Journal of Clinical and Experimental Neuropsychology

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Contribution of four lifelong factors of cognitive

reserve on late cognition in normal aging and
Parkinson’s disease

Maud Rouillard, Michel Audiffren, Cédric Albinet, Mohamed Ali Bahri,

Gaëtan Garraux & Fabienne Collette

To cite this article: Maud Rouillard, Michel Audiffren, Cédric Albinet, Mohamed Ali Bahri,
Gaëtan Garraux & Fabienne Collette (2016): Contribution of four lifelong factors of cognitive
reserve on late cognition in normal aging and Parkinson’s disease, Journal of Clinical and
Experimental Neuropsychology, DOI: 10.1080/13803395.2016.1207755

To link to this article: http://dx.doi.org/10.1080/13803395.2016.1207755

Published online: 12 Aug 2016.

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JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY, 2016
http://dx.doi.org/10.1080/13803395.2016.1207755

Contribution of four lifelong factors of cognitive reserve on late cognition

in normal aging and Parkinson’s disease
Maud Rouillarda,b, Michel Audiffrenb, Cédric Albinetb,c, Mohamed Ali Bahria, Gaëtan Garrauxa,d
and Fabienne Collettea,e
a
GIGA-CRC In Vivo Imaging, University of Liège, Liège, Belgium; bCentre de Recherches sur la Cognition et l’Apprentissage (UMR
CNRS 7295), Sport Sciences Faculty, University of Poitiers, Poitiers, France; cLaboratoire Sciences de la Cognition, Technologie,
Ergonomie (SCoTE), University of Toulouse, INU Champollion, Albi, France; dDepartment of Neurology, CHU of Liège, Liège, Belgium;
e
Psychology and Cognitive Neuroscience Research Unit, University of Liège, Liège, Belgium

ABSTRACT ARTICLE HISTORY

Introduction. Cognitive reserve (CR) was proposed to explain how individual differences Received 7 February 2016
in brain function help to cope with the effects of normal aging and neurodegenerative Accepted 24 June 2016
diseases. Education, professional solicitations, and engagement in leisure and physical KEYWORDS
activities across the lifetime are considered as major determinants of this reserve. Aging; Brain atrophy;
Method. Using multiple linear regression analyses, we tested separately in healthy Cognition; Cognitive reserve;
elderly and Parkinson’s disease (PD) populations to what extent cognitive performance Education level; Leisure
in several domains was explained by (a) any of these four environmental lifespan activities; Occupation;
variables; (b) demographic and clinical variables (age, gender, depression score, and, Parkinson’s disease; Physical
for the PD group, duration of disease and dopaminergic drugs). We also tested for an activity
interaction, if any, between these lifespan variables and brain pathology indexed by
global atrophy measured from high-resolution anatomical magnetic resonance ima-
ging. Results. Age was negatively associated with cognitive performance in the PD
group. In healthy elderly participants, we observed significant positive associations
between cognitive performance and (a) education, (b) leisure activities, and (c) profes-
sional solicitation (decisional latitude). Furthermore, participants with greater brain
atrophy benefited more from CR. In PD patients, education and professional solicita-
tions contributed to cognitive performance but to a lesser extent than in controls. CR
factors modulated the relationship between cognition and brain atrophy only in
patients with a slight or moderate brain atrophy. Conclusions. Education is the CR factor
that contributed the most to late cognitive functioning in both groups, closely followed
by leisure activity in normal aging and professional solicitations in PD. Our results also
provide evidence suggesting that the effects of CR does not express similarly in normal
aging and PD. From a broader perspective, these results seem to indicate that CR
factors the most consistently practiced across lifespan (education and professional
solicitation) are those that are the more strongly associated to late cognitive efficiency.

Cognitive reserve (CR) refers to differences in cogni-
tive processes as a function of sociocultural and envir-
onmental factors that explain how individuals will
cope with functional impairment in the presence of
pathology or other neurological insult (Stern, 2009).
Premorbid factors that contribute to CR include
genetic background, exposure to environmental fac-
tors (Mattson, 2000), life experiences and lifestyle
factors over the entire lifespan (Anstey &
Christensen, 2000; Baldivia, Andrade, & Bueno,
2008; Foubert-Samier et al., 2012; Milgram, Siwak-
Tapp, Araujo, & Head, 2006; Stern, 2003; Whalley,
Deary, Appleton, & Starr, 2004). Among lifespan fac-
tors, high education level, job complexity, and leisure-
related cognitive activities have all been interpreted as
building or sustaining CR.
In normal aging, the influence of CR on late
cognition was evidenced by the association
between cognitive efficiency and (a) higher level
of education (Fratiglioni & Wang, 2007; Meng &

CONTACT Fabienne Collette f.collette@ulg.ac.be GIGA-CRC In Vivo Imaging, Allée du 6 août 8, Bâtiment 30, Université de Liège, Sart
Tilman, 4000 Liège, Belgium.
F.C. is research director at the Belgian National Fund for Scientific Research (FRS-FNRS) (Belgium).
© 2016 Informa UK Limited, trading as Taylor & Francis Group
2 M. ROUILLARD ET AL.
D’Arcy, 2012), (b) job autonomy and complexity
(Andel, Silverstein, & Kareholt, 2015; Ansiau,
Marquié, Soubelet, & Ramos, 2005; Baldivia et al.,
2008; Bosma et al., 2003; Foubert-Samier et al.,
2012; Milgram et al., 2006; Schooler, Mulatu, &
Oates, 1999; Then et al., 2014), (c) a steady engage-
ment in leisure activities that solicits mental effort
(Wang, Xu, & Pei, 2012), (d) practice of physical
exercise and/or sustained social interactions
(Wang et al., 2012). Among these factors, there
has been longstanding evidence suggesting that
education is the strongest factor of CR (Baldivia
et al., 2008; Foubert-Samier et al., 2012; Kramer,
Bherer, Colcombe, Dong, & Greenough, 2004;
Milgram et al., 2006). Interestingly, these factors
also modulate the effect of pathologic cognitive
decline resulting from brain damage during
aging. Although most of the studies on pathologi-
cal aging were conducted in the context of
Alzheimer’s disease (Okonkwo et al., 2014; Stern,
2006, 2012), a recent meta-analysis provided evi-
dence that a higher education level was signifi-
cantly associated with better performance on tests
assessing various cognitive functions in
Parkinson’s disease (PD; Hindle, Martyr, & Clare,
2014; see however Pai & Chan, 2001, for contra-
dictory results). However, the influence of the
other factors of CR in PD has not been
investigated.
These studies clearly established that life experi-
ences and lifestyle factors are associated to the way
people will be able to cope with physiological brain
changes associated to the aging processes.
However, no study has examined the respective
contribution of multiple lifetime factors of CR to
cognitive performance. Furthermore, it is currently
unclear whether these CR factors modulate global
cognition as a whole or whether some of them are
preferentially related to performance in specific
cognitive domains (Richards & Sacker, 2003). The
present study aims at addressing these issues by
examining the relative contributions of four CR
factors (education, work complexity, and leisure
and physical activities) on cognitive performance
in normal aging and PD patients. Participants per-
formed a comprehensive neuropsychological
assessment and were administered questionnaires
quantifying the four CR factors of interest. The
relationship between cognitive performance and
CR factors was modeled separately in the two
groups with multiple regression analyses, and
patterns of associations were compared to deter-
mine whether PD modifies the effects of CR on
cognitive performance.
Method
Participants
Forty-seven healthy older adults and 49 patients diag-
nosed with PD matched for age and gender were
included. Healthy controls were recruited from local
seniors’ organizations and were paid for their partici-
pation. PD patients were recruited from a local clinical
database (MoVeRe group, Academic Hospital, Liege,
Belgium) and through local advertisement. PD was
diagnosed according to the United Kingdom
Parkinson’s Disease Society Brain Bank (UKPDSBB)
clinical criteria (Hughes, Daniel, Kilford, & Lees,
1992). We excluded PD patients with severe motor
disabilities (score higher than 3 on the Hoehn and
Yahr Scale; Hoehn & Yahr, 1967), dementia (Emre
et al., 2007), or depression (Hospital Anxiety and
Depression Scale, HADS; Bjellanda, Dahlb, Haugc, &
Neckelmann, 2002; Zigmond & Snaith, 1983). To
minimize the risk of cognitive impairment in our
healthy participants, a total score lower than 130
(max score 144; Manard, Carabin, Jaspar, & Collette,
2014; Monsch et al., 1995; Schmidt et al., 1994) on the
Mattis Dementia Rating Scale (DRS; Mattis, 1976) or
lower than 27 on the Mini-Mental State Examination
(MMSE; Crum, Anthony, Bassett, & Folstein, 1993;
Folstein, Folstein, & McHugh, 1975) was considered
as an exclusion criterion. Furthermore, prior brain
surgery and any significant structural brain abnorm-
ality on computed tomography scan or magnetic reso-
nance imaging (MRI) were also considered as
exclusion criteria in both groups. Written informed
consent was obtained from all participants in accor-
dance with the Declaration of Helsinki. The Ethics
Committee of the University of Liege approved the
study.
All participants underwent clinical and cogni-
tive evaluations by a neurologist and a neuropsy-
chologist. Within the patient population, disease
stage was assessed using the Hoehn and Yahr
scale (Hoehn & Yahr, 1967), ranging from 1 to 5
(5 representing the most severe motor impair-
ments). Symptoms repercussion on daily life activ-
ities was evaluated using Part II of the Unified
Parkinson’s Disease Rating Scale (UPDRS; Fahn,
Elton, & Members, 1987), whose score has been
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 3

Table 1. Demographic and clinical characteristics.

Parkinson Controls
N = 49 N = 47 t(94) p
Age (years) 66.29 (8.61) 63.87 (8.22) 1.41 .16
Gender (M/F) 27/22 23/24 χ2 = 0.37 .55
MMSE (max = 30) 27.78 (1.49) 28.87 (1.12) –4.07 <.001
HADS 5.71 (3.22) 4.11 (2.52) 2.72 <.01
Hoehn & Yahr (max = 5) 1.60 (0.64)
Disease duration (years) 6.33 (4.29)
UPDRS II 10.16 (6.50)
PDQ39 26.21 (12.68)
LEDD (mg) 432 (329)
N = 43 N = 36 t(77)
Global brain atrophy 0.752 (0.0372) 0.754 (0.0374) 0.131 .90
ICV (ml) 1099 (130) 1099 (100) –0.006 1.00
TIV (ml) 1461 (167) 1462 (155) 0.011 .99
Note. Means; standard deviations in parentheses. HADS = Hospital Anxiety and Depression Scale; MMSE = Mini-Mental State
Examination; UPDRS = Unified Parkinson’s Disease Rating Scale; PDQ39 = Parkinson’s Disease Questionnaire; LEDD =
levodopa equivalent daily dose; ICV = intracerebral volume; TIV = total intracranial volume.

proposed to be sensitive to disease severity (Schrag,
Spottke, Quinn, & Dodel, 2009). Health-related
quality of life was estimated using the Parkinson’s
Disease Questionnaire (PDQ39; Jenkinson, Peto,
Fitzpatrick, Greenhall, & Hyman, 1995, 1997). All
PD patients were examined on their usual stable
dopaminergic medications. Forty-five of the 49
patients were taking a combination of several
classes of drugs. The Levodopa Equivalent Daily
Dose (LEDD; Tomlinson et al., 2010) ranged from
0 to 1321.67 mg. Four other patients were taking,
additionally, nondopaminergic antiparkinsonian
medications. Atrophy, intracerebral volume
(ICV), and total intracranial volume (TIV) were
not significantly different between groups (n = 43
for the Parkinson’s disease group and n = 36 for
the control group; see Table 1 for demographic
and clinical characteristics).
Factors of cognitive reserve
Each participant completed structured question-
naires to quantify the relative importance of four
factors that could contribute to CR during lifetime:
level of education, job solicitation, leisure activities,
and physical activities. For job solicitation, two
measures of CR were used: decisional latitude
and psychological job demand. Questionnaires
were completed by the participants and next were
checked with the neuropsychologist to clarify
ambiguous responses.
Level of education
Participants reported how old they were when they
left school, the highest educational level, and the
last degree they attained. Level of education was
expressed as the number of years at school/college/
university to attain the highest degree obtained
(Stern, Alexander, Prohovnik, & Mayeux, 1992).
Professional solicitations
Participants were asked to report their work
experience and how long they had been engaged
in each employment practiced for more than a
year. Data were expressed in full time equivalence
(FTE). Psychosocial job characteristics for the
three longest occupational tenures (Job 1, Job 2,
and Job 3) were assessed using an adapted French
version of Karasek’s Job Content Questionnaire
(JCQ; Karasek et al., 1998). Two work-related
dependent variables were used in the analyses:
decisional latitude (DL, 9 items) and psychological
job demands (PJD, 9 items). DL represents auton-
omy granted to workers in their job whereas PJD is
more related to psychological work requirement
(quantity of work, time constraint, stress, etc.).
Each item was rated using a Likert-type scale, ran-
ging from 1 (strongly disagree) to 4 (strongly
agree). A higher score refers to a high level of DL
or PJD whereas a lower score refers to a low level
of DL or PJD. DL and PJD were calculated in the
following way:
82 39
> ðDL; or PJD; Job 1
years on Job 1
FTE Job 1Þþ >
>
>6 7>
>
>
>4 ðDL; or PJD; Job 2
years on Job 2
FTE Job 2Þþ 5>
>
>
> >
>
>
< ðDL; or PJD; Job 3
years on Job 3
FTE Job 3Þ > =
>
> number of years worked in Jobs 1 þ 2 þ 3 >
>
>
> >
>
>
> >
>
>
> >
>
: ;

total number of life working years
4 M. ROUILLARD ET AL.
Leisure activities
The leisure questionnaire was created on the basis
of the Historical Leisure Activity Questionnaire
(HLAQ; Kriska et al., 1988) and other previously
published questionnaires (Hultsch, Hammer, &
Small, 1993; Hultsch, Hertzog, Small, & Dixon,
1999; Jopp & Hertzog, 2010; Soubelet, 2009).
Participants were interviewed on leisure activ-
ities that they were engaged in over their entire
life. A set of 66 predefined activities was pro-
posed but the participants were free to add
others as needed. They were next asked to select
the eight activities (out of school and job) that
contributed the most to their personal develop-
ment in each period of their life (6–18 years
old, 19–34 years old, 35–54 years old, more
than 55 years old). In order to decrease the
number of variables, we gathered social, intel-
lectual, and cultural activities in a single score.
Each activity was characterized by two variables:
frequency and mental solicitation. Subjects had
to report the average frequency of engagement
in each activity for each period on a 5-point
scale: never (0), very rarely (less than once a
year) (1), rarely (less than once a month) (2),
from time to time (from one to three times a
month) (3), often (from one to three times a
week) (4), and everyday (5). Mental solicitation
for each activity was also assessed as: very few
(1), a few (2), moderately (3), a lot (4), enor-
mously (5). Leisure activities score for a given
period was defined by frequency multiplied by
mental solicitation for each activity. This score
was divided by the number of years in the
corresponding period and next by 52 to obtain
a score per week. We averaged scores across
periods to obtain a global score over the life-
time. A higher score referred to a large involve-
ment in leisure activities.
Physical activity (PA)
Regular PA was assessed using a French version of
the HLAQ (Kriska et al., 1988). Participants had to
select, at the most, eight PAs that they practiced
the most during their lifetime (among 95 suggested
PAs), with the possibility of suggesting activities
not present in the initial list. Then, they were
asked, for each activity, to specify how many
years, how many months a year, and how many
hours a week they practiced, for the four periods:
6–18, 19–34, 35–54, and over 55 years old. The
outcome measure was the number of hours per
week practiced over lifetime. For each activity,
the score was calculated as follows to obtain a
weekly score.
hyears of practice
months
4
hours per weeki
years over the period
52ði:e: weeks per year Þ
We summed scores of activities performed during
each period. The final score was obtained by aver-
aging the four period scores. We characterized
activities according to their metabolic intensity
(metabolic intensities, METs) using the compen-
dium of PA (Ainsworth et al., 2011; Ainsworth
et al., 2000); only activities practiced from 6
METs and over were taken into consideration, as
some previous studies indicated that the effects on
cognition are particularly evident for vigorous
activities (Audiffren, André, & Albinet, 2011;
Smith et al., 2010; Warburton, 2006).
Neuropsychological testing
Cognitive functioning of healthy subjects and PD
patients was assessed with a comprehensive battery
including a global cognitive efficiency measure, a
visuospatial perception task, a verbal episodic
memory task, processing and perceptual speed
tasks, and executive function tasks.
Global cognitive efficiency
The Mattis DRS (Mattis, 1976) quantifies general
cognitive decline. This scale assesses attention, initia-
tion, construction, conceptualization, and memory
capacity. The total score on this scale was used as a
measure of global cognitive efficiency (max = 130).
Visuospatial perception
The Judgment of Line Orientation (JLO) is a mea-
sure of visuospatial judgment. Thirty-five stimuli
(five training trials) were presented to participants,
consisting in an array of 11 lines around a central
point (stimulus card) and two lines presented
above (target lines). Participants had to identify
the lines on the stimulus card that are exactly in
the same location and point in the same direction
as the target lines. Measure of performance con-
sists in the number of dual target lines correctly
identified (30 stimuli, one point for each correct
answer; Benton, Sivan, Hamsher, Varney, &
Spreen, 1994; Benton, Varney, & Hamsher, 1978).
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
Episodic memory
The original version of the Auditory Verbal
Learning Test (Rey AVLT) was used (Nucci,
Mapelli, & Mondini, 2012; Rey, 1941, 1964). A 15-
word list was read out loud five times by the exam-
iner. After each reading, participants had to recall as
many words as possible. The total number of correct
words recalled over the five trials was used in the
analyses (wordlist learning sum measure).
Processing speed
Speed of processing was assessed with a computer-
ized version of the Choice Reaction Time (CRT)
task initially proposed by Salthouse and Babcock
(Salthouse & Babcock, 1991). Participants had to
decide as quickly and accurately as possible
whether two letters are similar or dissimilar by
pressing the correct corresponding key. Seventy
trials were presented; the outcome measure was
the median reaction time (RT, in ms) for correct
responses over the 70 trials.
Attention/perceptual speed
The verbal version of the Symbol Digit Modality
Test (SDMT) was used (Smith, 1968, 1973, 1982),
which is the reverse of the Digit Symbol Test
(Wechsler, 1955). Participants had to convert
meaningless geometrical symbols into oral number
responses. Duration of the task was 90 seconds,
and outcome measure was the number of correct
responses (Drake et al., 2010; Smith, 1973).
Executive functions
Updating of working memory. A computerized
version of the running span memory task, adapted
from Morris and Jones (Morris & Jones, 1990) was
used. Consonant letters appeared one at a time on
a computer screen. Length of lists was 4, 6, 8, 10,
or 12 consonants (for a total of 15 lists).
Participants were not warned of list length and
had to remember and recall serially only the last
four letters of each list. One point was assigned for
each item recalled in the correct serial position.
The maximum score possible was 60.
Interference resolution. The. Golden’s version of
the Stroop test was used (Golden, 1978). The task
consisted in reading or identifying a maximum of
words or colors in 45 seconds on cards of 100
items. In the reading subtest (A), participants had
to read aloud names of colors written in black ink;
in the color subtest (B), they had to name the color
5
of crosses (XXX); in the color–word interference
subtest (C) they had to name the color of the
printed color words (for example, red written in
blue). The number of correct responses in each
condition was recorded. Inhibitory performance
was calculated by C – [(A × B)/(A+ B)], with a
score up to 0 indicating a good performance.
Strategic search in memory. Phonemic (P, R, and
V letters) and category (animals, fruits, and furni-
ture) fluency tasks were used. Participants were
asked to provide a maximum of words beginning
with the target letter or belonging to the semantic
category in 60 seconds (Cardebat, Doyon, Puel,
Goulet, & Joanette, 1990; Tombaugh, Kozak, &
Rees, 1999). Measures of performance were the
average of correct words given for each letter and
for each category, respectively.
Cognitive flexibility. Flexibility was assessed using
a modified version of the Wisconsin Card Sorting
Test (mWCST; Nelson, 1976). This version
includes 24 cards (used twice) that share only one
characteristic (form, color, or number) with the
four target cards placed in front of participants.
Participants were asked to match each of the 48
cards (one by one) with one of the four cards that
faced them, according to one changing rule (form,
color, or number) that had to be deducted on the
basis of correct/incorrect previous responses, and
this until six categories were successfully com-
pleted or all the cards had been used (for a com-
prehensive description of the procedure, see
Lineweaver, Bond, Thomas, & Salmon, 1999).
Perseverative errors across categories were used
for analyses, as they are considered as a good
measure of executive functioning (Bowden et al.,
1998).
Magnetic resonance imaging (MRI) data
Structural MRI data were acquired on a 3-T
head-only MR scanner (Magnetom Allegra,
Siemens Medical Solutions, Erlangen, Germany)
operated with an 8-channel head coil as part of
another study (Ziegler et al., 2014). In brief,
structural and quantitative maps of T1, T2*, pro-
ton density (PD), and magnetization transfer
(MT) at 1 × 1 × 1 mm3 resolution were calcu-
lated from a multiparameter protocol based on a
3D multiecho fast low angle shot (FLASH)
sequence (Weiskopf & Helms, 2008). We used
6 M. ROUILLARD ET AL.
SPM 12 (The FIL Methods Group [and Honorary
Members], 2014) implemented in MATLAB
2011a (Mathworks, USA) to estimate global
brain atrophy level from MT maps. The contrast
in these MT images, which is higher than in
typical T1-weighted images, enables more accu-
rate distinction between gray and white matter,
especially for the basal ganglia and substantia
nigra (Helms, Draganski, Frackowiak,
Ashburner, & Weiskopf, 2009). MT maps were
processed using unified segmentation in order to
create masks of gray matter, white matter, and
cerebrospinal fluid (Ashburner & Friston, 2005).
Global brain atrophy was estimated on a sub-
ject-by-subject basis from the brain tissue-to-intra-
cranial volume ratio. We used a custom-made
Matlab function and SPM12 to compute the
volume of gray matter, white matter, and cere-
brospinal fluid (CSF) from the aforementioned
MT maps. Tissue volume (intracerebral volume,
ICV) was obtained by summing gray and white
matter volumes, while total intracranial volume
(TIV) corresponded to the sum of gray matter,
white matter, and CSF volumes. The output mea-
sure for each subject was the ratio between ICV
and TIV.
Statistical analysis
Statistical analyses were performed with IBM
SPSS Statistics 20. Mean values of neuropsycho-
logical and CR measures were first compared
between the two groups of participants, using
Student t tests. Second, correlational analyses
were performed to examine the bivariate rela-
tions between each CR measure. Finally, multi-
ple regression analyses were conducted to
determine which measure(s) of CR explained
cognitive performance in healthy older people
and PD patients separately. We used hierarchi-
cal linear regression models with the enter
method to assess simultaneously the respective
contribution of confound (or control) variables
and CR measures on cognitive performance. In
these models, variables of noninterest (“control
variables”) that could influence cognition were
entered in a first block (age, gender, HADS
depression score for both groups, and the dura-
tion of disease and LEDD for the PD group; see,
for example, Austin, 2001; Dik, Deeg, Visser, &
Jonker, 2003; Kåreholt, Lennartsson, Gatz, &
Parker, 2011), while the second block included
the five CR measures of interest (education,
decisional latitude, and psychological job
demands for work solicitation, leisure activities,
and physical activity scores). As we were first
interested to determine the additional part of
variance brought by CR variables on cognition
when noninterest variables are controlled for,
we checked whether the part of explained var-
iance significantly increases from the first to the
second block. Then, we explored the unique
significant variance explained by each CR factor
in the second block. For each analysis, we used
z score (calculated in each group separately) for
all variables except for age and gender.
Percentage of unique significant variance
explained by each factor is detailed in the text.
All prerequisite associated with the use of sta-
tistical analyses were met except for multicolli-
nearity of LD and PJD measures of professional
solicitations.
Finally, in order to determine whether the
factors of cognitive reserve moderate the rela-
tionship between neuropsychological test scores
and brain pathology, we performed supplemen-
tary linear regression analyses on cognitive mea-
sures explained by one (or several) of these CR
factors, with the hypothesis that participants
with the larger atrophy will benefit the most
from the presence of a high cognitive reserve.
These analyses were performed in the two
groups separately, and we checked for an effect
of CR at various levels of brain atrophy ranging
from the 10th to the 90th percentile. The 10th
percentile corresponds to a very important atro-
phy and 90th to a small one. Thirty-six healthy
controls and 43 patients were included in this
analysis.
Results
Group comparisons
With regard to structural brain changes, no differ-
ence between groups was observed for global brain
atrophy, intracerebral volume (ICV), and total
intracranial volume (TIV; see Table 1). PD patients
obtained significant lower performance than con-
trols in all neuropsychological measures, except for
the interference index on the Stroop test and the
number of perseverative errors on the mWCST
(see Table 2). With regard to factors of CR, PD
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 7

Table 2. Performance in cognitive tasks.

Parkinson Controls
Neuropsychological tasks (N = 49) (N = 47) t p
Mattis DRS 135.10 (5.25) 139.64 (3.48) t(94) = –4.97 <.001
JLO 21.18 (4.68) 24.43 (3.66) t(94) = –3.77 <.001
Rey AVLT 43.63 (10.66) 52.96 (10.57) t(94) = –4.30 <.001
CRT (ms) 886 (183) 818 (141) t(94) = 2.04 <.05
SDMT 42.29 (12.56) 50.51 (10.41) t(94) = –3.48 <.001
Running span 33.13 (13.88) 41.17 (11.10) t(93) = –3.12 <.005
Stroop test –4.18 (8.52) –2.77 (7.87) t(92) = –0.83 .41
Phonemic fluency 35.12 (10.30) 41.23 (11.54) t(94) = –2.74 <.01
Category fluency 41.22 (9.60) 49.02 (9.84) t(94) = –3.93 <.001
mWCST (perseverative errors) 38.09 (19.27) 33.02 (24.41) t(94) = 1.13 .26
Note. Raw data. Means; standard deviations in parentheses. Mattis DRS = Mattis Dementia Rating Scale; JLO = Judgment of Line
Orientation; Rey AVLT = Rey Auditory Verbal Learning Test; CRT = Choice Reaction Time; SDMT = Symbol Digit Modality Test;
mWCST = modified Wisconsin Card Sorting Test.

Table 3. Cognitive reserve scores.

Parkinson Min–max Controls Min–max
Cognitive reserve factors (N = 49) (values) (N = 47) (values) t(94) p
Education 11.27 (3.30) 6–20 13.32 (3.33) 6–20 –3.03 <.005
Decisional latitude 869 (451) 0–1750 874 (391) 0–1476 –0.058 .95
Psychological job demands 680 (328) 0–1204 688 (294) 0–1232 –0.12 .91
Leisure activities 0.08 (0.04) 0.02–0.25 0.09 (0.05) 0.04–0.29 –1.13 .26
Physical activities 1.70 (1.85) 0–8.46 2.79 (3.04) 0–12.83 –2.12 <.05
Note. Raw data. Means; standard deviations in parentheses.

patients showed significant lower educational level
and lower score of PA (see Table 3).
Determinants of cognitive efficiency in normal
aging
Significant general effects of Block 1 (control vari-
ables) and Block 2 (CR variables) were not observed
for global cognitive efficiency and visuospatial per-
ception. The addition of the five CR measures did
not significantly increase the amount of explained
variance either. Nevertheless, when the other vari-
ables were controlled, 13.8% of the Mattis DRS
variance was explained by educational level in
Block 2.
For processing speed, Blocks 1 and 2 were signifi-
cant, but Block 2 did not significantly increase the
overall explained variance. However, processing
speed was negatively explained by age (12.1%), and
female gender was associated with better perfor-
mance than male gender for 13%.
With regard to episodic memory and attention/per-
ceptual speed, both blocks were significant, and Block
2 significantly increased the overall explained var-
iance. In Block 1, age was a predictor of both episodic
memory and attention/perceptual speed. In Block 2,
memory performance was positively explained by
education (14.5%) and negatively by psychological
job demand (7.2%) while significant unique percen-
tage of variance in speed performance was associated
positively to education (11.6%) and leisure activities
(8.5%), and negatively to psychological job
demand (7.2%).
For executive functions, Block 1 and Block 2
were not significant for interference resolution, flex-
ibility, and strategy search in semantic memory as
assessed by phonemic verbal fluency. However,
when the other variables were controlled, age was
significant in Block 1 for interference resolution.
The addition of the five CR measures did not
significantly increase the amount of explained var-
iance in the inhibitory performance but leisure
activities reached a p value of .037, accounting for
9.1% of the variance. For flexibility, the addition of
the five CR measures did not significantly increase
the amount of explained variance by age either, but
in Block 2, when the other variables were con-
trolled, age explained 13.5% of the variance.
Furthermore, decisional latitude was near signifi-
cant (p = .050) and explained 7.2% of the variance.
Finally, Block 2 (even if not significant) signifi-
cantly increased the amount of explained variance
for the phonemic fluency performance, with lei-
sure activities positively explaining 8.9% of unique
variance and psychological job demand negatively
explaining 9.6% of it.
8 M. ROUILLARD ET AL.

Figure 1. Percentage of the variance explained by cognitive reserve (CR) factors on cognitive functioning in normal aging.
(A) Variance level (in percentages, represented by circles) in cognitive performance explained by five CR factors
(represented by concentric circles): education, decisional latitude (DL), psychological job demands (PJD), leisure, and
physical activities (PA). (B) Percentage of variance explained by age, gender, and depression. DRS = Dementia Rating
Scale; JLO = Judgment of Line Orientation; AVLT = Auditory Verbal Learning Test; CRT = Choice Reaction Time; SDMT =
Symbol Digit Modality Test; mWCST = modified Wisconsin Card Sorting Test.

Block 1 was not significant for updating of Determinants of cognitive efficiency in

working memory and strategy search in semantic Parkinson’s disease subjects
memory as assessed by the category verbal fluency,
Significant general effects of Block 1 (with a nega-
contrary to Block 2, which also significantly
tive effect of age and an effect of gender for visuos-
increased the percentage of overall explained var-
patial perception) and Block 2 were observed for
iance. Education was a reliable positive predictor
global cognitive efficiency, episodic memory, visuos-
for the running span and category fluency perfor-
patial perception, processing speed, and attention/
mance, accounting for 16.2% and 22.5% of the
perceptual speed, but Block 2 did not significantly
variance, respectively. Decisional latitude positively
increase the overall explained variance (p = .054
explained 6.6% of additional unique variance for
for visuospatial perception, p = .12 for processing
category fluency performance.
speed, and p = .31 for attention/perceptual speed).
These results are graphically described in Figure 1
Age explained negatively most of total variance
(see Appendix A, Tables A1, A2, and A3, for a detailed
(20.2% for global cognitive efficiency, 14.4% for
presentation of the models).
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
the visuospatial perception, 14.2% for episodic
memory, 36% for processing speed, and 42% for
attention/perceptual speed). Education explained
(positively) 12.3% of global cognitive efficiency
and 11.9% of the episodic memory variance.
Processing speed and visuospatial perception
scores were positively explained by decisional lati-
tude at work (9% and 7.5%, respectively) and
negatively by psychological job demand (8.6%
and 10.9%, respectively). Attention/perceptual
speed was also negatively explained by psychologi-
cal job demand (4%).
For executive functions, Block 1 and Block 2 were
not significant for the category fluency task (search
strategy in semantic memory) and flexibility.
Nevertheless, when the other variables were con-
trolled, age explained part of the unique variance in
Block 1. The addition of the five CR measures did not
significantly increase the amount of explained var-
iance either. Concerning the phonemic fluency task
(search strategy in semantic memory), Block 1 was not
significant, but Block 2 was significant and increased
the percentage of overall explained variance.
Education explained positively 19.6% of the variance.
For interference resolution and updating of working
memory, Blocks 1 and 2 were significant, but Block 2
did not significantly increase the overall explained
variance. Interference resolution and updating of
working memory variances were negatively explained
by age (25.7% and 20.9%, respectively). Moreover, for
interference resolution, female gender was associated
to better performance than male gender for 11%,
while for updating of information in working mem-
ory, education explained 5.9% of the variance.
These results are graphically described in
Figure 2 (See Appendix B, Tables B1, B2, and B3,
for a detailed presentation of the models).
Benefits of cognitive reserve on cognitive
functions according to brain atrophy
To determine whether the factors of cognitive reserve
moderate the relationship between neuropsychologi-
cal test scores and brain pathology, we performed
supplementary linear regression analyses. More pre-
cisely, we assessed whether the benefit of cognitive
reserve will vary according the amount of brain atro-
phy, with participants at the 10th percentile having a
large atrophy. Models showing a significant effect of
CR for one or several levels of brain atrophy are
detailed in Tables 4 and 5.
9
In healthy participants, linear regression analyses
revealed a significant effect of education at various
levels of brain atrophy on global cognitive efficiency
(effect from the 10th to the 50th percentile), episodic
memory (effect from the 10th to the 50th percentile),
attention/perceptual speed (effect from the 10th to the
50th percentile), and executive functions (updating of
working memory and strategic search in memory
with the category fluency task (effect from the 10th
to the 90th percentile for the two analyses). With
regard to decisional latitude, the positive effect of
decisional latitude on executive functions (updating
of working memory) is still present but less pro-
nounced (effect from the 50th to the 75th percentile).
Concerning leisure activities, the only effect that
remains significant from the 75th percentile is on
attention/perceptual speed, and no more effect was
observed for executive processes. These effects indi-
cate, as predicted, that participants with the larger
atrophy are the ones benefiting the most from CR.
In the Parkinson’s disease group, linear regression
analyses revealed an effect of education according to
level of brain atrophy on global cognitive efficiency
(from the 50th to the 90th percentile), episodic mem-
ory (from the 50th to the 90th percentile), and execu-
tive functions (updating of working memory: from
the 50th to the 75th percentile; and strategic search in
memory with the phonemic fluency task: from the
10th to the 90th percentile). Concerning decisional
latitude, there is an effect for visuospatial perception
and processing speed for a mean atrophy (50th per-
centile). As a whole, these results indicate that the
effects of CR are the most beneficial for PD patients
with a slight and moderate level of brain atrophy.
Discussion
The aim of the present research was to measure the
respective contribution of four cognitive reserve fac-
tors—education, work complexity, leisure and phy-
sical activities—as predictors of cognitive
performance in normal aging and PD. We were
also interested in determining whether the occur-
rence of PD is associated with changes in the respec-
tive contribution of these various CR measures on
cognition. Although some previous studies showed
that PDs’ medication can influence cognition (i.e.,
Cools, 2006), in the present study we did not observe
an LEDD effect on cognitive performance. Results
can be summarized in the following way.
10 M. ROUILLARD ET AL.

Figure 2. Percentage of the variance explained by cognitive reserve (CR) factors on cognitive functioning in the
Parkinson’s disease (PD) group. (A) Variance level (in percentages, represented by circles) in cognitive performance
explained by five CR factors (represented by concentric circles): education, decisional latitude (DL), psychological job
demands (PJD), leisure, and physical activities (PA). (B) Percentage of variance explained by age, gender, and depression.
DRS = Dementia Rating Scale; JLO = Judgment of Line Orientation; AVLT = Auditory Verbal Learning Test; CRT = Choice
Reaction Time; SDMT = Symbol Digit Modality Test; mWCST = modified Wisconsin Card Sorting Test.

In healthy aging, the number of years of education
is the more important predictor of cognitive function-
ing: People with a higher education level show better
global cognitive efficiency, episodic and working
memory performance, attentional abilities, and search
strategy in semantic memory. Leisure activities also
appear to be a good predictor of cognitive perfor-
mance. Indeed, higher implication in leisure activities
is associated with higher attentional and executive
(inhibition, flexibility, and phonemic fluency) abilities.
With regard to job solicitations, only decisional
latitude has a positive effect on executive abilities
(flexibility and updating of working memory) whereas
psychological job demand influences negatively sev-
eral aspects of cognition (episodic memory, attention/
perceptual speed, semantic fluency). Contrary to our
expectations, the overall level of physical activity dur-
ing the lifespan does not predict cognitive efficiency.
Importantly, the relationship between CR measures
and cognition does not appear to be influenced by age
and gender (except for processing speed and age for
flexibility). Finally, when significant, the CR measures
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 11

Table 4. Significant results for healthy subjects from Table 5. Significant results for Parkinson’s disease patients
regressions. from regressions.
Atrophy Lower Higher Atrophy Lower Higher
Percentile b Effect t p SE limit limit Percentile b Effect t p SE limit limit
Education Education
Mattis DRS Mattis DRS
10th –0.050 0.424 2.193 .036* 0.193 0.030 0.818 10th –0.062 0.598 1.318 .195 0.454 –0.320 1.515
25th –0.028 0.422 2.679 .012* 0.158 0.101 0.743 25th –0.030 0.622 1.933 .061 0.322 –0.029 1.272
50th –0.007 0.420 2.628 .013* 0.160 0.095 0.746 50th –0.005 0.641 2.651 .012* 0.242 0.152 1.130
75th 0.030 0.417 1.751 .090 0.238 –0.068 0.901 75th 0.031 0.668 3.079 .004* 0.217 0.229 1.107
90th 0.041 0.416 1.537 .134 0.270 –0.135 0.966 90th 0.038 0.674 2.934 .006* 0.230 0.209 1.139
Rey AVLT Rey AVLT
10th –0.050 1.709 3.112 .004* 0.549 0.590 2.827 10th –0.062 1.152 1.229 .227 0.938 –0.745 3.049
25th –0.028 1.542 3.446 .002* 0.447 0.630 2.453 25th –0.030 1.209 1.818 .077 0.665 –0.136 2.554
50th –0.007 1.373 3.026 .005* 0.454 0.449 2.297 50th –0.005 1.253 2.508 .016* 0.500 0.242 2.264
75th 0.030 1.092 1.617 .116 0.676 –0.284 2.468 75th 0.031 1.318 2.936 .006* 0.449 0.410 2.225
90th 0.041 1.009 1.314 .198 0.768 –0.555 2.572 90th 0.038 1.331 2.801 .008* 0.475 0.370 2.291
SDMT Running span memory task
10th –0.050 1.764 3.813 .001* 0.463 0.822 2.707 10th –0.062 1.807 1.670 .103 1.082 –0.384 3.998
25th –0.028 1.569 4.162 .000* 0.377 0.801 2.336 25th –0.030 1.649 1.957 .058 0.843 –0.057 3.355
50th –0.007 1.371 3.587 .001* 0.382 0.593 2.150 50th –0.005 1.503 2.246 .031* 0.669 0.148 2.858
75th 0.030 1.043 1.832 .076 0.569 –0.116 2.202 75th 0.031 1.255 2.073 .045* 0.605 0.029 2.480
90th 0.041 0.945 1.461 .154 0.647 –0.373 2.263 90th 0.038 1.200 1.874 .069 0.640 –0.096 2.497
Running span memory task Phonemic fluency task
10th –0.050 1.943 3.441 .002* 0.565 0.793 3.092 10th –0.062 2.185 2.210 .033* 0.989 0.185 4.184
25th –0.028 1.930 4.197 .000* 0.460 0.993 2.867 25th –0.030 1.813 2.586 .014* 0.701 0.395 3.231
50th –0.007 1.917 4.110 .000* 0.466 0.967 2.867 50th –0.005 1.523 2.892 .006* 0.527 0.458 2.589
75th 0.030 1.896 2.731 .010* 0.694 0.482 3.311 75th 0.031 1.100 2.326 .025* 0.473 0.144 2.057
90th 0.041 1.890 2.395 .023* 0.789 0.282 3.497 90th 0.038 1.014 2.026 .050* 0.501 0.002 2.027
Category fluency task
10th –0.050 1.883 4.265 .000* 0.442 0.983 2.782 Decisional latitude
25th –0.028 1.749 4.864 .000* 0.360 1.017 2.482 JLO
50th –0.007 1.614 4.426 .000* 0.365 0.871 2.357 10th –0.062 0.0035 1.088 .283 .0029 –0.003 0.009
75th 0.030 1.390 2.560 .015* 0.543 0.284 2.496 25th –0.030 0.0035 1.971 .056 .0018 –0.000 0.007
90th 0.041 1.323 2.144 .040* 0.617 0.066 2.580 50th –0.005 0.0037 2.425 .020* .0015 0.001 0.007
75th 0.031 0.0041 1.622 .113 .0025 –0.001 0.009
Decisional latitude
90th 0.038 0.0042 1.482 .146 .0028 –0.002 0.010
Running span memory task
CRT
10th –0.050 0.019 1.383 .176 0.013 –0.009 0.046
25th –0.028 0.017 1.670 .105 0.010 –0.004 0.038
10th –0.062 –0.066 –0.569 .573 0.116 –0.301 0.169
50th –0.007 0.016 2.055 .048* 0.008 0.000 0.032 25th –0.030 –0.106 –1.489 .145 0.071 –0.250 0.038
75th 0.030 0.014 2.127 .041* 0.007 0.001 0.027 50th –0.005 –0.137 –2.199 .034* 0.063 –0.264 –0.011
90th 0.041 0.013 1.848 .074 0.007 –0.001 0.028 75th 0.031 –0.183 –1.772 .084 0.103 –0.392 0.026
90th 0.038 –0.192 –1.668 .103 0.115 –0.425 0.041
Leisure activities
Note. SE = standard error; Mattis DRS = Mattis Dementia Rating Scale;
SDMT
10th –0.050 122.52 1.165 .253 105.16 –91.69 336.73
Rey AVLT = Rey Auditory Verbal Learning Test; JLO = Judgment of
25th –0.028 112.27 1.364 .182 82.32 –55.41 279.96 Line Orientation; CRT = Choice Reaction Time.
50th –0.007 101.95 1.666 .105 61.18 –22.69 226.58 *p < .05.
75th 0.030 84.75 2.154 .040* 39.34 4.613 164.89
90th 0.041 79.61 2.001 .054* 39.80 –1.451 160.68
Note. SE = standard error; Mattis DRS = Mattis Dementia Rating Scale; visuospatial abilities and processing speed whereas
Rey AVLT = Rey Auditory Verbal Learning Test; SDMT = Symbol psychological job demand negatively influences
Digit Modality Test.
*p < .05. the same variables as well as attention/perceptual
speed. Disease duration, depression, medication,
explain a rather important part of the variance in and previous leisure and physical activity level
cognitive performance (ranging from 6.6% to 22.5%). do not explain cognitive performance in our PD
We observed a different pattern of results in patients. Importantly, age is shown to be the most
our group of PD patients. Indeed, only education important factor explaining performance on most
level and decisional latitude at work were identi- of the cognitive measures. Finally, when signifi-
fied as predictors of cognitive performance. cant, the CR measures explain a rather important
Patients with a higher level of education have part of the variance in cognitive performance
better global cognitive efficiency and higher per- (from 5.9% to 42%).
formance in episodic memory and executive abil- Finally, when brain atrophy is taken into account
ities (updating of working memory and phonemic in our regression analyses, we observed in healthy
fluency tasks). With regard to job solicitations, participants that larger atrophy is associated to a
decisional latitude shows a positive effect on higher positive effect of education on global
12 M. ROUILLARD ET AL.
cognitive efficiency, episodic memory abilities,
attention/perceptual speed, and executive functions
(updating of working memory and category fluency
tasks). Moreover, we also observed an effect of
decisional latitude and leisure activities on cognition
even if these effects were less pronounced. In PD
patient an effect of education (and to a lesser extent
of decisional latitude) was also observed on these
measures, but, contrary to healthy subjects, these
effects were the most beneficial when associated
with a moderate level of brain atrophy.
Cognitive reserve factors explaining cognition
in normal aging
In agreement with previous studies (Foubert-Samier
et al., 2012; Ghisletta, Bickel, & Lövdén, 2006;
Wilson et al., 2003), we observed that education
attainment and leisure activities are determinants
of cognitive performance in old age. These results
suggest a protective effect of cognitive stimulation
across the lifespan. The protective effect of educa-
tion may depend on exposure during a sensitive
period of brain development extending into late
adolescence (Knudsen, 2004). Alternatively, it may
be that educational activities at any age are benefi-
cial (Howard-Jones, Washbrook, & Meadows, 2012;
Timiras, 1995; Wight et al., 2002), as structural
brain characteristics and cognitive abilities can be
modulated throughout the lifespan (Richards &
Deary, 2005).
With regard to leisure activities, the second
most important CR factor in our healthy aging
group, results are consistent with previous ones
(Ghisletta et al., 2006; Wilson et al., 2003) as we
showed a positive influence of leisure activities on
attention/perceptual speed and executive func-
tions. Nevertheless, no association was observed
for our global measure of cognition or episodic
memory measure, contrarily to earlier papers
(Kåreholt et al., 2011; Wilson et al., 2003).
Although further studies are necessary to under-
stand these discrepancies, we could suggest that
gathering intellectual and social leisure activities
or assessing simultaneously the influence of var-
ious factors of CR could have influenced the pat-
tern of results observed.
Surprisingly, our results show little impact of
working occupation, although previous studies have
shown a positive impact on several cognitive pro-
cesses (Andel et al., 2015; Ansiau et al., 2005; Baldivia
et al., 2008; Bosma et al., 2003; Foubert-Samier et al.,
2012; Milgram et al., 2006; Mulatu & Schooler, 1999;
Schooler et al., 1999; Then et al., 2014). Moreover, we
observed opposite effects of two aspects related to job
solicitation on cognitive performance, with a positive
impact of decisional latitude but a negative one for
psychological job demand. This is consistent with
studies showing that various kind of job solicitations
(level of control and autonomy, complexity, stress,
etc.) will influence the building up of CR (Li, Wu, &
Sung, 2002; Lupien, Maheu, Tu, Fiocco, & Schramek,
2007; Marin et al., 2011).
To our knowledge, no study has yet focused on
the effect of physical activity over the lifetime on
cognition. Here, vigorous physical activity (6 METs
and over) practiced across the lifetime does not show
any significant effect on current cognitive efficiency.
This result is quite surprising in view of the health
benefits of physical activity (Wang et al., 2012;
Warburton, 2006) and the tremendous number of
studies showing a positive effect of these activities on
cognition (Chang et al., 2010; Dik et al., 2003;
Richards, Hardy, & Wadsworth, 2003; Smith et al.,
2010). A possible explanation could be that positive
effects of physical activity are limited in time, and
thus its assessment over the lifespan would not show
a positive effect on cognition if the participants
stopped practicing when they grew older. Indeed,
the few studies that focused on the persistence of
the benefits of physical activity across time showed
that the long-lasting effect is around 12 months
(Kelly et al., 2014). Accordingly, more than half of
our participants had not practiced intense physical
activity in the last month, as assessed by the National
Aeronautics and Space Administration/Johnson
Space Center Physical Activity Scale (Ross &
Jackson, 1990; data not shown).
At this time, very few studies have explored simul-
taneously the influence of several factors of CR in
cognitive abilities of healthy older people. Some
authors proposed that education is the most impor-
tant factor of CR (Baldivia et al., 2008), while others
suggested that occupation (job solicitation) could be a
better long-term predictor of cognitive decline than
education (Li et al., 2002). Regarding our results,
education, followed by leisure activities, appears to
have a more protective effect on cognition than job
solicitation. As the synergistic effects of those factors
could slightly vary according to the characteristics of
the studied sample, it is difficult to draw firm conclu-
sions at this time. However, our results underscore the
importance of examining different factors of CR in the
same group of participants, to clearly disentangle their
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
unique implication for cognitive performance in
old age.
Cognitive reserve factors explaining cognition
in Parkinson’s disease
To our knowledge, education, occupation, and leisure
and physical activities have never been studied simul-
taneously as factors of CR in PD. We observed a
positive relationship between educational level and
cognition. These results are consistent with previous
findings showing that a high level of education is
associated with better global cognition, memory, and
executive functions in PD (Hindle et al., 2016; Hindle
et al., 2014; Koerts, Tucha, Lange, & Tucha, 2013). Job
solicitation still has a little impact on cognitive func-
tions, and, as observed in normal aging, a job asso-
ciated to a high level of decisional latitude appears to
have positive impact on late cognition in PD
(although in a lesser extent than in normal aging),
whereas high psychological job demand has a negative
impact. Finally, we do not observe a positive effect of
leisure activities, contrary to what was observed in
normal aging, and practice of lifelong physical activ-
ities does not influence later cognition in our sample
of PD participants either (as in normal aging).
Interestingly, our results point out that CR vari-
ables the most frequently practiced in a lifetime (edu-
cation and job solicitation were practiced during
hours, for years) are those that seem the most protec-
tive against cognitive decline due to a pathological
condition, and that the relative contribution of these
variables slightly varies between normal aging and PD.
Moreover, age strongly influences cognitive perfor-
mance in PD, but not in normal aging (note that
mean age is similar between our two groups). As a
whole, these results suggest that the mechanisms of
CR are not exactly similar in normal and pathological
aging. In normal aging, most aspects of CR seem to
provide good protection against cognitive decline. In
PD, a more aggressive advance of aging could override
the beneficial effect of the less consistently practiced
factor of CR across the lifespan—that is, leisure activ-
ity. In that context, we can ask the question of the
relevance of time-limited stimulation programs to
prevent the effects of neurodegeneration on cognition.
Indeed, a positive impact of mental or physical train-
ing programs on cognition and the brain was reported
in normal aging (Valenzuela & Sachdev, 2007;
Voelcker-Rehage & Niemann, 2013), mild cognitive
impairment (Buschert et al., 2011), Alzheimer (Groot
et al., 2016), and Parkinson (Tanaka et al., 2009)
13
patients. However, the duration of these benefits
after the program cessation is not well established,
and we cannot reject the hypothesis of a short-term
beneficial impact once the program ended.
Impact on cognitive reserve and brain atrophy
on cognitive functions
To the best of our knowledge, this is one of the first
studies that compared the interaction between cogni-
tion, CR factors, and brain atrophy in healthy aging
and Parkinson’s disease. Many previous studies are
limited in their interpretability because they only
address two factors of a tripartite relationship
(Hindle et al., 2016; Opdebeeck, Martyr, & Clare,
2016; Poletti, Emre, & Bonuccelli, 2011). There is
agreement that a high CR would have a beneficial
effect on cognition but the primary hypothesized role
of cognitive reserve is that it protects cognition against
dementia-associated neuropathology (Stern, 2009).
Therefore, quantification of neuropathology must be
included in studies of cognitive reserve. To our knowl-
edge, only one study in PD has looked at such a
tripartite relation. Lucero et al. (2015) evaluated
whether educational level would modify correlation
between brain pathology and cognition and showed
that education could protect PD patients’ cognition
against cortical β-amyloid pathology. Here, we used
global brain atrophy as estimated from high-resolution
anatomical MRI as a gross marker of the effect of
normal aging or Parkinson’s disease. In healthy elderly
subjects, educational attainment (and to a lesser extent
decisional latitude and leisure activities) modified the
relationship between brain atrophy and the clinical
expression of cognitive decrease such that those with
higher education maintain better cognitive function in
the presence of cerebral atrophy. These findings pro-
vide support for the cognitive reserve theory during
normal aging (Stern, 2009) and suggest that education
may protect people’s cognition against brain atrophy.
Our results revealed that the association between atro-
phy and cognition in healthy subjects is not simple but
instead varies mainly according to educational attain-
ment. Specifically, among those with lower education,
increased atrophy is predictive of worse cognitive per-
formance, whereas among those with higher educa-
tion, brain atrophy is not predictive of cognitive
impairment. Our results are consistent with previous
studies in healthy aging and in AD in that education
modifies the relationship between atrophy and cogni-
tion (see, for example, Solé-Padullés et al., 2009).
14 M. ROUILLARD ET AL.
Our study addresses a significant gap in cognitive
reserve research in PD. Indeed, most studies on cog-
nitive reserve in PD to date have investigated the
association between education and cognition without
considering the level of neuropathology (Koerts et al.,
2013; Poletti et al., 2011; see also Hindle et al., 2014, for
a meta-analysis). Our results are in agreement with the
previously demonstrated influence of educational
attainment to protect against cognitive impairment
in AD but very interestingly showed that the protec-
tive effect of CR on cognition is mainly evidenced for a
slight to moderate level of brain atrophy in PD (here,
from the 25th–50th percentile, and not at the 10th
percentile as in healthy participants). Even if we do
not have a clear explanation for this pattern of results
at this time, we could suggest that some neuropatho-
logical processes specific to PD (such as neurotoxic or
inflammatory processes; Mosley, Hutter-Saunders,
Stone, & Gendelman, 2012; Nagatsu & Sawada,
2006) that do not affect brain atrophy per se add
burden on brain functioning. Consequently, that sup-
plementary burden will counteract the protective
effect of cognitive reserve when brain atrophy became
too important. In agreement with that proposal,
Lucero et al. (2015) recently showed a significant
relationship between cortical β-amyloid pathology,
educational level and cognitive performance in PD
patients.
Even if the results we obtained need to be repli-
cated, they appear particularly interesting as they
emphasize the relationships between cognitive effi-
ciency, cognitive reserve, brain reserve, and the pre-
sence (vs. absence) of neurodegenerative processes.
Indeed, even if a high level of CR does not prevent
neuropathology (PD in this case), lifelong positive
stimulations (and more particularly education) seem
to influence cognitive functioning until at least a
moderate level of brain atrophy. So, taking simulta-
neously into account cognitive efficiency, level of CR,
and importance of brain atrophy in clinical practice
could help to predict the cognitive evolution of PD
patients.
Study limitation
This study brings some information on how life
experiences and lifestyle factors over the entire life-
span are (positively or negatively) associated to late
cognitive efficiency in healthy and pathological aging.
However, due to our transversal design, such evidence
remains correlative, and the existence of a causality
link between CR and cognition cannot be formally
inferred. Similarly, we cannot exclude the presence of
a reverse causality effect, with people with inherently
higher cognitive abilities (at least in some domains)
being more likely to engage in longer education, to
have jobs with higher decisional latitude, and to have
more mentally demanding leisure activities (but not
necessarily in physical activities). Further studies are
obviously necessary to better understand the relation-
ships between earlier cognitive abilities, lifestyle fac-
tors, cognitive reserve, and late cognitive efficiency.
Data from epidemiological cohort seem particularly
relevant to disentangle the relationships between these
factors (see, for example, Dekhtyar et al., 2015).
Conclusion
Our results indicate that life experiences influence late
cognition in normal and pathological aging, but not
exactly in the same way. More particularly, it seems
that the CR factors the most consistently practiced
across lifespan (education and professional solicita-
tions) are the most associated with cognitive effi-
ciency. Even if these data need replication, they
appear particularly relevant in the context of neuro-
plasticity occurring in late life (Maguire, Woollett, &
Spiers, 2006; Stern et al., 1992). Indeed, as it is difficult
to handle education or job position in seniors, future
studies should be interested to determine whether a
continuous engagement (in opposition to short-term
training programs) in leisure and/or physical activities
in older people has a beneficial effect on cognitive
changes associated to normal and pathological ageing
(see, for example, Wang et al., 2012).
Acknowledgements
We thank Meg Inscoe and Karima Smouk for English
correction of the manuscript.
Disclosure statement
No potential conflict of interest was reported by the
authors.
Funding
M.R. was supported by a research grant from the Fonds
Rahier, University of Liège (Belgium); and by the
Fondation Marcel Bleustein-Blanchet Pour la Vocation
(Paris, France).
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
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Appendix A

Table A1. Significant results of Block 1 for healthy subjects from multiple regressions.
Semipartial
Block 1 b t p SE correlation2 Lower limit Higher limit
Rey AVLT
Age –0.036 –2.144 .038 0.017 .0841 –0.071 –0.002
Gender 0.595 2.161 .036 0.275 .0853 0.040 1.149
CRT
Age 0.061 3.910 .000 0.016 .2372 0.030 0.093
Gender 0.805 3.174 .003 0.254 .1568 0.294 1.317
SDMT
Age –0.056 –3.279 .002 0.017 .1954 –0.090 –0.021
Stroop test
Age –0.036 –2.053 .046 0.018 .0835 –0.071 –0.001
Note. SE = standard error; AVLT = Auditory Verbal Learning Test; SDMT = Symbol Digit Modality Test; CRT = Choice Reaction Time.

Table A2. Significant results of Block 2 for healthy subjects from multiple regressions.
Semipartial
Block 2 b t p SE correlation2 Lower limit Higher limit
Mattis DRS
Education 0.434 2.592 .013 0.168 .1376 0.095 0.774
Rey AVLT
Education 0.446 3.264 .002 0.137 .1452 0.169 0.722
PJD –0.586 –2.295 .027 0.255 .0718 –1.103 –0.069
CRT
Age 0.061 2.691 .011 0.023 .1211 0.015 0.107
Gender 1.104 2.789 .008 0.396 .1296 0.302 1.905
SDMT
Education 0.398 3.098 .004 0.128 .1156 0.138 0.658
PJD –0.587 –2.445 .019 0.240 .0724 –1.073 –0.101
Leisure activities 0.336 2.661 .011 0.126 .0853 0.080 0.592
Running span memory task
Education 0.471 3.272 .002 0.144 .1624 0.180 0.762
DL 0.583 2.078 .044 0.280 .0655 0.015 1.150
Stroop test
Leisure activities 0.344 2.162 .037 0.159 .0912 0.022 0.667
Phonemic fluency task
PJD –0.676 –2.246 .031 0.301 .0955 –1.286 –0.067
Leisure activities 0.343 2.164 .037 0.158 .0888 0.022 0.664
Category fluency task
Education 0.555 3.805 .001 0.146 .2247 0.260 0.850
mWCST
Age 0.064 2.683 .011 0.024 .1347 0.016 0.113
Leisure activities 0.318 2.024 .050 0.157 .0767 0.000 0.637
Note. SE = standard error; PJD = psychological job demands; DL = decisional latitude; DRS = Dementia Rating Scale; AVLT = Auditory Verbal
Learning Test; SDMT = Symbol Digit Modality Test; CRT = Choice Reaction Time; mWCST = modified Wisconsin Card Sorting Test.
20 M. ROUILLARD ET AL.

Table A3. Description of model results for each cognitive tests in healthy subjects.
Neuropsychological tasks F df p Adjusted R² Variation of F
Mattis DRS
Model 1 .44 3, 43 .73 –.038
Model 2 1.34 8, 38 .26 .055 F(5, 38) = 1.85, p = .13
JLO
Model 1 .58 3, 43 .63 –.028
Model 2 1.16 8, 38 .35 .027 F(5,38) = 1.48, p = .22
Rey AVLT
Model 1 3.89 3, 43 <.02* .16
Model 2 4.42 8, 38 .001* .37 F(5, 38) = 3.94, p = .006*
CRT
Model 1 7.11 3, 43 .001* .29
Model 2 2.75 8, 38 <.02* .23 F(5, 38) = .35, p = .83
SDMT
Model 1 4.03 3, 43 .013* .165
Model 2 5.61 8, 38 .000* .445 F(5, 38) = 5.33, p = .001*
Running span memory task
Model 1 .67 3, 43 .57 –.022
Model 2 3.51 8, 38 .004* .303 F(5, 38) = 5.02, p = .001*
Stroop test
Model 1 2.52 3, 43 .070 .090
Model 2 1.65 8, 38 .14 .102 F(5, 38) = 1.11, p = .37
Phonemic fluency task
Model 1 .66 3, 43 .58 -.023
Model 2 1.83 8, 38 .10 .127 F(5, 38) = 2.48, p < .05*
Category fluency task
Model 1 1.10 3, 43 .36 .006
Model 2 3.29 8, 38 .006 * .285 F(5, 38) = 4.35, p = .003*
mWCST
Model 1 1.83 3, 43 .16 .051
Model 2 1.94 8, 38 .082 .140 F(5, 38) = 1.89, p = .12
Note. DRS = Dementia Rating Scale; JLO = Judgment of Line Orientation; AVLT = Auditory Verbal Learning Test; SDMT = Symbol Digit Modality
Test; CRT = Choice Reaction Time; mWCST = modified Wisconsin Card Sorting Test.
*Significant results.

Appendix B
Table B1. Significant results of Block 1 for Parkinson’s disease patients from multiple regressions.
Semipartial
Block 1 b t p SE correlation2 Lower limit Higher limit
Mattis DRS
Age –0.066 –4.440 .000 0.015 .3025 –0.097 –0.036
JLO
Age –0.043 –2.957 .005 0.015 .1274 –0.073 –0.014
Gender –0.633 –2.486 .017 0.254 .09 –1.146 –0.119
Rey AVLT
Age –0.061 –4.080 .000 0.015 .2570 –0.091 –0.031
Gender 0.531 2.027 .049 0.262 .0635 0.003 1.059
CRT
Age 0.069 5.066 .000 0.014 .3215 0.041 0.096
SDMT
Age –0.084 –6.958 .000 0.012 .4844 –0.108 –0.060
Running span memory task
Age –0.067 –4.214 .000 0.016 .2767 –0.098 –0.035
Stroop test
Age –0.057 –3.713 .001 0.015 .2275 –0.088 –0.026
mWCST
Age 0.047 2.872 .006 0.016 .1513 0.014 0.080
Note. SE = standard error; DRS = Dementia Rating Scale; JLO = Judgment of Line Orientation; AVLT = Auditory Verbal Learning Test; SDMT =
Symbol Digit Modality Test; CRT = Choice Reaction Time; mWCST = modified Wisconsin Card Sorting Test.
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 21

Table B2. Significant results of Block 2 for Parkinson’s disease patients from multiple regressions.
Semipartial
Block 2 b t p SE correlation2 Lower limit Higher limit
Mattis DRS
Age –0.060 –3.920 .000 0.015 .2016 –0.091 –0.029
Education 0.407 3.067 .004 0.133 .1232 0.138 0.676
JLO
Age –0.051 –3.388 .002 0.015 .1436 –0.081 –0.021
DL 0.650 2.450 .019 0.265 .0751 0.113 1.188
PJD –0.713 –2.947 .005 0.242 .1089 –1.203 –0.223
Rey AVLT
Age –0.051 –3.364 .002 0.015 .1421 –0.081 –0.020
Education 0.389 2.993 .005 0.130 .1189 0.126 0.652
CRT
Age 0.081 5.624 .000 0.014 .36 0.052 0.110
DL –0.712 –2.814 .008 0.253 .09 –1.224 –0.200
PJD 0.635 2.752 .009 0.231 .0864 0.168 1.102
SDMT
Age –0.087 –6.563 .000 0.013 .4199 –0.114 –0.060
PJD –0.431 –2.022 .050 0.213 .0396 –0.863 0.001
Running span memory task
Age –0.064 –3.864 .000 0.017 .2088 –0.098 –0.031
Education 0.295 2.059 .046 0.143 .0590 0.005 0.586
Stroop test
Age –0.068 –3.948 .000 0.017 .2570 –0.102 –0.033
Gender 0.936 2.577 .014 0.363 .1096 0.201 1.572
Phonemic fluency task
Education 0.513 3.473 .001 0.148 .1962 0.214 0.813
Note. SE = standard error; PJD = psychological job demands; DL = decisional latitude; DRS = Dementia Rating Scale; JLO = Judgment of Line
Orientation; AVLT = Auditory Verbal Learning Test; SDMT = Symbol Digit Modality Test; CRT = Choice Reaction Time; mWCST = modified
Wisconsin Card Sorting Test.

Table B3 Description of model results for each cognitive tests in subjects with Parkinson’s disease
Neuropsychological tasks F df p Adjusted R² Variation of F
Mattis DRS
Model 1 4.42 5, 43 .002* .26
Model 2 3.82 10, 38 .001* .37 F(5, 38) = 2.47, p = .049*
JLO
Model 1 5.11 5, 43 .001* .30
Model 2 4.18 10, 38 .001* .40 F(5, 38) = 2.41, p = .054
Rey AVLT
Model 1 4.35 5, 43 .003* .26
Model 2 4.18 10, 38 .001* .40 F (5, 38) = 2.99, p = .023*
CRT
Model 1 7.34 5, 43 .000* .40
Model 2 4.98 10, 38 .000* .45 F(5, 38) = 1.88, p = .12
SDMT
Model 1 11.37 5, 43 .000* .52
Model 2 6.47 10, 38 .000* .53 F(5, 38) = 1.24, p = .31
Running span memory task
Model 1 4.22 5,43 .003* .25
Model 2 3.36 10,38 .003* .33 F(5, 38) = 2.01, p = .10
Stroop test
Model 1 3.54 5, 43 .009* .21
Model 2 2.26 10, 38 .034* .21 F(5, 38) = .99, p = .44
Phonemic fluency task
Model 1 0.81 5, 43 .55 .013
Model 2 2.35 10, 38 .028* .002 F(5, 38) = 3.65, p = .009*
Category fluency task
Model 1 1.13 5, 43 .36 –.02
Model 2 1.01 10, 38 .45 –.06 F(5, 38) = .91, p = .49
mWCST
Model 1 2.28 5, 43 .063 .12
Model 2 1.61 10, 38 .14 .11 F(5, 38) = .94, p = .46
Note. DRS = Dementia Rating Scale; AVLT = Auditory Verbal Learning Test; JLO = Judgment of Line Orientation; SDMT = Symbol Digit Modality
Test; CRT = Choice Reaction Time; mWCST = modified Wisconsin Card Sorting Test.
*Significant results.