Efficacy of Dual-task Telerehabilitation to Prevent Worsening in Activities of Daily Living in People With Parkinson's Disease at High Risk for Dementia: A Proof-of-concept Study
Phase: NA
Conditions: PARKINSON DISEASE (Disorder), Mild Cognitive Impairment (MCI)
Sponsor: University Hospital Tuebingen

 
 
 
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Titel 
„Efficacy of dual-task telerehabilitation to prevent worsening in activities of daily living  
in people with Parkinson’s disease at high risk for dementia: A proof-of-concept study“ 
 
„Wirksamkeit der Dual-Task-Telerehabilitation zum Erhalt der Aktivitäten des täglichen 
Lebens bei Personen mit Morbus Parkinson und hohem Demenzrisiko“ 
 
Version 2 Date: 09.02.2026 
 
Verantwortlichkeiten/Responsibilities 
Ärztlicher Direktor Neurodegeneration: Prof. Dr. Thomas Gasser _____________________________ 
 
Beteiligte an der Studie/Persons involved in the study: 
Prof. PD Dr. Inga Liepelt-Scarfone, Dept. of Neurodegeneration, Hertie Institute for Clinical Brain 
Research (Principal Investigator) _______________________________________________________ 
M.Sc. Merle Bode (Co-Principal Investigator) 
Prof. Dr. Kathrin Brockmann, Dept. of Neurodegeneration, Hertie Institute for Clinical Brain Research 
 
Funding: 
Innovationspreis der Parkinson Stiftung 2025 (Kategorie Klinische Forschung/Category Clinical 
Research) 
 
 
Contact person for the ethic commission: 
Prof. PD Dr. Inga Liepelt-Scarfone 
Abteilung für Neurologie mit Schwerpunkt Neurodegenerative Erkrankungen 
Hertie-Institut für Klinische Hirnforschung 
Universität Tübingen 
Hoppe-Seyler-Straße 3 
72076 Tübingen 
Telefon: 07071 29 80424, Telefax: 07071 29 4490; inga.liepelt@uni-tuebingen.de 

 
 
 
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1. Table of contents
1. 
Table of contents .......................................................................................................... 2 
2. 
List of abbreviations ..................................................................................................... 4 
3. 
Study summary ............................................................................................................. 5 
3.1. 
Background ......................................................................................................... 5 
3.2. 
Preliminary work ................................................................................................ 7 
4. 
Objectives of the study ................................................................................................. 8 
4.1. 
Primary Aim ........................................................................................................ 8 
4.2. 
Secondary Aim .................................................................................................... 8 
4.3. 
Exploratory Aim .................................................................................................. 8 
5. 
Outcomes ...................................................................................................................... 8 
5.1. 
Primary Outcome ............................................................................................... 8 
5.2. 
Secondary Outcome ........................................................................................... 8 
5.3. 
Exploratory Outcome ......................................................................................... 9 
5.4. 
Hypothesis and research questions ................................................................... 9 
6. 
Study population .......................................................................................................... 9 
6.1. 
Inclusion criteria ................................................................................................. 9 
6.1.1. 
Diagnosis of cognitive impairment ..................................................................... 9 
6.1.2. 
Diagnosis of cognitive ADL impairment ........................................................... 10 
6.2. 
Exclusion criteria .............................................................................................. 10 
6.3. 
Sample size ....................................................................................................... 11 
6.4. 
Recruitment ...................................................................................................... 11 
6.4.1. 
Anonymous Pre-Screening procedure ............................................................. 11 
6.5. 
Patient reimbursement .................................................................................... 12 
6.6. 
Insurance .......................................................................................................... 12 
7. 
Methods ...................................................................................................................... 14 
7.1. 
Study design ..................................................................................................... 14 
7.2. 
Randomization and blinding ............................................................................ 14 
7.3. 
Study procedure ............................................................................................... 14 
7.4. 
Assessments for study visits ............................................................................. 15 
7.4.1. 
Screening .......................................................................................................... 15 
7.4.2. 
Assessments of study participants ................................................................... 15 
7.4.2.1. 
Clinical assessments ......................................................................................... 15 
7.4.2.2. 
Biomarker assessment ..................................................................................... 16 
7.4.2.3. 
Retrospective assessments .............................................................................. 16 
7.4.2.4. 
Neuropsychological assessments ..................................................................... 16 
7.4.3. 
Informant ADL assessments ............................................................................. 17 
7.4.4. 
Assessments of training motivation and satisfaction with training ................ 17 
7.5. 
Intervention ...................................................................................................... 17 
7.6. 
Timeline of study assessments and procedures .............................................. 18 
7.7. 
Study duration .................................................................................................. 18 
8. 
Radiation application ................................................................................................. 18 
9. 
Benefit-risk assessment .............................................................................................. 18 
9.1. 
Individual benefit of study participation/statement for cost-benefit analysis 18 
9.2. 
Risks and possible adverse events ................................................................... 19 
9.2.1. 
Clinical assessments ......................................................................................... 19 

 
 
 
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9.2.2. 
Biomarker sampling ......................................................................................... 19 
9.2.3. 
Neuropsychological testing .............................................................................. 19 
9.2.4. 
Informant ADL Assessments ............................................................................. 19 
9.2.5. 
Assessments of satisfaction with training ........................................................ 19 
9.2.6. 
Intervention ...................................................................................................... 19 
9.3. 
Criteria for study termination .......................................................................... 20 
9.3.1. 
Criteria for terminating study participation of individual study participants .. 20 
9.3.2. 
Criteria for termination of the whole study ..................................................... 20 
10. 
Biometrics ................................................................................................................... 22 
10.1. 
Study outcomes ................................................................................................ 22 
1.1. 
Sample size calculation .................................................................................... 22 
1.2. 
Statistical analysis ............................................................................................. 22 
10.3.1. 
Between group comparison ............................................................................. 22 
10.3.2. 
Efficacy of intervention ..................................................................................... 23 
10.3.3. 
Safety, feasibility and satisfaction of intervention ........................................... 23 
10.3.4. 
Between group comparison of PDD conversion at 12-months follow-up ........ 23 
10.3.5. 
Prediction of responsiveness to treatment ...................................................... 23 
11. 
Data management and protection ............................................................................. 23 
11.1. 
Data collection .................................................................................................. 23 
11.2. 
Which data are collected; is it possible to identify the donor? ....................... 24 
11.3. 
Transfer of data to collaboration partners ...................................................... 24 
11.4. 
Image and sound recordings ............................................................................ 24 
11.5. 
Withdrawal of study participation ................................................................... 24 
11.6. 
Period of data storage ...................................................................................... 24 
11.7. 
Erasure of personal data .................................................................................. 25 
12. 
Telemedical Assessment ............................................................................................ 25 
12.1. 
Data Registration .............................................................................................. 25 
12.2. 
Software information, certificate, producer .................................................... 25 
12.3. 
Contraindication and risk for product use ....................................................... 25 
12.4. 
Datatransfer, Data storage, Authorized access, Encryption type, deletion ..... 26 
12.5. 
Temporary Access Link to the program ........................................................... 27 
13. 
Biomaterial ................................................................................................................. 27 
13.1. 
Type of Biomaterial and Responsibilities ......................................................... 27 
13.2. 
Storage of biomaterial ...................................................................................... 28 
13.3. 
Withdrawal of Consent .................................................................................... 28 
13.4. 
Biobank Storage ............................................................................................... 28 
14. 
Attachments ............................................................................................................... 28 
15. 
Reference list .............................................................................................................. 29 

 
 
 
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2. List of abbreviations 
 
ABC-PD 
Amyloid-Beta in Cerebrospinal Fluid as a Risk Factor for Cognitive 
Dysfunction in Parkinson’s Disease 
ADL 
 
Activities of Daily Living 
Bayer ADL  
Bayer Activities of Daily Living Scale 
BDNF  
Brain-derived neurotrophic factor 
CT 
 
Cognitive Training 
CMT 
 
Control Motor Training 
CONSORT 
Consolidated Standards of Reporting Trials  
DCT 
 
Dual Cognitive Training 
FAQ 
 
Pfeffer Functional Activities Questionnaire 
GDS 
 
Geriatric Depression Scale 
HRQL  
Health related quality of life  
MDS-UPDRS-III Movement Disorder Society Unified Parkinson’s Disease Rating Scale 
MoCA  
Montreal Cognitive Assessment 
NFL 
 
Neurofilament light chain protein 
PD  
 
Parkinson’s Disease 
PD-CN  
Parkinson’s Disease with Normal Cognition 
PDD 
 
Parkinson’s Disease Dementia 
PD-MCI  
Parkinson’s Disease with Mild Cognitive Impairment 
PDQ39  
Parkinson’s Disease Questionnaire 
PwPD  
People with Parkinson’s Disease 
RBANS  
Repeatable Battery for the Assessment of Neuropsychological Status 
UKT 
 
Universitätsklinikum Tübingen 
MDS-UPDRS 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale  
SWE 
 
Skala zur Allgemeinen Selbstwirksamkeitserwartung  
WIE 
 
Wechsler Intelligenztest für Erwachsene 
 
 

 
 
 
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3. Study summary 
3.1. Background 
Approximately 60% to 83% of people with Parkinson’s Disease (PwPD) develop dementia 
during the course of their disease [1], leading to devastating consequences for affected 
persons and caregivers [2]. Therefore, preventing Parkinson’s disease dementia (PDD) seems 
one of the biggest challenges in Parkinson’s Disease (PD), but so far effective interventions to 
delay conversion to PDD are lacking. The stage of mild cognitive impairment (PD-MCI) can be 
defined as the intermediate stage of cognitive dysfunction between normal cognitive function 
and dementia [3], affecting around 40-50% of PwPD after 5 years [3-5]. However, PD-MCI is a 
heterogeneous concept; while only around on third of PwPD with PD-MCI progress to PDD, 
others remain cognitively stable or even revert to normal cognition [6]. This heterogeneity 
poses a challenge for clinical care as interventions must start at a point where both objective 
PDD risk and patients’ needs converge. However, as only a small proportion of PwPD with PD-
MCI progress to PDD, additional markers are needed to identify those persons at high risk of 
developing PDD in the near future. 
The fundamental feature differentiating PwPD with PDD from those PD-MCI is the loss of the 
ability to perform activities of daily living (ADLs) [7], which includes basic ADLs such as dressing 
or bathing to complex instrumental ADLs such as shopping or managing medication [8]. While 
PwPD maintain their basic ADL skills longer during their disease course, they report problems 
in more complex ADL skills - even in mild stages of cognitive decline [9]. About 30%-50% of 
patients with PD-MCI already report first signs of ADL problems [10, 11], and complex ADL 
impairment worsens during the transition phase from PD-MCI to PDD [12]. Recently, we found 
that early signs of complex ADL problems related to cognitive impairment (cognitive ADL) 
increased the risk for the development of PDD within study period [13]: almost half (47.6%) 
of PwPD with PD-MCI who had cognitive ADL impairment converted to dementia within three 
years [13]. Therefore, people with PD-MCI and complex ADL problems associated with 
cognition may be a promising target group for interventions, as they are a high-risk group for 
serious and rapidly progressive cognitive deterioration.  
Most important, self-determination is a basic human need [14] and PwPD with ADL 
impairment report shame and self-stigma, often leading to withdrawal from activities [15, 16]. 
Therefore, PwPD wish to maintain their independence in life as long as possible [17]. To date, 
no pharmacological intervention for both treatment of cognition and ADLs indicative of 
dementia is available in PwPD with PD-MCI [18-21]. Hence, the value of non-pharmacological 
interventions for the treatment of cognitive impairment in the prodromal stage of PDD is 
increasingly recognized [12]. Digital cognitive trainings (CTs) have been shown to improve 
cognition as assessed by cognitive tests [22], but their positive effect on complex ADLs are 
only sparsely investigated in PwPD [23-26]. It should also be noted that treatment-induced 
changes in complex ADLs are rarely considered a primary outcome. Currently, no study has 
examined the effects of digital CT on prolonging the transition time from PD-MCI to PDD. 

 
 
 
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Participants often have to travel long distances to attend on-site training. Travelling alone is 
particularly challenging for PwPD at high risk of PDD conversion, since travelling is a cognitively 
complex ADL [41], which is expected to be impaired in this high-risk group. Travel difficulties 
limit access to healthcare, making PwPD dependent on support from relative, increasing the 
burden on patients and their caregivers. Telerehabilitation has recently been discussed as a 
feasible and effective treatment solution for overcoming this limitation [11]. The success of 
unsupervised home-based interventions may be hindered by patients’ insecurity to exercise 
on their own [27, 28]. However, first studies in PwPD have shown acceptance (drop-out rate 
<15%) and feasibility of home-based digital CTs in PwPD [29], positively impacting cognition 
[23, 24, 26, 29, 30], but showing only minor improvements in ADLs [24, 26].  
Ideally, an economic and low-threshold multidomain intervention combining lifestyle factors 
such as physical activity, nutrition and cognitive activities should be used to increase one’s 
odds of preventing cognitive decline and future dementia [31]. Many ADLs require motor-
cognitive function, as individuals must simultaneously coordinate motor and cognitive actions 
[32, 33]. For instance, the ADL of cooking involves actions such as monitoring the stove, while 
keeping track of time, and chopping ingredients. PwPD must often perform each of these, 
previously habitual actions, intentionally and consciously because of the deterioration in 
motor automaticity that occurs with basal ganglia impairment [34]. PwPD, in particular those 
with PD-MCI, show deficits in motor-cognitive function [35], and they also show impaired 
attentional-control (attention and executive function) [36]. This is problematic because 
attentional control is needed for compensation of deteriorated motor automaticity [37, 38]. 
Consequently, impaired attentional control is related to poor performance in ADL tests in 
PwPD with PD-MCI [36, 39] and with motor tasks in PwPD [40, 41]. Because attentional-control 
impairments are also linked to an increased risk of falling, PwPD tend to practice especially 
challenging everyday situations less often [35, 42]. This vicious cycle emphasizes the 
importance of treatments to improve and maintain motor-cognitive function, and hence ADL 
function. Dual-task cognitive training, which combine cognitive and motor exercises in 
trainings shows great potential, as they have been demonstrated to improve motor-cognitive 
task coordination and to enhance attentional-control [43-45]. First evidence verified that an 
on-site dual task cognitive training (DCT) enhances ADL function in PwPD [46], and that 
improvements in executive functions (one component of attentional control) are associated a 
measurable change in home-based physical activity in PD-MCI [47], implicating a direct 
consequence on persons everyday behavior due to training [47]. To the best of our knowledge, 
no home-based digital DCT with the primary aim to enhance cognition and/or complex ADLs 
in PwPD has been conducted. 
A recent feasibility study presents a solution for this problem [48]. In a small sample of non-
demented PwPD, a supervised DCT on a bicycle ergometer showed encouraging results in 
improving physical and cognitive function. This on-site concept could be adapted as a safe and 
practical method for incorporating dual-tasking exercises into home-telerehabilitation. 

 
 
 
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Therefore, we propose a safe and novel leg-strengthening DCT, specifically designed for PwPD 
with the high-risk profile who may otherwise fall through the net of healthcare. 
Cognitive motor rehabilitation has been shown to provide some of the most effective motor 
improvements in PwPD [34]. Based on previous results, our DCT has the potential to improve 
objectively measured physical activity, such as leg-strength [47, 49]. This is of utmost 
importance as, besides cognitive impairment [12], motor symptoms especially problems in 
gait, also negatively affect ADL function in PD [50-56]. Improving motor-cognitive aspects of 
ADL impairment and leg-strength may increase PwPDs’ ability and self-confidence to engage 
in different ADL actions. This translates into measurable changes in daily movement patterns.  
To date, insight into the pathomechanisms of treatment effects that reflect a person's 
resilience to dementia is urgently needed. Biomarkers may be promising to evaluate short- 
and long-term effect of treatments on ADLs. The neurofilament light chain protein (NFL) was 
recommended to assess the efficacy of neuroprotective interventions in PD [57]. First data 
suggest that behavioral interventions, such as exercise can lower NFL levels in non-PD cohorts 
[58]. In PwPD, ADL impairment especially in early stage of deterioration was linked to higher 
NFL levels [59-61] (see section preliminary work). Apart from NFL, reduced levels of the brain-
derived neurotrophic factor (BDNF) are linked to increased dopaminergic neurodegeneration 
[62] and lower cognition in non-demented PwPD [63-65]. Accordingly, increased BDNF levels 
in PwPD have been reported after CT [66] and DCT [67].  
3.2. Preliminary work 
As an import premise of the proposed study, we confirmed that PwPD with PD-MCI and 
cognitive ADL impairment are at high risk for PDD [13]. Further data of our team indicate that 
higher cerebrospinal fluid NFL values were associated with complex ADL function in non-
demented PwPD [61], supporting the potential of this biomarker to reflect improvement in 
ADLs. Especially, motor associated ADL in early stages of cognitive impairment were 
correlated to NFL values. In addition, memory domain impairment did correlate with NFL 
levels in these PwPD. Therefore, our data are in accordance with previous reports of an 
association of NFL with markers for motor symptoms (assessed by the Movement Disorder 
Society Unified Parkinson’s Disease Rating Scale, MDS-UPDRS-III [60, 68], global cognitive 
symptoms [68-71] and morbidity milestones [72]. 

 
 
 
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4. Objectives of the study 
The primary focus of the proposed intervention trial is to enhance cognition and ADL function 
through a telerehabilitation DCT in the long-term. The trial will include a homogeneous group 
of PwPD with PD-MCI and cognitive ADL impairment assessed by the patient rated cognitive 
score of the Pfeffer Functional Activities Questionnaire (FAQ).  
4.1. Primary Aim 
Specifically, this project will define efficacy of a standardized motor-cognitive dual-task 
telerehabilitation training (DCT) vs. an active control motor training (CMT) in PwPD with PD-
MCI to improve ADLs and cognition (especially attentional control).  
4.2. Secondary Aim 
The efficacy of the DCT vs. an active CMT to improve health related quality of life (HRQL) after 
intervention will be the secondary outcome. Safety and feasibility of the intervention will be 
another secondary outcome. Most importantly, we will evaluate if the DCT can prevent further 
decline in cognition and ADLs and maintain HRQL in the long-term, and identify markers 
(social-demographic, clinical, biomarkers) predicting positive treatment response.  
4.3. Exploratory Aim 
Conversion to PDD (exploratory outcome) will be assessed 12 months after baseline 
assessment. Responsiveness of treatment of participants will also be explored.  
 
5. Outcomes  
Table 1 gives an overview of study assessments at each clinical visit. 
5.1. Primary Outcome 
Primary outcomes for the evaluation of treatment effects will be the informant rated 
cognition score of the FAQ [73] and the motor-auditory Stroop task [74]. The task involves 
participants walking while giving spoken responses to the words “high” and “low”. The words 
are delivered with congruent and incongruent tones  
5.2. Secondary Outcome 
Secondary outcomes will include (i) composite neuropsychological test performance (z-score), 
the (ii) total score in the Montreal Cognitive Assessment (MoCA) [75], (iii) the Bayer Activities 
of Daily Living Scale (Bayer ADL scale, [76]) (supplemented by the frequency of the individual 
activities), the informant ratings in the (iv) FAQ total and motor score [73], (v) HRQL 
(Parkinson’s Disease Questionnaire, PDQ-39 [77]), (vi) general self-efficacy scale (GSE) [78], 
(vii) Chair Stand Test (viii), Timed-up-and-go-test (ix), NFL (x), and BDNF (xi). The composite 
score of neuropsychological performance will be calculated as mean z-score of tests assigned 
to the following domains: executive function, attention, memory, language, and visuo-spatial 
abilities.  

 
 
 
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5.3. Exploratory Outcome 
Conversion to dementia will be a further outcome for the 12-month follow-up, verified by 
Level II testing (see section 6.1.1 for details). The identification of markers predicting long-
term outcome at time of pre-test as another exploratory outcome.   
5.4. Hypothesis and research questions 
We hypothesize a significant improvement in the informant rated cognitive ADL performance 
and cognition, especially attentional control (the motor-auditory Stroop task), and in 
participants assigned to the DCT compared to the CMT after training (short term effects). 
Impairment of both cognition and ADL lowers HRQL in PwPD [79, 80]. As our DCT is designed 
to improve ADL and cognition, we anticipate that this training will have a superior effect on 
improving HRQL than the CMT. We hypothesize that PwPD assigned to the DCT will show 
better ADL and cognitive performance after 12 months (long-term effects) compared to the 
CMT. As an exploratory finding, we expect fewer PDD converters in DCT participants than in 
CMT participants.  
 
6. Study population 
PwPD with PD-MCI (see section 6.1.1 for details of cognitive diagnosis) and cognitive ADL 
impairment will be included.  
6.1. Inclusion criteria 
- PD diagnosis confirmed by a neurologist 
- PD diagnosis at least for one year 
- Age between 51-80 years 
- German as their mother tongue 
- Diagnosis of PD-MCI according to the Level II criteria of the Movement Disorder Society 
(MDS, see section 6.1.1 for details of the diagnostic process) 
- Cognitive ADL impairment as defined by the FAQ quotient (see section 6.1.2 for details) 
- An informant who has given consent to provide information about the participant's 
activities of daily living (ADLs) and who lives in the participant’s home. 
- Access to a WIFI Network at home 
- Unimpaired or corrected vision and hearing 
- Appropriate text comprehension and reading ability 
- Ability to communicate well with the investigator, to understand and comply with the 
requirements of the study 
- Provide written informed consent to participate in the study and understand the right to 
withdraw consent at any time without prejudice to future medical care 
 
6.1.1. Diagnosis of cognitive impairment 
Patients will be classified as PD-MCI according to Level-II Movement Disorder Society 
recommendations if cognitive impairment  is present but does not significantly interfere with 
everyday function [81]. Patients will be classified as PDD according to Movement Disorder 

 
 
 
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Society Task Force criteria [7] if cognitive impairment is present and severe enough to impair 
ADL function unrelated to motor or autonomic symptoms and at least one behavioral 
symptom is present to support diagnosis. Cognitive impairment will be defined according to 
Level-I (impairment of global cognition) for patients with minimal assessments, or Level-II 
(performance below 1.5 standard deviation of the population mean reported in the test 
manuals on at least two tests) for patients assessed using a full cognitive battery. Patients not 
meeting either of the diagnostic criteria will be classified as PD-CN.  
6.1.2. Diagnosis of cognitive ADL impairment 
The self-rated Functional Activities Questionnaire (FAQ) [73] is used to define cognitive ADL 
function. The FAQ consists of 10 items asking about the ability to perform ADL tasks (ranging 
from “normal or never did but could do now” to “dependent”). The FAQ allows the 
differentiation between ADL impairment associated with cognition (FAQ cognition) and ADL 
impairment associated with motor ability (FAQ motor). A quotient of both scores (FAQQ) > 
1.008, indicating more cognitive- than motor-driven ADL impairment, is used as cut-off to 
differentiate between PD-MCI patients with and without cognitive-driven ADL impairment. 
6.2. Exclusion criteria 
- Diagnosis of PDD 
- Intake of anti-dementia drugs 
- Deep brain stimulation 
- History of brain disease other than PD (e.g. head trauma, stroke, encephalitis) also 
including muscular diseases (e.g. myestenia gravis or myopathy) 
- Pre-existing condition that limits limb movement (e.g. muscular injuries, knee and hip 
disorders 
- severe cardiovascular diseases with heart failure 
- severe respiratory diseases (e.g. asthma and lung disease) 
- severe other accompanying illnesses with impairment of lung function  
- renal insufficiency 
- acute stage of infectious disease 
- acute stage of cancer 
- other disease with pronounced physical weakness 
- History of brain disease other than PD, e.g., head trauma, stroke, encephalitis 
- Alcohol, medication, or drug dependency or abuse (except for nicotine) 
- Signs of severe depression indicated by either the 15 item version Geriatric Depression 
Scale (> 5 points)  
- Acute psychosis 
- Any disability or issues that may prevent the subject from completing the informed 
consent form or other study requirements 
- Other neurodegenerative disease which renders the subject unable to communicate 
well with the investigator or to understand and comply with the requirements of the 
study 
- Participation in any clinical investigation of a new compound or therapy within 4 weeks 
prior to baseline visit, and any other limitation of participation based on local 
regulations 
Eligibility for the study will be assessed by a study physician. Eligibility can also be determined 
by a general practitioner or a licensed specialist. 

 
 
 
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6.3. Sample size  
As described in Section 10.2, the sample size analysis indicates that 42 people (21 in each 
intervention group) with PD-MCI and cognitive ADL impairment should be recruited. In our 
recent study [13], out of 216 PwPD, 29 (13.4%) were classified as having PD-MCI with 
cognitive-driven ADL impairment, which was 32.6% of PD-MCI patients.  
6.4. Recruitment 
To end-up with 42 PwPD with PD-MCI (21 per treatment group), 312 PwPD need to be 
screened, estimated based on our prevalence rates for PD-MCI in previous cohorts [36]. 
Patients are recruited from the Parkinson's outpatient clinic in the Department of 
Neurodegenerative Diseases and on the Parkinson's ward. Around 1200 PwPD are treated 
annually in the university hospital of Tübingen. Between March 30th, 2014 and December 
31th, 2017, we recruited a large cohort of 268 PD patients within the frame of the” Amyloid-
Beta in cerebrospinal fluid as a risk factor for cognitive dysfunction in Parkinson’s Disease” 
(ABC-PD, ethic protocol 686/2013B01) study. The last follow-up visit was conducted between 
February 2023 and January 2025 (PRICOG, ethic protocol 702/2022BO1). Participants of the 
study who had consent to be contacted again for study participation offers will be contacted. 
Patients will be contacted either via phone or in written form.  
Based on a previous ethic vote (local ethical number: 199/2011 B01), we are allowed to 
contact patients via (e)-mail and to ask them in their interest to take part in a novel study if 
they have given us previous permission for this procedure. In addition, self-help groups will 
be contacted and infored about the possibility to pre-screen for possible study participation 
(see attachment Promotional material for participation in the anonymous pre-screening and 
study for details). 
6.4.1. Anonymous Pre-Screening procedure 
The anonymous online pre-screening will be conducted using the REDCap online platform 
[82]. This anonymous online pre-screening procedure will assess eligibility for study inclusion. 
Patients can access the platform via an invite link or QR code and fill out the questionnaires 
and provide the necessary information to assess the inclusion and exclusion criteria.  
To protect anonymity, no personally identifiable information such as age or gender is 
collected. Since the REDCap program does not store IP addresses, direct re-identification is 
not possible. The necessary information for pre-screening for study eligibility and screening 
for study participation will include the following questions and assessments: age between 51 
and 80, German as their mother tongue, profession of the physician who made the PD 
diagnosis, alcohol consumption, history of alcohol abuse, drug dependency or abuse (except 
for nicotine), digital short version of the 15-item Geriatric Depression Scale (GDS) and the FAQ. 
Patients who confirm that they are aged 50 years or over, that German is their mother tongue, 
that they have been diagnosed with PD by a neurologist, and that they have no history of 
acute or chronic drug, medication or alcohol abuse or signs of severe depressive symptoms, 
as indicated by a GDS score of ≤5 points and an FAQ score of >1.008, will be eligible for further 
in-house screening. Those who are not eligible to participate in the study will be notified after  

 
 
 
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the survey has been completed. If there are indications that a reason for exclusion exists, the 
person will be informed that they are not suitable for current study participation. Once all the 
data has been entered into the online screening platform, the patient will receive feedback 
informing them that they fulfil the criteria for the in-house secondary screening. The contact 
details of the study team will also be provided. Patients who are eligible for secondary 
screening will have the opportunity to contact the study team via email to arrange a further 
screening appointment. It is not possible to contact the person who conducted the survey...  
6.5. Patient reimbursement  
No reimbursement is provided for online pre-screening or in-house pre-screening. Patients 
are reimbursed with 20€ for the in-house screening visit (limited to 52 subjects) and with 50€ 
for the pre-test, post-test and the follow-ups at 6 and 12 months.  
6.6. Insurance  
The study will be covered by clinical trial insurance, which will cover any consequential 
damage resulting from the study procedures. The insurance also includes travel accident 
cover. Please see the attached insurance offer. 
Insurance Provider: HDI Global SE 
Insurance Number Policy: 5701031103013 
Insurance Period: 23.12.2025 – 01.10.2027 
Name and address of the insurance company: HDI Global SE, HDI-Platz 1, 30659 Hannover 
Deutschland, E-Mail: info@hdi.global 
 
 
 
 

 
 
 
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Table 1. Overview of study assessments per visit 
FUNCTION 
ASSESSMENT 
STUDY VISIT 
TIME 
 
 
SCRENNING 
PRE-TEST 
POST-TEST 
FOLLOW-UP 1 
(6 months) 
FOLLOW-UP 1 
(12 months) 
(min) 
 
 
T-1 
T0 
T1 
T2 
T3 
 
Demographics, history & medication 
 
 
 
 
 
 
Socio-demographic history 
Age 
X 
 
 
 
 
1 
 
Gender 
X 
 
 
 
 
1 
 
Education 
 
X 
 
 
 
3 
 
Occupation 
 
X 
 
 
 
4 
Cognitive reserve 
Lifetime of Experiences Questionnaire 
 
X 
 
 
 
10 
History of PD 
Age at first PD symptom onset 
 
X 
 
 
 
1 
 
Age at diagnosis 
X 
 
 
 
 
1 
 
Family history of PD or dementia 
 
X 
 
 
 
4 
Medication & diseases 
Medication 
 
X 
X 
X 
X 
5 
 
Concomitant diseases 
X 
X 
X 
X 
X 
8 
Safety parameter 
(Severe) adverse events (SAE/AE) 
 
 
X 
 
 
5 
Feasibility parameter 
Investigator feasibility 
 
 
X 
 
 
- 
Satisfaction with training 
Patients questionnaire 
 
 
X 
 
 
5 
Activity of daily living function 
 
 
 
 
 
 
Participants‘ ratings 
Pfeffer Functional Activity Questionnaire (FAQ) 
X 
 
 
 
 
5 
 
Pill-Questionnaire 
X 
 
 
 
X 
8 
Informant ratings 
(modified) Bayer ADL Scale 
 
X 
X 
X 
X 
10 
 
Pfeffer Functional Activity Questionnaire 
 
X 
X 
X 
X 
5 
Cognitive battery 
 
 
 
 
 
 
Global cognition 
Montreal Cognitive Assessment 
Form  
C 
Form 
A 
Form 
B 
Form  
C 
Form 
A 
12 
Executive function 
Lexical fluency (RWT) 
 
Form 
A 
Form 
B 
Form 
A 
Form 
B 
4 
 
modified Wisconsin Card Sorting Test 
 
X 
X 
X 
X 
20 
Attention 
Motor-auditory Stoop Task 
 
X 
X 
X 
X 
6 
 
Digit-Symbol Test (WIE) 
 
X 
X 
X 
X 
6 
 
Number-Letter Sequences (WIE) 
 
X 
X 
X 
X 
8 
Language 
Boston Naming Test (RBANS) 
 
Form 
A 
Form 
C 
Form 
D 
Form 
A 
5 
 
Semantic fluency (RWT) 
 
Form 
A 
Form 
C 
Form 
D 
Form 
A 
4 
Memory 
Word list Learning & Recall (RBANS) 
 
Form 
A 
Form 
C 
Form 
D 
Form 
A 
12 
 
FigureRecall (RBANS) 
 
Form 
A 
Form 
B 
Form  
A 
Form 
B 
8 
Visual-spatial ability 
Figure Copy (RBANS) 
 
Form 
A 
Form 
B 
Form 
A 
Form 
B 
8 
 
Benton Line Orientation 
 
Odd 
Even 
Odd 
Even 
10 
Motor and non-motor symptoms 
 
 
 
 
 
 
Quality of life 
PDQ-39 
 
X 
X 
X 
X 
12 
Depression 
Geriatric Depression Scale (GDS) 
X 
 
 
 
 
5 
 
Beck Depressions Inventory II (BDI-II) 
 
X 
X 
X 
X 
8 
Self-efficiency 
General self-efficacy scale (GSE) 
 
X 
X 
X 
X 
5 
Motor function 
MDS-UPDRS Part III-IV 
 
X 
X 
X 
X 
10 
 
Hoehn & Yahr Scale  
 
X 
X 
X 
X 
4 
 
Chair Stand Test 
 
X 
X 
X 
X 
2 
 
Timed Up and Go Test 
 
X 
X 
X 
X 
4 
Laboratory 
 
 
 
 
 
 
Blood withdrawal 
Neurofilament Light Levels / Brain-Derived 
Neurotrophic Factor 
 
X 
X  
 
X 
10 
 
Proteomics profile 
 
X 
X 
 
X 
Total Time (min) 
41 
208 
196 
176 
194 
 
Legend. X*. Assessments will be included for the definition of the composite score of neuropsychological test performance (z-score). MDS-UPDRS. Movement Disorder Society 
Unified Parkinson’s disease rating scale; PDQ-39. Parkinson’s Disease Questionnaire; RBANS. Repeatable Battery for the Assessment of Neuropsychological Status; RWT. 
Regensburger Wortflüssigkeitstest WIE. Hamburg Wechsler Intelligence test.  
 

 
 
 
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7. Methods 
7.1. Study design 
We will conduct a single-center randomized, controlled non-pharmacological intervention 
trial with pre- (T0) and post (T1)-testing, 6-month (T2) as well as 12-month follow-up (T3) in 
PwPD with PD-MCI and cognitive ADL impairment. A screening visit (T-1) will be conducted to 
verify eligibility of participants for study inclusion. The study will follow the Consolidated 
Standards of Reporting Trials (CONSORT) statement for trials of non-pharmacological 
treatments.  
7.2. Randomization and blinding 
The investigator who will perform the clinical assessments will be blinded to participants’ 
assignment to treatment arms. Participants will be instructed to not inform the investigator 
of the kind of treatment received. After recruitment, all participants will be randomly 
allocated (1:1) to either the DCT or the CMT through a computer program 
(http://www.randomizer.org). 
 
7.3. Study procedure 
An anonymous online pre-screening will be conducted to identify patients eligible for in-house 
screening. Pre-screening is also available for in-house patients who have given consented to 
participate in the study.  
Prior to the respective assessments, every prospective participant will be informed in oral and 
written form about the general goal of the study and how the assessments will be performed. 
In particular, the informed consent form will contain comprehensive information about 
contents, objectives, duration, procedures, voluntariness, and possible risks of the study 
participation. Any kind of questions will be considered and answered. In case of agreement to 
study participation, the participant has to sign two copies of the informed consent form. One 
copy will be given to the participant and the other copy will be stored at the local study centre 
in a separate folder (not in the medical records).  
In addition to the patients, informants will be contacted and interviewed. Therefore, informed 
consent will also be obtained from patients’ informants using a separate informant informed 
consent form. The patients will be asked to choose the caregiver who will then be contacted 
for the informant assessment.  
For patients who participated in the online screening, the online pre-screening survey results 
will be verified. The in-house screening further rule-out study eligibility (see section 7.4.1 for 
details). Patients will be assigned to one treatment after the verification of Level II diagnosis 
of PD-MCI (pre-test visit) status and confirmation of all in- und exclusion criteria. If suitability 
for the study is confirmed by the screening visit, a trial training session with the ergometer 
training in sitting position will be conducted for at least 35 minutes to familiarise potentially 
suitable study participants with the training. During the motor skills trial training, the training 
intensity is determined and the resistance for cycling on the ergometer is set. This resistance 
of the ergometer is kept constant throughout the entire training period. Only participants who 

 
 
 
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report no health issues and feel capable of meeting the demands will be considered for further 
participation. 
Randomised patients will start the home training within ten days (see section 7.5 for details). 
Post-intervention testing (T1) will be scheduled within ten days of the last home training 
session. In addition, the 6-month (T2) and 12-month follow-up (T3) are planned with an 
interval of max +/- 3 weeks around the post-testing date. 
7.4. Assessments for study visits 
The explanation of study requirements and informed consent will be conducted as first 
procedure.  
7.4.1. Screening  
Pre-screening is also available for in-house patients who have given consent to participate in 
the study. For patients who participated in the online screening, the online pre-screening 
survey results will be verified. The in-house screening (expected to be conducted in 42 
participants) further rule-out whether the ADL limitations are so severe that they indicate 
dementia and if the cognitive ADL impairment is related to worsening in global cognition 
assessed by the Montreal Cognitive Assessment (MoCA). Patients who meet the inclusion and 
exclusion criteria for study participation, have a MoCA score of less than 26 points (a Level I 
diagnosis of PD-MCI), an FAQQ greater than 1.008, and no impairment in activities of daily 
living (ADLs) indicative of PDD according to the Pill Questionnaire will qualify for pre-testing. 
7.4.2. Assessments of study participants 
Please see Table 1 for an overview of study clinical scales and questionnaires conducted at 
each visit.  
 
Table 2. Overview of clinical study assessments per visit 
FUNCTION 
ASSESSMENT 
TIME (min) 
Cognitive reserve 
Lifetime of Experiences Questionnaire* 
10 
History of PD 
Age at first PD symptom onset* 
1 
 
Age at diagnosis* 
1 
 
Family history of PD or dementia* 
4 
Medication & diseases 
Medication 
5 
 
Concomitant diseases* 
8 
Safety parameter 
(Severe) adverse events (SAE/AE)* 
5 
Participants‘ ratings 
Pill-Questionnaire 
8 
Motor function 
MDS-UPDRS Part III-IV# 
10 
 
Hoehn & Yahr Scale# 
4 
 
Chair Stand Test 
2 
 
Timed Up and Go Test 
4 
Max. total time for in-house assessment 
38  
Max. total time of assessment, which can be assessed which an additional phone interview 
29  
Total time  
67  
Legend: #: For patients with an appointment in the outpatient clinic data will be assessed within the frame of the clinical 
daily routine; MDS-UPDRS. Movement Disorder Society Unified Parkinson’s disease rating scale. *. Information can be 
assessed within the frame of phone interview 
 
7.4.2.1. 
Clinical assessments  
Table 2 present an overview of planned in-house clinical assessments. If individuals are too 
tired to complete all of the tests, the measurements marked with an asterisk can alternatively 

 
 
 
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be assessed within an additional phone interview (max. total 29 minutes). In the Timed Up 
and Go Test, participants rise from a chair, walk three meters, turn, return, and sit down. In 
the Chair Stand Test, participants perform five sit-to-stand repetitions without arm support. 
Participants satisfaction will be assessed after each training session needing around 5 Minutes 
time.  
 
Table 3. Overview of clinical assessments conducted at home by study patients 
FUNCTION 
ASSESSMENT 
TIME (min) 
Participants‘ ratings 
Pfeffer Functional Activity Questionnaire (FAQ) 
5 
Quality of life 
PDQ-39 
12 
Depression 
Geriatric Depression Scale (GDS)+ (Screening visit) 
5 
 
Beck Depression Inventory II+ 
8 
Self-efficiency 
General self-efficacy scale (GSE) 
5 
Legend: +. Only one of the assessment is used in one study visit. PDQ-39. Parkinson’s Disease Questionnaire.  
 
The questionnaires described in Table 3 will be given to the study participants, who can then 
complete them at home. The patient will only complete the FAQ at the screening visit, when 
the GDS will also be applied. The questionnaire will take a maximum of 25 minutes to 
complete during one study visit. 
7.4.2.2. 
Biomarker assessment  
Fasting before blood sampling is not necessary for biomarker analysis.  
 
Biomarker assessment will contain the following assessment: 
 
 Blood collection 
 
 
 
10 min 
Total time for biomarker sampling:                    10 min 
 
Through venipuncture, the following samples will remain in the Hertie Institute for Clinical 
Brain Research (ethic proposal: 199/2011BO1) until sample analysis (see section 13.4): 
 14 ml of venous blood in 2 à 7 ml Serum tube 
7.4.2.3. 
Retrospective assessments 
Data collected in the clinical routine, e.g., demographics, medication intake, concomitant 
diseases and procedures, disease and motor severity, detailed neuropsychological 
assessments, and detailed non-motor symptom assessments, will be included in the data 
analysis. If these parameters are collected when participating in other observational clinical 
studies, these will also be included.  
7.4.2.4. 
Neuropsychological assessments 
The aim is to diagnose PD-MCI and PDD according to the Level-II recommendations of the 
Movement Disorder Task Force [7, 81, 83]. Therefore, the following five domains (see Table 
1) will be quantitatively assessed using three subtests of the Wechsler Intelligence Test for 
Adults (WIE), the Regensburger Word Fluency Test, the modified Wisconsin Card Sorting Test, 
and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS):  
At least two tests are assigned to each cognitive domain:  
 Executive functions: Lexical fluency (Regensburger Word Fluency Test), modified 
Wisconsin Card Sorting Test 
 Attention: Digit-Symbol Test (WIE), Letter-Number Sequencing (WIE) 

 
 
 
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 Language: Boston Naming Test (RBANS), semantic fluency (Regensburger Word 
Fluency Test) 
 Memory: Delayed Recall (RBANS), Figure Delayed Recall (RBANS) 
 Visuospatial abilities: Copy (RBANS), Benton Line Orientation 
 
The Montreal Cognitive Assessment (MoCA) will serve as global cognitive screening scale. 
Additionally, the German version of the Motor-auditory Stoop Task [74] will be designed. The 
task involves participants walking while giving spoken responses to the words “high” and 
“low”. The words are delivered with congruent and incongruent tones. To avoid learning 
effects parallel version of tests (MoCA, Regensburger Word Fluency Test, RBANS) will be 
included if available (see Table 1).  
7.4.3. Informant ADL assessments 
As independent impression the modified Bayer ADL Scale (10 min) and the informant rated 
version of the FAQ informant questionnaires (5 minutes) will be applied, needing informants 
to be available for at least 15 minutes.  
7.4.4. Assessments of satisfaction with training 
During the intervention period, participants’ motivation will be addressed, as well as the 
importance of exercising at home irrespective of training group. These aspects have been 
reported by professionals as important contributors to compliance with home-based exercise 
[27]. Satisfaction surveys will be administered after each session. 
7.5. Intervention  
For 8 weeks, both DCT and CTM group will train 3 times a week for 30 minutes. Both groups 
will leg-cycle on a bicycle ergometer (e.g., Mini-Ellipsentrainer, aktiv shop GmbH) in a seated 
position. The DCT group will perform the cycling along with CT, while the CMT will only 
perform the cycling exercise. After randomization, which will be conducted at day of pre-test, 
participants will be trained on the use of the ergometer in the clinic. During the trial training 
within the screening, the training intensity is individually determined and the resistance for 
cycling on the ergometer is set. This resistance of the ergometer is kept constant throughout 
the entire training period. 
Adherence and feasibility will be ensured as follows. Ongoing technical assistance will be 
provided, videoconferences will be conducted prior training (1-2 days) to anticipate technical 
problems. To further increase training safety, participants will sit in a comfortable chair during 
the lower limb ergometer training. The seating position will be supervised. After the first 
training session, another video call will be conducted to enquire about difficulties and to 
answer questions. Booster sessions will be provided whenever desired.  
Those assigned to dual task CT will be taught how to handle the tablet computer and to use 
the HeadApp/NEUROvitalis Digital CT (https://www.prolog-shop.de). Each session of the CT 
will consist of three exercises á 10 minutes covering attention, working memory and executive 
function. The program will automatically adapt the difficulty level to participants’ 
performance. A training schedule for each session will be preprogramed, remotely accessible 
and modifiable if needed. At sessions 8 and session 16, the training schedule will be altered 
by changing the cognitive tasks for each cognitive function.  
 

 
 
 
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7.6. Timeline of study assessments and procedures  
An Overview of the timeline of different study phases is presented in Figure 1.  
 
 
Figure 1. Overview of timelines and milestones during the study funding period 
 
7.7. Study duration  
The end of the funding period is 31.08.2027. Based on the project investigator's experience of 
working on similar projects, we anticipate that the final analysis and submission for 
publication will take another year. 
 
8. Radiation application 
Not applicable  
 
9. Benefit-risk assessment 
9.1. Individual benefit of study participation & statement for cost-benefit analysis 
Since the effectiveness of the training has not yet been investigated, the positive effects on 
study participants cannot be anticipated. A comparable study using a DCT on an ergometer 
has so far only been conducted as an in-house training session in a very small study group [48], 
with different outcomes than this study. First evidence has shown that telerehabilitation 
improves cognition in PwPD [23, 24, 26, 29, 30], and online Occupational Therapy program 
can positively affect motor skills, cognitive function, and ADL function in PD patients [84]. 
Patients often have to travel long distances to attend on-site training. Travelling alone is 
particularly challenging for our target group, since travelling is a cognitively complex ADL [41], 
which is expected to be impaired in PwPD with PD-MCI and cognitive ADL impairment. These 
travel difficulties limit access to healthcare, making PwPD dependent on support from relative, 
increasing the burden on patients and their informants. Because our training is a home-
training, requiring no travelling, our training facilitates access to healthcare. Improving motor-
Sep-Nov
Dec
Jan-Feb Mar-May
Jun-Aug
Sep-Nov Dec
Jan-Feb Mar-May
Jun-Aug
contract signed and returned
IRB approval & trial registration 
Design of dual task cognitive training
Design of clinical trial report form & database programming
Training of staff
Recruitment of eligbile patients/screening visit
Baseline tests/ pre-tests
Biomarker collection and processing
Conduction of intervention
Post-tests with assessment of short-term effects
6 moths follow-up  testing for assessment of mid-term effects
12 months follow-up testing for assessment of long-term effects
Data entry 
Analysis of biomaterial 
Statistical analysis of short- and mid-term effects and preparation of 
manuscripts
Statistical analysis of long-term effects and preparation of 
manuscripts
2026
2027
2025
Execution
Analysis
Study 
Phase
Tasks & Milestones
Planning

 
 
 
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cognitive aspects of ADL impairment and leg-strength may increase PwPDs’ ability and self-
confidence to engage in different ADL actions. This translates into changes in daily movement 
patterns. Hence, implementing the DCT at home can help participants in maintaining and 
improving autonomy in daily life. 
In summary, based on the current evidence, we believe that the benefits of participating in 
the study outweigh any potential disadvantages. 
9.2. Risks and possible adverse events  
The potential risks and side effects of participating in the study are described below. In 
general, no negative effects on individuals are known from the use of paper and pencil tests. 
However, there is a risk that individuals with limited resilience may become fatigued during 
the clinical visit. Therefore, care was taken in advance to ensure that only the minimum of 
essential information will be collected, and some of the questions could also be asked during 
a telephone interview. 
9.2.1. Clinical assessments 
The Timed Up and Go and Chair Stand pose minimal to low risk when conducted with 
appropriate supervision and standardized safety protocols. In people with gait instability 
or/and orthostatic dysfunction, the risks potential risks include falling during transfer or/and 
walking. Additionally, risks include vertigo, or fainting. For people with gait instability, the test 
is performed by two investigators to prevent falls and stabilise the patient. Those who 
experience severe difficulties and a fall tendency during the task will not be given the 
opportunity to complete it. The other assessments pose no relevant risk.  
9.2.2. Biomarker sampling 
The amount of blood intended to be taken (2x 7 ml serum blood) is harmless to health. 
Venipuncture is usually well-tolerated and rarely associated with complications. However, at 
the site of injection, it may cause symptoms such as local pain, small bruises, induration, and 
dizziness a. In rare cases infection, phlebitis (thrombophlebitis), a thrombosis, or it can wash 
away the smallest blood clots (embolisms) and small scars on the site of injection. Circulatory 
reactions (so-called vagovasal reactions) can also occur. In very rare cases abnormal 
sensations around the puncture due to unintentional nerve injury (median nerve in some 
cases with long-lasting sensory and motor deficits). 
9.2.3. Neuropsychological testing 
No relevant risk.  
9.2.4. Informant ADL Assessments 
No relevant risk.  
9.2.5. Assessments of training motivation and satisfaction with training 
No relevant risk.  
9.2.6. Intervention 
During the lower limb ergometer training, participants will sit in a comfortable chair. 
Therefore, risk for falls is minimized. Informants will be instructed to supervise participants 
seating position according to the instructor’s recommendation. Regarding the DCT, the 
computer tablet is stabilized on the arm by a specialist holder. This holder allows the 
participants to perform cognitive tasks in a comfortable sitting position. Therefore, we 

 
 
 
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expected minimal safety risks for our study participants. However, it is possible for 
participants to overexert themselves during training, especially if the training is repeated on 
several consecutive days. The individual resistance level of the machine will be determined 
on-site during a supervised trial session and should not result in any visible strain after 30 
minutes. The determined resistance level will be kept constant throughout the training period. 
In principle, it is possible that test subjects might not release the foot strap of the ergometer 
and therefore injure themselves. To minimize the risk of injury, we recommend wearing sturdy 
(sports) shoes during the training. 
9.3. Criteria for study termination  
9.3.1. Criteria for terminating study participation of individual study participants 
Participants can withdraw from the study at any time, for any reason or no reason. No written 
statement is required. A verbal statement is sufficient. Participants will be excluded from the 
study if they develop any of the conditions listed in the exclusion criteria before completing 
the post-test. If any of these conditions develop after the post-test but before the follow-up 
examinations, the respective participant will not be asked to undergo further testing. 
9.3.2. Criteria for termination of the whole study 
The study will be terminated if it is not possible to recruit at least 20% of the calculated sample 
size of study participants, even if a sufficient number (> n= 60) of PwPD with PD-MCI and 
cognitive ADL impairment are identified and contacted for study participation. This would 
suggest that there is no need for our training. Another reason for terminating the study is if 
more than 75% of people PwPD randomised to the intervention group drop out. This would 
mean that it would not be feasible to conduct our telerehabilitation for study participants.  
 
 
 

 
 
 
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Table 4. Overview of primary and secondary study outcomes and predictors  
FUNCTION 
ASSESSMENT 
OUTCOME 
 
 
 
PRIMARY 
SECONDARY 
PREDICTOR 
 
 
 
 
 
Socio-demographic history 
Age 
 
 
X 
 
Gender 
 
 
X 
 
Education 
 
 
X 
 
Occupation 
 
 
X 
Cognitive reserve 
Lifetime of Experiences Questionnaire 
 
 
X 
History of PD 
Age at first PD symptom onset 
 
 
X 
 
Age at diagnosis 
 
 
X 
 
Family history of PD or dementia 
 
 
X 
Medication & diseases 
Medication 
 
 
X 
 
Concomitant diseases 
 
 
 
Safety parameter 
(Severe) adverse events (SAE/AE) 
 
 
X 
Feasibility parameter 
Investigator feasibility 
 
X 
 
Satisfaction with training 
Patient‘s questionnaire 
 
X 
 
 
 
 
 
 
Informant ratings 
(modified) Bayer ADL Scale 
 
X 
 
 
Pfeffer Functional Activity Questionnaire 
X 
 
 
 
 
 
 
 
Global cognition 
Montreal Cognitive Assessment 
 
X 
 
Executive function 
Lexical fluency (RWT) 
 
X* 
X* 
 
modified Wisconsin Card Sorting Test 
 
X* 
X* 
Attention 
Motor-auditory Stoop Task 
X 
 
 
 
Digit-Symbol Test (WIE) 
 
X* 
X* 
 
Number-Letter Sequencing (WIE) 
 
X* 
X* 
Language 
Boston Naming Test (RBANS) 
 
X* 
X* 
 
Semantic fluency (RWT) 
 
X* 
X* 
Memory 
Word list learning & Recall (RBANS) 
 
X* 
X* 
 
Figure Recall (RBANS) 
 
X* 
X* 
Visual-spatial ability 
Copy (RBANS9 
 
X* 
X* 
 
Benton Line Orientation 
 
X* 
X* 
 
 
 
 
 
Quality of life 
PDQ-39 
 
X 
 
Depression 
Beck Depressions Inventory II (BDI-II) 
 
 
X 
Self-efficiency 
General self-efficacy scale (GSE) 
 
X 
X 
Motor function 
MDS-UPDRS Part III-IV 
 
 
X 
 
Hoehn & Yahr Scale  
 
 
X 
 
Chair Stand Test 
 
 
X 
 
Timed Up and Go Test 
 
X 
 
Laboratory 
 
 
 
 
Blood withdrawal 
Neurofilament 
Light 
Level/ 
Brain-Derived 
Neurotrophic Factor 
 
X 
 
 
Proteomics profile 
 
 
X 
Legend. X*. Assessments will be included for the definition of the composite score of neuropsychological test performance 
(z-score). PDQ-39. Parkinson’s Disease Questionnaire; Repeatable Battery for the Assessment of Neuropsychological Status. 
RWT. Regensburger Wortflüssigkeitstest; WIE. Hamburg Wechsler Intelligence test. 
 
However, an undersample would require adjustments to the analytical procedures (e.g. the 
calculation of effect sizes) and will be conducted at least on a descriptive level also with this 

 
 
 
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very small sample size. However, we expect the greatest gain in information after a study 
discontinuation to come from the publication of the low feasibility and low acceptance of 
the training in our target patient group. Due to the limited number of studies, we believe 
that the results of our training study still provide valuable additional knowledge. 
 
10. Biometrics 
This section describes the sample size analysis and the statistical procedure used to test the 
questions and hypotheses. 
10.1. 
Study outcomes 
An overview of the parameters used as primary, secondary, and exploratory endpoints is 
provided in Table 4. For primary and secondary outcomes change in the DCT compared to the 
CMT (group x time interaction) will be defined. The composite score of neuropsychological 
performance will be calculated as mean z-score of tests assigned to the following domains: 
executive function, attention, memory, language, and visuo-spatial abilities.  
Feasibility of the investigator includes a comparison of the total number of treatment sessions 
between groups during the intervention period, the total time of the intervention in minutes, 
the quotient of the total intervention time per participant by the maximum required 
treatment time, the number of participants lost to follow-up between randomization and the 
post-test, and the reason for dropping out of the study. 
The number of PwPD with diagnosis of PDD at 12-month follow-up will for each study group 
will serve as exploratory outcome. Table 4 indicates possible predictors for response to 
treatment.  
10.2. 
Sample size calculation 
The required sample size was calculated using G*Power. Medium effect sizes (d=0.56) are 
estimated based on the non-telerehabilitation dual-task cognitive-motor intervention versus 
cycling exercises only in a small sample [48]). Additional, efficacy of a previous 12-week home-
based digital cognitive training  in PD-MCI patients ([29]) also revealed moderate effect sizes 
(g = 0.31). Therefore, an effect size of f=28 were included in the sample size analysis. With a 
power of 80% and an alpha level of 5% for an ANOVA repeated measures within-between 
interaction (drop-out rate of 20% per group) over four time points (correlation among 
repeated measures r=0.40), 21 PwPD per group need to be included.  
10.3. 
Statistical analysis 
Statistical analyses will be conducted using R (https://www.r-project.org/), IBM SPSS Statistics 
(Version 29) and Jasp (https://jasp-stats.org/).  
10.3.1. Between group comparison 
Comparisons are made between the groups in the pre-test for PwPD, who were randomly 
assigned to either the DCT or the CMT, appropriate to the data level. The Mann-Whitney U or 
Mann-Whitney-U or Welch test will be applied for non-parametric numeric data, and the t-
test for independent samples for parametric numeric data. The Χ² test or Exact Fisher Test will 
be applied for between-group comparison of for categorical variables. If the intervention 

 
 
 
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groups differ in their baseline profiles, confounding variables will be included in adjustable 
analyses of treatment effects. 
10.3.2. Efficacy of intervention  
The effect of the intervention on primary and secondary outcome parameters (time [pre-test, 
post-test, follow-up] x group [DCT, CMT] interaction) will be analyzed with ANOVA repeated 
measures within-between interaction or linear mixed effects models to add between-group 
covariates. Participants will be added as random effects and random slopes of time will be 
tested for improved model fit. Bayesian tests will be also calculated (mixed ANOVA for mixed 
model, t-test for post-hoc comparisons).  
If the efficacy analysis of intervention is underpowered due to problems in recruitment effect 
size analysis will be conducted to rate treatment effects.   
10.3.3. Safety, feasibility and satisfaction of intervention  
The feasibility of training will be assessed as number of participants undergoing 
randomization/ number of participants undergoing post assessment as well as the difference 
between the total maximum recommended training time and the actual training time 
performed by each participant. Additionally, learning rate will be assessed by the change in 
the quotient of correct answers to total answers. The elapsed distance in kilometers cycled by 
participants will also be assessed. Safety will be assessed based on the number of adverse 
events. Satisfaction with the training will be assessed using a survey after each session. The 
analysis will include an average of a 6-point Likert scale (1 = “not at all”, 6 = “very satisfied”) 
over items covering various aspects.  
10.3.4. Between group comparison of PDD conversion at 12-months follow-up  
Long-term follow-up status of PDD among study groups will be compared with logistic 
regression models. 
10.3.5. Prediction of responsiveness to treatment  
Exploratory linear regression models will be used to examine the responsiveness to 
intervention (change scores) for possible predictors with forward selection to identify 
variables influencing the responsiveness. To minimize the number of variables into the 
regression models correlation between each single variable and the change score of interest 
will be conducted. Only variables with at least a moderate association with the change score 
(r ≥ 0.30) will be included in the regression models. The change scores will be calculated for 
the following study intervals: between pre-test and post-tests, between pre-test and 6-
months follow-up and between pre-test and 12-months follow-up.  
In addition, the protein profile associated with treatment response will be explored by 
proteomics analysis.  
 
11. Data management and protection 
11.1. 
Data collection 
Data collection and use of personally identifiable information in this study complies with the 

 
 
 
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General Data Protection Regulation (EU) 2016/679. Participants will be given the appropriate 
information on dealing with data collected in the study and asked to sign a separate informed 
consent form concerning data protection.  
11.2. 
Which data are collected; is it possible to identify the donor? 
A list ofparticipants’name, age, and contact data are collected in a separate folder and will be 
stored in a lockable office of the Principal investigator or his/her representative. As a database 
platform, the REDCap electronic data capture tool will be used [82]. The database will be 
secured with password protection, individually assigned to each team member with database 
access. Pseudonymized data will be saved in the database inside the firewall of the medical 
faculty, using a 4-digit number not associated with any demographics of the study participant. 
Thus, the identification of a participant using only the code number is not possible and 
confidentiality will be ensured by use of these identification codes. The informatics manager 
and PIs will only receive coded information that has been entered into the database under 
those identification numbers. Data stored will included the measurements described in Table 
1.  
Electronic communication with outside collaborators will involve only unidentifiable 
information. 
11.3. 
Transfer of data to collaboration partners 
In cooperation with the IB Hochschule für Gesundheit und Soziales Standort Stuttgart, 
Paulinenstr. 45, 70178 Stuttgart, we are planning to share data with students of this private 
University for data analysis reported either as a Bachelor or Master thesis. Only 
pseudonymized data will be transferred.  
If the patient agreed for this procedure, pre-processed blood samples will be transferred to 
- 
Prof. Dr. Andrea Pilotto,  
- 
Digital Neurology and Biosensors Laboratory & Neurobiorepository and Laboratory of 
advanced biofluid markers 
Spedali Civili of Brescia, Brescia, Italy.  
 
Prof. Dr. Andrea Pilotto will conduct Proteomics analysis to identify proteins associated with 
a positive treatment response, especially in the long-term. For this analysis further clinical 
data (e.g. outcome data to define treatment response) will be transferred.  
11.4. 
Image and sound recordings 
Not applicable.  
11.5. 
Withdrawal of study participation 
Participants can withdraw from the study at any time, for any reason or no reason. No written 
statement is required. A verbal statement is sufficient. Participants will be excluded from the 
study if they develop any of the conditions listed in the exclusion criteria before completing 
the post-test. If any of these conditions develop after the post-test but before the follow-up 
examinations, the respective participant will not be asked to undergo further testing. 
11.6. 
Period of data storage 
Data will be stored for 10 years.  

 
 
 
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11.7. 
Erasure of personal data 
Participants have the right to gain information about stored data, to correct false data, to 
demand the erasure of personal data, and to demand the anonymization of their data. The PI 
of the study, Prof. PD Dr. Inga Liepelt-Scarfone (phone: +497071-2980424, fax: +497071-
294490, e-mail: inga.liepelt@uni-tuebingen.de), and the Co-PI M.Sc. Merle Bode (phone: 
+497071-2980424, fax: +497071-294490, e-mail: Merle.Bode@med.uni-tuebingen.de) are 
responsible for the adherence of all law regulations.  
Contact information: Hertie Institute for Clinical Brain Research, Department of 
Neurodegeneration, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. 
 
12. Telemedical Assessment 
12.1. 
Data Registration  
Access to the software program is provided via a tablet. The tablet will be made available to 
the test subjects for the duration of the training. Recommended is the use of Tablets with 
Android operating system from version 9 (Pie API 28, screen size from 10 inches) and Tablets 
with Apple operating system iPadOS 13 (screen size from 9.7 inches).  
We will use the HeadApp/NEUROvitalis Professional Online programm, which enables 
cognitive teletherapy under the supervision of a therapist, without physical contact. 
HeadApp/NEUROvitalis Professional Online can be installed and used on multiple devices, 
including PCs and mobile devices. One license covers the training of up to 10 patients 
exercising simultaneously. 
12.2. 
Software information, certificate, producer 
HeadApp / NEUROvitalis is a class I medical device for the therapy of cognitive impairments. 
HeadApp / NEUROvitalis is software for cognitive rehabilitation therapy / brain performance 
training. The platform provides numerous therapy programs for those affected by cognitive 
impairments in the areas of attention, memory, executive functions and language. The 
software meets all the provisions of the Medical Device Directive MDD (93/42/EEC), which 
apply to it.  
Producer 
HelferApp GmbH 
Zur Klus 31 
39175 Gommern OT Wahlitz 
Tel.: +49 392 00 491 491 
E-Mail: info@helferapp.com 
 
12.3. 
Contraindication and risk for product use  
Patients with impaired vision and reading ability, poor hearing and impaired text 
comprehension and children under 12 years of age should not use HeadApp / NEUROvitalis or 
only use it under therapeutic supervision. 

 
 
 
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No residual risks and undesirable side effects are known when using HeadApp / NEUROvitalis. 
According to IEC 62304, the HeadApp / NEUROvitalis software was classified in safety class A: 
No injury or damage to health is possible.  
The medical device must be used in an environment that avoids distractions and disturbances 
during exercise.  
12.4. 
Datatransfer, Data storage, Authorized access, Encryption type, deletion 
Therapy material is constantly being downloaded from servers on the Internet, and therapy 
progresses are stored on servers. A constant internet connection is necessary for this. A speed 
of at least 4 Mbps is necessary to ensure smooth work. 
If a mobile data connection is used, an average data consumption of 200 Mbit (0.2 GB) per 
patient and month can be expected. 
HeadApp / NEUROvitalis communicates with various web servers via the HTTPS protocol. The 
attached document, 'HeadApp Info Data Protection and Server', provides an overview of all 
the technical and data privacy issues. Figure 2 visualises the data flow. 
The HTTPS connection to the servers described in the document must be allowed in the 
firewall.  
 
 
Figure 2. Overview of data flow using the HeadApp/Neurovitalis 
 
All servers are located in Germany/EU and are rented from Amazon Web Services (AWS) and 
its resellers. AWS guarantees secure data storage in accordance with EU regulations, is 
certified under the EU–US Data Privacy Framework (DPF), and adheres to the DPF principles.  
The user data server uses AES-256 encryption to ensure the highest security for stored data. 
Similarly, data on the therapy data server is encrypted with AES-256 to protect sensitive 
information from unauthorized access. AES-256 encryption is extremely secure. It is currently 
the most secure encryption algorithm available and is widely used in government and military 
applications, as well as by companies in highly regulated industries. The encryption uses a 256-
bit key length, which is considered practically unbreakable—even with the most advanced 

 
 
 
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computational power and algorithms. This provides the same level of security used by banks 
and other financial institutions to safeguard sensitive customer information. Additionally, TLS 
encryption version 1.3 is used for secure data transmission, offering the highest currently 
available security level for Transport Layer Security.  
Participants will log in to the training using a pseudonymised code. During the training period 
of the study, both the study participant and the supervising neuropsychologist will have access 
to the data. Afterwards, the study participant the supervising neuropsychologist can access 
the data at all time. Data will be transferred to the study center every three months as csv file. 
Data will be stored on the HeadApp/Neurovitalis server until the complete dataset has been 
transferred to the study centre. Once this has been done, the data will be deleted from the 
company's server. 
All members of the study team will then have access to the trainings data. The data on the 
server will be deleted once it has been transferred. 
12.5. 
Temporary Access Link to the program 
Download Programm is available under the following link: 
https://www.headapp.com/en/download-en/?td=o 
LogIn Data:  
• 
Login (E-Mail): headapp@uni-tuebingen.de 
• 
Passwort: 72076 
The following access code is valid until 31.12.2025. 
 
First steps with HeadApp: 
- 
Launch HeadApp in your browser at https://start.headapp.com and log in using the 
above credentials for the Professional version. Alternatively, you can download the 
app from the App Store or Play Store. 
- 
You can use the login on multiple devices simultaneously. 
- 
After logging in, you will be taken to the patient list. To start training or screening, 
create a "test patient." 
 
A 
brief 
overview 
and 
decription 
of 
the 
subtests 
be 
found 
via 
this 
link: 
https://www.headapp.com/wp-content/uploads/HeadApp-Klappflyer-A3-innen.pdf.  
Additionally, we attached the manual of the HeadApp/Neurovitalis program including an 
overview of tests.  
 
13. Biomaterial 
13.1. 
Type of Biomaterial and Responsibilities 
Serum BDNF and NFL parameters will be analysed in cooperation of the Neurobiobank of the 
Hertie Institute for Clinical Brain Research and the Neurolaboratory of the 
Universitätsklinikum Tübingen (UKT). A structured and integrated exploration of biomaterial 
in combination with the analysis of the extensive quantitative dataset obtained in this study 
bears the chance for a better molecular, biochemical, and eventually functional understanding 
of one of the most debilitating symptoms associated with PD, i.e., cognitive deterioration. 
Additionally, some biomaterial will be transferred to our collaborator, Professor Andrea 

 
 
 
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Pilotto, for proteomics analysis (see Section 11.3 for details). Proteomics data will be analysed 
as potential predictor for treatment response.  
13.2. 
Storage of biomaterial 
All samples will be stored at -80°C until the time of analysis. To maximize confidentiality, all 
biomarker samples and information associated with the samples will be coded to prevent the 
exposure of the subjects’ information and identity. This coding process allows location and 
destruction of a sample at the subject’s request. In addition, sample information is stored in 
one secured electronic database, while biomarker data is stored in an independently secured 
database on a different computer. No one except the investigators of the UKT will have access 
to the database to deduce the identity of the patient. Samples will be destroyed after analysis 
of BDNF and NFL values. 
13.3. 
Withdrawal of Consent 
The test subject may request the anonymisation or deletion of stored data, as well as the 
destruction of stored biological samples, at any time and without providing reasons. However, 
this only applies if the samples and data have not already been released to other researchers 
or anonymised. 
13.4. 
Biobank Storage 
Sample storage in the Hertie Institute for Clinical Brain Research (ethic proposal: 
199/2011BO1) is only temporary until sample biomarker analysis.  
 
14. Attachments 
See attachments: 
 Patient information sheet and informed consent form 
 Patient data privacy statement 
 Informant information sheet and informed consent form 
 Informant data privacy statement 
 HeadApp Information on Dataprotection and Server 
 Promotional material for participation in the anonymous pre-screening and 
study 
 Insurance offer and insurance conditions 
 
 
 

 
 
 
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