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Lookup NU author(s): Professor Johannes AttemsORCiD, Dr Tuomo Polvikoski
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Recent studies suggest the existence of brain-first and body-first subtypes within the Lewy body disorder (LBD) spectrum, including Parkinson’s disease. These studies primarily focused on α-synuclein propagation through the parasympathetic vagal and olfactory bulb routes, leaving the possibility of a sympathetic nervous system spreading route unexplored. In the present study, we analyzed two postmortem datasets, which included 173 and 129 cases positive for Lewy pathology. We observed a clear distinction between brain-first and body-first subtypes in early prediagnostic cases with mild Lewy pathology. Brain-first cases displayed minimal peripheral organ pathology in prediagnostic phases, contrasting with marked autonomic involvement in prediagnostic body-first cases. Utilizing the SuStaIn machine learning algorithm, we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions. Our study supports the existence of three prediagnostic LBD subtypes and highlights the sympathetic nervous system alongside the parasympathetic system in LBD onset and progression.
Author(s): Andersen KB, Krishnamurthy A, Just MK, Van Den Berge N, Skjaerbaek C, Horsager J, Knudsen K, Vogel JW, Toledo JB, Attems J, Polvikoski T, Saito Y, Murayama S, Borghammer P
Publication type: Article
Publication status: Published
Journal: Nature Neuroscience
Year: 2025
Pages: epub ahead of print
Online publication date: 13/03/2025
Acceptance date: 05/02/2025
Date deposited: 07/04/2025
ISSN (print): 1097-6256
ISSN (electronic): 1546-1726
Publisher: Nature Research
URL: https://doi.org/10.1038/s41593-025-01910-9
DOI: 10.1038/s41593-025-01910-9
Data Access Statement: The BBAR dataset utilized in this paper has been previously published in full in the supplementary section of ref. 16. https://www.nature.com/articles/s41593-025-01910-9#ref-CR16 Code availability All code and notebooks for the SuStaIn algorithm are available through GitHub at https://github.com/ucl-pond/pySuStaIn.
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