Biological Psychology 142 (2019) 108–115

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Biological Psychology
journal homepage: www.elsevier.com/locate/biopsycho

The importance of age in the search for ERP biomarkers of aMCI T

Susana Cid-Fernández , Mónica Lindín, Fernando Díaz
⁎

Laboratorio de Neurociencia Cognitiva, Departamento de Psicoloxía Clínica e Psicobioloxía, Universidade de Santiago de Compostela, Galicia, Spain

ARTICLE INFO ABSTRACT

Keywords: Alzheimer’s Disease (AD) has become a major health issue in recent decades, and there is now growing interest in
Amnestic mild cognitive impairment (aMCI) amnestic mild cognitive impairment (aMCI), an intermediate stage between healthy aging and dementia, usually
Aging AD. Event-related brain potential (ERP) studies have sometimes failed to detect differences between aMCI and
N2 control participants in the Go-P3 (or P3b, related to target classification processes in a variety of tasks) and
P3
NoGo-P3 (related to response inhibition processes, mainly in Go/NoGo tasks) ERP components. The aim of the
Go/NoGo
Event-related potentials (ERPs)
present study was to evaluate whether the age factor, which is not usually taken into account in ERP studies,
modulates group differences in these components. With this aim, we divided two groups of volunteer partici-
pants, 34 subjects with aMCI (51–87 years) and 31 controls (52–86 years), into two age subgroups: 69 years or
less and 70 years or more. We recorded brain activity while the participants performed a distraction-attention
auditory-visual (AV) task. Task performance was poorer in the older than in the younger group, and aMCI
participants produced fewer correct responses than the matched controls; but no interactions of the age and
group factors on performance were found. On the other hand, Go-P3 and NoGo-N2 latencies were longer in aMCI
participants than in controls only in the younger subgroup. Thus, the younger aMCI participants categorized the
Go stimuli in working memory and processed the NoGo stimuli (which required response inhibition) slower than
the corresponding controls. Finally, the combination of the number of hits, Go-P3 latency and NoGo-N2 latency
yielded acceptable sensitivity and specificity scores (0.70 and 0.92, respectively) as regards distinguishing aMCI
participants aged 69 years or less from the age-matched controls. The findings indicate age should be taken into
account in the search for aMCI biomarkers.

1. Introduction (aMCI; Petersen et al., 2001, 2009). Individuals with aMCI show an
increased risk of developing AD relative to healthy aging: longitudinal
The world’s population is aging, owing to decreased birth rates and studies have revealed that aMCI patients have an 80% chance of de-
increased life expectancy (Park & Reuter-Lorenz, 2009). The ac- veloping AD within 6 years of diagnosis (Petersen et al., 2001, 2009,
celerated increase in aging is accompanied by an increase in the pre- 1999). The prevalence of MCI at present is difficult to calculate, as it
valence of neurodegenerative diseases. depends on the precise diagnostic criteria (Ward, Arrighi, Michels, &
Alzheimer’s Disease (AD) is the most common form of dementia and Cedarbaum, 2012). Despite this, as AD increases doubles every 5 years
is becoming increasingly more prevalent (Andreasen & Blennow, 2005; after age 65 (Jones, Bruns, & Petersen, 2017), it is worthy to evaluate
Bennys, Rondouin, Benattar, Gabelle, & Touchon, 2011), at great cost to adults with aMCI from several years before that age.
affected individuals and their families and to society as a whole (Park & Characterization of aMCI is important to enable correct diagnosis
Reuter-Lorenz, 2009). The prevalence and incidence rates of AD in- and prognosis, thus increasing the probability of clinical intervention
creases exponentially with age, with the most notable rise from 70 years before brain damage becomes irreversible (Bredesen, 2014). The search
on, as the late-onset form of AD accounts for more of the 95% of af- for aMCI markers has therefore received a great deal of attention in the
fected (Reitz, Brayne, & Mayeux, 2011). last two decades. Useful biomarkers should be able to detect the neu-
However, most AD patients experience some memory decline before ropathology and must be validated in neuropathologically confirmed
reaching the clinical threshold for the diagnosis of AD (Petersen et al., cases. In addition, biomarkers should also be precise, reliable, non-in-
2001). The state in which there is greater memory loss than expected vasive, simple to obtain and inexpensive (Thies, Truschke, Morrison-
for normal aging, but which does not affect daily living and does not Bogorad, & Hodes, 1998). Although several aMCI biomarkers have been
meet the criteria for AD, is termed amnestic Mild Cognitive Impairment proposed (Albert et al., 2011), they are expensive (e.g. functional

⁎
Corresponding author.
E-mail address: [email protected] (S. Cid-Fernández).

https://doi.org/10.1016/j.biopsycho.2019.01.015
Received 14 November 2018; Received in revised form 24 January 2019; Accepted 25 January 2019
Available online 02 February 2019
0301-0511/ © 2019 Elsevier B.V. All rights reserved.
S. Cid-Fernández et al. Biological Psychology 142 (2019) 108–115

magnetic resonance imaging) and/or invasive (e.g. positron emission but only when the sample was split into different age groups. Lindín
tomography, cerebrospinal fluid measures) and have either not been et al. (2013) used the AV task and analyzed the mismatch negativity
validated (Jack et al., 2011) or show limited sensitivity and specificity (MMN), a component related to automatic and pre-attentive processing
(DeKosky & Marek, 2003; Reitz & Mayeux, 2014; Reitz et al., 2011). of stimuli (Näätänen, Paavilainen, Rinne, & Alho, 2007). The MMN
The event-related brain potentials (ERP) technique is a suitable tool amplitude was smaller in the aMCI than in the control participants, but
for use in the search for biomarkers, as it is non-invasive and relatively only in the group aged 50–64 years and not in older participants (Lindín
inexpensive, and has already shown to be useful in the search for bio- et al., 2013). In addition, in a Stroop task study, Ramos-Goicoa, Galdo-
markers of aMCI and AD (e.g. Cespón, Galdo-Álvarez, & Díaz, 2013; Álvarez, Díaz, and Zurrón, (2016) observed longer P3b latency in aMCI
Cespón, Galdo-Álvarez, & Díaz, 2015; Cespón, Galdo-Álvarez, Pereiro, than in healthy participants, but only in the younger subgroup (64 years
& Díaz, 2015; Correa-Jaraba, Lindín, & Díaz, 2018; Lindín, Correa, old or less). Altogether these results show that some important effects
Zurrón, & Díaz, 2013; for reviews, see Jackson & Snyder, 2008; Vecchio (and potential aMCI biomarkers) may be masked when the age factor is
& Määttä, 2011). not taken into account in the analyses. Indeed, Ramos-Goicoa et al.
In previous studies involving the search for biomarkers of aMCI, we (2016) suggested that the age factor may have some influence in the
used the ERP technique to record the brain activity of participants while mixed results found in the literature regarding P3b latency.
they performed a distraction-attention auditory-visual (AV) task (Cid- In line with this observation, the age ranges of the mentioned stu-
Fernández, Lindín, & Díaz, 2017; Cid-Fernández, Lindín, & Díaz, 2017; dies differ considerably: while the participants of the study that ob-
Cid-Fernández, Lindín, & Díaz, 2014; Lindín et al., 2013). In this task, served group differences in P3b latency are the youngest (younger
participants are presented with pairs of auditory-visual stimuli, and subgroups age range = 51–64 years old; Ramos-Goicoa et al., 2016)
they are asked to attend to the visual stimuli (making a Go/NoGo task) those of studies that did not find such differences were quite (Mudar
and to ignore the auditory stimuli (consisting of a passive oddball task et al., 2016; age range = 54–86 years old; aMCI mean age = 68.5 years
with three stimuli: standard, deviant and novel). The following ERP old; control mean age = 65.4 years old) or much (López Zunini et al.,
components associated with the processing of visual stimuli (preceded 2016; aMCI mean age = 75.6 years old; control mean age = 72.4 years
by standard auditory stimuli) were identified and evaluated: (1) N2b old) older. On the other hand, only the study that used the eldest
(Go-N2) and P3b (Go-P3), in response to Go visual stimuli, and (2) sample was able to observe differences regarding P3b amplitude, as this
NoGo-N2 and NoGo-P3, in response to NoGo visual stimuli. The Go-N2 parameter was larger in the control than in the aMCI group (López
and NoGo-N2 amplitudes were smaller in aMCI than in control parti- Zunini et al., 2016).
cipants, indicating deficits in the evaluation of target stimuli in working In the present study, we used the AV task to evaluate (1) possible
memory (WM) and in response inhibition processes, respectively, in differences between control (healthy) participants and aMCI partici-
participants with aMCI. No differences were observed between the pants in task performance (reaction time -RT- and number of correct
groups in relation to the Go- and NoGo-P3 components, or in Go- and responses), in the Go-N2 and -P3 ERP components (in response to visual
NoGo-N2 latencies (Cid-Fernández et al., 2014b, 2017a; Mudar et al., stimuli that required a response), and in the NoGo-N2 and -P3 ERP
2016). components (in response to visual stimuli that required to withhold a
Go-P3 (or P3b) is a widely studied ERP component, typically max- prepotent response); and (2) whether these differences are modulated
imal at parietal electrodes in young adults, with latencies of by age. For this purpose, two age subgroups were established for sta-
300–700 ms after stimulus presentation. The stimuli that elicit this ERP tistical comparison: participants aged 69 years or less and participants
component are attended stimuli that require a response, e.g. the target 70 years or more. We tested whether the Age factor interacts with the
stimuli of an oddball task, or the Go stimuli of a Go/NoGo task. Go-P3 is Group factor (aMCI vs controls), to clarify whether important group
typically interpreted as a correlate of context updating (when a target effects on the parameters of the aforementioned ERP components may
stimulus is presented) or of stimulus classification in working memory be overlooked.
(Coles & Rugg, 1996; Donchin & Coles, 1988; Kutas, Iragui, & Hillyard, According to previous reports, we expected to find differences be-
1994). Most studies using an oddball task have reported longer P3b tween groups in the behavioural measures, with poorer performance in
latencies in aMCI patients than in healthy controls (e. g. Bennys, Portet, the aMCI than in the control participants (longer RT and fewer correct
Touchon, & Rondouin, 2007; Lai, Lin, Liou, & Liu, 2010; Li et al., 2010; responses). By contrast, we did not expect to find any general group
Papadaniil et al., 2016; Papaliagkas, Kimiskidis, Tsolaki, & differences in the Go- and NoGo-P3 latencies, and only expected to find
Anogianakis, 2008; Parra, Ascencio, Urquina, Manes, & Ibáñez, 2012), longer Go-P3 latencies in the aMCI than in the control participants in
although other studies did not observe any differences (Papaliagkas, the younger subgroups, in accordance with Ramos-Goicoa et al. (2016).
Kimiskidis, Tsolaki, & Anogianakis, 2011). Regarding the P3b ampli- In addition, we did not expect to find group differences for the Go-P3
tude, most studies did not reveal differences between groups (e. g. amplitude, in the global sample or in either of the age subgroups. Fi-
Bennys et al., 2007; Golob, Irimajiri, & Starr, 2007; Lai et al., 2010; nally, we were also expecting to find some age-dependent differences
Papadaniil et al., 2016; Papaliagkas et al., 2008, 2011), although in between groups for the Go-N2 (or N2b) and NoGo-N2 latencies, as (1)
some studies this parameter was significantly smaller in aMCI patients in previous studies using the A-V task we failed to observe any group
than in healthy controls (Li et al., 2010; Parra et al., 2012). differences regarding these parameters, and (2) it seems that there are
On the other hand, the NoGo-P3 component peaks around the significant changes in the N200 subcomponents in MCI adults com-
300–500 latency window at central electrodes after presentation of a pared to healthy adults across studies, despite some contradictions
NoGo stimulus that requires a prepotent response to be withheld. This between results (for a review see Howe, 2014).
has been interpreted as an index of response inhibition processes
(Bokura, Yamaguchi, & Kobayashi, 2001; Jackson, Jackson, & Roberts, 2. Materials and methods
1999; Nakata, Sakamoto, Inui, Hoshiyama, & Kakigi, 2009). Studies
evaluating the NoGo-P3 parameters have generally not found any dif- 2.1. Participants
ferences between MCI participants and controls (2017a, Cid-Fernández,
Lindín, & Díaz, 2014; Mudar et al., 2016). However, López Zunini et al. Sixty-five volunteers were recruited from Primary Care Health
(2016) observed smaller NoGo-P3 amplitudes in aMCI than in control Centers in Santiago de Compostela, Galicia (Spain), after being referred
participants, interpreting this result as an indicator of impaired motor to our research group by their general practitioners (GPs). The parti-
response inhibition processes in aMCI. cipants had no history of clinical stroke, traumatic brain injury, motor-
In two previous ERP studies carried out in our laboratory, differ- sensory deficits or alcohol or drug abuse/dependence, and they were
ences between aMCI participants and healthy controls were observed, not diagnosed with any significant medical or psychiatric illnesses.

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Each participant then underwent the following neuropsychological 2.2. Procedure

tests: 1) the Spanish version of the Mini-Mental State Examination
(MMSE; Lobo et al., 1999); 2) the Spanish version of the Californian The distraction-attention auditory-visual task was adapted from
Verbal Learning Test (CVLT; Benedet Álvarez & Alexandre, 1998), Escera, Alho, Winkler, and Näätänen, (1998). Participants were pre-
which assesses short-delay free recall, short-delay recall with semantic sented with 500 pairs of auditory-visual (A-V) stimuli. Each pair of
cues, and long-delay free recall; 3) the Spanish version of the Cam- stimuli consisted of a visual stimulus (200 ms duration) preceded by an
bridge Cognitive Examination (CAMCOG-R), which assesses deteriora- auditory stimulus (150 ms duration), separated by an interval of 300 ms
tion in specific domains, such as language, attention-calculation, praxis, (SOA). Each pair of stimuli was separated by an interval of 2 s. Parti-
perception and executive functioning (Huppert et al., 1996); and (4) the cipants were asked to attend to the visual stimuli and to ignore the
Spanish version of the Lawton-Brody Instrumental Activities of Daily auditory stimuli. They should respond pressing one button with one
Living (IADL) scale (Vergara et al., 2012). hand if the visual stimulus was a letter, another button with the other
Participants were classified into two groups: Control (31 subjects, hand if it was a number (33% each; Go stimuli), and withhold their
aged between 52 and 86 years, with normal cognitive functioning) and responses if it was a triangle (34%; NoGo stimuli). The task procedure is
aMCI (34 subjects aged between 51 and 87 years). The aMCI partici- further explained in Cid-Fernández et al. (2017b; see Fig. 1; and
pants met the general criteria for MCI outlined by Albert et al. (2011) 2017b).
and the criteria for aMCI proposed by Petersen (2004). Thus, all aMCI
participants fulfilled the following criteria: 1) memory complaints
corroborated by an informant; 2) performance of less than 1.5 SDs 2.3. EEG recording
below age norms in the CVLT; 3) no significant impact on activities of
daily living; and 4) no dementia. For a more extensive description of the The EEG was recorded via 49 electrodes placed in an elastic cap
global samples, see Juncos-Rabadán, Facal, Lojo-Seoane, and Pereiro (Easycap, GmbH), according to the International 10-10 System. All
(2013). The aMCI and control participants were matched according to electrodes were referenced to an electrode attached to the tip of the
age and level of education. nose, and an electrode positioned at Fpz served as ground. The hor-
In order to evaluate whether the age factor modulates the differ- izontal electrooculogram (EOG) was recorded via two electrodes placed
ences between the groups, two subgroups were established in each at the outer canthi of both eyes, whereas the vertical EOG was recorded
group: 69 years or less and 70 years or more. In each age subgroup, via two electrodes placed supra and infraorbitally to the right eye. The
aMCI and control participants were also matched according to age and EEG was continuously digitized at a rate of 500 Hz (bandpass
level of education. The demographic and neuropsychological measures 0.01–100 Hz), and the electrode impedance was maintained below 10 k
of the participants are summarized in Table 1, together with the dif- Ω.
ferences between groups, calculated by the corresponding analysis. Once the signal was stored, it was passed through a digital
To control for the effects of depression, volunteers with scores of 0.1–30 Hz (24 dB/octave slope) bandpass filter, and ocular artefacts
more than 10 in depression screening (Geriatric Depression Scale; were corrected using the Gratton, Coles & Donchin method (Gratton,
Yesavage et al., 1983) were not included in the study. All participants Coles, & Donchin, 1983).
had normal audition and normal or corrected-to-normal vision. All With the aim of evaluating the ERP components of interest (Go-N2,
were right-handed, as assessed by the Edinburgh inventory (Oldfield, NoGo-N2, Go-P3 and NoGo-P3 components), the EEG was segmented
1971). Right after the neuropsychological evaluation, participants un- by extraction of auditory stimulus-locked epochs of 1450 ms (150 ms
derwent the psychophysiological evaluation. pre-auditory stimulus). The epochs composed by the standard auditory-
In addition, all participants gave their written informed consent target visual pairs with correct responses were evaluated. All epochs
prior to taking part in the study. The research project was approved by were corrected to the mean voltage of the first 150 ms of each epoch,
the Galician Clinical Research Ethics Committee (Xunta de Galicia, and segments exceeding ± 100 μV were automatically rejected. The
Spain). The study was performed in accordance with the ethical stan- epochs were then averaged separately for the Go and NoGo trials (Go
dards established in the 1964 Declaration of Helsinki (Lynöe, Sandlund, and NoGo conditions, respectively), and a minimum of 38 artefact-free
Dahlqvist, & Jacobsson, 1991). epochs were averaged for each condition.

Table 1
Mean values and standard deviations (in parentheses) of the demographical and neuropsychological measures considered.
* * *
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
Years of education 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 (short-delay free recall) 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 (short-delay cued recall) 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 free recall) 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 recall) 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 (Orientation) 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 (Attention and Calculation) 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 (Praxis) 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 (Perception) 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 (Executive function) 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: control group; aMCI: amnestic MCI group; y.o.: years old; MMSE: Mini-Mental State Examination; CVLT: California Verbal Learning Test; CAMCOG-R: Cambridge
Cognitive Examination.
* ANOVA (Group), signification level < 0.05.

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Fig. 1. Grand-average event-related brain potential waveforms for the age subgroups in the control (blue/light grey line) and aMCI (orange/dark grey line) groups,
for each condition (Go: upper panel; NoGo: lower panel) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version
of this article).

2.4. Data analysis 2.5. Statistical analysis

Reaction times (RTs, between the onset of the visual stimulus and Two-factor analysis of variance (ANOVA), with the between-subject
pressing the key) for correct responses and the number of correct re- factors Group (two levels: Control, aMCI) and Age (two levels: 69 or less
sponses (Hits) were evaluated in the Go condition. years old and 70 or more years old), was applied to the RTs, Hits and
The Go-N2 (in the 250–430 ms interval) and the Go-P3 (in the amplitudes and latencies of the Go-N2 and -P3 and the NoGo-N2 and
450–750 ms interval) components (after the Go visual stimulus), and -P3 components. Whenever the ANOVAs revealed significant effects due
the NoGo-N2 (in the 200–360 ms interval) and the NoGo-P3 (in the to the factors or their interactions, post hoc comparisons of the mean
400–650 ms interval) components (after the NoGo visual stimulus) values (adjusted to Bonferroni correction) were conducted. Differences
were also evaluated. The peak amplitudes (in microvolts) and latencies were considered significant at p ≤ 0.05.
(in milliseconds) of the Go- and NoGo-N2 and -P3 components were Finally, receiver operating characteristic (ROC) curves were con-
evaluated at the midline electrode where the amplitude was maximal structed for those ERP and behavioral parameters in which the Group
(Pz for Go-P3, Cz for Go-N2, NoGo-N2 and NoGo-P3). factor exerted a significant main effect or interaction. These parameters

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Table 2 3.2.2. Go-P3 and NoGo-P3

Number of correct responses (Hits) and reaction times (RT, from the visual The two factor ANOVAs (Group × Age) applied to the Go-P3 am-
stimulus onset to the button press), and amplitudes (in microvolts) and la- plitude at Pz, did not show any significant main effects or interactions.
tencies (in milliseconds, from the visual stimulus onset) for P3b and NoGo-P3 The two factor ANOVA (Group × Age) applied to the Go-P3 latency
components for each age group.
at Pz revealed a significant effect of the Group × Age interaction (F (1,
YOUNGER (≤ 69 years old) OLDER (≥ 70 years old) 54) = 4.5, p = .039), as this parameter was significantly longer in the
aMCI than in the control participants, but only in the younger subgroup
CONTROL aMCI CONTROL aMCI
(≤ 69 years old; p = .049; see Fig. 1).
Hits 224.2 (5.2) 215.5 (19.3) 210.1 (21.0) 200.3 (25.7) The two factor ANOVAs (Group × Age) applied to the NoGo-P3
RT 605.5 (86.7) 640.6 (64.4) 660.5 (107.3) 679.6 (96.2) amplitude and latency at Cz did not show any significant main effects or
N2b Amp (Cz) −10.3 (7.0) −6.4 (4.6) −6.7 (9.2) −5.2 (4.8) interactions of the factors.
N2b Lat (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 Lat (Cz) 536.2 (22.7) 578.4 (51.4) 598.5 (58.9) 570.0 (64.2)
3.3. ROC curves
P3b Amp (Pz) 4.6 (7.4) 7.4 (5.9) 8.4 (9.1) 6.4 (5.7)
P3b Lat (Pz) 528.5 (80.4) 597.4 (87.9) 588.1 (111.1) 547.3 (108.1) The number of hits discriminated groups (aMCI versus controls) with
NoGo-P3 Amp (Cz) 10.8 (4.9) 11.0 (4.9) 10.4 (7.2) 11.0 (7.6) sensitivity and specificity scores of 0.59 and 0.62, respectively
NoGo-P3 Lat (Cz) 477.0 (74.4) 504.4 (53.5) 521.9 (77.2) 501.4 (97.2)
(AUC = .68). In addition, the Go-P3 latency (at Pz) showed sensitivity
RT: reaction time; Amp: amplitude; Lat: latency. and specificity scores of 0.65 and 0.66, respectively, for distinguishing
control and aMCI participants aged ≤ 69 years (AUC = 0.71). For the
same comparison (control versus aMCI in the younger subgroup), the
were also combined by constructing a binary logistic regression model, NoGo-N2 latency (at Cz) showed sensitivity and specificity scores of
with the parameters included as the explanatory variables (covariates) 0.60 and 0.67, respectively.
and the group of interest as the dependent variable. The predicted The number of hits and Go-P3 latency at Pz were then combined
probabilities were saved as a new variable and ROC curves were with the aim of distinguishing aMCI participants aged ≤ 69 years from
computed. An area under the curve (AUC) of 1.0 corresponds to a their control counterparts, yielding a sensitivity score of 0.82 and a
perfect prediction, whereas a value of 0.5 indicates a useless model. specificity score of 0.75 (AUC = 0.79). For the same comparison, the
combination of NoGo-N2 latency (at Cz) and Go-P3 latency (at Pz)
yielded sensitivity and specificity scores of 0.70 and 0.67, respectively,
3. Results while the combination of NoGo-N2 latency at Cz and the number of hits
yielded sensitivity and specificity scores of 0.80 and 0.75, respectively.
The RTs, number of hits, and amplitudes and latencies of the Go- Finally, the three parameters (number of hits, NoGo-N2 latency at
and NoGo-N2, and Go- and NoGo-P3 components are summarized in Cz and Go-P3 latency at Pz) were combined with the aim of distin-
Table 2, and the ERP waveforms evaluated are depicted in Fig. 1. guishing aMCI from control participants of 69 years-old or less, ob-
taining a sensitivity score of 0.70 and a specificity score of 0.92.
3.1. Behavioural measures
4. Discussion
The two factor ANOVA (Group x Age) applied to the RTs revealed a
significant effect of the Age factor (F (1, 59) = 4.2, p = .045), as this The RT was significantly longer and the number of hits significantly
parameter was significantly longer in the older (70 or more years old) lower in the older (≥ 70 years old) than in the younger (≤ 69 years
than in the younger (69 or less years old) participants (see Table 2). old) participants. In addition, the number of hits was lower in the aMCI
There were no other significant effects or interactions regarding the than in the Control group (although this effect was only marginally
RTs. significant). The Go-P3 (or P3b) and the NoGo-N2 latencies were sig-
The two factor ANOVA (Group x Age) applied to the number of hits nificantly longer in the aMCI than in the control participants, but only
also revealed a significant effect of the Age factor (F (1, 59) = 8.6, in the younger subgroup (≤ 69 years old). In addition, the NoGo-N2
p = .005), as this parameter was significantly smaller in the older than latency was significantly longer in the older than in the younger par-
in the younger participants (see Table 2). In addition, a marginally ticipants, but only in the control group.
significant effect of the Group factor was observed (F (1, 59) = 3.4, It is generally agreed that older adults react more slowly than
p = .07), as this parameter was smaller in the aMCI than in the Control younger adults, as demonstrated in a variety of cognitive tasks (Glisky,
group (see Table 2). No significant interaction of the factors was ob- 2007; Salthouse, 2000). In fact, the slower RT in the older than in the
served. younger participants supports previous findings obtained with the AV
task in healthy subjects (Cid-Fernández, Lindín, & Díaz, 2016) and with
other tasks in healthy subjects (Lucci et al., 2013) and subjects with
3.2. ERP components aMCI (Ramos-Goicoa et al., 2016). However, the differences between
groups in this parameter are not always statistically significant (e.g.
3.2.1. Go-N2 and NoGo-N2 Cid-Fernández et al., 2014b; Correa-Jaraba, Cid-Fernández, Lindín, &
The two-factor ANOVAs (Group × Age) did not show any sig- Díaz, 2016).
nificant main effects or interactions of the factors for the Go-N2 am- Moreover, the older participants provided fewer correct responses
plitude and latency or the NoGo-N2 amplitude at the Cz electrode lo- than the younger participants. Although a similar tendency was ob-
cation. served in previous studies using the AV task, the differences was not
The two-factor ANOVA (Group × Age) applied to the NoGo-N2 found to be statistically significant (Cid-Fernández et al., 2014b, 2016).
latency at Cz showed a significant effect of the Group × Age interaction The discrepancy in the results of the different studies may be due to the
(F (1, 50) = 6.1, p = .017), as this parameter was significantly longer different age cut-off used here (69/70 years old in the present study;
(p = .004) in the aMCI than in the control participants, but only in the 64/65 years old in the previous studies). Besides, it seems that the
younger subgroup (69 or less years old), and significantly longer general increase in RTs across aging studies is usually associated with
(p = .039) in the elder controls (70 or more years old) than in the little or no decrease in accuracy (Ratcliff, Thapar, & McKoon, 2010). In
younger controls (69 or less years old; see Fig. 1). addition, the control participants provided a greater number of correct

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responses than the aMCI participants, although the difference was only amplitude might differ between groups (aMCI and controls) only in the
marginally significant (0.07). This is consistent with the findings of a younger subgroup, and therefore might account for the apparently
previous study using the AV task (Cid-Fernández et al., 2014a), where contradictory results regarding these parameters in previous literature.
this result was significant. This hypothesis should be tested in future studies using larger samples,
Regarding the ERP parameters, the aMCI participants showed where probably would reach significance.
longer Go-P3 and NoGo-N2 latencies than control participants, but only Regarding the ROC curves, the Go-P3 latency, the NoGo-N2 latency
those in the younger subgroup. This may indicate that the aMCI par- and the number of correct responses alone did not yield sensitivity and
ticipants aged 69 years or less old categorized the Go stimuli in the specificity scores (equal or over 0.70) that would enable groups to be
working memory more slowly and were slower regarding early re- distinguished. The same was true for the combination of the NoGo-N2
sponse inhibition processing than their control counterparts. However, and Go-P3 latencies. However, the combination of the Go-P3 latency
this difference was not observed in the participants aged 70 years or and the number of hits may be useful for distinguishing aMCI from
more. The latency values show that the evident (and significant) dif- control participants of age 69 years or less (sensitivity = 0.82 and
ference between the younger aMCI and control participants disappears specificity = 0.75). Similar results were found for the combination of
in the older subgroups (see Table 2 and Fig. 1). the NoGo-N2 latency and the number of hits (sensitivity = 0.80 and
These results may be able to explain at least in part the contra- specificity = 0.75), and for the combination of the three parameters
dictory results reported in other studies regarding Go/NoGo tasks per- (sensitivity = 0.70, specificity = 0.92).
formed by aMCI participants. On one hand, López Zunini et al. (2016) Finally, it is worth noting that the results of the present study might
did not find any group differences between aMCI and control partici- be restricted to cognitive control tasks. More ERP studies evaluating
pants in the latencies of the NoGo-N2 and Go and NoGo-P3 ERP com- these components, with other tasks and larger samples, would be ne-
ponents. The mean ages of their participants (control, mean age = 72.4 cessary to draw more general conclusions about the modulations of age
y-o; aMCI, mean age = 75.6 y-o) resemble the mean ages of our elderly in the search of aMCI biomarkers.
subgroup, so it is reasonable that they were not able to capture dif-
ferences in latencies between control and aMCI participants as those 5. Conclusions
observed in the present study in the younger age subgroup.
On the other hand, Mudar et al. (2016) found group differences in Task performance was worse in the older old participants ( > 70
N2 latency (globally, including both Go- and NoGo-N2), as this para- years old) (longer RTs and less correct responses) than in the younger
meter was longer in the aMCI than in the control group. The mean ages old participants (50–69 years old). In addition, the aMCI participants
of their groups (control, mean age = 65.4 y-o; aMCI, mean age = 68.5 processed both the Go and the NoGo stimuli more slowly than the
y-o) are much more alike our younger subgroup, so it is possible that control participants (longer NoGo-N2 and Go-P3 latencies in the
they were able to capture this global effect due to the age of their former), although only in the younger old subgroup.
sample (younger than in López Zunini et al., 2016). However, they did In conclusion, aMCI was found to affect NoGo-N2 and Go-P3 la-
not find differences in Go-P3 latency as those reported in this study, but tencies in this study because modulation by the age factor on the group
this might be explained by the different age range of the aMCI adults, as effects was taken into account. Hence, it seems important to consider
in Mudar et al. (2016) it was slightly higher than in our study (our this factor in future studies aiming to search for ERP biomarkers of
study = 51 years-old onwards, their study = 57 years-old onwards). aMCI.
The present results may reflect a decline in aMCI that becomes
evident early in aging (slower Go-P3 latency and slower NoGo-N2 la- Acknowledgements
tency in younger aMCI relative to younger healthy adults), and in-
triguingly disappears in later aging stages (absence of differences in Go- This study was supported by grants from the Spanish Government,
P3 and NoGo-N2 latencies between older aMCI relative to older healthy Ministerio de Economía y Competitividad (PSI2014-55316-C3-3-R;
adults). Although we are not able to infer the cause of this pattern from PSI2017-89389-C2-2-R), with FEDER Funds; the Galician Government,
this study, it might reflect a hypothetical compensatory mechanism that Consellería de Cultura, Educación e Ordenación Universitaria, Axudas
would allow the aMCI patients to preserve their speed of stimulus ca- para a Consolidación e Estruturación de Unidades de Investigación
tegorization after an early decline. Alternatively, this result might in- Competitivas do Sistema Universitario de Galicia: GRC (GI-1807-USC);
dicate that those adults diagnosed with aMCI at an earlier age may Ref: ED431-2017/27, with FEDER funds.
show larger impairments than those diagnosed later in aging. Any of
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