obse ed longe Go-P3 la encies in
middle-aged aMCI pa icipan s han in age-ma ched con ols using a
S oop ask and a qui e lowe cu -o age (64/65 yea s old; age ange o
he younge subg oups: 51–64 yea s old), indica ing ha ega dless o
he cause o his e ec i seems o be qui e obus ac oss asks in ela-
i ely young elde ly. Hence, he age ac o can mask some in e es ing
e ec s in he sea ch o aMCI bioma ke s, and migh accoun o some
o he con adic o y esul s in he li e a u e ega ding P3b and o he
ERP componen s.
On he o he hand, N2 ampli udes did no show any g oup di e -
ences, as in p e ious s udies (López Zunini e al., 2016;Muda e al.,
2016). Using he AV ask, a p e ious s udy obse ed lowe Go- and
NoGo-N2 ampli udes in aMCI han in con ol pa icipan s in he S an-
da d Condi ion (s anda d audi o y- isual s imuli pai s; Cid-Fe nández
e al., 2014b), while ano he s udy did only obse e di e ences be-
ween g oups in his condi ion o Go-N2 ampli ude as a ma ginally
signi ican e ec (Cid-Fe nández e al., 2017b). In he p esen s udy (see
Fig. 1 and Table 2), he e is a endency in line wi h he signi ican
esul s discussed h oughou his a icle: i seems ha Go- and NoGo-N2
ampli ude migh di e be ween g oups (aMCI and con ols) only in he
younge subg oup, and he e o e migh accoun o he appa en ly
con adic o y esul s ega ding hese pa ame e s in p e ious li e a u e.
This hypo hesis should be es ed in u u e s udies using la ge samples,
whe e p obably would each signi icance.
Rega ding he ROC cu es, he Go-P3 la ency, he NoGo-N2 la ency
and he numbe o co ec esponses alone did no yield sensi i i y and
speci ici y sco es (equal o o e 0.70) ha would enable g oups o be
dis inguished. The same was ue o he combina ion o he NoGo-N2
and Go-P3 la encies. Howe e , he combina ion o he Go-P3 la ency
and he numbe o hi s may be use ul o dis inguishing aMCI om
con ol pa icipan s o age 69 yea s o less (sensi i i y = 0.82 and
speci ici y = 0.75). Simila esul s we e ound o he combina ion o
he NoGo-N2 la ency and he numbe o hi s (sensi i i y = 0.80 and
speci ici y = 0.75), and o he combina ion o he h ee pa ame e s
(sensi i i y = 0.70, speci ici y = 0.92).
Finally, i is wo h no ing ha he esul s o he p esen s udy migh
be es ic ed o cogni i e con ol asks. Mo e ERP s udies e alua ing
hese componen s, wi h o he asks and la ge samples, would be ne-
cessa y o d aw mo e gene al conclusions abou he modula ions o age
in he sea ch o aMCI bioma ke s.
5. Conclusions
Task pe o mance was wo se in he olde old pa icipan s ( > 70
yea s old) (longe RTs and less co ec esponses) han in he younge
old pa icipan s (50–69 yea s old). In addi ion, he aMCI pa icipan s
p ocessed bo h he Go and he NoGo s imuli mo e slowly han he
con ol pa icipan s (longe NoGo-N2 and Go-P3 la encies in he
o me ), al hough only in he younge old subg oup.
In conclusion, aMCI was ound o a ec NoGo-N2 and Go-P3 la-
encies in his s udy because modula ion by he age ac o on he g oup
e ec s was aken in o accoun . Hence, i seems impo an o conside
his ac o in u u e s udies aiming o sea ch o ERP bioma ke s o
aMCI.
Acknowledgemen s
This s udy was suppo ed by g an s om he Spanish Go e nmen ,
Minis e io de Economía y Compe i i idad (PSI2014-55316-C3-3-R;
PSI2017-89389-C2-2-R), wi h FEDER Funds; he Galician Go e nmen ,
Conselle ía de Cul u a, Educación e O denación Uni e si a ia, Axudas
pa a a Consolidación e Es u u ación de Unidades de In es igación
Compe i i as do Sis ema Uni e si a io de Galicia: GRC (GI-1807-USC);
Re : ED431-2017/27, wi h FEDER unds.
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