Duodenal alpha-Synuclein Pathology and Enteric Gliosis in Advanced Parkinson's Disease

Background: The role of the gut-brain axis has been recently highlighted as a major contributor to Parkinson's disease (PD) physiopathology, with numerous studies investigating bidirectional transmission of pathological protein aggregates, such as alpha-synuclein (aSyn). However, the extent and the characteristics of pathology in the enteric nervous system have not been fully investigated. Objective: We characterized alpha Syn alterations and glial responses in duodenum biopsies of patients with PD by employing topography-specific sampling and conformation-specific alpha Syn antibodies. Methods: We examined 18 patients with advanced PD who underwent Duodopa percutaneous endoscopic gastrostomy and jejunal tube procedure, 4 untreated patients with early PD (disease duration <5 years), and 18 age- and -sex-matched healthy control subjects undergoing routine diagnostic endoscopy. A mean of four duodenal wall biopsies were sampled from each patient. Immunohistochemistry was performed for anti-aggregated aSyn (5G4) and glial fibrillary acidic protein antibodies. Morphometrical semiquantitative analysis was performed to characterize alpha Syn-5G4(+) and glial fibrillary acidic protein-positive density and size. Results: Immunoreactivity for aggregated alpha-Syn was identified in all patients with PD (early and advanced) compared with controls. alpha Syn-5G4(+) colocalized with neuronal marker beta-III-tubulin. Evaluation of enteric glial cells demonstrated an increased size and density when compared with controls, suggesting reactive gliosis. Conclusions: We found evidence of synuclein pathology and gliosis in the duodenumof patients with PD, including early de novo cases. Future studies are required to evaluate how early in the disease process duodenal pathology occurs and its possible contribution to levodopa effect in chronic patients. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.