Progression in Cognition and Associated Activities of Daily Living (ADL) Impairment in Parkinson's Disease
Conditions: Parkinson Disease
Sponsor: University Hospital Tuebingen

 
 
 
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Progression in cognition and associated activities of daily living impairment  
in Parkinson’s disease (PRICOG-PD) 
 
„Verschlechterung der geistigen Leistungsfähigkeit und damit einhergehende 
Alltagseinschränkungen bei Morbus Parkinson (PRICOG-PD)“  
 
Version 3 Date: 15.02.2023 
 
 
 
 
 
Finanzierung/Funding: 
Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of 
Tübingen  
 
 

 
 
 
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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 ................................................................................................. 5 
4. 
Objectives of the study ................................................................................................. 6 
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 .......................................... 7 
6.2.1. 
Inclusion criteria ................................................................................................. 7 
6.2.2. 
Exclusion criteria ................................................................................................ 7 
6.3. 
Recruitment ........................................................................................................ 8 
7. 
Statistics and Sample size estimation .......................................................................... 8 
8. 
Assessments .................................................................................................................. 9 
8.1. 
Retrospective Data ........................................................................................... 11 
8.2. 
Neuropsychological testing .............................................................................. 11 
8.3. 
Home-based movement assessment (Accelerometer).................................... 12 
8.4. 
Caregiver IADL assessments ............................................................................. 12 
8.5. 
Biomaterial collection ...................................................................................... 12 
8.5.1. 
CSF and blood collection .................................................................................. 12 
8.5.2. 
Tissue collection ............................................................................................... 13 
8.5.3. 
Analysis of biomaterial ..................................................................................... 13 
8.5.4. 
Storage of biomaterial ...................................................................................... 13 
9. 
Risks and possible adverse reactions, end of the study ............................................ 14 
9.1. 
Comprehensive non-motor symptom assessment .......................................... 14 
9.2. 
Neuropsychological testing .............................................................................. 14 
9.3. 
Home-based movement assessment (Accelerometer).................................... 14 
9.4. 
Caregiver ADL Assessments ............................................................................. 14 
9.5. 
Biomaterial (Blood and CSF) collection ............................................................ 14 
10. 
End of the study .......................................................................................................... 15 
11. 
Data protection ........................................................................................................... 15 
11.1. 
Data collection .................................................................................................. 15 
11.1.1. 
Which data are collected; is it possible to identify the donor? ....................... 16 
11.1.2. 
Shall patients be informed about novel scientific findings? ............................ 16 
11.1.3. 
Period of data storage ...................................................................................... 16 
11.1.4. 
Erasure of personal data .................................................................................. 16 
11.2. 
Transfer of data to collaboration partners ...................................................... 16 
11.3. 
Information and informed consent .................................................................. 18 
12. 
Insurance ..................................................................................................................... 19 
13. 
Information text and text of the informed consent .................................................. 19 
14. 
Reference list .............................................................................................................. 19 

 
 
 
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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 
AIC 
 
Akaikes information criterion 
AD 
 
Alzheimer’s Disease 
ADDI  
Alzheimer’s Disease Data Initiative  
ADL 
 
Activities of Daily Living 
AUC 
 
Area Under the Curve 
Bayer ADL  
Bayer Activities of Daily Living Scale 
CERAD-Plus 
Consortium to Establish a Registry for Alzheimer’s Disease Plus 
CI 
 
Confidence Interval 
CSF 
 
Cerebrospinal Fluid 
FAQ 
 
Pfeffer Functional Activities Questionnaire 
GLMM  
General linear mixed model 
HR 
 
Hazard Ratios 
IADL 
 
Instrumental Activities of Daily Living 
IQ-CODE 
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 
PD-ABB-Scale PD Angehörigen Belastungs- und Befindlichkeitsskala 
PDD 
 
Parkinson’s Disease Dementia 
PD-CN  
Parkinson’s Disease with Normal Cognition 
PD-MCI  
Parkinson’s Disease with Mild Cognitive Impairment 
RBD 
 
REM (Rapid Eye Movement) Behavior Disorder 
UKT 
 
Universitätsklinikum Tübingen 
UPDRS-III 
Unified Parkinson’s Disease Rating Scale Part III (Motor Part) 
ROC 
 
Receiver Operating Characteristic 
SWE 
 
Skala zur Allgemeinen Selbstwirksamkeitserwartung  
WIE 
 
Wechsler Intelligenztest für Erwachsene 
ZCBI 
 
Zarit Caregiver Burden Inventory 
 
 

 
 
 
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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]. 
Patients with PD have an almost 6-fold increased risk of developing cognitive impairment 
and PDD compared to age-matched controls [5]. Identification of a high-risk group for 
converting to PDD (i.e., those PD patients who are in the prodromal dementia phase) is 
essential to develop and implement early and effective treatments for preventing or 
delaying dementia. Mild cognitive impairment (PD-MCI) is one of the greatest risk factors for 
future PDD [6]. A recent meta-analysis found that, on average, 31% of patients with PD-MCI 
converted to PDD within seven years; however, 24% of patients with PD-MCI reverted back 
to normal cognitive function [7]. Consequently, the false positive rate for predicting PDD 
among patients with PD-MCI is high, and better predictive markers to define patients at high 
risk for PDD development are urgently needed. Therefore, a combination of different 
markers, including clinical, genetic, and other biomarker data, are proposed to increase 
ability to predict cognitive worsening and dementia [8-11].  
Significant impairments in activities of daily living (ADL) function, in addition to impaired 
cognition, are the core criterion for diagnosing Parkinson’s Disease dementia [12]. Recent 
studies have shown that even patients with mild cognitive impairment display first signs of 
ADL dysfunction [13-15], possibly indicating a group at risk for dementia [16]. As the diagnosis 
of ADL deficits requires these to be solely caused by cognitive deficits, an important step for 
accurate diagnoses is the measurement of ADL deficits in PD. To confirm the diagnosis of PDD, 
ADL disabilities should be primarily caused by cognitive, not motor, dysfunction [17, 18]. 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 (IADL) function is impaired in the earlier stages whereas basic ADL can be 
preserved for a long time [19]. Based on data of the first follow-up in our non-demented 
sample (ethic protocol: Baseline 686/2013BO1; Follow-up 284/2018BO1, see below 3.2 
Preliminary data), we were able to show that the presence of both mild cognitive IADL 
impairment and PD-MCI dramatically increases the risk for PDD: nearly 50% with baseline 
profile of both markers converted to dementia within three years. In general, our results argue 
for the importance of differentiating between cognitive and motor aspects of ADL function in 
PD. Patients with PD-MCI and cognitive IADL impairment may be a valuable target group for 
clinical trials aiming to slow down development of dementia. However, this assumption needs 
to be confirmed by future longitudinal data.  
In PD, it is unclear whether self- or informant-reports are more useful for judging ADL 
impairments in the clinical routine, as the loss of functional independence is an important 
outcome of disease progression. Although IADL is commonly assessed by an informant who 
can reliably give information regarding patients’ level of functioning, cognitive IADL data was 
collected from both patients and informants in our study. While discrepancies between self- 
and informant-ratings are greatest in PDD patients [20], between-group comparisons on IADL 
item, total, and subscore levels did not show differences between raters. However, it is known 

 
 
 
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that self-reports on the impact of cognitive changes on IADL function are more sensitive in 
early stages of cognitive decline [21]. Recently, analysis in this cohort showed that agreement 
between patient- and informant-ratings of IADL function using Pfeffer Functional Activities 
Questionnaire (FAQ) items were moderate, with only few items reaching substantial 
agreement [22]. Ratings of patients and informants were associated with patients’ cognitive 
status, but also other characteristics. Therefore, it is currently unclear whether ratings of 
patients and/or caregiver have a higher prognostic ability to predict decline in cognition and 
everyday function. We therefore propose a second follow-up of an already existing large PD 
cohort to longitudinally investigate the association between IADL function rated by either 
patients themselves or caregivers, cognition, and other clinical and biomarker measures.  
 
3.2. Preliminary data 
Methods. The study was conducted as the first follow-up (Title: Cognitive driven ADL 
impairment as a predictor for PDD; ethic protocol: 284/2018BO1) of “Amyloid-Beta in 
Cerebrospinal Fluid as a Risk Factor for Cognitive Dysfunction in Parkinson’s Disease” (ABC-
PD) study (ethic protocol: 686/2013BO1).  
The FAQ quotient (cut-off >1), indicating more cognitive than motor-driven IADL impairment, 
defined cognitive IADL impairment status at baseline (FAQQ>1). The FAQ is a ten item IADL 
assessment scored on a 4-point Likert scale ranging from normal (score=0) to dependent 
(score=3) ADL function (max. points 30) [23]. The 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 [24]. Hazards ratios (HR) were used to compare the impact of 
different baseline classifications on dementia conversion. 
Results. Of 268 patients with PD assessed at baseline, 108 (40.3%) had PD-MCI. After a period 
of 3.8±0.8 years, 182 (61.2%) patients were re-assessed and 164 analysed (17 excluded due to 
deep brain stimulation, one patients without classification of cognitive group). At follow-up, 
93 (56.7%) patients fulfilled criteria for normal cognitive function (PD-CN), 54 for PD-MCI 
(32.9%), and 17 (10.4%) had developed dementia. Predictive ratio of baseline cognitive IADL 
impairment (n=37; 21.3%) for dementia conversion was descriptively higher than for PD-MCI, 
but highest in patients with both markers [HR=12.01, 95%-confidence interval (CI): 4.47-
32.23)]. Nearly half of patients (n=10, 47.6%) with baseline classification of cognitive IADL 
impairment and PD-MCI converted to dementia. Baseline status of cognitive IADL impairment 
was associated with higher non-motor burden, worse cognitive performance, and more 
severe IADL progression over the study period. In a post-hoc Receiver Operating Characteristic 
(ROC) analysis, the FAQ quotient (cut-off >1.008) was confirmed to best predict conversion to 
dementia compared to other IADL scores. Only two patients with baseline status of cognitive 
IADL impairment in our sample scored below the newly identified FAQ quotient cut-off of 
1.008 resulting in a total of 35 (21.3%) patients with values above this defined cut-off. The 
FAQ motor score [AUC(area under the cure)=0.60, 95%-CI: 0.52-0.67, p=0.13], reflecting 
predominantly motor aspects on IADL function, was not associated with PDD conversion. 
 

 
 
 
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4. Objectives of the study 
Based on previous analyses in the sample we suggest that monitoring of both cognition and 
cognitive ADL impairment reflect neurodegeneration associated to PDD development. This 
study evaluates markers predicting cognitive and ADL long-term outcome in our sample. 
Additionally, we will investigate whether ratings of patients or informants best predicted 
decline of cognitive impairment and/or everyday function. Clinical data along with other 
clinical marker and biomarker status will be investigated.  
 
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>1.008) are at higher risk for 
worsening in cognition and conversion to PDD than PD-MCI patients with ADL impairment 
primarily related to motor function (FAQQ≤1.008).  
 
1. Prediction of cognitive progression along with progression in IADL function over time 
Aim 1.1: Prediction of conversion rates to PD-MCI (among PD-CN) and PDD (among non-
demented patients) according to baseline IADL, cognitive, genetic, and 
biomarker profiles in blood and CSF 
Aim 1.2: Prediction of progression in cognitive scales according to cognitive, IADL, 
genetic, and biomarker profiles in blood and CSF 
Aim 1.3: Prediction of worsening in available ADL scales (patient-/informant-ratings) 
according to cognitive, IADL, genetic, and biomarker profiles in blood and CSF 
 
2. Defining the interaction of progression in markers over time 
Aim 2.1: Evaluation of progression in varying cognitive tests assessed along with change 
in ADL function, non-motor markers and, if available, biomarker status 
Aim 2.2: Evaluation of progression in IADL function (patient-/informant-ratings) along 
with change in cognition, non-motor markers and, if available, biomarker status 
 
5. Study duration 
Total duration of the study is 2 years.  
 
6. Study population 
6.1. Study population 
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.  
Follow-up visits were conducted between July 2018 and September 2020, all patients of the 
ABC-PD study were contacted for re-examination.  
We propose a second follow-up of the already existing longitudinal cohort described above 
with a longitudinal assessment including neuropsychological in-depth endophenotyping and 
CSF biomarker analyses. In total 182 patients will be invited to participate in the second 

 
 
 
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follow-up assessment. If patients are not able to attend a clinical visit in-house, possibility of 
assessments at patients’ homes shall be offered. Moreover, if patients are not able to give 
consent for study participation (confirmed by an independent physician), the legal guardian 
will be contacted to give study consent for participation. Legal guardians are defined as 
persons with legal care directive or lasting power of attorney. For drop-outs different 
reasons for drop-out will be coded (e.g. deceases, disabled, disinterested/refuse study 
participation, unable to reach/unknown address). 
 
Diagnosis of cognitive impairment:  
Patients were classified as PD-MCI according to Level-II Movement Disorder Society 
recommendations if cognitive impairment  was present but did not significantly interfere 
with everyday function [25]. PDD was defined according to Movement Disorder Society Task 
Force criteria [17] if cognitive impairment was present and severe enough to impair ADL 
function unrelated to motor or autonomic symptoms and at least one behavioral symptom 
was present to support diagnosis. Cognitive impairment was 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 were classified as PD-CN. Cognitive status at 
follow-up was defined as the primary study outcome. 
 
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 
• 50–95 years of age. 
• Diagnosis of PD according to the United Kingdom Brain Bank criteria. 
• 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. 
 
6.2.2. 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 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. 

 
 
 
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6.3. Recruitment 
Participants of the already recruited ABC-PD cross-sectional cohort (ethic protocol: 
284/2018BO1) 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 145 patients will be primarily 
conducted between January 2023 and June 2024. During the executive project phase, 
around 7 to 9 patients will be assessed per month. Patients will be contacted either via 
phone or in written form. Reasons for drop-outs will be registered for data analysis. 
 
7. Statistics and Sample size estimation 
All following hypotheses will be tested a priori; no post-hoc corrections of p-values will be 
conducted. 
 
Characterization of study groups: Between-group comparisons at clinical visits will be 
conducted using Mann-Whitney-U or Welch test (two groups) or Jonckheere-Terpstra test 
(>2 groups) for numerical variables and Χ² test or Exact Fisher Test for categorical variables. 
Post-hoc comparisons for IADL and cognitive variables between groups will be corrected for 
between-group covariates via linear regression models with group status as dummy coded 
variable. When follow-up cognitive groups are compared (PD-CN vs. PD-MCI vs. PDD), 
analyses with covariates will be run twice with reference category set as either PD-CN or PD-
MCI. 
 
Prediction of cognitive progression along with progression in ADL function over time:  
In patients who completed all visits, the predictive values of baseline/follow-up IADL 
(patients’ self-impression vs. informant-rating), stratification (cognitive IADL impairment vs. 
motor IADL impairment), cognitive status (PD-CN vs. PD-MCI), and both markers combined 
(PD-MCI + cognitive IADL impairment) will be calculated using multivariate Cox Proportional-
Hazard models. Akaikes information criterion (AIC) and concordance index (C-index) [26] will 
be used as model fit indices. Logistic regression with follow-up cognitive diagnosis (PD-CN vs. 
PD-MCI or non-demented vs. PDD) as dependent variable will evaluate whether baseline 
status of cognitive IADL impairment (FAQ quotient >1.008) predicted risk of PDD conversion 
independent of other clinical variables (e.g., cognitive status), biomarker profile, and 
covariates. As a post-hoc exploratory analysis to identify which subscore best predicted PDD 
conversion, ROC curves will be calculated for all FAQ scores (self- and caregiver-assessment). 
The optimal score/cut-off will be chosen according to the highest Youden Index.  
Linear regression will be applied to investigate predictors of neuropsychological scores and 
IADL measures at follow-up(s).  
 
2. 
Defining the interaction of progression in markers over time 
Generalized linear mixed effects models (GLMMs) will evaluate progression in 
neuropsychological tests and IADL scores over time. Correlation analyses are planned to 
investigate association in change of scores over time of different measures.  

 
 
 
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Sample size calculation:  
Between the baseline and first follow-up 17 (10.4%) patients developed PDD within a mean 
follow-up interval of 3.78 ± 0.84 years (range: 1.67-5.79 years), with higher rates of 
converters in patients with baseline status of cognitive ADL impairment (29.7%). Estimated 
follow-up interval between first and second follow-up are expected to be very similar, and a 
higher rate of patients with cognitive ADL impairment were identified. Moreover, the risk for 
PDD development is increased in later disease stages [27, 28]. Therefore, a maximum of 
additional 15 converters are expected. 
Monte Carlo simulation-based calculations of observed power (R package simr, version 1.0.6), 
revealed a minimum sample size of n = 64 (Power = 94.00%; 95%-CI: 83.45-98.75) to detect 
the three-way interaction in the GLMM evaluation of the progression in the FAQ total score 
in different study groups (e.g., PD-NC vs. PD-MCI), and of n = 71 (Power = 92.00%; 95%-CI: 
80.77-97.78) for the three-way interaction in the GLMM evaluating progression of FAQ motor 
score.  
8. Assessments 
The explanation of study requirements and informed consent will be conducted as first 
procedure.  
 
Table 1: Overview of clinical in-house assessments and assessments which can alternatively 
be assessed within an additional phone interview.  
Assessment of PD patients 
Time 
Explanation of the study requirements 
10 min 
Informed written consent  
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 
Cognitive test battery: 
 
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 
Pill-Questionnaire 
5 min 
Total time of mandatory in house assessments 
115 min 
Optional: Dementia Apraxia Test (DATE) 
5 min 
Optional: Kölner Apraxie Screening 
8 min 
Total maximum time of optional in house assessments 
13 min 
Assessments, which can be alternatively assessed within an additional phone interview 
 
Demographics & lifestyle 
 
Age, gender, education, occupation, family history of neurodegenerative diseases, 
smoking/drinking behavior, height & weight# 
5 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 
History and self-awareness of cognitive deficits# 
5 min 
Total maximum time of additional phone interview 
17 min 
Legend: *: For patients with an appointment in the outpatient clinic data will be assessed within the frame of the clinical daily routine; 
#. Information can be assessed within the frame of phone interview 
 
 

 
 
 
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Table 2: Overview of clinical assessments conducted at home by study patients 
Patient questionnaires (filled out at home):  
 
Parkinson’s Disease Non-Motor Symptoms Questionnaire (PD-NMS-Q) 
3 min 
Beck Depression Inventory – II (BDI-II) 
5 min 
Beck Anxiety Inventory (BAI)  
2 min 
Pfeffer 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 
Skala zur Allgemeinen Selbstwirksamkeitserwartung (SWE) 
5 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 
Total time of clinical assessment conducted at home by patients:  
43 min 
Optional: Home-based movement assessment (accelerometry device) 
7 days 
 
The Kölner Apraxie Test included for validation of the Dementia Apraxia Test (DATE) as well as 
the Skala zur Allgemeinen Selbstwirksamkeitserwartung (SWE) will be applied as additional 
study outcome. All other scales and measurement were also included in the first follow-up of 
the sample (Title: Cognitive driven ADL impairment as a predictor for PDD; ethic protocol: 
284/2018BO1). 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, not including the 
optional blood marker sampling.  
 
If patients agree to the optional CSF and/or blood collection (see also 8.5): 
 
• Blood collection 
 
 
 
15 min 
• CSF 
 
 
 
 
 
30 min 
• Bed rest after CSF collection  
 
30 min 
Total time for biomarker sampling:                    75 min 
 
Invasive biomarker sampling will not be conducted for patients, who are not able to give 
consent for study participation.  
 
Caregiver assessments:  
To validate the patients’ self-impression, the following caregiver questionnaires and interview 
scales will be applied, needing caregivers to be available for at least 38 minutes. Caregiver 
assessments will only be performed if the respective patient has agreed to the interview. 
 
Table 3: 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 
Questionnaires: 
 
Pfeffer Functional Activities Questionnaire (FAQ) 
4 min 
Bayer Activities of Daily Living Scale (Bayer ADL) 
5 min 
PD Angehörigen Belastungs- und Befindlichkeitsskala (PD-ABB-Scale) 
8 min 
Zarit Caregiver Burden Inventory (ZCBI) 
5 min 
Total Time of caregiver assessment:  
38 min 

 
 
 
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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 [17, 18, 25]. Therefore, the following five domains will be 
quantitatively assessed using the Consortium to Establish a Registry for Alzheimer’s Disease 
(CERAD-Plus) battery, three subtests of the Wechsler Intelligence Test for Adults (WIE), and 
one subtest of the Leistungsprüfsystem für 50- bis 90-Jährige (LPS 50+). At least two tests are 
assigned to each cognitive domain:  
 
• Executive functions: Lexical and Phonemic Fluency (CERAD-Plus), Trail Making Test 
Part B (CERAD-Plus) 
• 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), 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 
(MoCA) will serve as global cognitive screening scales. In addition, the DATE  
will be applied. The DATE by Johnen and colleagues [29] was developed to assess limb and 
buccofacial apraxia in neurocognitive disorder patients with Alzheimer’s disease and 
frontotemporal dementia. Based on scores in the first follow-up, progression in the DATE 
performance over time will be investigated. For validation purpose, the Kölner Apraxie 
Screening [30] will be included as well. Patients’ performance in the DATE and KAS will be 
videotaped for data analysis. Videotaped data will be solely used for scoring of the DATE and 
KAS, also including registration of patient’s body parts and face. After scoring of patient’s 
test performance and finalization of study analysis, videodata will be deleted. Only, 
information of patients test performances as a result of the videoanalysis will be shared with 
collaboration partners.  
In addition, we will validate a novel scoring algorithm of patients’ cube drawing (CERAD-
PLUS test battery) proposed as a measure for retrograde procedural memory [31]. 
Therefore, investigators will be trained for this novel scoring method by the collaborating 
group of Prof. Rejko Krüger, University of Luxembourg. Patients’ performance will be scored 
by the investigators during test session, therefore, no additional time for patients’ 
examination is expected.  
 

 
 
 
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8.3. Home-based movement assessment (Accelerometer) 
Physical activity directly influences health-related quality of life in PD [32], with specific 
aspects of physical activity decreasing with the severity of cognitive impairment [33]. 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, FDA registered and CE marked) 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).  
 
8.4. Caregiver IADL 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 Scale (Bayer ADL) consists of 25 questions answered by the caregiver 
that evaluate the patient’s ability to perform ADL. The Informant Questionnaire on Cognitive 
Decline in the Elderly (IQ-CODE), a brief screening tool for dementia, compares patients’ 
current abilities to how they were two years ago. In addition, caregiver burden will be assessed 
using two questionnaires, the Parkinson’s Disease Angehörigen Belastungs- und 
Befindlichkeitsskala (PD-ABB-Scale) and the ZARIT Caregiver Burden Inventory (ZCBI). 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 caregiver evaluations of ADL impairments.  
 
8.5. Biomaterial collection 
8.5.1. CSF and blood collection 
Blood and CSF samples will be collected in the morning, on an empty stomach. If patients do 
not agree for a lumbar puncture, fasting for blood sampling is not necessary for biomarker 
analysis.  
 
Blood collection: For patients with no CSF withdrawal about 40 ml venous blood will be 
collected for data analysis and storage of blood in the neurobank of the Hertie-Institut für 
klinische Hirnforschung (ethic proposal: 199/2011BO1). This amount does not represent any 
health hazard. For study related analysis of serum neurofilament light chain 10 ml of venous 
blood (1 Serum tube) will be collected. If the patient agrees for withdrawal of CSF additional 
12,5 ml venous blood (2 serum tube, 1 NaF (glucose) 2,5 ml, total amount of venous blood 
52,5 ml) will be taken for safety analysis in the Zentrallabor of the UKT.  
 
Through venipuncture, the following samples will remain in the Hertie-Institut für klinische 
Hirnforschung (ethic proposal: 199/2011BO1): 
• 20 ml of venous blood in 2 large EDTA tubes 
• 10 ml of venous blood in 1 Serum tube 
 

 
 
 
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Blood in the Neurobiobank will be stored and used for targeted biomarker search, for 
explorative proteomic and metabolomics approaches, as well as for the determination of 
genetic markers in those without DNA analysis by using the NeuroChip (e.g. APOE Genotype, 
MAPT, COMT, and GBA).  
 
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., 
ethic proposals 46/2010 and 404/2010). Subjects will be closely monitored during and after 
the procedure. Patients need to rest for 30 min after CSF collection and will be informed that 
occurrence of side effects of this procedure might be interfere with their driving abilities. 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 of 400 μL Liquor will be sent to the Neurochemisches Labor to conduct 
analyses of neurodegenerative markers such as Abeta1-42 and Abeta1-40.  
 
8.5.2. Tissue collection 
Not applicable. 
 
8.5.3. 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, 
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. Available data will be 
included into data analysis. This includes genetic information received from DNA analysis by 
using the NeuroChip, especially information on genetic variants associated with dementia and 
PD, as well as CSF levels of Abeta1-42, phosphor- and total Tau 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: Abeta1-42, Abeta1-40, Abeta1-38, phosphor Tau 181, NF 
heavy, neurogranin, BASE-1, and alpha-synuclein.  
At time of follow-up, a maximum of 50 PD patients is expected to give a third CSF sampling. 
Levels of CSF biomarkers indicating cognitive worsening [8, 9, 34-37] will be measured using 
the solid phase enzyme essays from Fujirebio Germany GmbH: Abeta1-42, Abeta1-40, 
phosphor- and total Tau. In addition, blood (serum) neurofilament light chain will be analysed 
in cooperation with Prof. Dr. med. Björn Falkenburger of the Universitätsklinikum Dresden.  
 
8.5.4. 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 
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 

 
 
 
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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. Comprehensive non-motor symptom assessment  
No relevant risks. 
 
9.2. Neuropsychological testing 
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 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). 
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.  
Side effects of lumbar puncture:  
• Frequent side effects (1 of 2-3 cases): 
o The needle prick can hurt locally at the site of injection 
o Small bruises at the site of injection without further complication or functional 
deficits 
• Occasional side effects (< 10 von 100 cases): 
o Contact between the side of the lumbar puncture needle and a spinal nerve 
root can result in anomalous sensations (paresthesia) for a short time period 
(seconds)  
o Circulatory reactions (so-called vagovasal reactions) with occurrence of 
dizziness. Patients body position will be stabilized (lateral position) if symptoms 
occur. Lumbar puncture will be interrupted if circulatory symptoms did not 
meliorate and vanish in the lateral body position.   

 
 
 
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• Rare side effects (< 3 von 100 cases): 
o Post spinal headache, nausea, vomiting, increased sensitivity to light and dorsal 
pain, lasting for hours or days after the lumbar puncture. In rare cases those 
symptoms can last for several days or weeks.  
o Local infection at the side of injection. 
o As a consequence of the circulatory reactions a syncope (period without 
consciousness, circulatory collapse) can occur.  
• Very rare cases (single cases reported in the literature). Those side effects occur in very 
rare cases, but can’t be excluded as a consequence of the lumbar puncture: 
o Strong post-lumbar puncture headache in upright and sitting position, which 
requires an additional puncture in the region of the spine and an epidural blood 
patch. During this procedure injection autologous blood (10-20 ml) into the 
epidural space at the site of the dural puncture closing the puncture due to 
coagulation. This injection can be performed ambulatory or ad the ward, 
normally within 1-2 hours after the lumbar puncture in very rare cases.  
o (Bacterial) Meningitis after lumbar puncture, subdural hematoma or brain 
oedema can occur. Normally symptoms restitute after some time, without long 
lasting functional deficits. The risk for those side effects is increased in patients 
with genetic or acquired coagulation disorders.  
o Temporary deficits of single of cerebra nerves including temporary functional 
deficits like hearing loss or problems in vision. 
o Pulmonal deficits causing problems in breathing and severe circulatory 
reactions causing life threatening events shortly after the lumbar puncture. 
Often specific primary diseases promote these side effects.  
o Spinal cord inflammation 
o Provocation of seizure disorders (z.B. migraine, epilepsy). 
 
So far, severe side effects has never occurred during the conduction of several study related 
lumbar punctures performed every year at the Department of Neurodegenerative diseases at 
the UKT ever since atraumatic needles have been available. 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% [38]. 
 
10. End of the study 
Execution phase & recruitment: June 2024 
Data analysis expected: December 2024 
Anticipated study end: December 2024 
11. Data protection 
11.1. 
Data collection 
Data collection and use of personally identifiable information in 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.  

 
 
 
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11.1.1. 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 Principal investigator or his/her representative. As a database 
platform, the REDCap electronic data capture tool will be used [39]. 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 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. 
 
11.1.2. Shall patients be informed about novel scientific findings? 
If participants meanwhile 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. 
 
11.1.3. Period of data storage 
Data will be stored for 10 years.  
 
11.1.4. 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, Prof. PD Dr. Inga Liepelt-Scarfone (phone: +497071-2980424, fax: +497071-
294490, e-mail: inga.liepelt@uni-tuebingen.de), and PD 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. 
 
11.2. 
Transfer of data to collaboration partners 
If the patient agreed for this procedure, pre-processed blood samples will be transferred to 
Prof. Dr. med Björn Falkenburger, Fetscherstraße 74, 01307 Dresden, for further analysis of 
serum neurofilament light chain. Samples are coded with a pseudonym (Lab-ID 2). If more 
than one sample is transferred coded with two different identifiers (Lab-ID 2) for one 
sample, additionally the patient pseudonym will be transferred and the information which 
samples belong to the same person.  

 
 
 
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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 anonymized 
data will be transferred.  
In addition, we will ask the participants to give consent for shipment of plasma samples and 
clinical study data for proteomics analysis. Currently, Janssen Research & Development is 
forming a consortium including different collaboration partners for harmonization of 
proteomics analysis and building of large cohorts to analyse samples and clinical data in the 
spectrum of normal age and neurodegenerative diseases (“Alzheimer’s Disease and Related 
Dementias (ADRD) Proteomics Consortium“). Different PIs of cohort are represented in the 
steering committee of this consortium, regulating access to proteomics and clinical data. The 
consortium is not regulated by a pharmaceutical company and independent from industrial 
interests. Data will be stored in the cloud hosted by the Alzheimer’s Disease Data Initiative 
(ADDI) located in the United States (Aridhia). Aridhia completed the ISO 27001 certification 
in June 2019, maintaining this certification through multiple audits. ISO 27701 certification 
was achieved in June 2022. The Azure-hosted Aridhia DRE is also HITRUST CSF certified and 
holds several UK certifications (for details please see 
https://knowledgebase.aridhia.io/aridhia-security-and-
compliance/https://knowledgebase.aridhia.io/aridhia-security-and-compliance/ ). 
Aridhia achieves compliance with General Data Protection Regulation through the 
implementation of ISO 27701 policies and processes which ensure that: 
• 
Information is processed on a lawful and transparent basis. 
• 
Strong data security is achieved through design. 
• 
Information security governance and accountability within Aridhia is clear. 
• 
Individuals’ privacy rights are respected. 
Within the DRE, security controls include: 
• 
All user access is via HTTPS URL protected by a rooted certificate issued by DigCert 
SHA2 Secure Server CA, utilising sha256RSA signature algorithm with sha256 
signature hashing algorithm. Will only utilise TLS 1.2 protocols or above. 
• 
Encryption in transit: All internal network traffic is protected by HTTPS, TLS 1.2, or 
above protocols. 
• 
Encryption at rest: By default, Microsoft Azure encrypts data using FIPS 140-2 
compliant 256 AES encryption for storage accounts and virtual machine disks. 
• 
Two-factor authentication is required to access DRE services. 
• 
The secure workspace boundary is created through a virtual network configuration 
and enforced through a permissions model. 
• 
An Intrusion Detection System and Intrusion Protection System is implemented with 
security alerts automatically raised to Aridhia’s Service Desk Team. 
• 
Data upload and data extraction is only permitted through an approval process. 
• 
All uploads go through a malware scanning process. 
• 
Full audit reporting of events. 
Operational Processes: The DRE is a managed service, where Aridhia performs the following 
operations: 

 
 
 
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• 
OS patching (scheduled and ad hoc in the event of emergency updates). 
• 
Nightly back-ups of the environment. 
• 
All support teams have separate privileged admin accounts and these require 2FA. All 
support team actions are logged. 
• 
Regular audits of the privileged accounts. 
• 
All Aridhia employees who have access to the operational environment go through a 
criminal record check. 
• 
Mandatory security training at inductions and periodic refresher training for all 
employees. 
• 
All changes to the platform are subject to change control. 
• 
Incident management and CSIRT processes. 
• 
Monthly audit of key ISO27001 controls. 
• 
Quarterly BCP/DR exercises. 
• 
Data is backed up to the Azure region agreed with the customer, either the local 
Azure region or a remote region within the same territory, as per customer’s 
statutory and legal obligations. 
• 
Back-ups are tested on a bi-monthly basis to ensure the data is recoverable. 
• 
All environments are monitored, with security, back-up failures, and capacity alerts 
being automatically logged with the Operations and Service Desk teams. 
• 
The Aridhia DRE has a Recovery Point Objective of 24 hours and a Recovery Time 
Objective of 72 hours. 
For data analysis we will ask the patients and informants for written informed consent for 
transfer of plasma samples and clinical data to the proteomics database of the Proteomics 
Consortium. If applicable, we will also ask to give consent for transfer of samples and data of 
previous study visits. Only pseudonymized data will be transferred. If data/biosamples of 
more than one clinical visit is provided to the Proteomics Consortium, an identifier allowing 
to identify which data belong to the same persons will be coded. It is not possible for 
members of the consortium to download data on local workstations or storage media.  
Additionally, patients’ consent will be asked for a data transfer of the investigator scored 
results of the cube analysis along with clinical data needed for validation of the novel scoring 
system. Data will be transferred to Prof. Dr. Rejko Krüger, Luxembourg Institute of Health, 
Transversal Translational Medicine (TTM) Initiative, 1A-B, rue Thomas Edison, 1445 Strassen, 
Luxemburg. Only pseudonymized data will be transferred. 
 
11.3. 
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 to 
study participation, the participant has to sign two copies of the informed consent form. One 
form 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, caregivers will be contacted and interviewed. Therefore, 
informed consent will also be obtained from patients’ caregivers using a separate caregiver 

 
 
 
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informed consent form. The patients will be asked to choose the caregiver who will then be 
contacted for the caregiver assessment.  
 
12. Insurance 
A road accident insurance (SV SparkassenVersicherung AG Hessen-Nassau-Thüringen, 
Wiesbaden) including insurance for accidence during study visit will be offered (limited to 145 
patients and 90 companions/caregivers).  
Insurance Nr.: 50100561414 
Date:  01.03.2023 - 31.12.2024 
Maximal insurance costs for patient and cargiver:  
100.000 EUR disability case  
  50.000 EUR death  
  10.000 EUR salvage costs 
    5.000 EUR cosmetic surgeries 
 
13. 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 
• Legal guardian information sheet and informed consent form 
• Legal guardian data privacy statement 
• Questionnaires for informants 
• Offer and conditions of road accidence insurance (including accidence 
insurance during study visit) 
 
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Longitudinal Progression: A Prospective Cohort Comparison With Other Phenotypes. 
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Fereshtehnejad, S.M., et al., Clinical criteria for subtyping Parkinson's disease: 
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van Uem, J., et al., Health-related quality of life in patients with Parkinson's disease-A 
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Bjornestad, A., et al., Clinical milestones in Parkinson's disease: A 7-year population-
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Aarsland, D., et al., Parkinson disease-associated cognitive impairment. Nat Rev Dis 
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