doi:10.1093/brain/awu201 Brain 2014: 137; 2743-2758 I 2743
BRAIN
A JOURNAL OF NEUROLOGY
Genetic impact on cognition and brain function
in newly diagnosed Parkinson's disease:
ICICLE-PD study
Cristina Nombela, 1 '* James B. Rowe, 2,3,4 '* Sophie E. Winder-Rhodes, 1 Adam Hampshire, 5
Adrian M. Owen, 6,7 David P. Breen, 1 Gordon W. Duncan, 8 Tien K. Khoo, 9 Alison J. Yarnall, 8
Michael J. Firbank, 8 Patrick F. Chinnery, 10 Trevor W. Robbins, 4 John T. O'Brien, 11
David J. Brooks, 12,13 David J. Burn, 8 the ICICLE-PD study group and Roger A. Barker 1
1 John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
2 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
3 Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, UK
4 Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK
5 Computational, Cognitive and Clinical Neuroscience Laboratory, Imperial College London, London, UK
6 Brain and Mind Institute, University of Western Ontario, London, Canada
7 Department of Psychology, University of Western Ontario, London, Canada
8 Institute for Ageing and Health, Newcastle University, Newcastle, UK
9 Griffith Health Institute and School of Medicine, Griffith University, Gold Coast, Australia
10 Institute of Genetic Medicine, Newcastle University, Newcastle, UK
11 Department of Psychiatry, University of Cambridge, Cambridge, UK
12 Imperial College London, London, UK
13 Department of Clinical Medicine, Positron Emission Tomography Centre, Aarhus University, Denmark
*These authors contributed equally to this work.
Correspondence to: Cristina Nombela,
John van Geest Centre for Brain Repair,
University of Cambridge, Cambridge Biomedical Campus,
CB2 OPY, UK
E-mail: dra.cristinanombela@gmail.com
See Dujardin (doi:10.1093/brain/awu218) for a scientific commentary on this article.
Parkinson's disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits
varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change
soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the 'Dual
Syndrome' hypothesis for cognitive impairment in Parkinson's disease, which distinguishes an executive syndrome (affecting the
frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and
semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson's disease cohort
(n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging
study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging
assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to
probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms
associated with cognitive change in Parkinson's disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii)
rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-e2, 3, 4. We identified performance deficits in all three
Received January 20, 2014. Revised May 11, 2014. Accepted June 14, 2014. Advance Access publication July 30, 2014
© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.Org/licenses/by/3.0/), which permits unrestricted reuse,
distribution, and reproduction in any medium, provided the original work is properly cited.
2744 I Brain 2014: 137; 2743-2758
C. Nombela et al.
cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations
in Parkinson's disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on
planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with
spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study
demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson's disease, and that the
associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of
cognitive change in Parkinson's disease. Longitudinal data will confirm the extent to which these early neurocognitive changes,
and their genetic factors, influence the long-term risk of dementia in Parkinson's disease. The combination of genetics and func-
tional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical
trials against cognitive decline in Parkinson's disease.
Keywords: Parkinson's disease; cognition; functional MRI; genetics
Abbreviations: DLPFC = dorsolateral prefrontal cortex; ICICLE-PD = Incidence of Cognitive Impairment in Cohorts with Longitudinal
Evaluation - Parkinson's Disease; LEDD = levodopa equivalent daily dose; MMSE = Mini-Mental State Examination;
MOCA = Montreal Cognitive Assessment; NART = National Adult Reading Test
Introduction
Parkinson's disease was often considered to be primarily a motor
disorder although dementia has long been recognized as a feature
of the condition (Gowers, 1893). More recently the early onset
and heterogeneity of cognitive impairments in Parkinson's disease
have been recognized, even in the absence of dementia
(Muslimovic et al., 2005). The cognitive deficits of Parkinson's
disease affect visuospatial, attentional, executive and memory
functions (Janvin ef al., 2006; Hely et al., 2008; Elgh et al.,
2009; Aarsland and Kurz, 2010; Pedersen et al., 2013) due to
the combination of abnormal neurotransmitter systems (e.g. dopa-
minergic and cholinergic) and both cortical and subcortical Lewy
body pathology (Kehagia et al., 2010). We have proposed two
facets of cognitive deficits in Parkinson's disease, in a 'Dual
Syndrome' hypothesis: (i) changes in dopaminergic transmission
through the corticostriatal networks leading to deficits in planning,
working memory, response inhibition and attentional control; and
(ii) posterior cortical Lewy body pathology and secondary cholin-
ergic loss affecting visuospatial, mnemonic and semantic functions
(Kehagia et al., 2013).
Cognitive impairments are present at diagnosis in a significant
proportion of affected individuals with between 24% and 62% of
newly diagnosed patients with Parkinson's disease having deficits
in executive (e.g. Tower of London Task), visuospatial (e.g. Spatial
Rotations Task) or memory (e.g. Memory Encoding Task) perform-
ance compared to healthy controls (Foltynie et al., 2004a;
Williams-Gray et al., 2007a; Elgh et al., 2009; Yarnall et al.,
2014). By 3 years after diagnosis up to 57% of patients have
frontostriatal or visuospatial deficits and 10% have Parkinson's
disease dementia (Williams-Gray et al., 2007a) rising to 17% by
5 years (Williams-Gray et al., 2007a), 26% by 8 years (Aarsland
et al., 2003), 46% by 10 years (Williams-Gray et al., 2013) and
83% by 20 years (Hely et al., 2008). Thus only -15% of patients
with Parkinson's disease remain cognitively intact in the long
term (Aarsland et al., 2011). It is therefore important to ascertain
what determines cognitive decline, and how it relates to subse-
quent dementia.
Genetic factors are implicated in Parkinson's disease cognitive
impairments (Goldberg and Weinberger 2004; Morley et al.,
2012). For example, catechol-O-methyl transferase (COMT) is
involved in cortical dopamine degradation. A common polymorph-
ism at codon 158 (Val158Met) affects its enzymatic activity 4-fold
(Chen ef al., 2004), and influences executive task performance in
healthy individuals (Stokes et al., 2011; Fallon et al., 2013) and
patients with Parkinson's disease (Foltynie et al., 2004b; Williams-
Gray et al., 2007b). The way in which the polymorphism affects
cortical dopamine levels suggests that either too little or too much
dopamine worsens task performance, in accordance with an in-
verted U-shaped curve (Goldberg and Weinberger, 2004;
Williams-Gray et al., 2007b, 2009b; Rowe et al., 2008). Our hy-
pothesis was that the COMT polymorphism would affect dopa-
mine-dependent working memory and planning systems in
frontostriatal networks, and introduce a non-linear (U-shaped) re-
lationship between neurocognitive function and levodopa dose.
A second gene linked to cognitive performance and dementia in
Parkinson's disease is the microtubule-associated protein tau
(MAPT). The MAPT haplotype H1 (versus H2) not only predis-
poses to Parkinson's disease but also Parkinson's disease dementia
(Goris et al., 2007), possibly by altering the cortical expression of
4- versus 3-repeat isoforms of tau (Williams-Gray et al., 2009a).
Our hypothesis was that fronto-parietal systems for visuospatial
function, related to dementia with Parkinson's disease, would be
relatively preserved in H2 carriers versus H1 carriers.
Finally, apolipoprotein E (APOE) has been proposed to alter the
risk of Parkinson's disease dementia (Chen et al., 2004; Huang
et al., 2006; Goris et al., 2007; Williams-Gray et al., 2009b;
Chung et al., 2012; Gomperts et al., 2012, 2013) as well as
being a risk factor for Alzheimer's disease, even if it does not
significantly alter the risk of developing Parkinson's disease with-
out Parkinson's disease dementia (Peplonska et al., 2013;
Multhammer et al., 2014). APOE has three allelic variants
(APOE2, 3 and 4), and APOE4 carries the highest risk for
Alzheimer's dementia (Corder et al., 1993) with APOE2 carrying
the lowest. Our hypothesis was that memory systems centred
Early diagnosis of cognitive decline in Parkinson's disease
Brain 2014: 137; 2743-2758 I 2745
on the temporal lobe and hippocampus in particular would be
most impaired in APOE4 carriers.
In this study we examined the impact of these genetic factors
on cognitive function in a large cohort of patients with newly
diagnosed Parkinson's disease. We used functional AARI to meas-
ure regional brain functions during a range of tasks that encom-
pass the main cognitive deficits reported in Parkinson's disease
(Williams-Gray ef al., 2007a; Barone ef al., 2011; Ekman et al.,
2012; Hampshire et al., 2012; Winder-Rhodes et al., 2013;
Nagano-Saito et al., 2014; Yarnall et al., 2014). The results of
the comprehensive neuropsychological assessment undertaken by
the participants are published elsewhere (Yarnall et al. 2014). This
neuroimaging study focuses on a set of three tasks that provide
robust experimental models of important cognitive functions af-
fected by Parkinson's disease, including planning and working
memory (Tower of London Task), visuospatial function (Spatial
Rotations Task) and memory (abstract image encoding and recog-
nition). We sought to define how the early cognitive deficits in
newly diagnosed patients with Parkinson's disease map onto
changes in brain activation, and how these activations in patients
varied as a function of the common genetic variations in COMT,
MAPT and APOE.
Materials and methods
Subjects
The Incidence of Cognitive Impairment in Cohorts with Longitudinal
Evaluation - Parkinson's Disease (ICICLE-PD) study recruited a cohort
of 219 patients with incident Parkinson's disease from community and
outpatient clinics at the John van Geest Centre for Brain Repair,
Cambridge, UK (n = 49) and Parkinson's Disease clinics in
Newcastle-upon-Tyne/Gateshead, UK (n = 119) [from the ICICLE-
PD cohort, 169 patients agreed to participate in the functional MRI
study (separate day within 4 months from initial assessment)]. We
used the United Kingdom Parkinson's Disease Society (UKPDS) Brain
Bank diagnostic criteria (Hughes et al., 2002), with reconfirmation
after 18 months, to diagnose Parkinson's disease. Full inclusion and
exclusion criteria are described in Yarnall et al. (2014). In brief, exclu-
sion criteria were: parkinsonism diagnosed before the onset of the
incidence study; insufficient working knowledge of English to perform
the neuropsychological assessment; dementia at presentation [defined
as Mini-Mental State Examination (MMSE) score < 24 or Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV)
criteria for dementia or Movement Disorder Society criteria for demen-
tia]; lack of mental capacity to give informed consent under UK legis-
lation; history of parkinsonism following the onset of cognitive
impairment; history or examination suggestive of dementia with
Lewy bodies, multiple system atrophy, progressive supranuclear
palsy, repeated strokes or stepwise progression of symptoms indicative
of 'vascular parkinsonism'; and, exposure to dopamine receptor block-
ing agents at the onset of symptoms.
Unrelated age- and sex-matched controls were recruited from the
MRC Cognition and Brain Sciences Unit volunteer panel in Cambridge,
UK (n = 50) and from community sources at the Newcastle site
(n = 35). The Local Research Ethics Committee approved the study,
performed according to the Declaration of Helsinki, with all partici-
pants providing written consent.
Participants undertook a battery of standardized clinical and neuro-
psychological assessments including: the Unified Parkinson's Disease
Rating Scale (MDS-UPDRS) (Goetz et al., 2008); MMSE (Folstein
ef al., 1975); Montreal Cognitive Assessment (MOCA) (Nasreddine
ef al., 2005); National Adult Reading Test (NART) (Nelson and
O'Connell, 1978) estimate of premorbid IQ; verbal fluency for
words starting with the letter P/F (60s) (Benton, 1968) and semantic
fluency for animals (90s) (Goodglass ef al., 1972). Levodopa equiva-
lent daily dose (LEDD) value was calculated according to Tomlinson
ef al. (2010). Patients were assessed ON their usual dopaminergic
medication (Williams-Gray ef al., 2007b). Additional neuropsycho-
logical tests and the Geriatric Depression Scale-15 for depression are
reported by Yarnall ef al. (2014).
DNA was extracted from peripheral blood using standard phenol/
chloroform techniques. Genotyping for rs4680 (COMT Val158Met),
rs9468 (MAPT H1 versus H2 haplotype) and rs429358 plus rs7412
(APOE genotype 1-4) was performed using an allelic discrimination
assay and run on an HT7000 detection system (Applied Biosystems).
Experimental design
On the scanning day participants were trained for 30min to perform
the tasks and practice keyboard responses. Participants lay supine in
the MRI scanner, with auditory protection and head fixation using
foam-rubber pads. Stimuli were back-projected onto a screen, and
viewed via a mirror on the headcoil. Three functional MRI experiments
were performed.
Tower of London Task
We used a 'one-touch' modified version of the Tower of London Task
(Shallice, 1982; Williams-Gray ef al., 2007b), as a model of prefrontal
executive function in Parkinson's disease (Rowe ef al., 2001; Lewis
ef al., 2003). The task presented with two racks of three coloured
balls in different pockets. Participants determined the minimum
number of moves to rearrange the balls to match the racks (Owen
ef al., 1995; Baker ef al., 1996). The control task required one to
count the difference in the number of balls between the two displays.
Responses were made with a right hand button-box. The paradigm
lasted for 10min46s, with intermixed presentations of experimental
and control items, cued on the screen before each trial as 'plan' or
'substract', respectively, with three levels of difficulty (levels 2, 3 and 4
according to the number of moves or number of differences in the ball
count-dependent variable 2) and intertrial intervals of 5-1 5 s. No feed-
back was provided. The dependent variables were the latency of re-
sponse (including mainly the thinking time plus a small contribution
from the motor response time for the one-touch version of this task)
and accuracy.
Spatial Rotations Task
Spatial impairments in Parkinson's disease are independent of execu-
tive skills (Cronin-Golomb and Braun, 1997) and depend on the integ-
rity of posterior parietal cortex and a fronto-parietal network (Cohen
ef al., 1996; Zacks, 2008). We used this task to probe posterior cor-
tical function, analogous to earlier studies of Alzheimer's disease
(Jacobs ef al., 2012). Each item consisted of a reference pattern
(5x5 grid, top) and four response patterns (bottom). One response
pattern corresponded to the reference, after rotation by ±90° or
180°. Three randomized levels of difficulty (levels dependent variable
2, 3, 4) were defined by the complexity of the pattern. The control
condition required matching the reference and unrotated response
2746 I Brain 2014: 137; 2743-2758
C. Nombela et al.
patterns. The task lasted 10min46s, with alternate experimental and
control items (cued on screen by 'rotate' or 'match', respectively) and
intervening rest intervals of 5-15 s (cued by 'rotate' or 'match' for
experimental and control items, respectively). No feedback was pro-
vided. The dependent variables were the latency of response and
number of accurate responses.
Memory Encoding Task
Memory deficits in Parkinson's disease are most related to encoding
rather than impairments in retention or retrieval processes (Bronnick
et al., 2011). Encoding deficits generally have a different aetiology to
executive impairments (Kehagia et al., 2010), and are linked to hip-
pocampal function (Aarsland ef al., 2011). The Memory Encoding Task
was selected accordingly. Subjects viewed abstract pictures organized
in seven blocks (displayed alternatively with intertrial intervals of 5-
15s) of six images for 4s each, with a 1 s cross-hair fixation between,
and were asked to memorize them. Participants saw 30 different
images in the scanner; 18 of them appeared once (exposition fol-
d = once), 12 appeared twice (exposition fold = twice). After scanning
(20-min delay), participants completed a recognition test of these 30
images, intermixed with 32 lures. They reported whether they had
seen each picture before by two-alternate forced-choice button re-
sponses. No feedback was provided. The dependent variables were
the response latency, the number of accurate responses and the d'
score of hit rate versus false alarms.
MRI acquisition processing and analysis
A Siemens TIM Trio 3 T scanner (Siemens Medical Systems) was used
at one site and a 3 T Philips Intera Achieva scanner at the other.
Participants underwent high resolution magnetization prepared rapid
gradient echo scanning (MP-RAGE: repetition time = 2250 ms, echo
time = 2.98 ms, flip angle = 9°, inversion time = 900 ms,
256 x 256 x 192 isotropic 1 mm voxels). During functional MRI,
'BOLD-sensitive' T 2 * weighted echo-planar images were acquired
(repetition time = 2000 ms, echo time = 30 ms, flip angle = 78°,
32 x 3 mm sequential descending slices, in-plane resolution
3 x 3 mm, slice separation 0.75 mm) with 320 volumes for Tower of
London and Spatial Rotations Tasks and 250 volumes for Memory
Encoding excluding 10 initial dummy volumes.
MRI data were processed using Statistical Parametric Mapping
(SPM8, www.fil.ion.ucl.ac.uk/spm). Functional MRI data were con-
verted from DICOM to NIFTII format, spatially realigned to the first
image, and corrected for acquisition delay by sine interpolation with
reference to the middle slice. The mean functional MRI volume and
MP-RAGE were co-registered using mutual information, and the MP-
RAGE segmented and normalized to the Montreal Neurological
Institute (MNI) Ti template. The normalization parameters were
applied to all spatiotemporally realigned functional images and
upsampled to 2x2x2mm, before smoothing with an isotropic
Gaussian kernel with full-width half-maximum of 5 mm.
Individual analysis of all three tasks was modelled with the stimulus
onset times and durations per item. First level general linear modelling
included six regressors: stimuli were modelled as a boxcar function per
condition (experimental or control condition) and level of difficulty (2,
3 and 4) for Tower of London and Spatial Rotations Task whilst
Memory Encoding was modelled including all stimulus category (pic-
tures seen once and pictures seen twice, independently of encoding
success). A parametric modulator for each trial, value 1 / reaction
time, was included separately for each trial type and condition. Error
trials were modelled separately. Regressors were convolved with a
canonical haemodynamic response function and its first temporal de-
rivative. Six rigid-body motion correction parameters were included as
nuisance covariates. Contrast images were extracted for individuals
and entered into a second level region of interest analyses. For the
Tower of London and Spatial Rotations tasks, subjects were excluded if
they performed below threshold, as defined by two criteria: (i) long
thinking time to solve an item, defined as a latency of response >17s
[response time average + 2.5 standard deviations (SD) in the sample];
(ii) <1 correct answer per type of item (control and experimental task)
and level of difficulty (2, 3 and 4 in both Tower of London and Spatial
Rotations Tasks).
Functional MRI data were analysed by region of interest analysis at
the group level (see 'Results' section and Fig. 1) and corrected for
multiple comparisons [2-tailed significance level was set at P < 0.05
cluster-based false discovery rate (FDR)]. Then, region of interest ana-
lyses were performed using individual measures of averaged effect size
('beta' parameter estimates) for each region of interest, extracted
using MarsBaR (MARSeille Boite A Region d'lnteret) toolbox (http://
marsbar.sourceforge.net).
The independent a priori specification of regions of interest was
based on previous studies of Tower of London and Spatial Rotations
Tasks (Williams-Gray et al., 2007b; Hampshire et al., 2012). Beta
values in eight a priori regions of interest were extracted: right dorso-
lateral prefrontal cortex (DLPFC), left DLPFC, right frontopolar cortex,
bilateral posterior parietal cortex and precuneus. Additionally, caudate
nuclei (right caudate: x= -10, y=15, z = 2; left caudate: x= -10,
y = 15, z = 2, 10mm radius sphere) were included because of their
high relevance within the frontostriatal network in mediating executive
functions in healthy controls (Owen et al., 1996) and Parkinson's dis-
ease (Lewis ef al., 2003). A task-specific region of interest template for
Memory Encoding Task (Hampshire et al., 2012) was based on inde-
pendent 60 healthy control data: bilateral hippocampus (right
Figure 1 Statistical parametric maps contrasting activity in
active versus baseline conditions rendered into a canonical brain
in standard anatomic space. (A) Activity during planning minus
control condition on Tower of London Task across all groups.
(B) Activity during rotations minus baseline on Spatial Rotations
Task across all groups. (C) Activity during encoding (pictures
seen once) minus baseline on the Encoding Memory Task across
all groups. Figures show areas of signal change above a
threshold of P = 0.05 after FDR correction for the whole brain
volume.
Early diagnosis of cognitive decline in Parkinson's disease Brain 2014: 137; 2743-2758 I 2747
Table 1 Demographic and clinical variables for participants in each group and site
Contml Sitp 1
V_*_l I I LI \J I JILC 1
Pflrkin^nn'^
disease Site 1
fontrnl ^Jitp 5
ParkinQnn'Q
disease Site 2
P Cirnim
r v_r i uu u
P Site
P flrmm v litp
interaction
Gender (M/F)
27/22
25/24
17/18
57/45
0.549
0.407
0.697
Age (years)
63.83 ± 5.8
65.36 ± 7.9
66.23 ± 8.4
64.81 ±11.1
0.84
0.94
0.77
Years of education
15.30 ± 6.1
14.02 ± 2.6
13.1 ± 3.9
13.03 ± 3.8
0.001
0.001
0.009
MMSE
29.48 ± 0.7
29.10 ± 0.9
29.16 ± 1.05
28.94 ± 1.1
0.193
0.193
0.074
MOCA
27.69 ± 1.7
26.06 ± 2.2
26 ± 5.9
26.07 ± 2.7
0.278
0.183
0.146
NART
121.85 ± 5.2
114.58 ± 8.6
113.5 ± 25.5
116.69 ± 9.4
0.448
0.845
0.639
Semantic fluency
18.53 ± 5.4
14.38 ±4.2
12.37 ± 5.7
11.33 ±4.6
0.054
0.001
0.493
Category fluency
31.95 ± 7.5
22.04 ± 6.2
23.12 ± 8.4
21.21 ± 8.1
0.001
0.001
0.001
MDS-UPDRS-III
29.28 ± 11.02
25.36 ± 10.7
0.06
LEDD
484.56 ± 369
167.69 ± 129
0.001
Duration (months) Mean
21.1 ± 13.2
6.11 ±4.7
0.001
Median
19.2 ± 13.2
4.7 ±4.7
0.001
P-values are presented separately for comparisons of group (Parkinson's disease versus control), site (1 versus 2) and the interaction between site and disease, using
ANOVAs (except chi-squared tests of gender). Data are shown without correction for multiple comparisons (values in bold are significant after Bonferroni correction). In
view of the skewed distribution of symptom duration (Shapiro-Wilk test P < 0.001), the median values for duration are also show (*Mann-Whitney test P-value).
hippocampus, left hippocampus), left superior parietal gyrus, right
inferior frontal gyri pars triangularis and pars opercularis, left inferior
frontal gyrus, left occipital and a large region of interest including
posterior temporo-parieto-occipital area.
The region of interest and behavioural analyses used SPSS (version
21). The first set of analyses used initial parsimonious ANOVAs in
which categorical variables were run, including: region of interest,
task condition and difficulty as within-subject factors and disease
group (patients versus controls) and site (Cambridge versus
Newcastle) as between-subject factors. However, several continuous
cognitive and clinical variables have been shown in previous studies to
affect brain function (e.g. age, disease progression, levodopa doses)
(Williams-Gray etal., 2007a; Barone et a/., 2011; Taylor etal., 2013).
We therefore ran secondary ANCOVAs to control for the possible
effects of these variables. As there were many candidate variables,
the optimal approach we used was a stepwise multiple linear regres-
sion approach, progressively excluding variables, variables which ex-
plained minimal variance. We started each model with entry variables
of: age, sex, years of education, MMSE, MOCA, NART, letter and
category fluency UPDRS-III, LEDD and duration of disease. We
report both the significant contributory variables/covariates and the
percentage of variance they explained.
and an interaction between disease and site for category fluency
[F(1, 1 72) = 10.735; P< 0.001], with relatively higher scores in
controls at Site 1. Patients at Site 1 had longer duration of disease
[F(1, 107) = 100.624; P< 0.001], and were on a higher dose of
levodopa [F(1 ,107) = 48.402; P< 0.001] but were similar in their
motor severity (UPDRS-III subscale).
Table 2 compares key clinical and demographic markers for par-
ticipants in the main ICICLE-PD study and those completing the
functional MRI studies investigation, confirming that there were
no significant differences. Table 3 shows the COMT, AAAPT and
APOE genotype distributions among patients with Parkinson's
disease.
Tower of London Task
Across the two sites the number of patient participants
(Cambridge/Newcastle) completing the Tower of London task
was "patient = 1 1 7 (41/76) and the number of healthy controls
"control = 69 (43/16). Behavioural performance is illustrated in
Fig. 2.
Results
Demographics and neuropsychology
Gender, age, MOCA and MMSE scores were matched between
groups and sites (Table 1), with no significant interactions be-
tween these factors and site. For years of education there was a
main effect of site [F(1 ,172) = 23.431 ; P< 0.001] with fewer
years at Site 2, and a main effect of disease group
[F(1,172) = 19.760; P < 0.001] with controls having spent longer
in formal education, but no significant interaction. There were
corresponding differences between groups (higher score in
controls) and sites (higher scores at Site 1) in terms of category
fluency [disease: F(1, 172) = 15.544; P< 0.001, site: F(1,172) =
12.392; P< 0.001] and letter fluency scores [disease:
F(1 ,172) = 3.754; P < 0.054, site: F(1 ,172) = 10.735; P< 0.001]
Latency of response
The within subject factors of condition [control versus plan,
F(1, 186) = 497.432; P< 0.001] and difficulty [F(2,372) = 63.762;
P< 0.001] were significant with an interaction effect between
condition and difficulty on latency of response [F(2,370) =
73.744; P< 0.001], confirming that more difficult planning
items required longer response times. Repeated-measures
ANOVA confirmed an effect of site [F(1, 1 86) = 7.278,
P < 0.008, shorter at Site 1]. There was no main effect of disease
(F < 1) or interaction effect between disease and site (F < 1).
The addition of between subject demographic and neuropsy-
chological variables (age, years of education, MMSE, MOCA,
NART, semantic and category fluency scores) in separate re-
peated-measures ANCOVAs revealed a shorter response latency
in younger subjects [F(1, 1 86) = 6.090; P< 0.015], with a higher
number of years of education [F(1 ,186) = 4.033, P < 0.046],
2748 I Brain 2014: 137; 2743-2758
C. Nombela et al.
Table 2 Clinical and demographic values of the ICICLE-
Parkinson's disease (Yarnall et al., 2014) cohort and sub-
group participating in this functional MRI study
ICICLE-PD
Functional
MRI-ICICLE
n
219
141
Mean age
65.9
65.08
MDS UPDRS-IM severity
28.32
27.34
MOCA
25.70
26.06
Maleifemale
140:79
82:59
No differences were significant (x 2 and f-test contrasts between groups as
appropriate).
higher MMSE [F(1, 186) = 19.152; P< 0.001], higher MOCA
[F(1,186) = 5.378; P < 0.021] and greater letter fluency
[F(1, 186) = 48.06; P < 0.03]. No significant effects were found
for NART [F(1 ,186) = 1.290; not significant] or category fluency
[F(1,186) = 3.551; not significant].
In a separate analysis of patients with Parkinson's disease only, the
addition of disease-specific between -subject variables (UPDRS-III, LEDD
and duration) in repeated measures ANCOVA indicated that pa-
tients with higher UPDRS-III score took marginally longer to respond
[F(1,117) = 3.827, P< 0.05]. Neither LEDD nor duration had a signifi-
cant effect. Separate repeated-measures ANOVAs with COMT,
AAAPT and APOF genotype indicated no effect on latency (F < 1).
A stepwise multiple regression analysis in patients with
Parkinson's disease indicated that the MMSE explained significant
variance in latency in the resulting model [model F(4,117) = 8.395,
P < 0.004, MMSE f(116) = -2.897, P < 0.004, 6.7% of the vari-
ance explained r = 0.26].
Accuracy
Task condition [F(1 ,186) = 71 .414; P< 0.001] and difficulty
[F(2,372) = 47.9.3; P < 0.001] effects were significant with a sig-
nificant interaction between condition and difficulty [F(2,370) =
16.473; P< 0.001] confirming that more difficult planning items
were less likely to be completed. Repeated-measures ANOVA con-
firmed an effect of site [F(1, 1 86) = 20.586, P< 0.001, higher in
Site 1] but there was no effect of disease (F < 1) or interaction
between disease and site on accuracy [F(1, 186) = 2.353, not
significant].
The addition of between subject demographic and neuropsy-
chological variables in separate repeated-measures ANCOVAs
showed higher accuracy scores in younger participants
[F(1, 1 86) = 26.075; P < 0.001], with more years of education
[F(1, 186) = 9.601; P < 0.002], higher MMSE [F(1 ,186) = 19.331 ;
P < 0.001], higher MOCA [F(1,186) = 14.011; P < 0.001], higher
letter fluency score [F(1,186) = 14.725; P < 0.001] and higher cat-
egory fluency score [F(1,186) = 11.176; P < 0.001]. No significant
effects were found for NART [F(1,186) = 1.216; not significant].
In a separate analysis of patients with Parkinson's disease only,
the addition of between subject clinical variables revealed no sig-
nificant effect of UPDRS-III [F(3,1 17) = 3.827; not significant],
LEDD, duration, COMT, MAPT or APOF genotype (all F < 1).
Table 3 The distribution of the different polymorphisms of
the studied genes (COMT, MAPT and APOE) Parkinson's
disease participants per site
Genes
Polymorphism
Site 1
Site 2
Total
COMT
Met/Met
15
32
47
Met/Val
22
59
81
Val/Val
7
30
37
MAPT
H1/H1
26
85
111
H1/H2
16
34
50
H2/H2
2
2
4
APOE
APOE2
28
66
94
APOE3
11
50
61
APOE4
5
5
10
The stepwise multiple regression in the Parkinson's disease
group revealed a significant model [F(1, 1 17) = 12.298, P < 0.00
1] of explanatory variables that included years of education [f(1
16) = 4.224, P< 0.001], MOCA [f(1 16) = 3.321 , P < 0.001] and
NART [f(116)= -2.089, P < 0.039] explaining a total 24.5% of
the variance.
Functional MRI regional activity
The activity in regions of interest associated with planning was
estimated from the contrast of 'all planning tasks minus all con-
trol conditions'. Repeated-measures ANOVA showed no main
effect of disease [F(1 ,186) = 1 .353; not significant], site
[F(1, 1 86) = 1.723; not significant] or interaction (F<1).
There was a main effect of region of interest [Fig. 3;
F(7,1309) = 130.196; P < 0.001] and a significant interaction be-
tween region of interest and disease group [F(7,1 309) = 2.244;
P < 0.029]. Post hoc contrast indicated that the control
group had greater activation of the right frontopolar
[F(1,186) = 6.658; P< 0.011], right caudate [F(1, 1 86) = 11.368;
P< 0.001] and left caudate [F(1 ,186) = 5.081 ; P < 0.025] com-
pared to patients.
In the Parkinson's disease group, there was a trend towards an
effect of higher UPDRS-III score [F(1,134) = 3.359, P < 0.069] but
no effect of LEDD (F<1) or duration (F<1) on activation.
COMT genotype (contrasting Met/Met = 30 and Val/Val = 29),
site and LEDD intake (median split: high LEDD >275mg = 34,
low LEDD <275mg = 25) were used as between-subjects factors.
There was no significant effect of site (F<1), COMT, APOE
genotypes (F<1), or LEDD [F(1,117) = 1.387; not significant].
However, there was a significant interaction between genotype
and LEDD [LEDD x COMT, F(1 ,1 17) = 5.732; P < 0.020] with
post hoc f-tests confirming higher beta values in both Met/Met
homozygotes at low LEDD and Val/Val homozygotes at high
LEDD compared to Val/Val homozygotes at low LEDD and
Met/Met homozygotes at high LEDD within the right DLPFC
[f(58) = 2.530; P < 0.014], left DLPFC [f(58) = 2.050;
P< 0.045], right frontopolar [f(58) = 2.040; P < 0.008], right
caudate K(58) = 2.089; P < 0.045] and left caudate
[f(58) = 2.087; P < 0.040] (Fig. 3). There was no effect of
Early diagnosis of cognitive decline in Parkinson's disease
Brain 2014: 137; 2743-2758 I 2749
Al
15
13
£11
| 9
H 7
5
3
ci
3.5
g 2.5
1.5
Planning task - thinking time
II
M2 M3 M4
Level of dfflculty
Spatial rotations task - thinking time
A2
6
OB '
=
a
t i
L.
;
Planning task - Accuracy
B2
Hi
M2 M3 M4
Level of <fIGculty
Spatial rotations task - Accuracy
jiJ
6 5
° 4
- 1 *
I I I
R2 R3 R4
Level ofolffkulty
Encoding memoiy - thinking time
C2
33
9 23
R2 R3 R4
l*vel of (iffkulty
Encoding memorv - Accuracy
I -i 1 i|L_ii
Once Twice Unseen
Exposition fold
Control
Once Twice Unseen
Exposition fold
PD
Figure 2 Behavioural performance by groups on (A) Tower of London (planning items) where difficulty is manipulated by the number of
movements required; (B) Spatial Rotations Task (rotation items), where difficulty is manipulated by the complexity of the items to rotate;
and (C) Encoding Memory Task, where difficulty is manipulated by the number of expositions in the memory task. A1 and B1 show
response latency against the three level of difficulty for patients and controls. A2 and B2 show results in accuracy (the number of correct
responses) against levels of difficulty for patients and controls. C1 shows the number of correct, incorrect and unseen responses during the
post-scan test for patients and controls. C2 shows the number of correct responses for patients and controls, against exposure fold, (once
versus twice). *Significant interaction between condition and difficulty (A1 and A2), significant interaction between disease and difficulty
(B1 and B2), significant exposure effect (C1) and disease effect (C2), P < 0.05. PD = Parkinson's disease.
MAPT or APOE genotype on activation for the Tower of London
Task (F < 1).
Spatial Rotations Task
Across the two sites the number of patient participants
(Cambridge/Newcastle) completing the study was n Patient = 1 34
(46/88) and for healthy controls n Co nt ro i = 73 (49/24).
Behavioural performance is illustrated in Fig. 2.
Latency of response
Task condition [control versus planning, F(1 ,207) = 312.534;
P< 0.001] and difficulty [F(2,414) = 45.548; P< 0.001] along
with the interaction between them [F(2,414) = 14.665; P < 0.001]
were all significant, confirming that more difficult planning items
required more time to be solved. Repeated-measures ANOVA re-
vealed a significant effect of site [F(1 ,207) = 1 7.689; P < 0.001 ] but
no effect of disease (F < 1) with no significant interaction (F < 1).
2750 I Brain 2014: 137; 2743-2758
C. Nombela et al.
Figure 3 For the Tower of London Task (top left), the activation in regions of interest is presented separately by COMT genotype and
LEDD in patients (bottom). The y-axis of each graph represents the mean activation in terms of average parameter estimates. The data are
subdivided by a median split of LEDD (above versus below 275 mg/day) for each region of interest (top right). *P < 0.05.
There was also a significant interaction between difficulty and dis-
ease [F(2,414) = 2.988; P < 0.05], reflecting longer times to perform
more difficult items by patients than controls.
There was no significant effect of age (F < 1), MMSE (F < 1),
years of education [F(1 ,206) = 2.425; not significant], MOCA
(F<1), verbal and category fluency (F<1) or NART
[F(1 ,206) = 1 .744; not significant] on latency of response.
For the Parkinson's disease group, those with higher UPDRS-III
scores [F(1, 1 34) = 5.637, P< 0.019] showed longer response
latencies. There was a trend towards an effect of duration
[F(1,134) = 3.457, P < 0.065] but no effect of LEDD (F<1),
MAPI, COMT or APOE genotype on latency (F < 1).
A stepwise multiple regression in the Parkinson's disease group
revealed a minimal model [F(1 ,134) = 4.079, P < 0.045] including
just category fluency [£(116) = -2.020; P< 0.045], which ex-
plained only 2.9% of the variance.
Accuracy
Among within-subject factors, there was a significant effect of
condition [F(1 .207) = 179.697; P< 0.001] and difficulty
[F(2,414) = 21.691; P < 0.001] and a significant interaction
[F(2,414) = 66.130; P < 0.001]. There was an effect of site on
accuracy [F(1 ,207) = 42.611, P< 0.001, higher in Site 1] and a
trend towards a disease effect [F(1,207) = 3.319, P < 0.07, lower
score in patients] but there was no significant interaction.
Accuracy was higher in younger volunteers [F(1,207) =
3.715; P<0.05], and those with higher category fluency
[F(1,207) = 7.264;P < 0.008] with weak trends for years of edu-
cation [F(1 ,207) = 3.554; P< 0.061] and MOCA
[F(1 ,207) = 3.385; P < 0.067], but no effects of MMSE, NART
or verbal fluency [F(1,207) < 1.8; not significant].
The Parkinson's disease group with lower UPDRS-III score
achieved higher accuracy [F(1 ,134) = 6.839; P< 0.001] and
there was a weak trend for shorter duration of disease
[F(1,134) = 6.839; P < 0.079] but no effect of LEDD [F(1,134) =
2.702; not significant] or MAPT. A significant interaction between
MAPT and difficulty [F(2, 134) = 39.135; P< 0.001] was found,
confirming that H1 haplotype homozygotes achieved lower accur-
acy in the more difficult items (Fig. 4). There was no significant
effect of COMT or APOF genotype (F < 1).
The stepwise multiple regression in the Parkinson's disease
group revealed an explanatory model [F(2, 134) = 12.317,
P< 0.001] that included years of education [£(116 = 4.115;
P<0.001] and age [£(116) = -2.501; P< 0.014], which ex-
plained 15% of the variance.
Functional MRI regional activity
To determine brain regions specifically activated by the rotational
task, 'all rotation events minus baseline conditions' were analysed.
Repeated-measures ANOVA showed no effect of site, disease or
interaction effects between disease and site (all F<1). The re-
gions differed in their activity as revealed by a main effect of
region of interest [F(7,1428) = 85.004; adjusted P< 0.001] and
there was a significant interaction between site and region of
Early diagnosis of cognitive decline in Parkinson's disease
Brain 2014: 137; 2743-2758 I 2751
Rotation condition
Match condition
* 7
I 7
5
HI homozygotcs
H2 carriers
Figure 4 Behavioural responses in the Spatial Rotations Task, showing the number of correct responses during experimental (left) and
control (right) conditions, respectively. Repeated-measures ANOVA indicated a significant interaction between MAPT (H1/H1 versus H2
carriers) and difficulty at rotation condition during the Spatial Rotations Task. *P < 0.05. Difficulty is manipulated by the complexity of the
items to rotate in the Spatial Rotation Task.
interest [F(7,1428) = 3.374; adjusted P < 0.001] and between dis-
ease and region of interest [f (7,1 428) = 1.998; P < 0.05] such
that controls achieved greater activation than patients in a
subset of regions of interest. Post hoc t-tests analysis showed
that significant effects were localized to the left parietal
[f(207) = 1.917; P < 0.05] and precuneus [f(207 = 2.241 ;
P < 0.026].
In the Parkinson's disease patient group, the addition of be-
tween-subject variables (UPDRS-III, LEDD and duration) in separ-
ate repeated-measures ANCOVAs indicated a significant effect of
LEDD [F(1,134) = 1.696; P < 0.041] but no significant effect of
UPDRS-III or duration (all F<1) on region of interest activity.
Subsequent repeated-measures ANOVA including MAPT genotype
and site as between-subject factors confirmed an effect of MAPT
on beta activity within the regions of interest [F(1 ,134) = 6.600;
P < 0.011, Fig. 5]. Post hoc f-test analysis indicated that H2 car-
riers reached significantly higher values than H1 homozygotes in
the right caudate [«134) = 4.045; P< 0.047], left caudate
[«134) = 6.215; P< 0.014] and left parietal [«134) = 5.343;
P < 0.023, Fig. 5]. There was no effect of COMT or APOF on
region of interest activation during the Spatial Rotations Task
(F< 1).
Memory Encoding Task
Across the two sites the number of patient participants
(Cambridge/Newcastle) completing the encoding memory was
^Patient =
128 (41/87) and for healthy controls n Co ntroi = 80 (48/
32). Behavioural performance is illustrated in Fig. 2.
Latency of response
The within-subjects factor of exposure fold (once versus twice)
was significant [F(1,208) = 62.401; P < 0.001]: in both groups la-
tency of response was shorter for pictures exposed twice than for
pictures exposed once. Repeated-measures ANOVA revealed sig-
nificant effects of site [F(1 ,208) = 46.070; P < 0.001], but no dis-
ease effect or interaction between site and disease on latency.
There were no effects of age [F(1,208) = 1.203; not significant],
MMSE [F(1 ,208) = 1.293; not significant] years of education
(F < 1), letter fluency (F < 1), category fluency (F < 1), MOCA
[F(1 , 208) = 1.501; not significant] or NART (F<1). In patients
with Parkinson's disease, UPDRS-III (F<1), LEDD
[F(1, 128) = 2.402; not significant], duration (F<1), COMT,
MAPT or APOE (F < 1) had no significant effect on latency of
response. A stepwise multiple regression model
[F(1,128) = 14.245, P < 0.001] indicated that duration of disease
[f(128) = -3.774; P < 0.001] explained 12.4% of the variance.
Accuracy
There was a main effect of site [F(1 ,208) = 22.476; P< 0.001,
higher at Site 1] and disease [F(1, 208) = 4.165; P < 0.043] on
accuracy, indicating more recognized pictures by controls than
patients, but there was no interaction between disease and site
(F < 1). The exposure fold (once versus twice) affected accuracy
[F(1 ,208) = 170.973; P< 0.001], in both patient and control
groups with no interaction between disease and site. See Fig. 2
for details. Further analysis including d' scores per participant indi-
cated higher scores for controls for both pictures seen once
[«208) = 2.937; P < 0.004] and for those seen twice
[f(208) = 3.524; P < 0.001].
There was no significant effect of age [F(1 ,208) = 1 .203; not
significant], MMSE [F(1 , 208) = 1.293; not significant], years of
education (F<1), MOCA [F(1 ,208) = 1 .501 ; not significant],
letter fluency (F < 1), category fluency (F < 1) or NART (F < 1)
on encoding memory task.
In the Parkinson's disease group, there was no significant effect
of LEDD [F(1,128) = 2.402; not significant], UPDRS-III (F<1),
2752 I Brain 2014: 137; 2743-2758
C. Nombela et at.
Figure 5 For the Spatial Rotations Task (top left), the activation within each region of interest (top right) is plotted separately for H1
patient homozygotes and H2 patient carriers. The y-axes represent the mean parameter estimate, in arbitrary scaled units. See text for
details of the gene by region interaction. Post hoc f-test analysis indicated that region of interest and MAPT genotype interaction occurred
at marked areas (bottom). *P < 0.05.
duration (F < 1), COMT, MAPT or APOE genotype on accuracy.
The stepwise multiple regression analysis in patients revealed no
single significant explanatory variables for accuracy variance.
Functional MRI regional activity
The contrast between correctly encoded pictures 'seen once'
minus baseline was used for repeated-measures ANOVA of re-
gional activation. There were significant effects of site
[F(1 ,208) = 226.369; P< 0.001] and effect of disease
[F(1 ,208) = 6.050; P < 0.15] with higher beta values in controls
and in Site 1 . There was an interaction between site and disease
[F(1,208) = 22.878; P < 0.01]. The regions differed in the magni-
tude of activation [main effect of region of interest,
F(7, 1 260) = 11.920; P< 0.001] with an interaction between
region of interest and site [F(7,1 260) = 68.392; P< 0.001,
higher at Site 1] and interactions between region of interest and
disease [F(7, 1260) = 9.729; P < 0.001]. Post hoc f-tests revealed
significantly lower activations in patients within the left hippocam-
pus K(207)= -1.792; P< 0.048], left inferior frontal gyrus
[f(208) = -4.587, P < 0.001], right inferior frontal gyrus pars tri-
angularis [f(208) = -4.896, P < 0.001], right inferior frontal gyrus
pars opercularis [f(207) = -3.333, P< 0.001], left parietal
[f(180)= -4.139; P< 0.001], left occipital [f(207) = -7.056;
P< 0.001] and temporo-parieto-occipital areas
[f(207) = -5.008; P < 0.001],
There was a significant effect of AAOCA on accuracy
[F(1 ,207) = 4.959; P < 0.028] but not age (F<1), years of
education [F(1 ,207) = 2.262; not significant], AAMSE (F<1),
letter fluency [F(1 ,207) = 2.187; not significant] or category flu-
ency scores (F < 1) or NART (F < 1) .
In the Parkinson's disease group, there was an effect of LEDD
[F(1,107) = 7.992; P < 0.006] but no effect of UPDRS-III or dur-
ation (all F<1) on regional activity. The addition of between
subject variables (LEDD) in a repeated-measures ANCOVA re-
vealed an interaction between region of interest and APOE geno-
type [F(1 4,609) = 1.422; P < 0.05], with APOE4 carriers
manifesting lower activation. Post hoc t-test analysis showed
that the effect was focused on right hippocampus
[«107) = 1.866, P< 0.048], left hippocampus [f(107 = 2.635,
P<0.01], right inferior frontal gyri pars triangularis [f(107) =
2.739, P< 0.007], left inferior frontal gyrus [f(107 = 2.623,
P<0.01], left parietal [f(107 = 2.498, P<0.01], left occipital
[f(1 07 = 2.784; P < 0.007] and temporo-parieto-occipital areas
[f(107 = 2.702, P< 0.008] (Fig. 6). There was no significant
effect of COMT or MAPT genotype in region of interest activity
during the Encoding Memory Task (all F < 1).
In summary, our data showed a longer latency of response
(Spatial Rotations Task) and lower accuracy (Spatial Rotation and
Encoding Memory Tasks) in patients with respect to controls.
Score differences were stressed by demographical (age and years
of education), neuropsychological (verbal fluency, MMSE and
MOCA) and clinical (UPDRS-III, duration and LED) covariates.
Patient impairments were reflected in brain functional measures:
(i) working memory performance interacted with COMT poly-
morphisms and LEDD; (ii) spatial abilities was particularly impaired
Early diagnosis of cognitive decline in Parkinson's disease
Brain 2014: 137; 2743-2758 I 2753
Figure 6 Regional activation during encoding of items in the Encoding Memory Task (top left), illustrating the significant interaction
between regional activation and APOE genotype in Parkinson's disease patients (see text for details). The y-axes represent the mean
parameter estimate, in arbitrary scaled units. Post hoc t-test analysis indicated that region of interest and APOE genotype interaction
occurred at marked areas (bottom). *P < 0.05. TPO = temporo-parieto-occipital.
in H1 homozygotes (MAPI); and (iii) encoding abilities engaged
lower beta values as a function of APOE polymorphisms.
Discussion
The principal results of this study, in line with our hypotheses,
were that (i) soon after diagnosis, neurocognitive changes are evi-
dent in fronto-striatal and parieto-temporal systems; and (ii)
common polymorphisms in the COAAT, MAPT and APOE genes
are associated with differences in regional brain activity associated
with executive, visuospatial and memory functions, respectively.
Our results demonstrate a significant impact of these genes on
cortical activity associated with cognitive tasks, either alone or
through an interaction with dopaminergic medication. This study
goes beyond previous work, not only in the power afforded by the
cohort size, but also in its emphasis on early disease, with patients
being scanned within a median of 5 and 19 months from diagnosis
at the two sites, respectively — namely within 2 years of their
diagnosis.
Our cohort was also representative of Parkinson's disease soon
after diagnosis: our 168 patients did not differ in their demo-
graphic variables from the larger ICICLE-PD cohort of 219 patients
from which they were recruited (Yarnall et al., 2014). In ICICLE-
PD, the patients' age, UPDRS-III, cognitive abilities and years of
education were similar to previous large studies of community
acquired cohorts in the UK undertaken in the last decade
(Foltynie et al., 2004a, b; Williams-Cray et al., 2007a, 2009a;
Elgh et al., 2009; Fallon et al., 2013).
Tasks and cognition
Although Parkinson's disease is associated with dysfunction of the
fronto-striatal circuits supporting executive systems (Owen et al.,
1992; Kehagia et al., 2010), recent evidence indicates multiple
affected domains (Janvin et al., 2006; Hely et al., 2008; Elgh
et al., 2009; Aarsland and Kurz, 2010; Pedersen et al., 2013).
The dynamic nature of neurodegeneration, neurotransmitter loss
and progressive neuropathology led to the Dual Syndrome hy-
pothesis of cognitive deficits in Parkinson's disease (Goris et al.,
2007; Kehagia et al., 2013; Winder-Rhodes et al., 2013): frontos-
triatal dopaminergic dysfunction impairs planning, working
memory, response inhibition and attention control, while posterior
cortical pathology and cholinergic deficits impairs visuospatial,
mnemonic and semantic functions.
Our choice of functional AARI tasks succeeded in making differ-
ential demands on fronto-striatal and temporoparietal systems for
planning, spatial rotation and memory (Grant et al., 2013;
Hampshire et al., 2013). The Tower of London Task is an execu-
tive task that requires planning and working memory, which re-
cruits a frontoparietal network that includes the prefrontal
associative cortex (DLPFC) and posterior parietal cortex (Owen,
1998; Owen et al., 1998; Rowe et al., 2000, 2001). At all
stages of Parkinson's disease, impairments on this task have
2754 I Brain 2014: 137; 2743-2758
C. Nombela ef al.
been reported with longer response times, reduced accuracy and
poor neural efficiency with respect to age-matched controls
(Owen ef al., 1992; Owen, 1998; Perfetti et al., 2010) and re-
gional impairments identified by functional MRI and PET (Baker
et al., 1996; Owen et al., 1996; Williams-Gray et al., 2007b).
Lesion studies have confirmed that this task requires the integrity
of the prefrontal cortex (Bor et al., 2006) whereas pharmaco-
logical interventions and withdrawal indicate dopamine depend-
ence (Cools et al., 2002).
There was evidence of dopamine dependent Tower of London
deficits in some patients, with a non-linear relationship between
cortical dopamine tone and regional activation indicated by the
significant LEDD by COMT interaction. Specifically, prefrontal
cortex and caudate nuclei were more activated in Met/Met homo-
zygotes on low-dose dopaminergic medication and Val/Val homo-
zygotes on high-dose medication. This interaction is predicted by
the inverted 'U-shaped function' relating dopaminergic tone and
function, by which either too high or too low dopaminergic tone
impairs working memory and executive performance (Goldberg
and Weinberger, 2004; Williams-Gray et al., 2007b; Rowe
et al., 2008; Cools and D'Esposito, 2011; Fallon et al., 2013).
Our second task required mental spatial rotation, emphasizing
visuospatial functions. Impairments in this domain are predictive of
dementia in Parkinson's disease (Williams-Gray et al., 2009b).
Neuroimaging of similar spatial rotations tasks in healthy adults
indicates posterior parietal activation (Corballis, 1997) and pre-
frontal activation (Selemon and Goldman-Rakic, 1988; Goldberg
and Weinberger, 2004). Parkinson's disease increases response
latencies and errors on this task (Lee et al., 1998; Amick et al.,
2006), and reduces posterior parietal activation (Crucian et al.,
2003) . We replicated both effects, more so in MAPT H1
homozygotes.
The final task involved required visual episodic memory encod-
ing. This task evokes hippocampal and medial temporal lobe ac-
tivity during encoding in healthy controls (Dove et al., 2006),
which we replicated. We found that even in the early stages of
Parkinson's disease, a reduction was seen in the neocortical acti-
vation associated with this task, although the magnitude and dir-
ection of hippocampal effects was similar (Fig. 6). Parkinson's
disease- mild cognitive impairment and later stages of
Parkinson's disease impair episodic memory (Weintraub et al.,
2004) although the relationship of early poor memory perform-
ance to the development of Parkinson's disease dementia is un-
clear (Williams-Gray et al., 2009b). Memory impairment is
associated with reduced hippocampal volume in Parkinson's dis-
ease (Davidson et al., 2013; Pereira et al., 2013) as well as in early
Alzheimer's disease (Sahakian ef al., 1988), supported by objective
measures of impaired memory encoding (Weintraub ef al., 2011;
Beyer et al., 2013).
Genetic influences on cognitive systems
in Parkinson's disease
We examined common polymorphisms that modulate the behav-
ioural and neural consequences of Parkinson's disease. COMT
regulates prefrontal cortical dopamine metabolism (Chen et al.,
2004) and influences macroscopic cortical structure (Rowe et al.,
2010). Both functional MRI (Rowe et al., 2008; Williams-Gray
ef al., 2008; Fallon ef al., 2013) and F-DOPA PET (Wu ef al.,
2012) studies have shown significant functional consequences of
the Val157Met polymorphism in Parkinson's disease.
The COMT effect is complex, with modulation by both levo-
dopa therapy and task demands (Williams-Gray et al., 2007b,
2009a). Both the COMT genotype and dose of extrinsic dopamin-
ergic medication follow a non-linear U-shape function for a given
task, with either too-high or too-low frontal cortical dopamine
levels adversely affecting cognitive performance and activation
(Rowe et al., 2008). Consistent with the proposed dopaminergic
modulation of frontostriatal circuits, the interaction between
COMT genotype and LEDD was significant in dorsolateral and
frontopolar prefrontal cortices and caudate nuclei.
However, some studies do not find evidence for COMT modu-
lation of frontal dopamine function. For example, no interaction
between COMT genotype and Tower of London performance was
reported by Hoogland et al. (2010) or between COMT and pre-
frontal activation by Stokes ef al. (2011). In Hoogland ef al.
(2010) a different Tower of London version was used (Foltynie
et al., 2004b), and no functional MRI was conducted, perhaps
limiting the sensitivity to an effect of COMT. Interestingly, there
was an interaction between LEDD and COMT on verbal reasoning
consistent with a genotype interaction with dopaminergic medica-
tion to influence frontal cognitive ability in Parkinson's disease.
Stokes ef al. (2011) applied a similar MRI Tower of London ver-
sion to ours, but in fewer subjects and healthy middle-aged con-
trols. Here, the ICICLE-PD data from a larger sample corroborate
the COMT genotype modulation of frontostriatal function early in
the course of Parkinson's disease.
A second gene of interest was MAPT. The H1 haplotype in-
creases the risk of developing Parkinson's disease, and the risk
of early Parkinson's disease dementia (Goris ef al., 2007;
Williams-Gray ef al., 2009a). Here we show that H1 carrier pa-
tients were less accurate with difficult spatial rotations, and sus-
tained less activity in the parietal cortex and caudate nuclei
(Williams-Gray ef al., 2009a), essential areas for spatial rotations
(Harris ef al., 2000). Others have argued that there is no relation-
ship between MAPT haplotype and visuospatial performance
(Goldberg and Weinberger, 2004; Ezquerra ef al., 2008; Rowe
ef al., 2008; Morley ef al., 2012), which was the case here for
easy items. Our hypothesis is that as Parkinson's disease pro-
gresses, the difference between H1 and H2 haplotype will
emerge but initially only for more difficult visuospatial tasks. Our
data suggest that the posterior cortical functions underlying spatial
rotations task performance are not significantly regulated by dopa-
mine, in support of the dual syndrome hypothesis.
The third gene of interest was APOE. During memory encoding,
we found reduced brain activity within the temporo-parietal net-
work and impaired performance in carriers of APOE4. Although
the number of APOE4 carriers was small, this observation is con-
sistent with the literature (Pulkes et al., 2011; Domenger ef al.,
2012; Federoff et al., 2012; Peplonska ef al., 2013; Multhammer
ef al., 2014). It has been suggested that APOE4 Parkinson's dis-
ease carriers present more severe cortical atrophy (Wakabayashi
et al., 1998; Li et al., 2004) and more frequent cognitive decline
Early diagnosis of cognitive decline in Parkinson's disease
Brain 2014: 137; 2743-2758 I 2755
than patients without an APOE4 allele (Irwin et al., 2012). Our
data are the first to suggest that APOE4 also influences brain
activity in the caudate nuclei, hippocampus and posterior cortical
areas during a memory encoding task in recently diagnosed pa-
tients with Parkinson's disease, a result that is in agreement with
studies of Alzheimer's disease (Bookheimer and Burggren, 2009).
The specificity of gene x task interactions suggests a contrast
between COA/lT/dopamine effects on frontostriatal networks for
working memory and executive function, versus MAPT/APOE
modulation of temporo-parietal systems engaged in visuospatial
and mnemonic functions. Other genetic factors are likely to con-
tribute to cognitive function (Caccappolo et al., 2011; Chung
et al., 2012), but our data clearly support a role for COMT,
AAAPT and APOE in early disease expression, and possibly disease
onset (Goris et al., 2007). The influence of these genetic variants
is not necessarily specific to Parkinson's disease, and we saw in the
introduction how they have been associated with risk, imaging
and cognitive performance differences in several neurological
and psychiatric disorders. However, the variation of these three
genes appears to alter the neural substrates for major cognitive
domains even soon after diagnosis of Parkinson's disease, which
we suggest is directly relevant to their modification of the risk of
cognitive impairment or dementia in the context of Parkinson's
disease (APOE4, MAPT) and the potentially deleterious effects
of high dose levodopa therapy on some aspects of cognition in
a subset of patients (COMT). The mechanisms of these genetic
influences may include pharmacological interactions at the synapse
(especially for COMT in relation to cortical dopamine transmis-
sion). However, they may also include neuroplasticity conse-
quences of COMT, APOE and MAPT functional polymorphisms
in the context of Parkinson's disease pathogenesis, or develop-
mental effects even if these diminish with older age (e.g. for
COMT) (de Frias et al., 2005; Starr ef al., 2007; Rowe et al.,
2010).
Limitations
The large size of ICICLE-PD and the systematic recruitment meth-
ods have obvious advantages, but there remain methodological
and inferential limitations with this study. Even with 168 partici-
pants, the non-significant results of genetic variance or LEDD may
result in type II error. Our statistical methods prioritize type I
errors, especially with respect to the functional MRI studies.
Moreover, we suggest that more subtle effects of genotype, medi-
cation or other clinical-demographic factors may emerge with dis-
ease progression. We also rely on clinical diagnostic criteria,
Although we are relatively protected against potential misdiagnosis
as ICICLE-PD relies on reapplying the clinicopathologically vali-
dated diagnostic criteria after 18 months, and this is expected to
be >90% accurate.
Several performance and imaging results differed between sites,
despite the same research protocol (Yarnall et al., 2014). Site dif-
ferences are unlikely to reflect fundamental differences in the
onset, risks or pathology of Parkinson's disease. The site differ-
ences were not restricted to socioeconomic and cognitive meas-
ures, but also included the interval from diagnosis to scanning, and
the levodopa dose equivalent at the time of scanning.
Interestingly, the difference in UDPRS-III motor signs severity
was not significant suggesting that local treatment decisions
were effectively managing what may have been differential pro-
gression of the underlying disease between sites over time.
Although there may be some genetic variation between northern
and eastern England, we suggest that it is more likely that the
differences between sites arise from different referral pathways
and treatment practises. We fortunately obtained control partici-
pant data from both sites, to reduce the potential impact of re-
gional differences in culture, genetics, education, prior health and
access to care services. Socioeconomic and educational norms may
influence some cognitive score differences between sites, but the
sites remain comparable on the most important demographic and
cognitive tests metrics (age, gender, MMSE, AAOCA, NART). Most
importantly for the interpretation of the regional activations, the
behavioural data in the functional MRI tasks did not differ be-
tween sites. It remains to be seen whether geographical factors
continue to affect the cognitive and neural markers as disease
progresses, or whether the sites converge over time as their dif-
ferential delay to participation gradually becomes a smaller frac-
tion of the total disease duration.
We did not find many significant or large group effects in terms
of behavioural measures. This may at first seem disappointing,
given the behavioural deficits that emerge in studies of patients
with more advanced disease. However, the lack of major effects in
terms of behavioural data provides more relevance to the signifi-
cant differences between patients and controls in the functional
imaging: functional MRI may be more sensitive to the factors
that modify the function of neural systems than the cognitive
performance that depend on those systems at least at early
stages of the disease; and the specificity of region by group inter-
actions also raises the possibility that at early stages of the dis-
ease, compensatory mechanisms can allow for a normal
performance. It also reduces the ambiguity in interpreting func-
tional MRI data that otherwise arises if there are marked behav-
ioural differences such that activation differences could be the
cause or consequence of altered behaviour (Price and Friston,
1999; Poldrack, 2007).
This study is focused on the early presentation of Parkinson's
disease, with a median time from diagnosis to inclusion of 8
months. The genetic and clinical factors that we identify might
be used to study earlier or pre-manifest states in future studies
which would also avoid issues of treatment effects. However, this
was beyond the scope of the ICICLE-PD study. The potential
interaction between genetic variants and the rate of cognitive
decline following presentation of Parkinson's disease in the
ICICLEPD cohort (without dementia at presentation) will require
longitudinal investigation which will be the subject of future
research papers.
Conclusion
This functional imaging study in ICICLE-PD revealed that soon
after diagnosis, there are already changes in brain function and
cognitive performance in patients with Parkinson's disease. The
regional activations associated with three major cognitive domains
2756 I Brain 2014: 137; 2743-2758
C. Nombela et al.
interact with genotype in the context of Parkinson's disease. Even
recently diagnosed patients had impaired performance and altered
regional brain activity in three tasks that spanned frontostriatal
and parieto-temporal systems. The anatomical, functional, genetic
and behavioural data support the dual syndrome hypothesis for
Parkinson's disease cognition, with (i) an executive syndrome that
is frontally mediated, dopamine-dependant and modulated by
COMT genotype; versus (ii) a temporo-parietal system subject to
MAPT and APOE, but not dopaminergic modulation, that is
required for visuospatial and memory tasks.
Acknowledgements
We would like to thank all volunteers for their participation.
Funding
This study was supported by Parkinson's UK (C.N.), Lockhart
Parkinson's Disease Research Fund (T.K.K.), Michael J. Fox
Foundation (A.J.Y.), the National Institute for Health Research
(NIHR, RG64473) Cambridge Biomedical Research Centre, the
Wellcome Trust (JBR 088324); the Medical Research Couciil
Cognition and Brain Sciences Unit, Cambridge (MC-A060-
5PQ30); the NIHR Newcastle, Biomedical Research Unit based
at Newcastle-upon-Tyne Hospitals, NHS Foundation Trust and
Newcastle University; the NIHR Dementias and
Neurodegenerative Diseases Research Network (J.T.O.) and
Raymond and Beverly Sadder studentship (D.P.B.). The views ex-
pressed are those of the authors and not necessarily those of the
NHS, the NIHR or the Department of Health.
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