# Skin-Based α-Synuclein Deposits Detection Across the Prodromal Continuum of Synucleinopathies: Updated Evidence and Perspectives

## TL;DR

This paper reviews evidence that skin-based α-synuclein deposits can help detect early signs of synucleinopathies like Parkinson's disease before symptoms appear.

## Contribution

The paper provides updated evidence and perspectives on skin-derived biomarkers for early detection of synucleinopathies.

## Key findings

- Skin biopsy-based detection of phosphorylated α-synuclein is a promising biomarker for synucleinopathies.
- Cutaneous α-synuclein pathology may precede motor symptoms and predict progression to overt disease.
- Seed amplification assays in skin samples offer a minimally invasive diagnostic tool for prodromal synucleinopathies.

## Abstract

Parkinson’s disease (PD) and associated synucleinopathies are preceded by a prolonged prodromal phase during which neurodegenerative processes evolve years before the onset of motor or cognitive symptoms. Identifying biologically specific and accessible biomarkers during this window is critical for early diagnosis, risk stratification, and the development of disease-modifying therapies. Increasing evidence supports the skin as a key peripheral tissue involved in synucleinopathy, offering a minimally invasive source for in vivo detection of pathological α-synuclein. This review summarizes current evidence on skin-derived biomarkers across the prodromal continuum of PD, with particular emphasis on skin biopsy-based detection of phosphorylated α-synuclein and α-synuclein seed amplification assays (SAAs). Findings in high-risk prodromal phenotypes, including idiopathic REM sleep behavior disorder (iRBD) and pure autonomic failure (PAF), are critically reviewed. Emerging data suggest that cutaneous α-synuclein pathology may precede nigrostriatal dopaminergic degeneration and may predict phenoconversion to overt synucleinopathies. Important knowledge gaps are highlighted, including the lack of data in other prodromal phenotypes such as hyposmia. Overall, skin-based biomarkers appear to represent promising, scalable tools for biological diagnosis, prognostication, and enrichment of prodromal PD cohorts in clinical trials.