Cognitive-driven ADL Impairment as a Predictor for Parkinson's Disease Dementia (PDD)
Conditions: Parkinson Disease
Sponsor: University Hospital Tuebingen

 
 
 
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Cognitive-driven ADL impairment as a predictor for  
Parkinson’s disease dementia (PDD) 
 
 
Clinical Trial Gov - ID: 284/2018BO1 
 
Corrected version of the study protocol additionally approved by the local Ethics Committee of the 
Medical Faculty of the University of Tuebingen, Version 2 Date: 05.07.2018  
(First version approved by the local ethical committee 12.06.2018) 
 
 
Medical Director Neurodegeneration: Prof. Dr. Thomas Gasser _____________________________ 
 
 
Contributers tot he study:  
PD Dr. Inga Liepelt-Scarfone, Dept. of Neurodegeneration, Hertie Institute for Clinical Brain Research  
Dr. Kathrin Brockmann, Dept. of Neurodegeneration, Hertie Institute for Clinical Brain Research 
M.Sc. Sara Becker, Dept. of Neurodegeneration, Hertie Institute for Clinical Brain Research 
 
Funding: 
The proposed longitudinal follow-up is funded by the Michael J Fox Foundation (Grant ID: 15227); 
Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of 
Tübingen.  
 
 
Contact person for the ethic commission: 
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 .................................................................................................... 3 
3. 
Study summary ............................................................................................................ 4 
3.1. 
Background ......................................................................................................... 4 
3.2. 
Preliminary data ................................................................................................. 4 
4. 
Objectives of the study ................................................................................................ 5 
4.1. 
Hypothesis and research questions ................................................................... 6 
5. 
Study duration ............................................................................................................. 6 
6. 
Study population ......................................................................................................... 6 
6.1. 
Study population ................................................................................................ 6 
6.2. 
In- and exclusion criteria for follow-up assessment .......................................... 6 
6.2.1. 
Inclusion criteria ................................................................................................. 6 
6.2.2. 
Exclusion criteria ................................................................................................ 7 
6.3. 
Recruitment ........................................................................................................ 7 
7. 
Statistics and Sample size estimation.......................................................................... 7 
8. 
Assessments ................................................................................................................. 8 
8.1. 
Retrospective Data ............................................................................................. 9 
8.2. 
Neuropsychological testing ................................................................................ 9 
8.3. 
Comprehensive non-motor symptom assessment and Top-10 Priority List ... 10 
8.4. 
Home-based movement assessment (Accelerometer).................................... 10 
8.5. 
Caregiver ADL assessments .............................................................................. 11 
8.6. 
Biomaterial collection ...................................................................................... 11 
8.6.1. 
CSF and blood collection .................................................................................. 11 
8.6.2. 
Tissue collection ............................................................................................... 11 
8.6.3. 
Analysis of biomaterial ..................................................................................... 11 
8.6.4. 
Storage of biomaterial ...................................................................................... 12 
9. 
Risks and possible adverse reactions, end of the study ............................................ 12 
9.1. 
Neuropsychological testing .............................................................................. 12 
9.2. 
Comprehensive non-motor symptom assessment and Top-10 Priority List ... 12 
9.3. 
Home-based movement assessment (Accelerometer).................................... 12 
9.4. 
Caregiver ADL Assessments ............................................................................. 12 
9.5. 
Biomaterial (Blood and CSF) collection ............................................................ 12 
9.6. 
End of the study ............................................................................................... 13 
10. 
Data protection .......................................................................................................... 13 
10.1. 
Data collection .................................................................................................. 13 
10.1.1. 
Which data are collected; is it possible to identify the donor? ....................... 13 
10.1.2. 
Shall patients be informed about novel scientific findings? ............................ 14 
10.1.3. 
Period of data storage ...................................................................................... 14 
10.1.4. 
Erasure of personal data .................................................................................. 14 
10.2. 
Transfer of data to the Sponsor ....................................................................... 14 
10.3. 
Information and informed consent .................................................................. 14 
11. 
Insurance .................................................................................................................... 15 
12. 
Information text and text of the informed consent .................................................. 15 
13. 
Reference list ............................................................................................................. 15 

 
 
 
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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 
AD 
 
Alzheimer’s Disease 
ADL 
 
Activities of Daily Living 
CERAD  
Consortium to Establish a Registry of Alzheimer’s Disease 
CSF 
 
Cerebrospinal Fluid 
FAQ 
 
Pfeffer Functional Activities Questionnaire 
IQ-CODE 
The Informant Questionnaire on Cognitive Decline in the Elderly 
LPS 50+ 
Leistungsprüfsystem für 50- bis 90-Jährige 
MMSE  
Mini Mental State Examination 
MoCA  
Montreal Cognitive Assessment 
PD  
 
Parkinson’s Disease 
PDD 
 
Parkinson’s Disease Dementia 
PD-CN  
Parkinson’s Disease with Normal Cognition 
PD-MCI  
Parkinson’s Disease with Mild Cognitive Impairment 
PIB 
 
Pittsburgh Compound B, detects parenchymal Amyloid-beta 
RBD 
 
REM(Rapid Eye Movement) Behavior Disorder 
UKT 
 
Universitätsklinikum Tübingen 
UPDRS  
Unified Parkinson‘s Disease Rating Scale 
WIE 
 
Wechsler Intelligenztest für Erwachsene 
 
 
 

 
 
 
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3. Study summary 
3.1. Background 
Presence and severity of non-motor symptoms modulates the rate of Parkinson’s Disease (PD) 
progression with a high impact on patients’ quality of life [1-3]. One major clinical milestone 
in the course of the disease is the conversion to Parkinson’s disease dementia (PDD), 
dramatically increasing the risk for nursing home placement and mortality [4]. One of the 
greatest risk factors for PDD is the development of mild cognitive impairment in PD (PD-MCI) 
[5]. However, only a subgroup (26% to 39.1%) of patients with PD-MCI have been reported to 
convert to dementia, while others present with a stable cognitive status or revert to normal 
cognitive function [6-8]. For an early and effective treatment, the identification of a high-risk 
group for PDD among those with PD-MCI is essential. 
The core feature that differentiates PDD from PD-MCI is the loss of the ability to perform 
activities that are necessary for independent living [9, 10], emphasizing the importance of 
valid and reliable activities of daily living (ADL) assessments in PD [11]. To confirm the 
diagnosis of PDD, ADL disabilities should be primarily caused by cognitive, not motor, 
dysfunction [10, 12]. As PD is primarily a movement disorder, the distinction between motor 
and non-motor contributions to ADL in PD is an obvious challenge [13].  
ADL can be divided into basic (e.g. self-maintenance skills) and instrumental functions (e.g. 
complex skills). Of these, instrumental ADL function is impaired in the earlier stages whereas 
basic ADL can be preserved for a long time [14]. In Alzheimer’s disease (AD), the combination 
of slight ADL impairment and mild cognitive impairment increases the risk for dementia, as 
opposed to the presence of only one of these characteristics [15, 16]. In PD, there is also 
evidence to assume that mild ADL impairments in PD-MCI characterize those patients at high 
risk for PDD, as mild signs of ADL impairment are observed in a subgroup of PD-MCI patients 
as a potential prodromal sign for PDD [14, 17-20]. So far, only a few studies have focused on 
the interaction between cognitive performance and ADL function in PD. First reports indicate 
that the cognitive profile of those PD-MCI patients with and without mild signs of ADL 
impairment does not differ [18, 21]. This implicates that (i.) neuropsychological tests lack 
predictive value for PDD [22, 23], (ii.) the ADL instruments used might not be suitable to detect 
cognitive-driven ADL impairment as they cover the characteristic motor signs of PD, or (iii.) 
sample sizes of previous studies were too small to reveal a between-group effect. Therefore, 
an economic and valid ADL measure for cognitive decline is needed to evaluate the prognostic 
value of mild ADL impairment for PDD conversion. We propose the follow-up of an already 
existing large, non-demented baseline PD cohort to longitudinally investigate the association 
between ADL function and cognitive performance along with blood and cerebrospinal Fluid 
(CSF) biomarker profiles.  
 
3.2. Preliminary data 
Methods. In a cohort of 216 non-demented PD patients (41.2%, with PD-MCI), assessed within 
the frame of the ongoing “Amyloid-Beta in Cerebrospinal Fluid as a Risk Factor for Cognitive 
Dysfunction in Parkinson’s Disease” (ABC-PD) study, we developed a novel quotient score 
from the Pfeffer Functional Activities Questionnaire (FAQ) [24]. The FAQ is a 10 item 
instrumental ADL assessment scored on a 4-point Likert scale ranging from normal (score=0) 
to dependent (score=3) ADL function (max. points 30) [25].  

 
 
 
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The novel FAQ quotient was developed by differentiating cognitive and motor aspects of the 
individual items. Ten linear regressions were conducted defining each FAQ item as the 
dependent variable, and the Unified Parkinson’s Disease Rating Scale-Part III (UPDRS-III), 
motor assessment) as well as the Montreal Cognitive Assessment (MoCA) total score as 
independent variables, with age, sex, and disease duration entered as covariates.  
Results Part 1: Construction of FAQ-Quotient. As a result, the items 1-(accounting for 
finances), 2-(tax/business records) and 9-(remembering important events) showed 
associations with the MoCA score, whereas the items 3-(shopping alone), 4-(skills & hobbies), 
5-(using appliances), 6-(meal preparation), 10-(traveling out of house) were found to be 
significantly associated only with the UPDRS-III score. Item 7-(current events) and 8-
(information intake) were associated with both motor and cognitive function and were 
therefore included into both scores as a constant. Based on the regression analyses, the set 
of items for cognitive function was defined as, Scog = {1,2,7,8,9} while the set of items reflecting 
motor function was defined as Smot = {3,4,5,6,7,8,10}. If Si denotes the score obtained in item 
i for a patient and Si,max denotes the maximum score possible for item i, then the following 
subscores were defined as:  
   𝐹𝐴𝑄𝐶= ∑
𝑠𝑖
𝑠𝑖,𝑚𝑎𝑥
            
𝑖∈𝑆𝑐𝑜𝑔
𝐹𝐴𝑄𝑀= ∑
𝑠𝑖
𝑠𝑖,𝑚𝑎𝑥
𝑖∈𝑆𝑚𝑜𝑡
           𝐹𝐴𝑄𝑄= 𝐹𝐴𝑄𝐶+ 1
𝐹𝐴𝑄𝑀+ 1 
 
 
FAQQ: The quotient was formed by dividing the cognitive aspect (FAQC) by the motoric aspect 
(FAQM); a value >1 (FAQQ>1) indicates more cognitive- compared to motor-related ADL 
impairment.  
Results Part 2: Validation of FAQ-Quotient. Out of the 89 PD-MCI patients, 32.6% presented 
with FAQQ values >1, while 67.4% had an FAQQ ≤1. The frequency of males was comparable 
between both PD-MCI subgroups (FAQQ>1 65.5%, FAQQ≤1 63.3%; p=0.99). Logistic regression 
analyses showed that patients defined as PD-MCI FAQQ>1 were more impaired in tests 
assessing attention/working memory (p=0.033) and language performance (p = 0.019) than 
the PD-MCI FAQQ≤1 group, while motor symptom severity revealed no significant difference 
between groups (p=0.095). Therefore, subgrouping PD-MCI patients according to the 
cognitive and motor performance in the FAQ is suitable for differentiating between different 
levels of severity for cognitive impairment in PD.  
 
4. Objectives of the study 
The FAQ is an economic and easy to apply ADL scale. Items of the FAQ have been previously 
published [25, 26]; details of the construction of our FAQ parameters are currently under 
review for publication and will also be available without additional costs.  
The aim of our project is to evaluate whether the combination of PD-MCI along with cognitive-
driven ADL impairment predicts the future development of PDD and might be able to 
differentiate between those PD-MCI patients with a high risk for the development of PDD from 
those with stable PD-MCI. The identification of a high-risk group for PDD among those with 
PD-MCI is essential for upcoming clinical trials targeting cognitive impairment in its earliest 
stages.  

 
 
 
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4.1. Hypothesis and research questions 
Based on previous reports and preliminary results, we hypothesize that PD-MCI patients 
with a more pronounced cognitive-driven ADL impairment (FAQQ>1) are at higher risk for 
conversion to PDD than PD-MCI patients with ADL impairment primarily related to motor 
function (FAQQ≤1).  
1. Stratification of subgroups according to their baseline cognitive status (PD-MCI vs. 
normal cognition, PD-CN) and ADL function (cognitive-driven (FAQQ>1) vs. motor-driven 
(FAQQ≤1)).  
2. Defining progression of ADL impairment over time. 
Aim 2.1: Evaluation of stability and/or progression of ADL status between baseline and 
follow-up (FAQQ>1 vs. FAQQ≤1). 
3. Evaluation of the interaction between cognition and ADL function over time.  
Aim 3.1: Evaluation of conversion rates to PD-MCI and PDD according to baseline ADL 
status (FAQQ>1 vs. FAQQ≤1).  
Aim 3.2: Prediction of PD-MCI (among PD-CN) and PDD according to baseline ADL, 
cognitive, genetic, and biomarker profiles in blood and CSF.  
Aim 3.3: Progression of decline in cognition and ADL function in relation to Amyloid and 
Tau burden. 
 
5. Study duration 
Total duration of the study is 2 ½ years.  
 
6. Study population 
6.1. Study population 
Between March 30th, 2014 and December 31th, 2017, we recruited a large cohort of 262 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. Of 
the total baseline sample, 43% were diagnosed with PD-MCI (63% males, mean age of 
67.2±7.7 years) whereas 57% had normal cognitive function (61% males, mean age of 65.4±8.7 
years). Mean disease duration of the total sample was 5.1±3.9 years.  
We propose to follow-up the already existing ABC-PD cohort described above with a 
longitudinal assessment including neuropsychological in-depth endophenotyping and CSF 
biomarker analyses. The estimated mean follow-up interval is 46.6±6.6 months. 
 
6.2. In- and exclusion criteria for follow-up assessment 
The investigator will ensure that all patients considered for the study meet the inclusion and 
exclusion criteria described in Sections 6.2.1 and 6.2.2. 
 
6.2.1. Inclusion criteria 
 50 –90 years of age. 
 Diagnosis of PD according to the United Kingdom Brain-Bank criteria. 

 
 
 
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 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 their right 
to withdraw consent at any time without prejudice to future medical care. 
 
6.2.2. Exclusion criteria 
 Any disability 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 investigational compound or therapy 
within 4 weeks prior to baseline visit, and for any other limitation of participation 
based on local regulations. 
 Alcohol, medication or drug dependency or abuse (except for nicotine). 
 History of brain disease other than PD, e.g. head trauma, stroke, encephalitis, etc.  
 
6.3. Recruitment 
Participants of the already recruited ABC-PD cross-sectional cohort (ethic protocol 
686/2013B01) will be asked to participate in the follow-up assessment. Patients who did not 
agree to participate in a longitudinal study or who have asked not to be contacted after the 
first cross-sectional assessment will not be contacted again. A drop-out rate of 20% is 
expected for follow-up retention. Therefore, investigation of 209 patients will be conducted 
between August 2018 and April 2020. During the executive project phase, three patients will 
be assessed weekly (˞12 per month). Patients will be contacted either via phone or in written 
form. Reason for drop-outs will be registered for data analysis. 
 
7. Statistics and Sample size estimation 
The relative risk as well as the positive and negative Likelihood Ratios according to baseline 
group status for conversion to PD-MCI or PDD will be calculated. 
1. 
Between-group differences will be conducted using either a Student’s t-test, analyses of 
variance (ANOVA), or covariance analyses.  
2. 
For longitudinal within-group analyses of cognitive and ADL progression, we will use 
either paired t-tests or repeated ANOVA models. Additionally, Kaplan Mayer survival 
curves and Cox proportional hazard models stratified by the individual group status (e.g. 
PD-MCI with and without cognitive-driven ADL impairment) will be applied to estimate 
the time period to PD-MCI or PDD conversion.  
3. 
Associations between serum and CSF markers along with ADL and cognitive data will be 
carried out using multivariate regression analyses in order to evaluate the type of 
biomarker that best reflects the biological impact on phenotype and progression. 
 
Reports on conversion rates of new-onset PD-MCI and PDD are highly variable between 
studies [5]. At a mean follow-up interval of around four years, the frequency of PDD in large 

 
 
 
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PD cohorts is estimated to vary between 13% [7] and 28% [27], resulting in 27 to 58 patients 
with PDD in the present cohort at follow-up. New-onset PD-MCI is expected to be higher, with 
around 49 (36%) [6] to 107 (78%) cases in our cohort [27]. Of all PD-MCI patients, one-third 
are classified as having cognitive-driven compared to motor-driven ADL impairment, resulting 
in at least 16 to 35 new-onset PD-MCI patients classified as FAQQ>1 [24]. These estimates 
resemble the sample size of our preliminary data described above, for which between-group 
differences have been statistically verified. Therefore, we conclude that moderate to strong 
effects can be detected with 80% power in two-group comparisons.  
 
8. Assessments 
Table 1: Overview of assessments 
Assessment of PD patients 
Time 
Explanation of the study requirements 
10 min 
Demographics & lifestyle 
 
Age, gender, education, occupation, family history of neurodegenerative diseases, 
smoking/drinking behavior, height & weight 
5 min 
Neurological Assessments: 
 
Medication intake, concomitant diseases, and procedures 
10 min 
Unified Parkinson‘s Disease Rating Scale (UPDRS) Parts III-IV, Hoehn & Yahr Stage 
15 min 
Olfactory testing using the Sniffin Sticks 12 odor test 
3 min 
PD Non-Motor Symptom Scale, subscales 1-5 (PD-NMS-S) 
5 min 
Unified Multiple System Atrophy Rating Scale (UMSARS) I: History of autonomic symptoms 
2 min 
Cognitive test battery: 
 
History and self-awareness of cognitive deficits 
5 min 
Montreal Cognition Assessment (MoCA) 
10 min 
Mini Mental State Examination (MMSE) 
5 min 
Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-Plus, German Version) 
25 min 
Trail Making Test Parts A and B 
10 min 
Fragmented Words (Subtest of the Leistungsprüfsystem für 50- bis 90-Jährige, LPS 50+) 
5 min 
Digit-Symbol Test (Subtest of the Wechsler Intelligenztest für Erwachsene, WIE) 
5 min 
Similarities (Subtest of the WIE) 
5 min 
Letter-Number Sequencing (Subtest of the WIE) 
5 min 
Demenz Apraxie Test (DAT) 
5 min 
Pill-Questionnaire 
5 min 
Patient Questionnaires (can be filled out at home):  
 
Parkinson’s Disease-Non-motor Symptoms Questionnaire (PD-NMS-Q) 
3  min 
Beck Depression Inventory – II (BDI-II) 
5 min 
Geriatric Depression Scale (GDS) 
2 min 
Beck-Anxiety-Inventory (BAI)  
2 min 
Functional Activities Questionnaire (FAQ) 
2 min 
Parkinson’s Disease Activities of Daily Living Scale 
1 min 
Parkinson’s disease Questionnaire (PDQ-39) 
5 min 
Freezing of Gait Questionnaire (FOG) 
1 min 
Epworth Sleepiness Scale (ESS) 
2 min 
REM Sleep behavior questionnaire (RBDS-Q) 
2 min 
Apathy Evaluation Scale (AES) 
3 min 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Short  (QUIP-Kurz) 
3 min 
Unified Parkinson‘s Disease Rating Scale (UPDRS) Parts I-II 
6 min 
International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) 
2 min 
Patient Perception of Bladder Condition (PPBC) 
1 min 
Top-10 Priority List 
5 min 
Saarbrücker Persönlichkeitsfragebogen (SPF)/ Interpersonal Reactivity Index (IRI) 
5 min 
Total time of clinical assessment:  
185 min 
Optional Home-based movement assessment (Accelerometer) 
7 days 
 

 
 
 
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For this scientific study, all investigations will be performed in an ambulatory setting and need 
the study participants to be available for at least 3 hours and 5 minutes, not including the 
optional blood marker sampling (blood: 15 min, CSF: 30 min). To evaluate the association 
between the onset and severity of both motor and non-motor symptoms which might indicate 
disease progression and are therefore more pronounced in PD patients with mild ADL 
dysfunction, a comprehensive clinical assessment will be conducted.  
 
- 
If patients agree to the optional CSF and/or blood collection (see also 8.6): 
 
 Blood collection 
 
 
 
15 min 
 CSF 
 
 
 
 
 
30 min 
Total time for biomarker sampling:         
45 min 
 
Caregiver assessments:  
To validate the patient’s self-impression, the following caregiver questionnaires and interview 
scales will be applied, needing caregivers to be available for at least 40 minutes. Caregiver 
assessments will only be performed if the respective patient has agreed to the interview. 
 
Table 2: Overview of caregiver assessments 
Assessment 
Time  
Explanation of the study requirements 
10 min 
Interview-based ratings:  
 
Informant Questionnaire on Cognitive Decline in the Elderly (IQ-CODE) 
6 min 
Tübinger Activity of Daily Living Inventory for Parkinson’s disease 
6 min 
Questionnaires: 
 
Pfeffer Functional Activities Questionnaire (FAQ) 
4 min 
Bayer Activities of Daily Living Scale (Bayer ADL) 
5 min 
Top-10 Priority List 
5 min 
Saarbrücker Persönlichkeitsfragebogen (SPF)/ Interpersonal Reactivity Index (IRI) 
4 min 
Total Time of caregiver assessment:  
40 min 
 
8.1. Retrospective Data 
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 clinical studies, these 
will also be included.  
 
8.2. Neuropsychological testing 
The aim is to diagnose PD-MCI and PDD according to the Level-II recommendations of the 
Movement Disorder Task Force [9, 10, 12]. Therefore the following five domains will be 
quantitatively assessed using the Consortium to Establish A Registry of Alzheimer’ Disease 
(CERAD-Plus) battery, three subtests of the Wechsler Intelligence Tests for Adults (WIE), and 
one subtest of the Leistungsprüfsystem für 50- bis 90-Jährige (LPS50+). At least two tests are 
assigned to each cognitive domain:  
 

 
 
 
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 Executive functions: Lexical and phonemic fluency (CERAD-Plus), Trail Making Test 
Part B 
 Attention/working memory: Digit-Symbol Test (WIE), Letter-Number Sequencing 
(WIE) 
 Language: Boston Naming Test (CERAD-Plus), Similarities (WIE) 
 Memory: Word List learning, recall, and discriminability (CERAD-Plus) and Praxis 
recall (CERAD-Plus) 
 Visuospatial abilities: Praxis (CERAD-Plus), Fragmented Words (LPS-50+) 
The MMSE included in the CERAD-Plus, as well as the Montreal Cognitive Assessment will 
serve as global cognitive screening scales. 
 
8.3. Comprehensive non-motor symptom assessment and Top-10 Priority List 
The occurrence and progression of non-motor symptoms is known to be associated with a 
more rapid cognitive decline as well as dementia in PD [1]. Therefore, we aim to assess the 
most common non-motor symptoms in PD, especially those symptoms that increase the risk 
for cognitive worsening and PDD (e.g. hallucination, anxiety, depression, and apathy) [5, 12]. 
Most of the symptoms will be assessed by patient self-questionnaires, which can be filled out 
at home if the assessment in the clinic is too stressful for the patients.  
Information from the questionnaires will be used to identify those symptoms associated with 
a worsening of cognitive-driven ADL function and cognition in our sample, which might further 
help to characterize those PD patients with a potentially high risk for the development of PDD. 
Data of the Top-10 Priority List, in addition to selected clinical data, will be shared for clinical 
research purposes with Oxford University Associate Professor Michele Hu, and University of 
Luxembourg Professor Reijko Krüger, within the H2020-TWINN-2015 project (research 
receives no special funding within this grant). The aim of this subproject is to ascertain PD 
patients’ priorities for future research aims, giving insight into their special needs and hopes 
for future research. Aim of the three centres’ collaboration is two-folded: first to compare the 
priorities of PD patients, caregivers, and nurses among different countries (no additional 
information needed), and second to link the results of the Top-10 Priority List to the individual 
data assessed, including the clinical symptom profile and correspondence between patient 
and caregiver responses. Within the consent form, patients and caregivers will be asked about 
the possibility of sharing psedudonymized data with the collaboration partners.  
 
8.4. Home-based movement assessment (Accelerometer) 
Physical activity directly influences health-related quality of life in PD [28], with specific 
aspects of physical activity decreasing with the severity of cognitive impairment [29]. We will 
therefore conduct a home-based movement assessment in a random subgroup of patients, to 
examine the influence of physical activity on cognition and other non-motor symptoms in PD. 
Participants will be asked to wear an accelerometer (MoveMonitor, McRoberts, The 
Netherlands) on their lower back for 7 consecutive days in their home environment. The 
accelerometer is capable of data uptake for 7-10 days, and assesses various movement 
parameters (e.g. time spent sitting, lying, walking, and standing, as well as step count).  
 

 
 
 
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8.5. Caregiver ADL assessments 
Caregiver assessments have a crucial role determining a diagnosis of PDD, by examining 
whether patients are able to care for themselves and carry out their daily activities. The Bayer 
Activities of Daily Living (Bayer ADL) scale consists of 25 questions answered by the caregiver 
that evaluate the patient’s ability to perform activities of daily living. The Informant 
Questionnaire on Cognitive Decline in the Elderly (IQ-CODE), a brief screening tool of 
dementia, compares patients’ current abilities to how they were two years ago. This provides 
a useful marker for cognitive ADL progression, as well as helps to distinguish cognitive decline 
from normal aging. The caregiver assessment of ADL using the FAQ allows us to compare 
patient and caregivers’ evaluation of ADL impairments.  
 
8.6. Biomaterial collection 
8.6.1. CSF and blood collection 
Blood collection: Serum (about 89 ml) will be collected for routine analyses in the Zentrallabor 
and the Neurochemisches Labor of the Universitätsklinikum Tübingen (UKT), for targeted 
biomarker search, for explorative proteomic and metabolomics approaches, as well as for the 
determination of genetic markers (APOE Genotype, MAPT, COMT, and GBA). This amount 
does not represent any health hazard. Blood samples will be collected in the morning, on an 
empty stomach. 
Through venipuncture, the following samples will be taken for analysis and will remain in the 
Hertie Institut für klinische Hirnforschung (Ethic Proposal: 199/2011BO1): 
 10 ml venous blood for the determination of routine values in the Zentrallabor (1 
Serum tube) 
 3 ml of venous blood (1 PaxGene tube) for RNA Isolation 
 20 ml of venous blood in 2 large EDTA tubes 
 10 ml of venous blood in 1 Serum tube 
 
CSF collection: The lumbar puncture at level L3/L4 or L4/L5 of the spine will be performed by 
a qualified clinician. The applicants have extensive experience with this procedure (see e.g. 
Ethical proposals 46/2010 and 404/2010). Subjects will be closely monitored during and after 
the procedure. Up to 15 ml of CSF will be collected unless there is evidence of clinically 
significant coagulopathy or thrombocytopenia that would interfere with the safe conduct of 
the procedure. This amount does not represent any health hazard. The first 2 ml of CSF will be 
processed at the Zentrallabor to conduct standard analyses on cell count, protein, and glucose 
levels, while another aliquot will be sent to the Neurochemisches Labor to conduct analyses 
of neurodegenerative markers such as Abeta1-42 and Abeta1-40.  
 
8.6.2. Tissue collection 
Not applicable. 
 
8.6.3. Analysis of biomaterial 
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, 

 
 
 
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biochemical, and eventually functional understanding of one of the most debilitating 
symptoms associated with PD, i.e. cognitive deterioration.  
For all patients, DNA, CSF, and plasma were sampled at baseline. Using the NeuroChip, 
patients were screened for genetic variants associated with dementia and PD. CSF levels of 
Aß1-42, phosphor- and total Tau were determined within the frame of the ABC-PD study.  
In collaboration with the company ADX, represented by Hugo Vanderstichele and Erik Stroops, 
the following baseline CSF biomarkers were provided for further analysis of 200 patients: Aß1-
42, Aß1-40, Aß1-38, phosphor Tau 181, NF heavy, neurogranin, BASE-1, and alpha-synuclein. 
Thus, biomaterial will be primarily analysed locally, but will also be shared with non-profit 
research organisation partners such as ADX. 
At time of follow-up, a maximum of 100 PD patients are expected to give a second CSF 
sampling. Levels of CSF biomarkers indicating cognitive worsening [30-35] will be measured 
using the solid phase enzyme essays from Fujirebio Germany GmbH: Aß1-42, Aß1-40, 
phosphor- and total Tau.  
 
8.6.4. Storage of biomaterial 
All samples will be stored at -80°C until use. To maximize confidentiality, all biomarker samples 
and information associated with the samples will be coded to prevent the exposure of the 
subject’s 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. 
 
9. Risks and possible adverse reactions, end of the study 
9.1. Neuropsychological testing 
No relevant risks. 
 
9.2. Comprehensive non-motor symptom assessment and Top-10 Priority List 
No relevant risks. 
 
9.3. Home-based movement assessment (Accelerometer) 
No relevant risks. 
 
9.4. Caregiver ADL Assessments 
No relevant risks. 
 
9.5. Biomaterial (Blood and CSF) collection 
Venipuncture is usually well tolerated and is rarely associated with complications. However, 
at the site of injection it may cause symptoms such as bruising, small scars, induration, 
abnormal sensations around the puncture due to unintentional nerve injury (median nerve in 

 
 
 
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some cases with long-lasting sensory and motor deficits), infection, phlebitis 
(thrombophlebitis), a thrombosis, or it can wash away the smallest blood clots (embolisms). 
Circulatory reactions (so-called vagovasal reactions) can also occur. However, complications 
of this kind have rarely occurred so far. 
Lumbar puncture is a routine assessment in neurological hospitals. The risk of injury of nerves, 
bones or other viscera is possible in theory but is extremely unlikely because of atraumatic 
injection needles. The needle prick can hurt locally and, in 10 percent of cases, radiating in the 
legs due to touching one of the lumbal nerve roots may occur for the fraction of a second. In 
theory, a local hemorrhage or an infection is possible. However, this has never occurred during 
the thousands of lumbar punctures performed every year at the Neurology Department of the 
UKT in the context of diagnostic measures ever since atraumatic needles have been available.  
During a period of hours to days, headaches can occur in an upright position. In very rare cases, 
it can cause patients to become bedridden for several days, a clear indication for a blood 
patch. A blood patch is another “lumbar puncture” at the place where the first puncture was 
performed, without collection of CSF but this time injecting autologous blood into the tissue 
without penetrating the dura mater again. It is hypothesized that this procedure closes the 
hole leading to CSF leakage. Ever since the introduction of atraumatic needles, the frequency 
of post-puncture headache in people older than 50 years has decreased substantially and is 
now below 2% [36]. 
 
9.6. End of the study 
December 2020. 
 
10. Data protection 
10.1. 
Data collection 
Data collection and use of personally identifiable information for this study complies with the 
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.  
 
10.1.1. Which data are collected; is it possible to identify the donor? 
Data of every subject – name, age, disease duration, as well as all assessed parameters and 
results of the biomarker assessments – are collected in separate folders, and will be stored in 
a lockable office of the PI or his/her representative. As a database platform, the REDCap 
electronic data capture tool will be used [37]. The database will be secured with password 
protection, individually assigned to each team member with database access. Pseudo-
anonymized 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 PI will only 
receive coded information that has been entered into the database under those identification 
numbers. Electronic communication with outside collaborators will involve only unidentifiable 
information. 

 
 
 
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10.1.2. Shall patients be informed about novel scientific findings? 
If participants wish to be informed about their individual CSF Abeta1-42 results (as per 
indication on the ABC-PD cross-sectional patient consent form (ethic protocol 686/2013B01)), 
this will take place during a one-on-one consultation with the PI/representative. If the patient 
agrees, he/she will be informed about the cognitive outcome. Beyond these specific 
parameters, it is not planned to keep the participants informed about the individual study 
results. 
 
10.1.3. Period of data storage 
Data will be stored for 10 years.  
 
10.1.4. 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 PD Dr. Inga Liepelt-Scarfone (phone: +497071-2980424, Fax: +497071-
294490, E-mail: inga.liepelt@uni-tuebingen.de) and Dr. Kathrin Brockmann (phone: 
+497071-2980171; Fax: +497071-2925195, E-mail: kathrin.brockmann@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. 
 
10.2. 
Transfer of data to the Sponsor 
De-identified clinical data may be shared with The Michael J. Fox Foundation for Parkinson’s 
Research (the study funder, Grant ID: 15227; Grand Central Station, P.O. Box 4777, New 
York, NY 10163-4777. Tel: +1-800-708-7644). This data may be kept for storage at a central 
repository hosted either by The Michael J. Fox Foundation, its collaborators, or consultants, 
and will be kept indefinitely. In order to advance scientific discoveries, the de-identified data 
will be made publically available (with no personal identifying information) for the intended 
use of research in PD as well as other biomedical research studies that may not be related to 
PD. This is clearly stated in the patient and caregiver informed consent forms.  
 
10.3. 
Information and informed consent 
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 
for study participation, the participant has to sign two copies of the informed consent form. 
One will be given to the participant, and the other form will be stored at the local study centre 
in a separate folder (not in the medical records). 
In addition to the PD patients, a caregiver will be contacted and interviewed. Therefore, 
informed consent will also be obtained from the patient’s caregiver using a separate caregiver 

 
 
 
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informed consent form. The patient will be asked to choose the caregiver who will then be 
contacted for the caregiver assessment.  
 
11. Insurance 
The study is covered by the clinical trials insurance. No travel accident insurance will be 
offered. However, for CSF sampling, patients will be additionally insured to increase their 
safety in case of the above mentioned adverse events (AEs) or serious adverse events (SAEs) 
after lumbar puncture. SAEs are unanticipated, serious, and possibly related to the study 
procedures. SAEs will be reported to the local ethical committee in accordance with 
requirements. An appropriate application for a selected insurance will be filed with the help 
of the insurance management (contact person: Mrs. Iris Wolf) of the University of Tübingen. 
The insurance confirmation and the insurance conditions will be passed on to the Ethics 
Committee after the insurance has been taken out. The patient information is also provided 
with the most important information (contents and exclusions of the insurance, compensation 
amount, period of insurance, name and contact details of the insurer, insurance certificate 
number, obligations of the insured according to the insurance conditions) and the insurance 
confirmation and the insurance conditions are attached to the subject information as soon as 
they are available. 
 
Number of insurance police: 57 010311 03013 
Insurance Period: 15.08.2018 until 31.12.2020 
Amount of damage compensation: 500,000.00€ per participant, Maximum limit of indemnity 
is 5,000,000.00€ (for all 209 participants). 
 
12. Information text and text of the informed consent 
See attachments: 
 Patient information sheet and informed consent form 
 Patient data privacy statement 
 Caregiver information sheet and informed consent form 
 Caregiver data privacy statement 
 
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Fereshtehnejad, S.M., et al., Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression. 
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