This is a first R01 application from an early stage, new investigator and current NIEHS K01 awardee. Parkinson disease (PD) is a disabling neurodegenerative disease for which there is no cure. Years before the diagnosis of PD and the onset of motor symptoms, PD patients develop non-motor symptoms, including, importantly, constipation and gastrointestinal dysfunction. Constipation affects over 80% of PD patients and is one of the strongest risk factors for PD. Recent research shows that the enteric nervous system in the gut and the dorsal motor nucleus of the vagus nerve which anatomically links the GI system to the brain, are among the first and most severely affected by alpha-synuclein pathology characteristic of PD5 leading to the hypothesis that the gastrointestinal tract might be the site of initiation of PD. We propose to conduct a comprehensive investigation of the relation between human gut microbiome and PD, focusing on the pre- onset microbiome. We will do this by building on an ongoing Department of Defense funded project that has identified participants with pre-parkinson syndrome (PPS - defined as the co- occurrence of constipation, pRBD (probable rapid eye movement sleep behavior disorder) and hyposmia) that in a pilot study has been associated with a ~200 fold increase in PD risk. Studying the microbiome among this group, who are highly likely to develop PD or are already in the premotor state, will give us a unique look at the microbiome in PD patients prior to any potential disease-associated effects of changes in diet and lifestyle that may have confounded prior case-control studies. The proposed study will take advantage of 25 years of prospectively collected data on environmental and dietary exposures and disease outcomes in two prospective cohorts of men and women.

Public Health Relevance

Our appreciation of the impact of the gut microbiome on brain health, and especially PD, is in the early stages. This study will be the first to examine the gut microbiome in participants with premotor PD and compare it to healthy controls, controls with constipation and to recently onset PD cases. This project will thus advance our understanding of how the human gut microbiome contributes to the pathophysiology of PD and will contribute to the development of tools needed for a preclinical diagnosis and/or treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS097723-01
Application #
9156439
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sutherland, Margaret L
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$470,041
Indirect Cost
$105,144
Name
Harvard University
Department
Nutrition
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Palacios, Natalia; Hughes, Katherine C; Cereda, Emanuele et al. (2018) Appendectomy and risk of Parkinson's disease in two large prospective cohorts of men and women. Mov Disord 33:1492-1496