Role of altered gut immune response in Lewy Body Disease

Stanford University, Stanford CA

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Abstract

PROJECT SUMMARY/ABSTRACT Lewy Body Diseases (LBD), which include Parkinson's Disease (PD) and dementia with Lewy bodies (DLB), represents a spectrum of progressive, debilitating neurological disorders for which there is no cure. Emerging evidence indicates that for some individuals with LBD and those with prodromal LBD, including those with isolated REM Sleep Behavior Disorder (iRBD), peripheral organs are involved including the gut. Furthermore, peripheral insults including alterations to the gut microbiota, immune dysregulation, and toxin exposure have been implicated in disease pathogenesis. However, few studies have provided comprehensive characterization of pathologic, immunologic, microbiologic and physiologic parameters in patients with PD or iRBD thereby precluding definitive conclusions about the role peripheral organs have in pathobiology and disease signatures. The parent grant, “Role of altered gut immune response in Lewy Body Disease”, included a novel paradigm whereby the gut microbiome influences neurodegenerative disease through immune mechanisms. We hypothesized that altered gut neuro-immune interactions, mediated by microbial derived factors, promotes LBD progression. The parent grant included two Aims: Aim 1 using a multi-modal approach to characterized peripheral involvement in PD, iRBD and healthy controls and Aim 2 assessing whether the microbiota promotes LBD by gut immune mechanisms. In addition to our original Aims, the proposed administrative supplement will add critical neurological and gastroenterological assessments, which have been added to the Master Protocol for the overall Gut-Brain-Parkinson’s Disease Consortium (GBPDC). Together, in 10 iRBD, 30 PD (10 mild, 10 moderate, 10 severe) and 10 household controls, we propose adding Aim 3 to perform the following assessments not included in our parent grant: Research Flexible Sigmoidoscopies, Intestinal transit (Sitzmark), Rectal Balloon Expulsion Time, Anorectal Monometry, and Videofluoroscopic swallowing study with Penetration-Aspiration Scale, Dynamic Imaging Grade of Swallowing Toxicity, Modified Barium Swallow Impairment Profile and Functional Oral Intake Scale. In addition, we are adding 15 participant surveys (7 GI, 1 PD motor, 7 PD non-motor), an additional 6-month virtual assessment, and additional biological samples (screening labs, banked blood, PBMCs, skin biopsy) in the next year of the study as part of the GBPDC Master Protocol.