COGTIPS (COGnitive Training In Parkinson Study): The Effect of Online Cognitive Training on Cognition and Brain Networks in Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease, Impaired Cognition, Alteration in Cognition
Sponsor: Amsterdam UMC, location VUmc

 
 
 
 
Study protocol and analysis plan of the clinical trial 
COGnitive Training In Parkinson Study 
ClinicalTrials registration no. NCT02920632 
 
 
 
 
 
 
 
 
 
 
 
 
 
Based on the most recently approved Dutch study protocol, approved by the Medical Ethical 
Committee VUmc.  
Date approval of study: 1 Feb 2017.  
Date approval of amendments: 14 Jul 2017, 6 Dec 2017, 14 Sep 2018,  28 Sep 2020, 29 Oct 2020 

STUDY PROTOCOL 
Background 
Cognitive impairments are among the plethora of non-motor symptoms associated with 
Parkinson’s disease (PD) [1, 2]. Approximately 25% of PD patients suffer from significant 
cognitive impairments already at the time of diagnosis [3, 4], and up to 80% eventually 
develop PD dementia (PD-D) [5, 6]. Moreover, compared with people without PD, patients 
with PD have up to 5.9 times the risk to develop dementia [7]. Cognitive impairments have a 
negative impact on performing the activities of daily living [8, 9] and are an important 
modulator in the development of neuropsychiatric symptoms, including psychosis [10, 11]. 
Degeneration of dopaminergic and non-dopaminergic systems is one of the alleged causes 
of cognitive impairments [12, 13] and have therefore been targets for pharmacological 
treatments. Although these drugs have modest temporary effects on cognitive symptoms by 
improving the attentional capacity, they have no proven efficacy in preventing further 
cognitive decline in PD [14, 15]. Hence, non-pharmacological treatment options must be 
considered as an alternative treatment for alleviating cognitive dysfunction in PD. 
Cognitive training (CT) was developed after the first brain tumor resections and traumatic 
brain injury treatment during the World Wars [16], but is currently applied in numerous 
neurological and psychiatric diseases. Meta-analyses have confirmed its efficacy in relieving 
cognitive dysfunction in Alzheimer’s disease [17], mild cognitive impairment (MCI) [18], 
schizophrenia [19], and traumatic brain injury [20, 21]. Furthermore, a recent meta-analysis 
in PD yielded positive results of CT mainly in relieving ‘frontal’ cognitive dysfunction (i.e. 
executive dysfunction, and working memory and psychomotor speed impairment) [22]. This 
meta-analysis, however, included only seven randomized controlled trials (RCTs), with a 
maximum sample size of 73 PD patients [23]. Consequently, the authors called for larger 
trials in PD populations – a conclusion that had earlier been stated in a systematic review 
[24] – although the results cautiously implied cognitive training to be efficacious.  
Two study protocols have recently been published, describing a cognitive training 
intervention in PD [25, 26]. Both interventions are specifically aimed at patients who have 
already developed PD-related MCI [26] or PD-D [25], respectively. However, neural changes 
have been demonstrated early on in cognitively preserved PD [27-30]: at this stage 
compensatory local hyperactivity seems to counteract the progressive buildup of PD 
pathology that threatens global brain network function [31, 32]. At a later disease stage, this 
compensatory mechanism gradually fails and ultimately leads to brain-wide network failure 
and cognitive dysfunction [33-35]. An early-stage intervention to boost the compensatory 

phase during this window of opportunity is imperative to try and preserve cognitive functions 
and protect patients from cognitive decline.  
Cognitive training may induce reorganization of structural and functional networks in the 
brain: it has been proposed that CT leaves a ‘footprint’ on the brain, that prepares the brain 
for better and faster processing [36]. Multiple studies have provided evidence that CT can 
induce reorganization of the brain network infrastructure. For example, patients with 
amnestic MCI showed post-CT normalization of within- and between-network connectivity 
[37, 38] that correlated with improved performance on memory tasks [38]. In addition, CT can 
alter resting-state networks in multiple sclerosis [39-41], normalize task-related activity in 
patients with schizophrenia [42, 43], and enhance functional connectivity [36, 44, 45] and 
cerebral blood flow [36] in healthy elderly. To date, only a few reports have focused on the 
underlying neural alterations after CT in PD [46-48] in small and mainly exploratory studies 
(N = 10-30). Results were mixed, showing increased functional connectivity [47], increased 
local activation [46, 47], but also decreased local activation [48] in comparison with controls.  
In this study we aim to assess the efficacy of CT in a large sample of PD patients using a 
longitudinal design. Moreover, we aim to establish working mechanisms of CT by visualizing 
the within- and between-network changes that occur during training and to use the pre-
treatment network topology, combined with the demographic and clinical characteristics, to 
predict who will profit most from CT.  
 
Methods and design 
Study objectives 
In this study protocol we present COGTIPS – the “COGnitive Training In Parkinson Study”. 
The main research questions of this project are 1) What is the short-term and long-term 
effect of CT on objective and subjective cognitive functioning in PD? and 2) What are the 
neural mechanisms underlying the effect of CT in PD?  
The study objectives of the COGTIPS study involve assessing an easily-accessible, home-
based cognitive function training in individuals with mild subjective cognitive complaints in 
PD. Our primary objective is to assess the efficacy of an online CT program (compared to an 
active control condition) on executive functions. Our secondary objectives are to evaluate CT 
compared with an active control condition (AC) on 1) the efficacy on relieving subjective 
cognitive complaints; 2) the durability of the effect after six months, one year and two years; 
3) the rate of conversion to PD-MCI and PD-D after one year and two years; 4) the effect on 

brain network efficiency and connectivity. Furthermore, we aim to identify baseline brain 
network characteristics that predict treatment outcome. 
Based on previous literature on CT in PD and other neurodegenerative diseases, we 
hypothesize that compared with an active control condition 1) CT alleviates cognitive –mainly 
executive– dysfunction in PD patients, 2) CT relieves subjective cognitive complaints in daily-
life, 3) the CT effect endures for up to two years after finishing the intervention, and reduces 
the risk of conversion to PD-MCI and PD-D, and 4) CT improves brain network efficiency and 
connectivity. 
 
Study design and setting 
COGTIPS is a monocenter phase-III randomized controlled trial that will enroll one-hundred-
and-forty (140) PD patients. To assess the superiority of the online CT compared with an AC, 
participants are randomly appointed to either of the conditions in a 1:1 fashion (70 versus 
70). Eighty participants (i.e. 40 in each condition) will undergo pre- and post-training 
neuroimaging to assess CT-specific effects on functional and structural connectivity. This 
study was approved by the VU University Medical Center Medical Ethical Committee and this 
protocol is reported in accordance with SPIRIT guidelines [49]. 
The COGTIPS study will be performed at the Amsterdam University Medical Centers 
(Amsterdam UMC), location VUmc, an academic hospital with expertise in movement 
disorders located in Amsterdam, the Netherlands. We will enroll Dutch-speaking PD patients 
that have shown their interest in participation through 1) the outpatient clinic for movement 
disorders of the Amsterdam UMC, or community or academic hospitals in the area, 2) the PD 
patient association (“Parkinson Vereniging”), 3) advertisements in media like the Parkinson 
Magazine and national newspapers, 4) advertisements on participant recruiting websites 
such as ‘ParkinsonNext’ and ‘Hersenonderzoek.nl’, and 4) a database of PD patients that 
have previously shown interest in online cognitive training.  
 
Eligibility criteria 
Participants will be included on the basis of the presence of subjective cognitive complaints. 
We will focus on mild-to-moderate disease stage PD patients with mild cognitive complaints, 
to ensure that these patients are still within the ‘window of opportunity’. An overview of the 
inclusion and exclusion criteria is depicted in Table 1. 

Table 1 Overview of inclusion and exclusion criteria. 
Inclusion criterion 
Measured with 
Defined by 
Significant subjective cognitive complaints 
Parkinson’s Disease 
Cognitive Functional Rating 
Scale 
Score > 3 
Mild to moderate disease stage 
Hoehn & Yahr disease stage 
Score < 4 
Access to computer or tablet with access to 
Internet. Capability to use keyboard and 
computer mouse 
Phone interview 
- 
Signed informed consent 
- 
- 
General exclusion criterion 
Measured with 
Defined by 
Indication for dementia syndrome 
Self-administered 
Gerocognitive Examination 
Score < 14 
 
Montreal Cognitive 
Assessment 
Score < 22 
Current drug- or alcohol abuse 
CAGE AID-interview 
Score > 1 
Inability to undergo extensive 
neuropsychological assessments or eight 
weeks of home-based cognitive intervention 
- 
- 
Moderate to severe depressive symptoms 
Beck depression inventory 
> 18 
Presence of one or more impulse control 
disorders 
ICD criteria interview 
Positive screening 
Psychotic symptoms. Benign hallucinations 
with insight are not an exclusion criterion 
Schedule for Assessment of 
Positive Symptoms – PD 
Positive screening 
Traumatic brain injury 
Phone interview 
Cerebral contusion with 1) 
loss of consciousness for > 
15 minutes and 2) 
posttraumatic amnesia > 1 
hour 
Exclusion criterion for participation in 
magnetic resonance imaging 
Measured with 
Defined by 
A space occupying lesion  
Assessment by radiologist 
- 
Significant vascular abnormalities 
Assessment by radiologist 
Fazekas > 1 
Severe claustrophobia 
MRI safety screening 
questionnaire  
Positive screening 
Presence of metal in the body (e.g. 
pacemaker, neurostimulator) 
Pregnancy 
Difficulty with, or shortness of breath during 60 
minutes of lying still 
 
 
 

Participant timeline 
Figure 1 shows a global overview of the time schedule. A detailed description of the 
participant visits and assessments is shown in Table 2. 
Figure 1 Global overview of the COGTIPS time schedule. 
 
Pre-screening, screening and baseline assessment 
PD patients that have shown interest in participating in COGTIPS will first undergo pre-
screening for which they are required to sign informed consent and send this back by mail or 
E-mail. Pre-screening consists of a self-administered cognitive screening and questionnaires 
that are filled out at home (i.e. Self-administered Gerocognitive Examination [50]), and a 
phone interview. Patients are asked whether they are interested in participating in the 
subgroup that will undergo neuroimaging and if so, are screened for contraindications. After 
positive pre-screening, eligible patients are invited for an intake measurement. 
At intake, patients will sign informed consent for participation in COGTIPS. They first 
undergo face-to-face screening of cognitive dysfunction by the Montreal Cognitive 
Assessment [51, 52], motor impairment by the Unified Parkinson’s Disease – Rating Scale 
part III [53], psychotic symptoms by the Schedule for Assessment of Positive Symptoms – 
PD [54], depressive symptoms by the Beck Depression Inventory [55]) and impulse control 
disorders (ICDs) by an ICD criteria interview. Eligible patients will undergo the baseline 
assessment (‘T0’) which comprises an extensive neuropsychological assessment, structured 
interviews and questionnaires. A sub-population will undergo magnetic resonance imaging. 
Neuroimaging data will be acquired at the Amsterdam UMC, location VUmc, on a Discovery* 
MR750 3.0T MRI scanner (General Electric, Milwaukee) with a 32-channel head coil. We will 
obtain structural imaging (i.e. T1 and diffusion tensor imaging) and functional resting-state 

imaging. See appendix 1 for the scan parameters. All assessments are performed by study 
members that are blinded for the treatment condition. The screening and baseline 
assessment will be performed during a single visit to the Amsterdam UMC, location VUmc.   
Condition allocation and instructions 
Following a positive screening for eligibility, a non-blinded study member will allocate the 
participant to either the CT or AC condition. Participants will be consecutively assigned to 
either the CT or AC condition on the basis of a randomization sequence. The randomization 
sequence is generated in Microsoft Excel by using computer-generated random numbers. 
We will use stratified randomization in which two strata will be generated according to 
education level. Vocational education level (or lower) defined as an education level of 5 or 
lower according to a Dutch classification system [56], which is comparable to 11 or less 
years of education [57]. High education level is defined as level 6 or 7 according to the 
Verhage classification system, which is comparable to 12 or more years of education.  
A non-blinded study member will provide instructions to the participant concerning the log-in 
procedure for the training, the various training components, and the duration and frequency 
of training. After instructions, the participant will be asked to fill out a questionnaire 
concerning the patients’ expectations and credibility regarding the intervention [58]. 
Participants will additionally receive a hand-out with instructions to take home.   
Eight-week intervention period  
After the baseline assessment, participants may directly start with the 8-week intervention. A 
detailed description of the CT and AC interventions is provided below. Compliance will be 
monitored automatically and will be checked weekly. During the intervention, patients will 
receive biweekly questionnaires to ensure compliance and check for questions and problems 
performing the intervention. Non-blinded study members will follow-up on potential problems 
by phone.  
Post-intervention assessments 
After 24 intervention sessions, patients are invited for the post-intervention assessment. This 
assessment will be scheduled as close as possible to the last training session. Participants 
will first evaluate the intervention with a non-blinded study member. Directly afterwards, 
participants will undergo a post-intervention assessment (‘T1’). This assessment comprises a 
neuropsychological assessment and questionnaires (see Table 2). One team member (TB) 
will be de-blinded after the last T1 visit. All assessments after baseline will make use of 
parallel versions of neuropsychological tasks, if possible. 

After six months (‘T2’), one year (‘T3’) and two years (‘T4’), participants will again undergo an 
extensive neuropsychological assessment and questionnaires. At T3 and T4, motor 
symptoms will also be assessed. From T3 onwards will be a naturalistic follow-up. 
Blinding 
Outcome assessors will be blinded for the full length of their role as assessor, while non-
blinded team members will not assess participants at any point in this study. Blinded study 
members will not have access to the key of the randomization. Trial participants will be 
blinded for the full length of the study. Participants will be asked not to share any details of 
their intervention with the outcome assessor at any point in the study. When the participants’ 
condition is revealed to an outcome assessor, he or she will be replaced by another assessor 
for this participant. 
Drop-outs 
Participants that drop out of the study after being allocated to an intervention condition will 
not be replaced. We expect a low drop-out rate on the basis of our pilot study (one drop-out 
in 21 participants) and the low burden and short duration of both training conditions. In our 
sample size calculation, we conservatively account for 10% drop-out. 
In case a participant withdraws from the study after four weeks of training (or more), we will 
aim to schedule an exit-measurement to measure the intervention effect. 
Medication adjustments  
Participants and their neurologist will be requested to retain a stable medication regime 
during the study period, specifically during the intervention. Patients and their neurologist will 
be requested to inform the study team if medication changes are clinically necessary.  
 
 
 

Table 2 Tabular overview of the study time schedule including assessments and visits. 
Time-point T-2 
T-1 
T0 
T1 
T2 
T3 
T4 
Pre-screening  
Informed consent for 
pre-screening 
X 
 
 
 
 
 
 
SAGE 
X 
 
 
 
 
 
 
PD-CFRS 
X 
 
 
X 
X 
X 
X 
MRI safety screening 
X 
 
 
 
 
 
 
Alcohol abuse 
screening (CAGE-AID) 
X 
 
 
 
 
 
 
Eligibility screening 
Montreal Cognitive 
Assessment 
 
X 
 
X 
X 
X 
X 
ICD diagnostic criteria 
 
X 
 
X 
 
 
 
SAPS-PD† 
 
X 
 
 
 
 
 
Beck depression 
inventory 
 
X 
 
X 
X 
X 
X 
Hoehn & Yahr stage 
 
X 
 
 
 
X 
X 
Enrolment and allocation 
X 
  
  
  
  
Intervention 
Cognitive training 
 
 
←→ 
 
 
 
Active control 
condition 
 
 
←→ 
 
 
 
Assessments 
Neuropsychological assessment 
1 Tower of London 
X 
X 
X 
X 
X 
 Montreal Cognitive Assessment† 
 
X 
X 
X 
X 
 Pentagon copy 
X 
X 
X 
X 
X 
1/2 Stroop Color Word Test 
X 
X 
X 
X 
X 
1 COWAT (‘letter fluency’) † 
X 
X 
X 
X 
X 
2 WAIS-III digit span 
X 
X 
X 
X 
X 
3 Rey Auditory Verbal Learning Test‡ 
X 
X 
X 
X 
X 
3 Location Learning Test# 
X 
X 
X 
X 
X 
4 Boston naming test 
X 
X 
X 
X 
X 
4 Category fluency 
X 
X 
X 
X 
X 
5 Rey Complex Figure Test 
X 
X 
X 
X 
X 
5 Visual Form Discrimination Test 
X 
X 
X 
X 
X 
Questionnaires and interviews 
CFQ 
X 
X 
X 
X 
X 
Apathy scale 
X 
X 
X 
X 
X 
Parkinson anxiety scale 
X 
X 
X 
X 
X 
QUIP-RS 
X 
X 
X 
X 
X 
NZPAQ-SF 
X 
X 
X 
X 
X 

Credibility/expectancy questionnaire 
X 
 
 
 
 
Motor symptom assessments 
UPDRS-III - motor score 
X 
 
 
X 
X 
Medication use 
 
Levodopa equivalent daily dosage 
X 
X 
X 
X 
X 
Neuroimaging* 
MP-RAGE 
X 
X 
 
 
 
3D PSIR 
X 
X 
 
 
 
fMRI - resting state 
X 
X 
 
 
 
DTI 
X 
X 
 
 
 
*in a subsample of N = 80.  
Parallel forms of the same test are used at consecutive visits if available: †Three parallel forms; ‡Two parallel 
forms; #One parallel form. 
Cognitive domains: 1Executive functioning, 2Attention and working memory, 3Memory, 4Language, 5Visuospatial. 
Abbreviations: CFQ = Cognitive Failures Questionnaire; COWAT = Controlled Oral Word Association Test; DTI 
= diffusion tensor imaging; MP RAGE= magnetization-prepared 180 degrees radio-frequency pulses and rapid 
gradient-echo; (f)MRI = (functional) magnetic resonance imaging; NZPAQ-SF = New Zealand Physical Activity 
Questionnaire – Short Form; PD-CFRS = Parkinson’s Disease – Cognitive Functional Rating Scale; PSIR = 
phase-sensitive inversion recovery; QPE = Questionnaire for Psychotic Experiences; QUIP-RS = Questionnaire 
for Impulsive-Compulsive Disorders in Parkinson's Disease – Rating Scale; SAPS-PD: Scale for Assessment of 
Positive Symptoms for Parkinson’s disease; UPDRS = Unified Parkinson’s Disease Rating Scale; WAIS = 
Wechsler Adult Intelligence Scale. 
 
Interventions 
The intervention in this study aims to train cognitive abilities, with a focus on executive 
functions, working memory, attention, and processing speed. A modified version of the 
BrainGymmer online CT platform (www.braingymmer.com, a product by Dezzel Media B.V.) 
is used to provide the training at the patients’ home. We selected this method of cognitive 
training as it has been evaluated positively in our earlier pilot study in PD patients (see 
below), it is accessible for patients at home, and previous versions have been used in prior 
studies [59, 60]. A proof-of-concept in twenty PD patients showed that the experimental 
condition was evaluated as feasible and enjoyable. Moreover, the CT compared with an 
active control showed a medium interaction effect size on an executive functioning composite 
(i.e. Stroop Color Word Test, Trail Making Test and Controlled Oral Word Association Test), 
with a significantly positive change of executive functioning in the CT group but not in the 
active controls. Specifically, a large positive interaction effect size of CT on the Stroop color 
word test was found compared with controls (see Figure 2). 

 
Figure 2 Change on median neuropsychological performance on left: an executive function 
composite score (consisting of standardized scores of the Stroop color word test card III 
corrected for card II, the Trail making test part B corrected for part A and the Controlled Oral 
Word Association Test) and right: the Stroop color word test card III corrected for card II. 
Significant differences are shown with the corresponding p value. Abbreviations: AC = active 
control condition; CT = cognitive training; EF = executive function; Stroop CWT = Stroop 
color word test. 
 
Intervention characteristics 
In both conditions, 24 training sessions are performed: three times a week for a length of 
eight weeks. The training sessions last approximately 45 minutes, marginally dependent on 
the participants’ performance. Compliance and training performance data are automatically 
tracked when a participant performs a training session. Participants can independently 
schedule the three training sessions per week to ensure flexibility and a low training 
threshold. The training sessions can be paused at the participants’ discretion but they are 
advised to try and complete the entire training within one hour.  
Cognitive training 
In the experimental condition, 13 CT games are sequentially performed. The cognitive 
processes that the training games call upon are similar to processes that are tested during 
the neuropsychological assessments, but the games are substantially different from the 
neuropsychological tasks. The training games are equipped with a ‘dynamic difficulty 
adjustment’: the difficulty of training components is adaptive to the participants’ performance, 
and will increase or decrease depending on individual performance. This way, participants 

will be challenged to continuously perform at their maximal ability. Training games, their 
duration and the hypothesized cognitive loading are shown in Table 3.  
 
Table 3 Description of training games in the CT condition with their duration and the 
cognitive loading. 
Description 
Duration 
Cognitive loading 
Repeat a drum rhythm that increases in length 
3 mistakes 
Working memory, attention 
Flanker task 
80 s 
Cognitive flexibility 
Put a sequence in the correct prompted order 
180 s 
Visuospatial function, focused 
attention 
An ‘N-back’ task using bottles of various shapes and 
colors 
180 s 
Working memory 
Evaluate if a ‘totem pole’ comprising blocks of different 
forms and diameters matches a top view 
2 mistakes 
Visuospatial function, mental 
rotation 
Follow one or more moving targets (i.e. a bunny with a 
carrot) between several distractors 
4 mistakes 
Focused and divided attention 
Accept or decline stimuli based on switching rules with 
increasing speed 
90 s 
Cognitive flexibility, processing 
speed 
Remember an increasing number of colored squares 
120 s 
Working memory, attention 
Click an increasing number of stimuli (i.e. food on a 
barbeque) at the right time (i.e. when they are well-done) 
180 s 
Divided attention, psychomotor and 
processing speed 
Search birds with a certain color and form between an 
increasing number of distractors 
300 s 
Visuospatial function, processing 
speed 
Stack blocks of numbers that differ by one on top of 
another to reduce the number of blocks 
180 s 
Planning 
Remember the color and accessories of a penguin and at 
the same time the location of a fish 
180 s 
Working memory, processing speed 
Finish a puzzle within a limited time 
240 s 
Visuospatial function, processing 
speed 
 
Active control group 
An active control condition is used to correct for the nonspecific cognitive activity that 
participants in the CT group go through. In the control condition, participants undergo 
cognitive engagement using three games (i.e. solitaire, trivia questions and hangman) with a 
total duration of 45 minutes that will sequentially be performed and are hypothesized not to 
train specific cognitive functions.  
 
 

Outcomes 
Primary outcome 
The primary outcome is the efficacy of CT on executive functions, measured by the 
percentage correct change score on a previously used computerized self-paced version of 
the Tower of London (ToL) task [29]. The ToL measures several aspects of executive 
functions, including planning, inhibition, and working memory [61]. This neuropsychological 
task consists of a model of three pins with different lengths, and three differently colored 
beads. In this task, the goal is to get from a starting position to a target position in as minimal 
steps as possible. There are five planning conditions that range in difficulty, with possible 
solutions ranging from one to five steps (i.e. task-load S1-S5). After nine exercise items with 
feedback, 100 pseudo-randomized test trials will be presented with a maximum response 
duration of 45 seconds per trial and no feedback on accuracy.  
Secondary outcomes 
The secondary outcome measures include (i) subjective cognitive complaints, (ii) cognitive 
function (other than the ToL) and (iii) structural and functional connectivity and brain network 
characteristics. All outcomes described below are changes after intervention relative to 
baseline. 
1) Subjective cognitive dysfunction change after the intervention will be measured by the 
Parkinson’s Disease Cognitive Functional Rating Scale (PD-CFRS, [62]) score and the 
Cognitive Failures Questionnaire (CFQ) score at the end of the intervention (T1), and at 
follow-up (T2, T3, and T4). We use the PD-CFRS questionnaire as a Parkinson-specific 
and sensitive measurement of subjective cognitive function. This questionnaire will be 
filled out by the participant and if possible by a caregiver. We will additionally use the 
CFQ as this measure has been used more frequently and it is more sensitive to small 
cognitive errors in daily living such as memory problems, absent-mindedness and slips of 
action[63]; 
2) Cognitive function change after the intervention will be measured by 
- change on latent underlying cognitive factors in the neuropsychological assessment at 
T1 and at follow-up (T2, T3, and T4). Participants will undergo an extensive 
assessment battery of frequently-used and validated neuropsychological tests (see 
Table 2). See [64] for standard outcome measures of the neuropsychological tests. 
We will extract latent cognitive traits at baseline and measure training-induced 
changes on these factors at follow-up (see Analyses for a detailed description); 

- reduction of the risk of developing PD-MCI or PD-D at follow-up at one-year and two-
year follow-up. We will classify participants at the follow-up visits into level II PD-MCI 
[65] and probable PD-D [66] according to the most recent diagnostic criteria; 
3) Training-induced neural alterations will be measured with magnetic resonance imaging 
(MRI). Morphometric brain characteristics will be measured with standard measures (i.e. 
subcortical volume, cortical thickness, fractional anisotropy). We will measure functional 
connectivity by extracting independent components of simultaneously fluctuating blood-
oxygen level dependent signals that represent resting-state brain networks. Brain 
network characteristics will be measured by standard topological measures (i.e. 
modularity, global and local efficiency, betweenness centrality, see [67, 68]). 
Exploratory outcomes and covariates 
For exploratory purposes, the following outcomes will be collected.  
- Training-induced cognitive changes on individual neuropsychological tasks (see Table 2) 
will be assessed to increase comparability with other CT studies, and to increase 
replicability of the results in future research; 
- Improvement on the individual CT games will be measured in order to compare potential 
component-specific transfer effects. Performance on the CT components are collected 
automatically by the BrainGymmer online training module; 
- Alterations on psychiatric symptoms of anxiety, depression, apathy, and impulse control 
disorders, using the Parkinson anxiety scale, Beck depression inventory, Apathy scale, 
and Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease – Rating 
Scale, respectively. 
Additionally we will collect data on the following potential confounding factors: 
- Data on physical activity at each visit will be measured by the New Zealand Physical 
Activity Questionnaire – Short Form, a structured interview on mild, moderate and 
vigorous physical activity, as physical activity is known to positively influence cognitive 
function and potentially provide a neuroprotective effect.[69, 70]; 
- We will rate motor symptom severity by the Unified Parkinson’s Disease – Rating Scale 
part III and assess disease stage by the modified Hoehn & Yahr stage [71]; 
- Medication usage data are collected and transformed into a ‘levodopa equivalent daily 
dosage’ [33]. Dopamine replacement therapy may influence cognitive functions [72, 73]; 
- Intervention compliance will automatically be monitored by the training module. We will 
calculate total compliance as the proportion of completed training games out of 24 total 
sessions: [Ncompleted / Ntotal] x 100%, in which Ntotal is 13 games x 24 sessions in the CT 

condition, and 3 games x 24 sessions in the AC condition. We define non-compliance as 
a completion rate lower than 75%, in accordance with Petrelli and colleagues [74]. 
 
 
 

ANALYSIS PLAN 
Data-analyses will be performed on the Modified-Intention-To-Treat population, which 
comprises the compliant participants that underwent at least 75% of the intervention and at 
least one post-training assessment. We will compare the baseline characteristics of this 
sample to the Intention-to-Treat population (all randomized subjects). Secondary Per 
Protocol-analyses will be performed comprising the population that underwent the complete 
study protocol. Analyses will be performed with IBM SPSS version 22 (Armonk, NY, USA) 
and in R [75]. We will employ a statistical threshold of α = .05.  
The primary outcome will be analyzed using a multivariate mixed-model analysis using the 
accuracy on the five separate task-loadings (S1-S5) of the ToL at post-training visit (T1) as 
dependent measures, the training condition (CT vs. AC) as independent measure and 
baseline score of the outcome measures as covariates. We will construct a separate 
adjusted model with age, sex and years of education as additional covariates of no-interest. 
No imputation of missing values will be performed as this is not needed in linear mixed 
models. 
The secondary outcome measures will also be analyzed with linear mixed-models with 
baseline score of the outcome measures as covariates. Subjective cognitive dysfunction will 
be modeled with the total score of the PD-CFRS (both self-report and caregiver) and the 
CFQ a) at post-training (T1) and b) at all follow-up assessments (T2, T3 and T4) as 
dependent variables. We will perform a factor analysis on all neuropsychological assessment 
outcomes (see Table 2) at baseline using a factor analysis with regularized maximum 
likelihood estimation to produce latent cognitive traits. We will compute baseline trait scores 
(i.e. factor scores), and compute trait scores at follow-up measurements based on the 
baseline factor analysis. The effect of CT on cognitive functions will be assessed with a 
multivariate mixed-model comparable to the above, using the trait scores as dependent 
variables. The effect of CT relative to AC on neuropsychiatric symptoms will be analyzed 
using similar multivariate mixed-models with as dependent variables the Beck Depression 
Inventory, the Parkinson Anxiety Scale, the Apathy Scale and the Questionnaire for 
Impulsive-Compulsive Disorders in Parkinson's Disease – Rating Scale. Covariates will be 
added to the regression model based on a change-in-estimate method if there is a change of 
≥ 10% of the regression coefficient for the intervention variable. 
In order to analyze between-group differences in conversion to PD-MCI or PD-D, we will first 
classify patients at baseline, T3 and T4 as having normal cognition, PD-MCI or PD-D. We 
define conversion ‘down’ as conversion to a milder cognitive dysfunction classification, no 
conversion as classification in the same category at a later assessment visit and conversion 

‘up’ as conversion to a worse cognitive function classification. We will assess the association 
between the intervention and conversion rate with a Fisher’s exact test. Odds ratios and 
confidence intervals of the conversion ‘down’ and no conversion groups versus the 
conversion ‘up’ group will be computed as a measure of effect size. 
We will perform Fisher’s exact tests to verify if the demographic and clinical characteristics of 
the MRI subsample are similar to those of the full study sample. Functional MRI and diffusion 
tensor imaging data will be (pre)processed and analyzed with Statistical Parametric Mapping 
(SPM) software, FMRIB Software Library (FSL) and in-house Matlab (The MathWorks, Inc, 
Natick, MA, USA), scripts in combination with open-source toolboxes for (dynamic) network 
analysis [67, 68] to study the effects of cognitive training on the functional and structural 
brain network, respectively. We will also employ typical independent component analysis in 
combination with dual regression for resting-state functional connectivity and morphometric 
(e.g. cortical thickness) analysis on T1-weighted structural MRI to study within and between 
group-effects of our intervention. Moreover, to establish treatment response at the individual 
level, Multivariate Pattern classification (‘machine learning’) analyses will be performed to 
identify predictive markers (clinical, neuropsychological and neuroimaging) to be able to 
predict (in future patients) who is most likely to benefit from cognitive training. 
Sample size 
The sample size calculation is performed on the basis of a previous meta-analysis on the 
effects of CT on cognitive function [22]. This study showed an effect size of Hedges g = .23 
(i.e. f = .12), based on the effect of CT on improving global cognitive function. The sample 
size needed to detect this effect is 112, based on a repeated-measures analysis of variance, 
corrected for a moderate correlation between pre- and post-treatment measures (i.e. r ≈ .6). 
This sample size estimation also provides a good indicator for the power of our multivariate 
mixed-model regression analysis with adjustment for baseline measures. 
To ensure adequate power for the secondary study parameters, i.e. the development of PD-
MCI and PD-D at one and two years follow-up, with an α = .05 and β = .8, and based on a 
small drop-out (~10%) given the home-based, easily-accessible training, we will include 140 
participants. 
 
 
 

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Appendix 1 - MRI parameters 
All scans were acquired on a Discovery* MR750 3.0T MRI scanner (General Electric, 
Milwaukee) with a 32-channel head coil at the Amsterdam UMC, VU University (Amsterdam, 
the Netherlands). 
Resting-state fMRI: 272 volumes (~10 minutes) of T2*-weighted echo-planar images (EPI’s) 
with the following parameters: TR = 2200 ms, TE = 28 ms, flip angle = 80◦ , 42 axial slices 
(3.3 x 3.3 x 3.3 mm, matrix size 64 x 64). Sequential ascending acquisition according the 
hypophysis – fastigium (HYFA) line. High-order shimming (HOS) was performed to 
compensate for inhomogeneity in the magnetic field. Two reference scans in opposite phase-
encode directions are acquired prior to the resting-state acquisition to correct for 
susceptibility induced distortions during post-processing: TR = 8000 ms, TE = 60 ms. The 
field-of-view, position, orientation and matrix dimensions are identical to the resting-state 
scan.  
Diffusion-weighted MRI: Single Spin Echo multi-shell DWI with 73 diffusion weighted images 
(25 x b = 1000 s/mm2, 24 x b = 2000 s/mm2, 24 x b = 3000 s/mm2) and seven non-diffusion 
weighted (b = 0 s/mm2). TR = shortest (6000-7000 ms), TE = shortest (80-90 ms), 56 axial 
slices (2.5 x 2.5 x 2.5 mm, matrix size 128 x 128). Interleaved ascending acquisition 
according the hypophysis – fastigium (HYFA) line. High-order shimming (HOS) was 
performed to compensate for inhomogeneity in the magnetic field. Two reference scans in 
opposite phase-encode directions are acquired prior to the diffusion-weighted image to 
correct for susceptibility induced distortions during post-processing: TR = 8000 ms, TE = 60 
ms. The field-of-view, position, orientation and matrix dimensions are identical to the 
diffusion-weighted image 
Structural MRI: 3D sagittal MP-RAGE T1-weighted sequence according to ADNI-3 protocol 
with the following parameters: TI = 900 ms, TE = min full echo, flip angle = 8◦  168 slices (1 x 
1 x 1 mm, matrix size 256 x 256). 3D Cube sagittal Phase sensitive inversion recovery 
(PSIR) with the following parameters: TI = 650 ms , TR = 3000 ms, TE = minimum, 168 
slices (1 x 1 x 1 mm, matrix size 256 x 256).