The Dutch Parkinson and Cognition Study

Study Overview
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Brief Summary
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Parkinson Disease (PD) is a heterogeneous, progressive neurodegenerative disorder which is characterized by a variety of motor and non-motor symptoms. The DUPARC study is a single-centre longitudinal cohort study aimed at deeply phenotyping newly diagnosed PD patients. The main aim is to investigate the relationship between cognitive impairment and both cholinergic and dopaminergic neurodegeneration in the early stages of the disease. In addition, gastrointestinal and visual system dysfunction in PD and their role in the underlying pathology are further explored in a longitudinal setup. Treatment-naïve participants will undergo extensive motor- and non-motor assessment, imaging, and microbiome assessment at time of diagnosis, and will be followed for at least 3 years.

Detailed Description
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Rationale: Parkinson's disease (PD) is characterized by both motor and non-motor symptoms, including cognitive decline. Mild cognitive impairment (PD-MCI) is already present at time of diagnosis in 24-36% of PD patients. Cognitive impairment in PD is associated with both cholinergic and dopaminergic deficiencies in the brain. Although dopaminergic neuronal degeneration is quite well established in relationship to the motor impairment, the rate and extent of the cholinergic neuronal degeneration in the course of PD is unknown. It is also unclear how cholinergic and dopaminergic degeneration contributes to cognitive deficits found in early and more advanced PD and its role in the progression over time. Objectives: The primary objective is to establish the relationship between cognitive impairment and cholinergic neurodegeneration in de novo PD patients, by studying cholinergic imaging using [ 18 F]Fluoroethoxy-Benzovesamicol ([18F]FEOBV) positron emission tomography (PET) and neuropsychological performance over time. Secondary objectives include: (1) the investigation of possible predictive factors using optical coherence tomography and (2) to determine the relative contributions of PD diagnosis and dopaminergic medication use to the changes in microbiota composition observed in PD patients. Study design: At baseline patients will undergo the following investigations and questionnaires: Demographics, detailed medical history, neuropsychological assessment, imaging including MRI brain, dopaminergic Fluoro-18-L-Dihydroxyphenylalanine (18F-FDOPA) and cholinergic FEOBV PET, optical coherence tomography (OCT) and microbiota composition. At one year follow-up subjects will undergo motor-, neuropsychological, and microbiota assessment. At 3 year follow up baseline measurements will be repeated in its entirety with the exception of the genetic and gastrointestinal assessments. Study population: 150 de novo PD patients, recruited from the neurological practices in the northern area of the Netherlands and healthy control subjects. Healthy age-,sex- and constipation-matched controls will be assessed on microbiota composition Assessment and endpoints related to gastroenterological assessment have been approved under a separate research protocol (NL61123.042.17 - CCMO) and has been officially linked to the overall protocol.

Official Title
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The Dutch Parkinson and Cognition Study (DUPARC): A Prospective Study on Cognitive Pathology in de Novo Parkinson'Disease

Conditions
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Parkinson Disease

Participation Criteria
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Eligibility Criteria
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Inclusion criteria - Diagnosis Parkinson's disease Exclusion criteria: The refusal to be informed about an unforeseen clinical finding. Dopaminergic medication use. Exclusion from PET imaging: Pregnant women Breast feeding women Exclusion from MRI: MRI incompatible implants in the body (e.g. prosthesis, pacemakers, implanted heart valves) Any risk of having metal particles in the eyes due to manual work without proper eye protections Tattoos containing red pigments that form a safety risk. Exclusion from gastrointestinal assessment: Active or persistent primary disease of the gastrointestinal tract History of peritonitis, severe endometriosis, abdominal, intestinal or urogenital fistula, Hepatobiliary or pancreatic disease (except asymptomatic cholecystolithiasis) History of abdominal or anorectal surgery, except minor surgery such as uncomplicated appendectomy or cholecystectomy (>6 months ago). Severe gynaecological prolapse (grade III) Cancer and/or adjuvant treatment within the last 6 months Within the last three months: severe hypo- or hyperkalemia, narcosis, analgosedation, endoscopic procedure of the gastrointestinal tract, abdominal trauma Within the last three months: gastrointestinal tract infection, food intoxication

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Parkinson's disease patients<br>150 de novo treatment naive Parkinson's disease patients. | |
| Healthy control subjects<br>150 Healthy sex- and age-matched controls, also matched according to presence and severity of constipation, serving as a control group for microbiome composition analyses. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| [18F]FEOBV PET | Cortical and subcortical cholinergic innervation as measured by [18F] FEOBV PET imaging | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive screening | General cognitive performance will be assessed using a cognitive screening; the Montreal Cognitive Assessment (MOCA). The MOCA test covers the important cognitive domains including memory, attention, executive function, language and visuospatial abilities, resulting in one total score of cognitive performance. MOCA score ranges between 0 and 30, with higher scores representing better performance. | baseline | 
| Memory performance | Memory performance will be calculated as an average Z-score of two cognitive tests; the Rey auditory verbal learning test for measuring verbal memory and the location learning test for measuring visual memory. Based on established normative data, a z-score for each test outcome will be calculated, representing performance compared to an age-, gender- and educational level-matched control group. A Z-score of 0 (zero) represents a performance similar to the normative data. A positive z-score represents better performance, while a negative z-score represents worse performance. There is no minimum or maximum z-score. These z-scores from both tests will be averages to form one outcome measurement representing memory performance. | baseline | 
| Attention and working memory performance | Attention performance will be calculated as an average Z-score of three cognitive tests; the Stroop color-word test, the digit span and the Vienna test system reaction time measurement. Based on established normative data, a z-score for each test outcome will be calculated, representing performance compared to an age-, gender- and educational level-matched control group. A Z-score of 0 (zero) represents a performance similar to the normative data. A positive z-score represents better performance, while a negative z-score represents worse performance. There is no minimum or maximum z-score. These z-scores from all three tests will be averages to form one outcome measurement representing attention performance. | baseline | 
| Executive function performance | Executive function performance will be calculated as an average Z-score of four cognitive tests; the trail making test, the Wisconsin card sorting test, the Hayling Sentence completion test and the letter fluency test. Based on established normative data, a z-score for each test outcome will be calculated, representing performance compared to an age-, gender- and educational level-matched control group. A Z-score of 0 (zero) represents a performance similar to the normative data. A positive z-score represents better performance, while a negative z-score represents worse performance. There is no minimum or maximum z-score. These z-scores from all tests will be averages to form one outcome measurement representing executive performance. | baseline | 
| Visouspatial abilities | Cognitive visuospatial abilities will be calculated as an average Z-score of two cognitive tests; the Judgement of line orientation and the Map search subtest of the test of everyday attention. Based on established normative data, a z-score for each test outcome will be calculated, representing performance compared to an age-, gender- and educational level-matched control group. A Z-score of 0 (zero) represents a performance similar to the normative data. A positive z-score represents better performance, while a negative z-score represents worse performance. There is no minimum or maximum z-score. These z-scores from all tests will be averages to form one outcome measurement representing visuospatial abilities. | baseline | 
| Language performance | Language performance will be calculated as an average Z-score of two cognitive tests; the Boston Naming test and the verbal fluency test. Based on established normative data, a z-score for each test outcome will be calculated, representing performance compared to an age-, gender- and educational level-matched control group. A Z-score of 0 (zero) represents a performance similar to the normative data. A positive z-score represents better performance, while a negative z-score represents worse performance. There is no minimum or maximum z-score. These z-scores from all tests will be averages to form one outcome measurement representing language performance. | baseline | 
| Social cognition | Social cognition abilities will be represented as a z-score calculated from the performance on the FEEST; Facial Expression of Emotion Stimuli and tests. Based on established normative data, a z-score of the test outcome will be calculated, representing performance compared to an age-, gender- and educational level-matched control group. A Z-score of 0 (zero) represents a performance similar to the normative data. A positive z-score represents better performance, while a negative z-score represents worse performance. There is no minimum or maximum z-score. These z-scores from the FEEST test represents social cognition performance. | baseline | 
| Brain grey matter volume | Grey matter volume as measured by structural MRI. | Baseline, 3 year follow-up | 
| resting state functional MRI | resting state functional MRI | Baseline, 3 year follow-up | 
| MRI: Arterial spin labeling | cerebral blood perfusion as measured by arterial spin labeling MRI | Baseline, 3 year follow-up | 
| MRI: Diffusion weighted image | White matter assessment as measured by diffusion weighted image | Baseline, 3 year follow-up | 
| MRI: susceptibility weighted image | Brain hemorrhage and iron storage as measured by susceptibility weighted image | Baseline, 3 year follow-up | 
| Optical Coherence tomography | Imaging of the retinal cell layers | Baseline and 3 year follow-up | 
| fecal zonulin | fecal zonulin as one of the measures of intestinal wall permeability | baseline | 
| Microbiota composition | Taxonomic classification of gut microbiota composition based on 16s ribosomal RNA-gene sequencing. | Baseline and 1 year follow-up | 
| fecal alpha1-antitrypsin | fecal alpha1-antitrypsin as one of the measures of intestinal wall permeability | baseline | 
| serum zonulin | serum zonulin as one of the measures of intestinal wall permeability | baseline | 
| serum lipopolysaccharide binding protein | serum lipopolysaccharide binding protein as one of the measures of intestinal wall permeability | baseline | 
| multi-sugar urinary excretion test | multi-sugar urinary excretion test as one of the measures of intestinal wall permeability | baseline | 
| Genetic subtyping | Saliva samples will be collected for clinical-genetic subtyping based on genome wide single-nucleotide polymorphism (SNP) analysis using the Illumina Screening Array (GSA-MD) | Baseline | 
| Movement Disorders Society Unified Parkinson's Disease Rating Scale III | Motor assessment measured by the Movement Disorders Society Unified Parkinson's Disease Rating Scale III, a scale describing motor performance specific for patients with Parkinson's disease. Score between 0 and 72, with a higher score indicating more severe motor impairment. | Baseline, 1 year follow-up, 3 year follow-up | 
| Change in [18F] FEOBV PET over 3 years | Change in cortical and subcortical cholinergic innervation over a time period of 3 years, as measured by baseline and follow-up [18F] FEOBV | baseline, 3 year follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson Disease, Treatment naive, Cognition, PET imaging, Acetylcholine, Magnetic Resonance Imaging, Ophthalmology, Gastrointestinal Microbiome, Neurodegenerative Diseases, Genetic subtyping