Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03645226 |
| Other study ID # |
HMRF05162876 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 6, 2018 |
| Est. completion date |
March 29, 2023 |
Study information
| Verified date |
August 2023 |
| Source |
Chinese University of Hong Kong |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial 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.
Description:
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), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). These
diseases often run debilitating and progressive courses that affect millions of people
worldwide. Up till now, there is no curable treatment and hence the development of
disease-modifying agents is of utmost importance. However, it is often too late for
intervention once the patients start to have the clinical presentations of these diseases.
For example, it was reported that there would be at least 80% of dopaminergic neuronal loss
when one starts to develop clinical motor features of PD. Thus, researchers are now focusing
on identifying at-risk subjects for early intervention. There are on-going studies to look
for biomarkers to identify subjects at risk for PD through population based cohort and family
studies, such as the Honolulu-Asia Aging Study (HAAS) and the Prospective Validation of Risk
factors for the development of Parkinson Syndromes (PRIPS). However, these studies require a
very large sample size and long duration of follow-up for the outcome evaluation.1 Another
approach is to follow-up subjects at preclinical or premotor phase of PD. Among all the
premotor clinical markers that have been identified, REM sleep behavior disorder (RBD) is
associated with the highest likelihood ratio of developing PD.2 In addition, it has been
shown that almost all RBD patients (over 80%) eventually developed neurodegenerative diseases
(mean follow-up years = 14.2).3 Hence, RBD helps to understand the progression of underlying
neurodegenerative diseases and will serve as a potential window for neuroprotective
interventions.
Gastrointestinal dysfunction and synucleinopathy In addition to RBD, gastrointestinal
dysfunction often precedes the onset of motor symptoms in patients with PD. Studies reported
that constipation could precede the onset of motor symptoms in PD by 20 years. Comparing to
those with daily bowel open, men with bowel movement frequency of less than 1 per day had an
odds ratio of 2.7 in developing PD.4 In addition, PD with co-morbid RBD seem to have more
severe constipation than PD only subjects. Constipation and other gastrointestinal
dysfunction are also more common in patients with iRBD than healthy controls.5 According to
Braak staging, the involvement of pontine areas (Stage 2) could result in both RBD and
constipation. Hence, RBD and constipation may have an interactive effect in predicting
synucleinopathy.6
What is gut microbiota and its associations with PD 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.7 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.8
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.9 The crucial roles of gut microbiota in the pathogenesis of PD are also evidenced
by other observations.10 For example, catecholamine levels are altered in germ-free mice when
compared with control mice. Antibiotics are able to reduce Firmicutes/Bacteroidetes ratio and
prevent nigrostriatal dopaminergic neurodegeneration in MPTP model of PD. Probiotics increase
production of L-DOPA by Bacillus and alleviate constipation in PD patients. Fecal
transplantation decreased GI pathology in neurodegenerative diseases. Finally, H. pylori
infection seems to increase symptom severity of PD. Taken together, growing evidence suggests
that gut microbiota may play a critical role in pathogenesis, disease progression, and
symptom fluctuation of synucleinopathy.
The exact mechanisms underlying the association between microbiota and Parkinson's disease
remain unclear. It is believed that local and systemic inflammation and oxidative stress play
a critical role in the pathogenesis of Parkinson's disease.11 In human subjects, it has been
shown that proinflammatory dysbiosis is present in PD patients, which may trigger
inflammation-induced misfolding of α-Syn and development of PD pathology.12 Gut microbiota is
considered as an important but neglected organ for immune and inflammation. It has been shown
that anti-inflammatory butyrate-producing bacteria and proinflammatory proteobacteria were
significantly more abundant in feces and mucosa samples in patients with PD than healthy
controls.12 Taken together, these findings suggest that gut microbiota, which is likely to
increase inflammatory pathway, plays a critical role in the pathogenesis of Parkinson's
disease.
Limitations 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
should be further clarified. It has been shown that medications treating PD also affect the
gut microbiome.13 Moreover, the microbiota may be affected by a number of factors commonly
found in PD, such as constipation per se and diet.14. In this regard, 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. In this regard, a case-control study with high-risk subjects is able to recruit
sufficient cases at different stages of synucleinopathy.
Aims:
1. To identify the differences in colonic bacterial composition in mucosa and feces among
early PD converted from iRBD, iRBD, first degree relatives (FDRs) of patients with iRBD,
and healthy controls;
2. To correlate the abundance of those microbiota with clinical biomarkers of
synucleinopathy.
We hypothesize that
1. Colonic bacterial composition, especially those related to inflammation (such as
Blautia, Coprococcus, and Roseburia), in mucosa and feces is more abundant in different
stages of synucleinopathy, namely early PD without dementia (converted from iRBD), iRBD,
FDRs of patients with iRBD, and healthy controls with a dose-response pattern.
2. The abundance of microbiota is associated with other biomarkers, for example, subtle
motor signs and constipation, in relation to PD and RBD.
