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 thediagnosis 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 isone of the strongest risk factors for PD. Recent research shows that the enteric nervous system in the gut andthe dorsal motor nucleus of the vagus nerve which anatomically links the GI system to the brain, are amongthe first and most severely affected by alpha-synuclein pathology characteristic of PD5 leading to thehypothesis 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 Defensefunded 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) thatin a pilot study has been associated with a ~200 fold increase in PD risk. Studying the microbiome among thisgroup, who are highly likely to develop PD or are already in the premotor state, will give us a unique look at themicrobiome in PD patients prior to any potential disease-associated effects of changes in diet and lifestyle thatmay have confounded prior case-control studies. The proposed study will take advantage of 25 years ofprospectively collected data on environmental and dietary exposures and disease outcomes in two prospectivecohorts of men and women.
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 tohealthy controls; controls with constipation and to recently onset PD cases. This project will thus advance ourunderstanding of how the human gut microbiome contributes to the pathophysiology of PD and will contributeto the development of tools needed for a preclinical diagnosis and/or treatment.
|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|