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Parkinson disease

α-Synuclein signatures mark Parkinson disease subtypes

Nature Reviews Neurology volume 22, page 4 (2026)Cite this article

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The synuclein origin and 12 connectome (SOC) model proposes that there are two subtypes of Parkinson disease (PD): a brain-first subtype in which α-synuclein pathology originates in the brain and spreads to the periphery, and a body-first subtype in which the pathology originates in peripheral autonomic nerves and spreads to the brain. Recent research published in Brain indicates that these subtypes can be distinguished by patterns of cutaneous α-synuclein deposition.

Liu and colleagues recruited 126 patients with brain-first PD (defined clinically as REM sleep behaviour disorder preceding motor symptoms), 79 patients with body-first PD and 60 healthy control individuals. Phosphorylated α-synuclein immunostaining and α-synuclein seed amplification assays were performed on skin biopsies taken from the distal leg and the posterior cervical region (C7). Patients with body-first PD showed higher phosphorylated α-synuclein levels in the distal leg than in the C7 biopsies, whereas the opposite was true for patients with brain-first PD. Furthermore, seed amplification assays revealed accelerated α-synuclein seeding activity in the body-first group compared with the brain-first group.

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  1. Nature Reviews Neurology http://www.nature.com/nrneurol/

    Heather Wood

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  1. Heather Wood
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Correspondence to Heather Wood.

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Wood, H. α-Synuclein signatures mark Parkinson disease subtypes. Nat Rev Neurol 22, 4 (2026). https://doi.org/10.1038/s41582-025-01176-6

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  • DOI: https://doi.org/10.1038/s41582-025-01176-6

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