Abstract 3
Category: Clinical Science
At the end of the session, participants will be able to:
- Develop awareness of the ¼-century old hypothesis that the etiology of Parkinson’s Disease is external to the body in the form of an inhaled or swallowed agent that catalyses a sequence of events progressing centrally from the periphery in the gut.
- Become aware of the autonomic predominance of α-synuclein distribution within the spinal cord of PD, with no other dorso-ventral or rostro-caudal gradients or tendencies seen in mapped distribution of α synuclein.
- Discuss future directions for testing the hypothesis that the vagal nerve or olfactory system leads to the gut, which is “ground zero” for the etiology of Parkinson’s Disease.
COI Disclosure:
None to disclose.
Presenter
Pramath Kakodkar is a final-year resident in Diagnostic and Clinical Pathology at the University of Saskatchewan and will be starting neuropathology fellowship at Northwestern University in Chicago in 2026. His interests include neurodegenerative disease, brain tumors, and how molecular tools and digital pathology can complement classic morphologic diagnosis.
Recent projects have ranged from using amyloid PET to study primary progressive aphasia, to mapping alpha-synuclein along the spinal axis in Parkinson’s disease, to exploring malignant transformation in craniopharyngioma. He is also leading a study comparing large language models in clinical neuroscience diagnostics, with a focus on neuropathology.
Pramath Kakodkar1, Javera Tariq1, Ali H. Rajput2, Alex Rajput2, Roland N. Auer1
1Department Pathology and Lab Medicine, University of Saskatchewan, Saskatoon, Canada
2Neurology Division, University of Saskatchewan, Saskatoon, Canada
Target Audience:
Pathologists, Residents, Medical Students
CanMEDS:
Medical Expert (the integrating role), Communicator, Collaborator, Scholar
Spinal Cord α-Synuclein Mapping in Parkinson’s Disease
Abstract
It has been hypothesized that the etiology of Parkinson’s Disease (PD) lies outside the body via an inhaled/swallowed agent entering the body to cause protein-catalyzed misfolding of proteins akin to prion diseases. Early olfactory abnormalities and gut dysbiosis antedate a proposed march of α-synuclein misfolding through loci involving olfactory and autonomic systems in a body-first, not brain-first, sequence. Using anti-phospho-Ser129 α-synuclein antibodies and an immunohistochemical red readout, we mapped α-synuclein rostro-caudally, and at each level dorso-ventrally using Rexed’s laminae. A semi-quantitative scale was used. Lewy bodies, Lewy neurites and granular α-synuclein in 35 spinal cords from a sequential series of patients deceased from 2016 to 2021 showed no caudo-rostral gradient along the length of the spinal cord. However, α-synucleinopathy was highest in the thoracic cord, lowest in the sacral cord. Intermediate autonomic lamina VII of Rexed showed the highest α‑synuclein compared to dorsal sensory laminae I-IV (p=0.02) and to ventral motor laminae VIII-IX (p=0.02). Clinical stratification by Braak stage showed only that the autopsy cases with later, more severe Braak staging had earlier onset and longer disease duration. Our results show that directionality of spread within the spinal cord of PD is heterogeneous and does not correlate with Braak staging. The results lend no support for a gradient of α-synuclein within the spinal cord, neither along the neuraxis nor dorso-ventrally within any spinal level, while confirming the autonomic-predominant distribution of α-synuclein seen in the PD spinal cord.