Gut Microbiota in the Progression of Alpha-synucleinopathies

Gut Microbiota in the Progression of Alpha-synucleinopathies: a Prospective Follow-up Study

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.

Study Overview

• Status: Recruiting
• Conditions: REM Sleep Behavior Disorder
• Intervention / Treatment: Other: No intervention

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 Type: Observational
• Enrollment (Estimated): 490

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • The Chinese University of Hong Kong
    • Contact: Mandy Yu, MPH; Phone Number: 852-39197593; Email: mandyyu@cuhk.edu.hk
    • Contact: Rachel Chan, MPhil; Phone Number: 852-39197449; Email: Rachel.chan@cuhk.edu.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

We will recruit from the subjects who completed the baseline study, which represent different stages of α-synucleinopathies, namely patients with PD (Braak's stages 3 or 4) without dementia, patients with iRBD (Braak's stage 2), first degree relatives of iRBD patients (iRBD-FDRs, Braak's stage 0 or 1), and healthy controls (Braak's stage 0).

Description

Inclusion Criteria:

• recruit from the subjects who completed the baseline study

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.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composition of gut microbiota	Correlation of baseline gut microbiota features and the progression of α-synucleinopathy neurodegeneration.	2 years

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: January 13, 2022
• First Submitted That Met QC Criteria: April 25, 2022
• First Posted (Actual): April 29, 2022

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Gut microbiota; Parkinson's disease; REM sleep behavior disorder
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Sleep Wake Disorders; Neurodegenerative Diseases; Parasomnias; Proteostasis Deficiencies; REM Sleep Parasomnias; Mental Disorders; Synucleinopathies; REM Sleep Behavior Disorder
• Other Study ID Numbers: NTEC-2021-0614

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data will be handled and stored under Department of Psychiatry and PI will be responsible for the safekeeping.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No