Gastrointestinal (GI) symptoms are significant non-motor manifestations of Parkinson disease (PD) that can precede PD motor symptoms by years; cognitive dysfunction is an important late, non-motor manifestation. Braak’s hypothesis proposes that α-synuclein (αS) aggregates propagate along vagal or olfactory afferents to the central nervous system (CNS), leading to motor and non-motor features of PD. However, αS aggregates are also identified in enteric neurons in elderly people without PD. Squalamine prevention of αS aggregates improved constipation in PD. Density of nigrostriatal dopamine transporters (as assessed by 123I-FP-CIT SPECT) are relevant to cognitive processing in PD. αS oligomers in CSF is a marker of early synucleinopathies and αS protein misfolding in PD implies propagation from the gut to brainstem via the vagus nerve. The relationship between density of nigrostriatal dopamine or aS misfolding in gastrointestinal mucosa and the GI pathophysiology in human PD is unknown. To date, prior studies have typically addressed one pathological mechanism and one GI manifestation. Our multidisciplinary characterization of GI and neural phenotype in PD is key for this first study in 3 groups of humans of the mechanistic roles of the central neural circuitry, central dopamine receptors’ density, autonomic pathways, as well as αS expression in the gastrointestinal and colonic mucosa and microbiome in gut pathophysiology in human PD. Our overall hypothesis is that reduced nigrostriatal dopamine transmitter, autonomic dysfunction and increased αS expression or misfolding in the gastric, duodenal or sigmoid mucosa are associated with abnormal GI motor and barrier functions and with submucosal neuronal dopamine and αS expression in patients with PD with GI symptoms. We propose a prospective cohort design study with two aims in 3 groups, that is, PD patients with Hoehn and Yahr motor stages 1-3 with/without GI symptoms, and age-matched controls with n=24 per group: Aim 1: To compare GI motor functions (gastric emptying and accommodation, colonic transit, defecatory function), small bowel permeability, duodenal and stool microbiome and putative mechanisms (GI and sigmoid mucosal transcriptome, including αS misfolding, tight junction protein, and dopamine receptor expression). Aim 2: To quantitate nigrostriatal dopamine transporter expression, autonomic symptoms, and vagal and sympathetic functions using validated 123I-FP-CIT SPECT, COMPASS-31 questionnaires, and CASS scores, respectively and compare the central dopamine transporter expression and autonomic functions In sub-aims, we compare central and autonomic functions, GI transit and permeability, and mucosal αS mucosal expression or mis-folding in the 3 groups. The significance of the proposal lies in identification of mechanisms, and potential targets for future interventions directed to vagal and autonomic dysfunction, aggregation or misfolding of αS in gut mucosa, as well as dopamine expression to treat GI manifestations of PD.

Project Narrative/ Relevance Gastrointestinal symptoms including nausea, dysphagia, constipation, and defecatory dysfunction are significant non-motor manifestations of Parkinson disease that impact quality of life. The degenerative changes in the brain that result from Parkinson disease are thought to originate from abnormal proteins absorbed in the gastrointestinal tract. Thus, by characterizing how those proteins in the lining of the stomach and intestines or changes in the brain centers and nerves are associated with gastrointestinal symptoms, the proposed studies will identify targets for treatment such as medications that neutralize the abnormal proteins or restore normal nerve functions.