Gut Microbiota in the Progression of Alpha-synucleinopathies

Recruiting

• Conditions: REM Sleep Behavior Disorder
• Interventions: Other: No intervention

• Registration Number: NCT05353868
• Lead Sponsor: Chinese University of Hong Kong

Brief Summary

The aim of this study is to correlate baseline gut microbiota features and the progression of neurodegeneration in the established cohort of patients with early Parkinson's disease.

Detailed Description

Alpha-synucleinopathy is a major group of neurodegenerative diseases that include Parkinson's disease and Dementia of Lewy bodies. They are known to have a long preclinical development, and prodromal markers that indicate the onset of early phase of the neurodegenerative process present along the way. Among the markers, idiopathic REM sleep behavior disorder (iRBD), a distinct form of parasomnia characterised by the presence of dream-enactment behaviour and REM sleep without atonia, represent a particularly high conversion likelihood that makes it a de facto precursor of clinical diseases (14 years conversion rate \>95%). Thus, RBD serves as an exclusive opportunity for us to study the early-stage progression of α-synucleinpathies, and a window for early neuroprotective intervention.

In the context of α-synucleinopathic neurodegenerative diseases, high prevalence of gastrointestinal dysfunction and the presence of alpha-synuclein aggregates in the enteric nervous system at the early stage of disease have been found. These early findings were embedded in an influential Braak's hypothesis that the process of neurodegeneration can be started by 'unknown pathogen' from gut and spread to the central nervous system via vagus nerve in a caudal-rostral manner (medulla-\>pon-\>mid/forebrain-\>cortex). Human data showed that microbiome composition in patient with Parkinson's disease is different from control. The relative abundance of certain microbiotas, such as Enterobacteriaceae, have been shown to be associated with the severity of motor symptoms in patients with Parkinson's disease. It is hypothesized that microbiota dysbiosis resulting in a pro-inflammatory gut environment, which in turn create excessive oxidative stress and trigger alpha-synuclein misfolding cascade. While available evidence suggests that gut-brain hypothesis potentially plays a role in the disease process of α-synucleinopathies, the exact detail of microbiota involvement will need further examination. The key question of whether microbiota dysbiosis is driving or being driven by the process of neurodegeneration, need to be answered by prospective empirical studies that examine the longitudinal course of neurodegeneration from early to late stage, and to relate such course with the corresponding dynamic profile of the subjects' gut microbiota composition. Most of the available studies on this subject were cross-sectional studies that based on patients with Parkinson's disease, the terminal stage of the neurodegenerative process. There has been only two studies that include RBD patients, suggesting some alteration of microbiota happens in RBD stage already, but the number of RBD subjects included was small (n = 21 and 26), and there was no follow-up data (10, 11). In other words, there is no study that can answer such question at the moment. This remarkable gap in literature probably reflects two major obstacles researchers would face in planning such study: the difficulties in identifying and recruiting subjects with early-stage α-synucleinopathies, and the need for sufficient follow-up period to unfold the neurodegeneration process. In this regard, the investigators investigated gut microbiota composition in our established cohort of RBD and RBD family. Preliminary finding indicated gut dysbiosis has already occurred at or likely before the onset of RBD, at an even earlier stage of synucleinopathy (i.e., high-risk relatives of RBD). For example, consistent overabundance of Ruminococcaceae UCG-002 were found in RBD relatives, patient with RBD and early PD, as compared with controls.

In this study, the investigators will perform 3-year follow-up of clinical assessments and gut microbiota measurement. The investigators aim to correlate baseline gut microbiota features and the progression of neurodegeneration, e.g., emerged autonomic dysfunctions, phenoconversion, in the established cohort of patients with early Parkinson's disease, idiopathic RBD, first-degree relatives (FDRs) of patients with iRBD and healthy controls. Besides, the investigator will examine the associations between long-term gut microbiota changes and progression of neurodegenerative biomarkers and compare the long-term changes of gut microbiota between controls and different early stages of α-synucleinopathies.

Study Timeline

• Study First Submitted: 2022-01-13
• Study Start: 2022-02-01
• Study First Submitted QC: 2022-04-25
• Study First Posted: 2022-04-29
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-17
• Last Update Posted: 2024-04-19
• Primary Completion: 2024-06-30
• Study Completion: 2024-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 490

Inclusion Criteria

• recruit from the subjects who completed the baseline study

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Exclusion Criteria

• The use of probiotics or antibiotics within three months prior to sample collection;
• Pre-existing gastrointestinal diseases, such as inflammatory bowel disease.
• Not capable of giving informed consent for participation of the study.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Early PD	No intervention	1. Recruited in the baseline study as a subject of the Early PD group 2. Completed baseline assessment and stool sample collection 3. Being capable of giving informed consent for participation of the study
Health control	No intervention	1. Recruited in the baseline study as a subject of the 'healthy controls' group 2. Completed baseline assessment and stool sample collection 3. Being capable of giving informed consent for participation of the study
iRBD	No intervention	1. Recruited in the baseline study as a subject of the iRBD group 2. Completed baseline assessment and stool sample collection 3. Being capable of giving informed consent for participation of the study
First degree relatives of patient with iRBD	No intervention	1. Recruited in the baseline study as a subject of the 'First degree relatives of patients with iRBD' group 2. Completed baseline assessment and stool sample collection 3. Not cohabiting with iRBD proband

Primary Outcome Measures

Name	Time	Method
Composition of gut microbiota	2 years	Correlation of baseline gut microbiota features and the progression of α-synucleinopathy neurodegeneration.

Trial Locations

Locations (1)

The Chinese University of Hong Kong; 🇭🇰 Hong Kong, Hong Kong