Gut Microbiota Across Early Stages of Synucleinopathy: From High-risk Relatives, REM Sleep Behavior Disorder to Early Parkinson's Disease

NCT03645226 | Completed

• 1 other identifier: HMRF05162876
• Study Type: observational
• Target: 441
• Locations: 1 country
• Sites: 2

Brief Summary

With the global ageing population, neurodegenerative disorders including synucleinopathy are major burdens to patients, carers and society. Synucleinopathy refers to a group of neurodegenerative diseases characterized by abnormal aggregation of alpha-synuclein protein in the central nervous system (CNS). Common examples of synucleinopathy are Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Among all the premotor clinical markers that have been identified, a sleep disorder known as REM sleep behavior disorder (RBD) is associated with the highest likelihood ratio of developing PD. In addition, it has been shown that almost all RBD patients (over 80%) eventually developed neurodegenerative diseases after 14 years follow-up. Gut microbiota and synucleinopathy In recent years, several key studies have advanced our understanding regarding the roles that brain-gut-microbiota axis plays in the pathogenesis of brain diseases, including PD. It has been shown that gut microbiota is implicated in a series of pathophysiological changes in PD, including motor deficits, microglia activation, and αSyn pathology in mice model with overexpression of αSyn. Furthermore, some microbiotas, such as enterobacteriaceae, have been shown to be positively associated with the severity of PD symptoms, including postural instability and gait difficulty. Limitations in previous studies and knowledge gaps Nonetheless, the answers for several key questions regarding the roles of gut microbiota in the progression of synucleinopathy are still unclear. First, whether these microbiotas found in previous studies are the causes or the effects of PD. For example, medications treating PD may also affect the gut microbiome. Moreover, the microbiota may be affected by a number of factors commonly found in PD, such as constipation per se and diet. In this regard, an influential hypothesis of synucleinopahy was proposed by Braak et al at which the early premotor features including gastro-enterology symptoms, such as constipation and RBD would predate the onset of PD by some years. Thus, it is crucial to compare the microbiota among individuals at different stages of synucleinopathy. In view of slow progression of synucleinopathy and a relatively low prevalence of synucleinopathy in the general population, it is impractical to run a prospective study to examine this research question. Finally, gut microbiota is determined by both genetic and environmental factors. A family cohort design will help to understand the genetic and environmental influences on the association between microbiota and synucleinopathy.

Conditions

REM Sleep Behavior Disorder

Keywords

Idiopathic REM sleep; Parkinson's disease; Gut microbiota; Syncleinpathy

Outcome Measures

Primary Outcomes (3)

• Differential abundances of colonic mucosal and fecal microbial taxa by 16S ribosomal RNA sequencing across early stages of synucleinopathy

  To investigate differential abundances of colonic mucosal and fecal microbial taxa by 16S ribosomal RNA sequencing across early stages of synucleinopathy compared with healthy controls

  12 months

• Abundances of fecal microbial taxa by 16S ribosomal RNA sequencing in control and iRBD families

  To investigate the abundances of fecal microbial taxa by 16S ribosomal RNA sequencing among probands, first-degree relatives and spouses in both healthy control and iRBD families

  12 months

• Biomarkers of Parkinson's disease during early stages of synucleinopathy according to questionnaire and clinical interview

  To investigate the background risk and prodromal markers according to the MDS research criteria for prodromal Parkinson's disease in each group by questionnaire and clinical interview, for example , subtle motor signs , constipation and olfactory function

  12 months

Study Arms (4)

Early PD subjects converted from iRBD

1. Chinese aged 50 or above 2. Being capable of giving informed consent for participation of the study 3. PD diagnosis confirmed by neurologists according to the United Kingdom Parkinson's Disease Survey Brain Bank. Assessment tools including Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn \& Yahr Staging will be used for severity grading. 4. Onset of PD symptoms of \<5 years 5. In view of the heterogeneity of PD, we will only include those patients with RBD preceding the onset of motor symptom of PD.

Diagnostic Test: Colonoscopy

iRBD subjects

1. Age-and sex-matched with PD subjects 2. Chinese aged 50 or above 3. Being capable of giving informed consent for participation of the study 4. RBD diagnosis according to the International classification of sleep disorder 3rd edition (ICSD 3rd), fulfilling both the clinical and video-polysomnography (vPSG) criteria.

Diagnostic Test: Colonoscopy

First degree relatives of patients with iRBD

1. First degree relatives of patients with iRBD; 2. Age-and sex-matched with PD subjects 3. Chinese aged 40 or above; 4. Absence of dream enactment behaviors; 5. Not cohabiting with proband

Diagnostic Test: Colonoscopy

Healthy Controls

1. Age-and sex-matched with PD subjects; 2. Chinese aged 50 or above; 3. Being capable of giving informed consent for participation of the study; 4. Without a personal history or a family history of PD or RBD; 5. Absence of dream enactment behaviors; 6. A total score on REM Sleep Behavior Questionnaire (RBDQ-HK) less than 19, which is the suggestive cut-off of a diagnosis of RBD; 7. Absence of RSWA as measured by v-PSG.

Diagnostic Test: Colonoscopy

Interventions

Colonoscopy DIAGNOSTIC_TEST

All subjects will undergo standard mechanical bowel preparation with 4 liters of polyethylene glycol (Klean-Prep, Norgine Ltd., Middlesex, UK). Total colonoscopy will be performed by experienced endoscopists under conscious sedation with intravenous benzodiazepines and narcotics. A conventional intermediate-length colonoscope (Olympus Corporation, Tokyo, Japan) will be used. One mucosal biopsy will be taken in the descending colon. Biopsies will be performed using standard biopsy forces without needle (Olympus Corporation, Tokyo, Japan). Half of the samples will be immersed in 4 oC normal saline solution. All samples will be immediately sent to pathology department and will be stored in a -80 oC freeze for processing of microbiota analyses.

Early PD subjects converted from iRBD; First degree relatives of patients with iRBD; Healthy Controls; iRBD subjects

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

In the case-control study, we will recruit 7 groups of subjects, which represent different stages of Parkinson's disease, 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 (Braak's stage 0 or 1), healthy controls (Braak's stage 0). In the familial study, another 3 groups of subjects will be recruited to understand the genetic and environmental influences on differential microbiotas, including spouses of iRBD, spouses of healthy controls and first degree relatives of healthy controls. We will document the cohabiting status and contact frequency among family members within the same family and excluded FDRs who are cohabiting with the proband or spouses who are not cohabiting with the proband. In addition, we will also recruit FDRs and spouses with and without biomarkers of neurodegeneration (such as constipation).

You may qualify if:

• fulfill the groups criteria

You may not qualify if:

• Presence of narcolepsy and other neurodegenerative diseases (except for PD group) that may give rise to RBD and RWSA;
• A total score of the MOCA ≤ 22 and the CDR ≥ 1, indicating dementia;
• The use of probiotics or antibiotics within three months prior to sample collection;
• Pre-existing gastrointestinal diseases, such as inflammatory bowel disease.

Sponsors & Collaborators

• Chinese University of Hong Kong: lead

Study Sites (2)

The Chinese University of Hong Kong

Hong Kong, Hong Kong

Location

Shatin Hospital

Shatin, Hong Kong

Location

Biospecimen

Retention: SAMPLES WITHOUT DNA

1\. Stool sample will be collected by the patients for DNA extraction.

MeSH Terms

Conditions

REM Sleep Behavior Disorder; Parkinson Disease

Interventions

Colonoscopy

Condition Hierarchy (Ancestors)

REM Sleep Parasomnias; Parasomnias; Sleep Wake Disorders; Nervous System Diseases; Mental Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Endoscopy, Gastrointestinal; Endoscopy, Digestive System; Diagnostic Techniques, Digestive System; Diagnostic Techniques and Procedures; Diagnosis; Endoscopy; Diagnostic Techniques, Surgical; Digestive System Surgical Procedures; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures

Study Officials

• Yun Kwok Wing, Professor

  Chinese University of Hong Kong

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 19, 2018
• First Posted: August 24, 2018
• Study Start: May 6, 2018
• Primary Completion: March 27, 2023
• Study Completion: March 29, 2023
• Last Updated: August 30, 2023

Record last verified: 2023-08

Locations

HK (2)