c o r t e x 1 3 9 ( 2 0 2 1 ) 2 4 0 e2 4 8

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Research Report

Cognitive reserve and regional brain volume in

amyotrophic lateral sclerosis

Anna G.M. Temp a, Johannes Prudlo a,b,*, Stefan Vielhaber c,d,

Judith Machts c,d, Andreas Hermann a,e, Stefan J. Teipel a,f and
Elisabeth Kasper a,b
a
German Centre for Neurodegenerative Diseases (DZNE), Rostock, Germany
b
Department of Neurology, University of Rostock, Rostock, Germany
c
Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany
d
German Centre for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
e
Translational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University of Rostock,
Rostock, Germany
f
Department of Psychosomatic Medicine, University of Rostock, Rostock, Germany

article info abstract

Article history: Objective: We investigated whether cognitive reserve measured by education and pre-
Received 7 September 2020 morbid IQ allows amyotrophic lateral sclerosis patients to compensate for regional brain
Reviewed 31 December 2020 volume loss.
Revised 7 January 2021 Methods: This was a cross-sectional study. We recruited sixty patients with amyotrophic
Accepted 4 March 2021 lateral sclerosis from two specialist out-patient clinics. All participants underwent neu-
Action editor Brad Dickerson ropsychological assessment; the outcomes were standardized z-scores reflecting verbal
Published online 17 March 2021 fluency, executive functions (shifting, planning, working memory), verbal memory and
visuo-constructive ability. The predictor was regional brain volume. The moderating
Keywords: proxies of cognitive reserve were premorbid IQ (estimated by vocabulary) and educational
Amyotrophic lateral sclerosis years. We hypothesized that higher cognitive reserve would correlate with better per-
Cognitive reserve formance on a cognitive test battery, and tested this hypothesis with Bayesian analysis of
Cognition covariance.
Regional brain volume Results: The analyses provided moderate to very strong evidence in favor of our hypoth-
esis with regard to verbal fluency functions, working memory, verbal learning and
recognition, and visuo-constructive ability (all BF01 > 3): higher cognitive reserve was
associated with a mild increase in performance. For shifting and planning ability, the
evidence was anecdotal.
Conclusions: These results indicate that cognitive reserve moderates the effect of brain
morphology on cognition in ALS. Patients draw small but meaningful benefits from higher
reserve, preserving fluency, memory and visuo-constructive functions. Executive functions
presented a dissociation: verbally assessed functions benefitted from cognitive reserve,

* Corresponding author. Department of Neurology, Rostock University Medical Centre, German Centre for Neurodegenerative Diseases
(DZNE), Gehlsheimer Str. 20, 18147, Rostock, Germany.
E-mail addresses: [email protected] (A.G.M. Temp), [email protected] (J. Prudlo), [email protected].
de (S. Vielhaber), [email protected] (J. Machts), [email protected] (A. Hermann), stefan.teipel@med.
uni-rostock.de (S.J. Teipel), [email protected] (E. Kasper).
https://doi.org/10.1016/j.cortex.2021.03.005
0010-9452/© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
 c o r t e x 1 3 9 ( 2 0 2 1 ) 2 4 0 e2 4 8 241

non-verbally assessed functions did not. This motivates future research into cognitive
reserve in ALS and practical implications, such as strengthening reserve to delay decline.
© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC
BY license (http://creativecommons.org/licenses/by/4.0/).

The present study aimed to address this gap by deter-

1. Introduction mining if vocabulary as well as educational attainment as
cognitive reserve markers moderate the effect of
As a multi-systemic disorder, amyotrophic lateral sclerosis (ALS)
pathologyemeasured by regional brain atrophy-on cognitive
features motor impairment and cognitive-behavioral impair-
performance when controlling for brain size. We hypothesize
ment. The latter is present in approximately half of patients,
that high cognitive reserve has a compensatory effect and is
ranging from mild to severe enough symptoms in up to 15% of
associated with better performance.
all ALS patients to warrant a diagnosis of fronto-temporal de-
mentia (FTD) (Montuschi et al., 2015; Ringholz et al., 2005).
Characteristically, cognitive impairment in ALS entails verbal 2. Methods
fluency deficits, language deficits, and executive dysfunction
as well as behavioral changes such as apathy (Beeldman et al., We report how we determined our sample size, all data ex-
2016; Benbrika et al., 2019). On the pathological level, cognitive clusions, all inclusion/exclusion criteria, whether inclusion/
impairment is associated with transactive response DNA binding exclusion criteria were established prior to data analysis, all
protein 43 (TDP-43) pathology in non-primary motor areas manipulations and all measures in the study.
(Gregory et al., 2019; Prudlo et al., 2016). However, cognitively
non-impaired ALS patients are also reported to have sub- 2.1. Design
stantial extra-motor TDP-43 pathology (Gregory et al., 2019).
Similar to findings in Alzheimer's disease (AD), proxies of This was a prospective, observational cross-sectional study.
cognitive reserve may moderate the association between Our predictors were two cognitive reserve markers: educa-
such pathogenic factors and cognitive impairments, leading tional attainment (years of education) and vocabulary (as a
to better compensation with higher reserve. Cognitive proxy of premorbid IQ), and regionally-relevant brain volume.
reserve can be identified by detecting individual differences Which regional volume was chosen as predictor depended on
in functional task processing, which allows some individuals the outcome. The outcome variables included letter fluency
to compensate for increasing brain pathology, and in turn, and flexibility, category fluency and flexibility, working
perform to expected norms despite a high pathological memory, planning ability, shifting, verbal learning, verbal
burden (Stern, 2009). In contrast, brain reserve refers to the recognition and visuospatial ability.
physical capacity for the brain to better cope with brain
damage (Stern, 2009). Examples of proxies of cognitive 2.2. Ethical considerations
reserve which improve compensatory ability include
educational and occupational attainment, vocabulary size Data included in this analysis were from the ALS-FTD Intersite
(Scarmeas et al., 2003; Stern, 2009; Stern et al., 2005), social project of the German Centre for Neurodegenerative Diseases
connectivity and physical exercise (Xu et al., 2015). In a pre- (DZNE), sites Rostock and Magdeburg. All patients gave writ-
vious study, people with ALS-FTD had lower educational ten informed consent and study approval was obtained by the
attainment compared with ALS patients without FTD, sug- local ethics committees (reference numbers A2010e32 and
gesting that cognitive reserve may enable compensation A2011-56). Pseudonymized data (comma-separated values)
against cognitive impairment (Montuschi et al., 2015). While and an HTML results file are available on the Open Science
cognitive reserve is well-documented in AD (Stern, 2009; Xu Framework: https://osf.io/jv4mt/.
et al., 2015) and has recently been explored in fronto-temporal
lobar degeneration (FTLD) (Placek et al., 2016), reliable evidence 2.3. Participants
is lacking in ALS. In FTLD, executive control and verbal
fluency were partially mediated by markers consisting of We recruited 60 ALS patients. Persons with a history of brain
educational years and occupational attainment. injury, epilepsy, psychiatric illness or non-native command of
Within ALS, higher levels of education have been the German language were excluded from the study (Table 1).
suggested to result in a better ability to cope with impaired These exclusion criteria were established prior to the research
cerebral glucose metabolism (Canosa et al., 2020) while being conducted.
education and occupation are also associated with better The patients had bulbar (n ¼ 22), spinal (n ¼ 29) or unknown
cognitive performance (Montuschi et al., 2015; Canosa et al., (n ¼ 9) disease onsets. Phenotypically, they presented with
2014; Costello et al., 2019, 2021; Consonni et al., 2020). classical (n ¼ 44), predominant upper motor neuron involve-
Consequently, further evidence to support reserve-based ment (n ¼ 7), flail arm (n ¼ 4), flail leg (n ¼ 3) or another (n ¼ 2)
compensation in ALS is necessary. This has been consid- ALS type. According to the El Escorial criteria, 20 patients had a
ered a limitation within cognitive ALS research for some time possible ALS, 17 had a probable ALS, 13 had a definite ALS and
now (Canosa et al., 2016; Matias-Guiu et al., 2016; Montuschi the status of 10 patients was unknown. At examination, these
et al., 2015). 10 patients had pure upper or lower motor neuron syndromes
242 c o r t e x 1 3 9 ( 2 0 2 1 ) 2 4 0 e2 4 8

(Table 1). We applied these predictors separatelyerather

Table 1 e The participants’ demographic background
(n ¼ 60). than as a composite measureeto investigate their individ-
ual influences. Our outcomes were z-scores of ALS-specific
Variable Mean (SD) cognitive functions: letter fluency, letter flexibility, category
Women (n) 25 fluency, category flexibility (all indices corrected for speech
Age 59.93 (11.14) motor impairment (Abrahams et al., 2000; Aschenbrenner
Educational attainment (years) 12.68 (2.51)
and Tucha, 2001)), working memory (digit span backward
Premorbid IQ 98.62 (11.53)
(The Psychological Corporation, 1987)), shifting (Trail Making
Disease Duration (months) 22.55 (5.37)
ALS-FRS-R 38.58 (5.37) Test (TMT), corrected for motor impairment as ratio B/A
Progression Speed (ALSFRS-R d) .71 (.69) (Reitan, 1958)), planning ability (“Tower of London” task),
verbal learning and recognition as well as visuospatial ability
and did not meet the revised El Escorial criteria by Brooks et al. (Rey Complex Figure Test, copy).
(Brooks et al., 2000) However, these ten patients were diag- Legal copyright restrictions prevent public archiving of the
nosed with restrictive phenotypes of ALS (Ludolph et al., 2015), various clinical assessments and tests used in this study, which
see above. Of the 20 patients with possible ALS, two progressed can be obtained from the copyright holders in the cited references.
to probable ALS and 9 progressed to definite ALS. Patient
classification into ALS without cognitive-behavioral impair- 2.5. Procedure
ments (ALSni, n ¼ 31, 52%), with cognitive impairments (ALSci,
n ¼ 15, 25%) and with FTD (ALS-FTD, n ¼ 5, 8%) followed the ALS patients were recruited from Magdeburg and Rostock uni-
Strong (Strong et al., 2017) and Rascovsky (Rascovsky et al., versity hospitals as part of a prospective, bi-centric study.
2011) criteria using z-score cut offs of 2 to reflect impair- Control participants were recruited through public advertise-
ment. Z-scores were based on an age-, gender- and education- ments. At each site, two neuropsychologists administered the
matched sample of healthy controls (Kasper et al., 2015). neuropsychological test battery. Further procedural details can
Fifteen percent (n ¼ 9) were unclassifiable because their neu- be found in our previous publications (Kasper et al., 2015, 2016;
ropsychological testing was incomplete. Behavioral impair- Machts et al., 2014). No part of the study procedures or analyses
ment was assessed for classification using the Frontal Systems was pre-registered prior to the research being conducted.
Behavior Inventory but no participants were classified as ALS-
bi or -cbi (Grace and Malloy, 2001). See Table 1 for the partici- 2.6. MRI acquisition
pants’ background. All patients underwent genetic testing for
the C9orf72 repeat expansion (for details, please see Krüger MRI scanning was performed with two with 3 T Siemens
et al., 2016). Where a familial history, young onset or a juve- Magnetom VERIO scanners (Erlangen, Germany) using a 32-
nile variant of ALS indicated additional genetic testing, we channel head coil; one single scanner at each site (Rostock
tested for SOD1, VAPB and TARDBP mutations but not the FUS and Magdeburg, Germany). High-resolution T1-weighted
mutation. Three genetic mutations of ALS occurred in our anatomical images were acquired using the magnetization-
sample: C9orf72 (n ¼ 2), SOD1 (n ¼ 2), and VAPB (n ¼ 1). prepared rapid gradient echo (MPRAGE) sequence with the
following parameters: 256256 image matrix with 192 sagittal
2.4. Measurements slices, FOV 250  250  192 mm, voxel size 1  1  1 mm3, echo
time 4.82 ms, repetition time 2500 ms, and flip angle 7 . The
Our predictors were the cognitive reserve markers of anatomical T1-weighted images were co-registered to each
educational attainment (years spent in school and at uni- other, segmented into grey matter, white matter and cere-
versity or in vocational training) and premorbid IQ, brospinal fluid partitions using the CAT12 toolbox longitudi-
measured by passive vocabulary (Schmidt and Metzler, nal pipeline in MATLAB 2019a. Then, the Diffeomorphic
1992). Estimates of premorbid verbal IQ were obtained after Anatomical Registration Through Exponentiated Lie (DARTEL)
disease onset by asking the participants to identify correct algebra algorithm (Ashburner, 2007) was used in combination
target words among distractor pseudo-words. The number of with the default CAT12 brain template to normalize the mean
correctly identified target words was converted to an IQ es- T1-weighted image to the Montreal Neurological Institute (MNI)
timate based on published norms (Schmidt and Metzler, reference coordinate system. The estimated deformation field
1992). We chose passive vocabulary as a proxy for three was subsequently applied to the grey matter segments of all
reasons: firstly, it relies less on the patients' frequently time points to bring them in MNI space as well, followed by
impaired ability to access their mental lexicon actively modulation to preserve the total amount of grey matter and
(Pinto-Grau et al., 2018); secondly, ALS patients’ performance smoothing with an 8 mm Gaussian kernel. In phantom tests
on this specific test has previously been shown to remain according to the American College of Radiology guidelines
intact (Neudert et al., 2001), indistinguishable from healthy (American College of Radiology, 2018), both sites’ scanners
controls (Lange et al., 2016), and independent from physical met the criteria for geometric accuracy, high contrast spatial
disability (Osmanovic et al., 2020); thirdly, this particular test resolution, slice thickness accuracy, slice position accuracy,
has been shown to measure verbal-crystallised intelligence image intensity uniformity, percent signal ghosting and low
reliably (Schipolowski et al., 2014). Executive impairment is contrast object detectability. The conditions of our ethics
common and would diminish performance on classical IQ approval do not permit sharing of any raw imaging data
estimation tests such as the Raven matrices, performance on supporting this study with any individual outside the author
the passive vocabulary test fell within the normal range team under any circumstances.
 c o r t e x 1 3 9 ( 2 0 2 1 ) 2 4 0 e2 4 8 243

2.7. Statistical analysis Table 2 e Measures of dispersion and number of

participants in each domain.
As classical null hypothesis significance testing (NHST) only
permits the rejection of the null hypothesis but not the Variable N Mean (SD)
3
acceptance of an alternative hypothesis, we applied a Regional Volume (mm )
Bayesian modeling approach to allow us to quantify support Middle Frontal Gyrus 60 8900.04 (1309.23)
Superior Frontal Gyrus 60 10073.65 (1373.83)
in favor of the cognitive reserve hypothesis. Bayes factor (BF)
Left Hippocampus 60 3622.76 (513.95)
hypothesis testing (BFHT) facilitates the comparison of one or
Right Hippocampus 60 3369.38 (516.36)
more alternative hypotheses against the null hypothesis (i.e., Fluency Functions
the assumption that there is no effect of cognitive reserve Letter Fluency 50 1.14 (2.48)
markers on disease markers and cognitive performance, H0). Letter Flexibility 50 2.67 (4.65)
This encompasses the possibility to quantify evidence in favor Category Fluency 50 .71 (1.93)
of any hypothesis, including the hypothesis that cognitive Category Flexibility 49 1.16 (2.20)
Executive Functions
reserve exists in ALS (Goodman, 2008; Wagenmakers, 2007;
Shifting 53 .61 (1.25)
Wagenmakers, Marsman et al., 2018). Modelling took place in Planning Ability 34 .29 (1.29)
Jeffreys’ Amazing Statistics Program (The JASP Team, 2020). Working Memory 59 .86 (1.66)
We conducted ANCOVA to investigate the interaction ef- Verbal Memory
fects between regional volume and reserve markers on per- Verbal Learning 51 .46 (1.60)
formance. Known risk factors of cognitive impairment (ALS Correct Recognition 51 .35 (1.55)
Visuospatial Functions
onset type (Portet et al., 2001), sex, age, progression speed) as
Rey Figure Copy 42 1.31 (2.15)
well as recruitment location (Magdeburg vs Rostock) and total
intracranial volume (TIV) were corrected for by including them
into the null model. Recruitment location was incorporated
into the analyses to account for the potentially confounding associated with volume of the hippocampus (Benbrika et al.,
effects of two MRI scanners. As the C9orf72 repeat expansion is 2019; Carlin et al., 2000; Yochim et al., 2007). Cognitive test
associated with cognitive impairment (Irwin et al., 2013), we results within each domain, and the number of contributing
report the full results including both C9orf72-positive partici- participants can be found in Table 2.
pants. A summary of the results excluding the C9orf72 patients There was moderate evidence supporting the absence of a
can be found in Table 3; details can be found in the corre- correlation between premorbid IQ and ALSFRS-R score (non-
sponding HTML file on the Open Science Framework. parametric Kendall's t ¼ .02, BF01 ¼ 5.67).
To address potential issues with non-normally distributed
residuals in the ANCOVA we applied Markov-Monte Carlo 3.1. ALS-specific functions
chain sampling to each analysis 1,000 times. JASP was set to
report the best model first, and then compare all other models Letter fluency. The best model was Premorbid IQ*Middle Fron-
against this best model. We report the Bayes Factor (BF01) tal Gyrus (P(M) ¼ .07, P (Mjdata) ¼ .43, BFM ¼ 8.99): the best
quantifying evidence in favor of the best model against the hypothesis for our data is that higher premorbid IQ (b ¼ .06,
lower-ranked models, the BFM indicating the informativeness 95%CI [.02j.12]) and larger volume (b ¼ 3.438e-4, 95%CI
of our data given the prior (P(M)) and posterior distributions (P [-2.246e-4j9.512e-4]) are associated with an increased letter
(Mjdata) and the BF01 in comparison to the null model (Van fluency performance. This model accounted for 33% (R2 ¼ .33,
Doorn et al., 2019; Wagenmakers, 2007, 2017; Wagenmakers, 95%CI [.16j.48]) of the variance and explained our data 76 times
Love, et al., 2018; Wagenmakers, Marsman et al., 2018). We better than the null hypothesis model (BF01 ¼ 75.82, error
further report the effect size R2 and beta coefficients of the % ¼ 2.67). Consequently, letter fluency strongly supports the
predictors, along with their 95% credible intervals. cognitive reserve hypothesis in ALS.
We applied the following evidence categories: a BF01 above 3 Letter flexibility. The best model explaining fluctuations in
provides “moderate evidence”, a BF01 above 10 provides “strong letter flexibility performance contained the main effects of
evidence”, a BF01 above 30 provides “very strong evidence” and education, premorbid IQ, middle frontal gyrus volume and the
a BF01 above 100 provides “extreme evidence” in favor of the interaction between premorbid IQ and middle frontal gyrus
best hypothesis (Wagenmakers, Love, et al., 2018). We will (P(M) ¼ .07, P (Mjdata) ¼ .29, BFM ¼ 4.84, R2 ¼ .27, 95%CI
consider the cognitive reserve hypothesis supported, if an [.11j.42]). Higher education (b ¼ .34, 95%CI[-.19j.92]), premorbid
interaction between reserve and volume is the best model, or if IQ (b ¼ .06, 95%CI [-.05j.18]) and middle frontal gyrus volume
the reserve marker(s) alone provide the best model, and if the (b ¼ 3.50e-4, 95%CI [-7.296e-4j.002]) were associated with bet-
evidence favouring this best model is at least moderate. ter performance. This model was 29 times better than the null
hypothesis model (BF01 ¼ 29.31, error% 3.77). Thus, letter
flexibility provides strong evidence in favor of the cognitive
3. Results reserve hypothesis.
Category Fluency. The best model for fluctuations in cate-
Based on previous literature, we expected verbal fluency gory fluency consisted of the main effects of premorbid IQ and
functions to be associated with volume of the middle frontal middle frontal gyrus (P(M) ¼ .08, P (Mjdata) ¼ .20, BFM ¼ 2.95,
gyrus, executive functions with the superior frontal gyrus and R2 ¼ .25, 95%CI [.11j.41]). The effects of premorbid IQ (b ¼ .04,
verbal memory as well as visuospatial functions to be 95%CI [-4.696e-4j.08]) and middle frontal gyrus volume
244 c o r t e x 1 3 9 ( 2 0 2 1 ) 2 4 0 e2 4 8

(b ¼ 3.870e-4, 95%CI [-7.98e-5j8.891e-4]) improved perfor-

Table 3 e A summary of the evidence for cognitive reserve
mance. This model was four times better than the null hy- in ALS.
pothesis model (BF01 ¼ 4.38, error% ¼ 3.66), providing
moderate support for the cognitive reserve hypothesis. Cognitive Function Evidence BF01 (incl. BF01 (excl.
Category C9orf72) C9orf72)
Category Flexibility. Here, the best model consisted of the
main effects of education, premorbid IQ, middle frontal gyrus ALS-typically impaired functions
Letter Fluency Very strong 75.82 77.43
volume and the interaction between education and middle
Letter Flexibility Strong 29.31 33.41
frontal gyrus volume (P(M) ¼ .08, P (Mjdata) ¼ .35, BFM ¼ 6.42,
Category Fluency Moderate 4.38 3.78
R2 ¼ .27, 95%CI [.11j.44]). Education (b ¼ .05, 95%CI [-.19j0e31]), Category Flexibility Very strong 38.99 26.70
premorbid IQ (b ¼ .05, 95%CI [-.002j.11]) and middle frontal Planning Ability Inconclusive 1.18 1.29
gyrus volume (b ¼ 1.267e-4, 95%CI [-4.217e-4j6.504e-4]) were all Working Memory Very strong 70.02 20.57
positively associated with category flexibility performance. Shifting Inconclusive 1.88 2.94
This model performed 39 times better than the null hypoth- ALS-atypically impaired functions
Verbal Learning Extremely strong 131.19 134.26
esis model (BF01 ¼ 38.99, error% ¼ 3.01), providing very strong
Verbal Recognition Very strong 49.89 60.87
evidence in favor of cognitive reserve.
Visuo-constructive Strong 11.43 9.24
Planning ability. Premorbid IQ alone provided the best Ability
explanation for fluctuations in planning ability (P(M) ¼ .08, P
Note: This table contains the BF01 comparing the cognitive reserve
(Mjdata) ¼ .16, BFM ¼ 2.26, R2 ¼ .27, 95%CI [.09j.46]). Its effect hypothesis to the null hypothesis model. No ANCOVA supported
was protective but weak (b ¼ .03, 95%CI [-.01j.05]). This model the null hypothesis over the cognitive reserve hypothesis.
was not better or worse than the null model (BF01 ¼ 1.19, error
% ¼ 5.11).
Shifting. Performance fluctuation in shifting was best BFM ¼ 2.43). This hypothesis explained 31.8% of the variance
explained by premorbid IQ alone (P(M) ¼ .08, P (Mjdata) ¼ .17, (R2 ¼ .31, 95%CI [.14j48]) and was 11 times better than the null
BFM ¼ 2.47, R2 ¼ .18, 95%CI [.06j.32]). Its effect was positive but hypothesis (BF01 ¼ 11.43, error% ¼ 2.06).
weak (b ¼ .02, 95%CI [-.01j.05]). This model was not better than Table 3 summarises the evidence in favor of cognitive
the null model (BF01 ¼ 1.88, error% ¼ 2.20). reserve in ALS, highlighting that the evidence prevailed when
Working memory. The best model for working memory both C9orf72-positive participants were excluded from
performance showed that longer education (b ¼ .05, 95%CI analysis.
[-.12j.24]), higher premorbid IQ (b ¼ .04, 95%CI [.002j.08]) and
larger superior frontal gyrus volume (b ¼ 2.993e-4, 95%CI
[-6.693e-5j6.922e-4]) were associated with better performance 4. Discussion
(P(M) ¼ .08, P (Mjdata) ¼ .32, BFM ¼ 5.68). This model explained
32.5% of the variance in working memory performance (R2 We aimed to establish support for the cognitive reserve hy-
¼ .32, 95%CI [.17j.47]) and was 70 times better than the null pothesis in ALS, using vocabulary and education in addition to
hypothesis model (BF01 ¼ 70.02, error% ¼ 3.74). Consequently, regional volume. Verbal fluency functions provided very
there is very strong evidence favoring the cognitive reserve strong evidence in favor of the cognitive reserve hypothesis,
hypothesis in ALS patients’ working memory performance. which explained a moderate amount of variance in each
function even though there was a weak correlation between
3.2. ALS-non-specific functions individual predictors and outcomes: a higher IQ moderated
the influence of cortical atrophy, leading to better perfor-
Verbal learning. The best model for our data yielded that longer mance. Within the executive domain, results were inconclu-
education (b ¼ .17, 95%CI [.03j.30]) and larger hippocampal sive: there were weak associations between planning ability
volume on the left side (b ¼ .001, 95%CI [2.784e-4j.002] were and shifting with reserve factors and volume, which did not
associated with better verbal learning performance support the cognitive reserve hypothesis. Working memory,
(P(M) ¼ .08, P (Mjdata) ¼ .26, BFM ¼ 4.17). This model accounted however, provided strong evidence in its favor. Within the
for 43% of the variance (R2 ¼ .43, 95%CI [.26j.52]); it was 131 typically-preserved memory and visuospatial functions, our
times better than the null hypothesis model (BF01 ¼ 131.19, data provided strong to extremely strong support for the
error% ¼ 5.62). cognitive reserve hypothesis. In summary, our study shows
Verbal recognition. Here, the best model for our data showed that longer education and higher premorbid IQ were associ-
that longer education (b ¼ .20, 95%CI [.06j.34]) and larger hip- ated with higher cognitive performance. While this associa-
pocampal volume on the left side (b ¼ 8.405e-4, 95%CI [1.280e- tion provided a better explanation of cognitive performance
6j.002]) were associated with better verbal recognition per- than other currently known risk factors for cognitive impair-
formance (P(M) ¼ .08, P (Mjdata) ¼ .33, BFM ¼ 5.95). This model ment in ALS, the advantages derived from a larger reserve
explained 31% of the variance (R2 ¼ .31, 95%CI [.15j.46]) and were small.
was 50 times better than the null hypothesis (BF01 ¼ 49.89, It has previously been documented that ALS-FTD patients
error% ¼ 2.75), providing very strong evidence in favor of the have a typically lower educational attainment than those
cognitive reserve hypothesis. without FTD (Montuschi et al., 2015; Ringholz et al., 2005;
Visuo-constructive ability. The best model was that a higher Beeldman et al., 2016; Benbrika et al., 2019; Prudlo et al., 2016;
premorbid IQ (b ¼ .06, 95%CI [.01j.12]) was associated with Gregory et al., 2019; Stern, 2009; Scarmeas et al., 2003; Stern
better visuospatial performance (P(M) ¼ .08, P (Mjdata) ¼ .17, et al., 2005; Xu et al., 2015; Placek et al., 2016; Canosa et al.,
 c o r t e x 1 3 9 ( 2 0 2 1 ) 2 4 0 e2 4 8 245

2014, 2020), that occupation and education are associated with study provided evidence against the null hypothesis and in
verbal fluency, executive and memory functions (Canosa et favor of the cognitive reserve hypothesis.
al., 2014), and that ALS patients classified as having a “high Our results further suggest a dissociation between educa-
reserve” perform better on cognitive tasks (Costello et al., tional attainment and premorbid IQ (measured by passive
2019). Such findings support the notion that people with a vocabulary): premorbid IQ was included in the best models
higher reserve tend to perform better on cognitive tasks in more frequently than education, but when education was
general (Wilson et al., 2013). Recently, two studies have pro- included, its effect was stronger than that of premorbid IQ.
posed that premorbid lifestyle factors may influence ALS pa- Furthermore, there may be a dissociation as to which func-
tients’ cognitive performance longitudinally, and clinical tions benefit from cognitive reserve: functions related to ver-
expression cross-sectionally (Costello et al., 2021; Consonni bal and semantic ability were associated with vocabulary and
et al., 2020). A third study showed that higher education is education. Non-verbal, non-semantic executive functions did
associated with an increased pathological burden in medial not benefit from higher attainment in either reserve marker. It
frontal regions independently of the level of cognitive is conceivable that vocabulary is less-related to these func-
impairment in ALS patients, supporting the notion that the tions, explaining why no associations were observed. Con-
level of education results in a larger cognitive reserve and thus tradictions in results related to education and executive
provides a coping mechanism against brain pathology functioning highlight the necessity for further research
(Canosa et al., 2020). We extend these previous findings by (Canosa et al., 2014; Costello et al., 2019; Raaphorst et al., 2010).
describing the strength and nature of these previously pro- This information may be vital as cognitive impairment is
posed associations, and by adding estimates of pathology in associated with shorter survival (Gordon et al., 2010, 2011).
the form of regional volume while correcting for overall A key strength of this work is that we tested the cognitive
intercranial volume. The advantage of larger regional volume reserve hypothesis directly and quantified support in its favor
documented in our present study also lends support for the with BFHT, an approach more informative than NHST
hypothesis that physical brain reserve (Stern, 2009) may (Goodman, 2008; Wagenmakers, 2007; Wagenmakers, Love,
facilitate better coping with neuronal damage in ALS. This et al., 2018; Wagenmakers, Marsman et al., 2018). In combi-
hypothesis and our present findings are consistent with our nation with the separated reserve markersein contrast to a
previous work showing that ALSci and ALS-FTD patients composite measureethis reveals that passive vocabulary as
exhibit cortical thinning in comparison to ALSni patients an indicator of premorbid IQ should be considered in future
(Schuster et al., 2014), and with recent work documenting cognitive ALS research. Demographically, our participants’
higher longitudinally increasing atrophy rates with cognitive age in combination with their location means that they
impairment (van der Burgh et al., 2020). Specifically, language received their education in the German Democratic Republic
deficits may be associated with left-hemispheric fronto-tem- (GDR), free of charge, reducing potential confounds from
poral atrophy (Ash et al., 2015). However, the effect sizes of our socio-economic influences.
cognitive reserve proxies consistently exceeded those of Limitations include the absence of a non-verbal measure of
regional volume, suggesting that cognitive lifestyle factors are premorbid IQ. A non-verbal, non-executive measure of IQ
more influential than regional volume when it comes to would have been preferable. Similarly, genetic influences on
cognitive functioning in ALS. Our support for the cognitive IQ and cognitive reserve should be considered in future work.
reserve hypothesis is congruent with the above literature and Moreover, additional reserve markers, such as occupational
expands it by showing that ALS patients derive only small attainment or social and physical lifeetime activities, would
benefits from cognitive reserve. We further expand previous have expanded our understanding of cognitive reserve in ALS
findings by distinguishing between functions: while verbal further. Social cognition may also be impaired in ALS
fluency, memory, visuospatial functions and working mem- (Abrahams, 2011) but was not included in our battery. Further
ory benefit from a reserve, shifting and planning ability do not. research is required to address these limitations and replicate
This corresponds with Raaphorst et al. (Raaphorst et al., 2010) our findings.
who found no association between education and executive In addition, investigating the relationship between cogni-
functioning. tive reserve, cognitive impairment and other surrogate
Our findings are also congruent with AD research, sug- markers of pathology, or direct assessment or TDP-43 pa-
gesting that a higher cognitive reserve is associated with thology in clinico-pathological studies is promising: a high
better cognitive functioning (Stern, 2009; Xu et al., 2015). cognitive reserve was associated with fewer senile plaques in
Similarly, Placek et al. showed that executive control and AD (Bennett et al., 2003), a similar effect is conceivable in ALS
verbal fluency were mediated by educational and occupa- with regard to TDP-43 pathology.
tional attainment in FTLD (Placek et al., 2016). Our results In conclusion, our findings reveal that ALS patients’ verbal
partially replicate their findings: higher education predicted fluency functions, working memory, verbal memory and vi-
better verbal memory, working memory and category flexi- suospatial abilities are protected by their cognitive reserve: a
bility. The small but beneficial coefficient size has been shown higher reserve was associated with better performance
previously in AD when using hippocampal volume as a pa- despite volume loss. This protective effect was small, but it
thology marker (Lo et al., 2013), in addition to in multiple still explained a moderate amount of variance in perfor-
sclerosis (Benedict et al., 2010). Both these studies showed mance. Within the executive domain, shifting and planning
weak relationships between cognitive reserve and perfor- ability performances were not associated with cognitive
mance and failed to reject the null hypothesis, whereas our reserve markers. This study provides an additional compo-
246 c o r t e x 1 3 9 ( 2 0 2 1 ) 2 4 0 e2 4 8

nent with which to predict cognitive impairment in ALS; Aschenbrenner, S., & Tucha, O. (2001). Regensburger
however, further investigation into wider risk factors is € ttingen Germany: Hogrefe testzentrale.
Wortflüssigkeits Test. Go
required to improve our understanding of cognitive and Ashburner, J. (2007). A fast diffeomorphic image registration
algorithm. Neuroimage 38, 95e113.
behavioral dysfunction in ALS.
Ash, S., Olm, C., McMillan, C. T., Boller, A., Irwin, D. J.,
McCluskey, L., Elman, L., & Grossman, M. (2015). Deficits in
sentence expression in amyotrophic lateral sclerosis.
Study sponsorship Amyotroph Lateral Scler Frontotemporal Degener 16(1-2), 31e39.
https://doi.org/10.3109/21678421.2014.974617
German Centre for Neurodegenerative Diseases (DZNE), grant Beeldman, E., Raaphorst, J., Klein Twennaar, M., de Visser, M.,
RO010 to JP. Further funding from the “Fight ALS” initiative by Schmand, B. A., & de Haan, R. J. (2016). The cognitive profile of

Greipel. ALS: A systematic review and meta-analysis update. Journal of
professional cyclist Andre
Neurology Neurosurgery and Psychiatry 87(6), 611e619. https://
doi.org/10.1136/jnnp-2015-310734
Benbrika, S., Desgranges, B., Eustache, F., & Viader, F. (2019).
Credit author statement Cognitive, emotional and psychological manifestations in
amyotrophic lateral sclerosis at baseline and overtime: A
Dr Anna G. M. Temp; Conceptualization, application of sta- review. Frontiers in Neuroscience 13, 951. https://doi.org/10.3389/
tistical analysis, Writing e original draft writing. Johannes fnins.2019.00951
Prudlo; Supervision, Conceptualization, Funding acquisition, Benedict, R. H., Morrow, S. A., Weinstock Guttman, B.,
Cookfair, D., & Schretlen, D. J. (2010). Cognitive reserve
neurological data collection, manuscript review & editing.
moderates decline in information processing speed in
Stefan Vielhaber; Conceptualization, neurological data multiple sclerosis patients. Journal of the International
collection, manuscript review. Dr Judith Machts; Conceptual- Neuropsychological Society 16(5), 829e835. https://doi.org/
ization, neuropsychological test battery design, neuropsy- 10.1017/S1355617710000688
chological data collection, manuscript review & editing. Bennett, D. A., Wilson, R. S., Schneider, J. A., Evans, D. A., Mendes
Andreas Hermann; Conceptualization, manuscript review & de Leon, C. F., Arnold, S. E., Barnes, L. L., & Bienias, J. L. (2003).
Education modifies the relation of AD pathology to level of
editing. Stefan Teipel, Conceptualization, manuscript review
cognitive function in older persons. Neurology 60(12),
& editing. Dr Elisabeth Kasper: Conceptualization, neuropsy-
1909e1915. https://doi.org/10.1212/01.wnl.0000069923.64550.9f
chological test battery design, neuropsychological data Brooks, B. R., Miller, R. G., Swash, M., Munsat, T. L., & World
collection, Data curation, manuscript review & editing. Federation of Neurology Research Group on Motor Neuron
Diseases. (2000). El Escorial revisited: revised criteria for the
diagnosis of amyotrophic lateral sclerosis. Amyotrophic Lateral
Declaration of competing interest Sclerosis and Other Motor Neuron Disorders 1(5), 293e299. https://
doi.org/10.1080/146608200300079536
Canosa, A., Montuschi, A., Iazzolino, B., Calvo, A., Moglia, C.,
AGMT reports no disclosures. JP reports no disclosures. SV re-
Bertuzzo, D., Lopiano, L., Restagno, G., Brunetti, M., Ossola, I.,
ports no disclosures. JM reports no disclosures. AH reports no Lo Presti, A., Cammarosano, S., & Chio, A. (2014). Cognitive
disclosures. ST reports no disclosures. EK reports no disclosures. reserve in ALS with comorbid frontotemporal dementia (FTD):
A Population-Based Study (P5.081). Neurology 82.
Canosa, A., Pagani, M., Cistaro, A., Montuschi, A., Iazzolino, B.,
Fania, P., Cammarosano, S., Ilardi, A., Moglia, C., Calvo, A., &
Acknowledgements Chio, A. (2016). 18F-FDG-PET correlates of cognitive
impairment in ALS. Neurology 86(1), 44e49. https://doi.org/
The authors would like to thank the patients and their fam- 10.1212/WNL.0000000000002242
ilies for their participation in this project. We would also like Canosa, A., Palumbo, F., Iazzolino, B., Peotta, L., Di Pede, F.,
to thank professional cyclist Andre
Greipel for his “Fight ALS” Manera, U., Vasta, R., Grassano, M., Solero, L., Arena, V.,
donations initiative which continues to support the “Cogni- Moglia, C., Calvo, A., Chio, A., & Pagani, M. (2020). The
interplay among education, brain metabolism, and cognitive
tion in ALS” working group at DZNE Rostock.
impairment suggests a role of cognitive reserve in
amyotrophic lateral sclerosis. Neurobiology of Aging 98,
205e213. https://doi.org/10.1016/j.neurobiolaging.2020.11.010
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