Objective: To evaluate the presence of α-synuclein seeds (syn-seeds) in skin samples from PPMI participants, including prodromal, early and late Parkinson’s disease (PD) using a skin α-synuclein seed amplification assay (skin_synSAA).

Background: Syn-seeds have been established as a biomarker for Lewy body diseases and multiple system atrophy which can be detected from the cerebrospinal fluid (CSF) using CSF_synSAA. Recent findings suggest that syn-seeds can be detected in the skin of PD subjects, but biological implications associated with disease progression and clinical presentation remain unclear.

Method: Skin homogenates (SH) were generated using 3mm biopsy samples (neck C7) from PPMI participants. The SH were analyzed in triplicates at Amprion using skin_synSAA that was modified from the previously reported CSF_synSAA (Ma et al., 2024). A total of 287 participants included 64 early sporadic PD (<3y from diagnosis), 12 late sporadic PD (≥3yr from diagnosis), 49 PSG-confirmed REMsleep behavior disorder (RBD) prodromal, 73 possible RBD prodromal, 72 hyposmia prodromal, and 17 healthy control (HC) cases. Two skin samples were analyzed for a subgroup of participants within early PD, possible RBD, and hyposmia groups. All participants had extensive clinical characterization, and all PD and prodromal cases had a positive CSF_synSAA result.

Results: For PD subjects with a single skin sample, skin_synSAA was positive in 49% of the early cases and 67% of the late cases. However, positivity reached 71% and 100% in early and late PD cases with possible RBD, respectively. For prodromal subjects with a single skin sample, skin_synSAA was positive in 75% of PSG-confirmed RBD cases, 71% of possible RBD cases and 13% of hyposmia cases. When evaluating the subgroups with two skin samples, the sensitivity increased to 95% for possible RBD cases and 55% for hyposmia cases. All HC cases were negative in the skin_synSAA.

Conclusion: The results suggest that the skin_synSAA can serve as a biomarker test to evaluate the disease progression in sporadic PD cases. In addition, a strong correlation was observed between the positivity in skin_synSAA and the presence of RBD, with detection reaching almost 100% agreement with CSF_synSAA when using two skin samples. This suggests the presence of an undiscovered biological pathway for the disposition of syn-seeds into the skin of subjects with RBD.

References: Ma Y, Farris CM, Weber S, et al. Sensitivity and specificity of a seed amplification assay for diagnosis of multiple system atrophy: a multicentre cohort study. Lancet Neurol 2024; 23: 1225–37.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/detection-of-%ce%b1-synuclein-seeds-in-skin-samples-from-ppmi-participants/