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

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ClinicalTrials.gov Identifier: NCT03645226
Recruitment Status : Recruiting
First Posted : August 24, 2018
Last Update Posted : March 25, 2019
Sponsor:
Information provided by (Responsible Party):
Professor Wing Yun Kwok, Chinese University of Hong Kong

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.


Condition or disease Intervention/treatment
REM Sleep Behavior Disorder Diagnostic Test: Colonoscopy

  Show Detailed Description

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Study Type : Observational
Estimated Enrollment : 836 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Gut Microbiota Across Early Stages of Synucleinopathy: From High-risk Relatives, REM Sleep Behavior Disorder to Early Parkinson's Disease
Actual Study Start Date : May 6, 2018
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : August 31, 2021

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
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 < 3years
  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
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.

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
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.

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 50 or above;
  4. Absence of dream enactment behaviors;
  5. A total score on REM Sleep Behavior Questionnaire (RBDQ-HK) less than 19, which is the suggestive cut-off of a diagnosis of RBD;
  6. Not cohabiting with proband
Diagnostic Test: Colonoscopy
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.

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
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.

Spouses of patients with iRBD
  1. Spouses of patients with iRBD;
  2. Age-and sex-matched with PD subjects;
  3. Chinese aged 50 or above;
  4. Absence of dream enactment behaviors;
  5. A total score on REM Sleep Behavior Questionnaire (RBDQ-HK) less than 19, which is the suggestive cut-off of a diagnosis of RBD;
  6. Cohabiting with proband.
First degree relatives of healthy controls
  1. First degree relatives of healthy controls;
  2. Age-and sex-matched with PD subjects;
  3. Chinese aged 50 or above ;
  4. Absence of dream enactment behaviors;
  5. A total score on REM Sleep Behavior Questionnaire (RBDQ-HK) less than 19, which is the suggestive cut-off of a diagnosis of RBD;
Spouses of healthy controls
  1. Spouses of healthy controls;
  2. Age-and sex-matched with PD subjects;
  3. Chinese aged 50 or above;
  4. Absence of dream enactment behaviors;
  5. A total score on REM Sleep Behavior Questionnaire (RBDQ-HK) less than 19, which is the suggestive cut-off of a diagnosis of RBD;
  6. Cohabiting with proband.



Primary Outcome Measures :
  1. Differential abundances of colonic mucosal and fecal microbial taxa by 16S ribosomal RNA sequencing across early stages of synucleinopathy [ Time Frame: 12 months ]
    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

  2. Abundances of fecal microbial taxa by 16S ribosomal RNA sequencing in control and iRBD families [ Time Frame: 12 months ]
    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

  3. Biomarkers of Parkinson's disease during early stages of synucleinopathy according to questionnaire and clinical interview [ Time Frame: 12 months ]
    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


Biospecimen Retention:   Samples Without DNA
1. Stool sample will be collected by the patients for DNA extraction.


Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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).

Criteria

Inclusion Criteria:

  • fulfill the groups criteria

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03645226


Contacts
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Contact: Mandy Yu, MPH 852-39197593 mandyyu@cuhk.edu.hk
Contact: Rachel Chan, Mphil 852-39197792 rachel.chan@cuhk.edu.hk

Locations
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Hong Kong
The Chinese University of Hong Kong Recruiting
Hong Kong, Hong Kong
Contact: Mandy Yu, MPH    852-39197593    mandyyu@cuhk.edu.hk   
Contact: Rachel Chan, MPhil    852-39197449    Rachel.chan@cuhk.edu.hk   
Shatin Hospital Recruiting
Shatin, Hong Kong
Contact: Mandy Yu, MPH    852-26367593    mandyyu@cuhk.edu.hk   
Sponsors and Collaborators
Chinese University of Hong Kong
Investigators
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Principal Investigator: Yun Kwok Wing, Professor Chinese University of Hong Kong

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Responsible Party: Professor Wing Yun Kwok, Professor, Chinese University of Hong Kong
ClinicalTrials.gov Identifier: NCT03645226     History of Changes
Other Study ID Numbers: HMRF05162876
First Posted: August 24, 2018    Key Record Dates
Last Update Posted: March 25, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: In this stage, we didn't decide whcih information of IPD will share with other researchers.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Professor Wing Yun Kwok, Chinese University of Hong Kong:
Idiopathic REM sleep
Parkinson's disease
Gut microbiota
Syncleinpathy

Additional relevant MeSH terms:
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Disease
Parkinson Disease
Mental Disorders
REM Sleep Behavior Disorder
Pathologic Processes
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
REM Sleep Parasomnias
Parasomnias
Sleep Wake Disorders