Single-center Pathophysiological Study of the Role of Inflammation, Changes in the Intestinal Epithelial Barrier and the Intestinal Microbiota in Parkinson's Disease

Study Overview
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Brief Summary
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Converging evidence from the literature suggests that digestive inflammation may play a role in the development of Parkinson's disease (PD). The investigators showed in the laboratory in a pilot study that PD patients have digestive inflammation and that the level of inflammation was inversely related to the length of the disease course. This digestive inflammation could be at the origin of an increased intestinal permeability in a subpopulation of parkinsonian patients, cause or consequence of modifications of the intestinal microbiota, thus offering a potential portal of entry for a pathogen according to Braak's theory. To opponents of this theory, it could also reflect the spread of inflammation from the Central nervous System to the Enteral Nervous System (ENS), via the brain-gut axis. Investigators' hypothesis is that digestive inflammation occurs very early in Parkinson's disease and that it is associated with hyperpermeability of the intestinal epithelial barrier and a change in the intestinal microbiota composition. The investigators propose to study the inflammation markers in the ENS of patients with a pre-motor form of PD (idiopathic Rapid Eye Movement (REM) sleep behavior disorder, n = 20), early-stage PD (<5 years, without dopatherapy, n = 20), more advanced PD (> 5 years, n = 20) and control subjects (n = 20), on colonic biopsies taken during a rectosigmoidoscopy or a coloscopy. Intestinal permeability will be measured by ex-vivo techniques (in a Ussing chamber), the composition of the microbiota will be established by sequencing 16s RNA and the lesional load of phosphorylated alpha-synuclein will be evaluated by immunohistochemistry. All of these parameters will be correlated with clinical data on the severity of PD: duration of development, age, total Unified Parkinson's Disease Rating Scale (UPDRS) motor score and axial sub-score, cognitive tests (Montreal Cognitive Assessment, MoCA), existence of a probable idiopathic REM sleep behavior disorder (REM Sleep Behavior Disorder Screening Questionnaire RBDSQ), olfactory tests, complaint of dysautonomia (SCales for Outcomes in Parkinson's disease - autonomic dysfunction, SCOPA-Aut). The analysis of inflammation markers, the intestinal barrier and the microbiota could be a first step making it possible to formulate physiopathological hypotheses on the development of PD, to propose predictive biomarkers of the disease and its severity and to design early interventions in the hope of modifying the evolutionary course of the pathological process.

Official Title
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Single-center Pathophysiological Study of the Role of Inflammation, Changes in the Intestinal Epithelial Barrier and the Intestinal Microbiota in Parkinson's Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Procedure: Rectosignoidoscopy
* Procedure: Coloscopy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parkinson's Disease patients : patients with Parkinson's disease according to the criteria of the United Kingdom Parkinson's disease survey brain bank (UKPDSBB) aged over 18 years who have given their consent to participate in this study Idiopathic REM sleep behavior disorders patients: patients with an Idiopathic REM sleep behavior disorder confirmed by video-polysomnography (International Classification of Sleep Disorders-3 criteria), not explained by a pathology (narcolepsy, brainstem injury, neurodegenerative disease) aged over 18 years having given their consent to participate in this study Control: patients undergoing coloscopy for family screening for digestive polyps aged over 18 who have given their consent to participate in this study Exclusion Criteria: dementia (MINI MENTAL STATE EXAMINATION score <24) history of authenticated colonic disease (inflammatory disease, adenocarcinoma) or functional colopathy in control subjects or having preceded the first signs of Parkinson's Disease or Idiopathic REM sleep behavior disorder for more than 5 years, respectively in Parkinson's Disease and Idiopathic REM sleep behavior disorder patients history of prescription of antibiotic treatment, acute gastrointestinal illness or hospitalization for an acute medical pathology or for a surgical procedure in the last month anticoagulant treatment or coagulopathy pregnant or breastfeeding women, woman not benefiting from effective contraception if of childbearing age adults under tutorship, curatorship or under legal protection For patients with Idiopathic REM sleep behavior disorder: - presence of Parkinson's Disease according to United Kindom Parkinson's Disease Brain Bank criteria For control: presence of a Parkinson's Disease according to United Kindom Parkinson's Disease Brain Bank criteria complaint of nighttime unrest in favor of a probable Idiopathic REM sleep behavior disorder

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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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Idiopathic REM sleep behavior disorders<br>Group of 20 Patients with an Idiopathic REM sleep behavior disorder confirmed by video-polysomnography (International Classification of Sleep Disorders-3 criteria), not explained by a pathology (narcolepsy, brainstem injury, neurodegenerative disease) | Procedure: Rectosignoidoscopy<br>* Rectosignoidoscopy for colonic biospsies collection<br>Procedure: Coloscopy<br>* Coloscopy for colonic biospsies collection<br>|
| Other: Beginning Parkinson's disease<br>Group of 20 patients with Parkinson's Disease which has been progressing for less than 5 years and who have not received dopatherapy | Procedure: Rectosignoidoscopy<br>* Rectosignoidoscopy for colonic biospsies collection<br>Procedure: Coloscopy<br>* Coloscopy for colonic biospsies collection<br>|
| Other: Parkinson's disease state Phase<br>Group of 20 patients with Parkinson's Disease for more than 5 years | Procedure: Rectosignoidoscopy<br>* Rectosignoidoscopy for colonic biospsies collection<br>Procedure: Coloscopy<br>* Coloscopy for colonic biospsies collection<br>|
| Other: Control<br>Group of 20 patients undergoing coloscopy for family screening for digestive polyps | Procedure: Coloscopy<br>* Coloscopy for colonic biospsies collection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TNF-α | TNF-α in colonic biopsies measured by ELISA | In the three months following the inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IFN-γ | IFN-γ in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| IL-6 | IL-6 in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| IL-1β | IL-1β in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| IFN-α2 | IFN-α2 in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| MCP-1 (CCL2) | MCP-1 (CCL2) in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| IL-8 (CXCL8) | IL-8 (CXCL8) in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| IL-10 | IL-10 in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| IL-12p70 | IL-12p70 in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| IL-17A | IL-17A in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| IL-18 | IL-18 in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| IL-23 | IL-23 in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| IL-33 | IL-33 in colonic biopsies measured by ELISA | In the three months following the inclusion | 
| Permeability slopes for sulfonic acid | Permeability slopes for sulfonic acid (low molecular weight) and dextran (high molecular weight) measured in a Ussing chamber | In the three months following the inclusion | 
| Diversity of the intestinal microbiota | Bacterial diversity in each group by genetic sequencing of 16s RNA | In the three months following the inclusion | 
| Relative abundance of the intestinal microbiota | Relative abundance of different families or genera or bacterial species in each group by genetic sequencing of 16s RNA | In the three months following the inclusion | 
| Quantification of phosphorylated alpha-synuclein | Presence or absence of inclusion of phosphorylated alpha-synuclein, if presence: quantification (in thioflavin fluorescence intensity and amplification time in minutes) | In the three months following the inclusion | 
| Duration of progression | Disease duration of progression as Parkinson's disease clinical severity parameter | At inclusion | 
| Age | Age as Parkinson's disease clinical severity parameter | At inclusion | 
| Total Unified Parkinson Disease Rating Scale motor score | Total Unified Parkinson Disease Rating Scale motor score as Parkinson's disease clinical severity parameter | At inclusion | 
| Unified Parkinson Disease Rating Scale axial sub-score | Unified Parkinson Disease Rating Scale axial sub-score as Parkinson's disease clinical severity parameter | At inclusion | 
| Montreal Cognitive Assessment score | Montreal Cognitive Assessment score as Parkinson's disease clinical severity parameter | At inclusion | 
| Presence or absence of a probable Idiopathic REM sleep behavior disorders | Presence or absence of a probable Idiopathic REM sleep behavior disorders (REM Sleep Behavior Disorder Screening Questionnaire score ≥ 5) as Parkinson's disease clinical severity parameter | At inclusion | 
| Olfactory tests | Olfactory tests (Sniffin 'sticks test score) as Parkinson's disease clinical severity parameter | At inclusion | 
| Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction score | Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction score as Parkinson's disease clinical severity parameter | At inclusion |