Objective: To compare the distribution of α-synuclein seeds (syn-seeds) between skin and CSF samples from PPMI participants, including prodromal, early Parkinson’s disease (PD), and late PD using α-synuclein seed amplification assay (synSAA).

Background: Syn-seeds are a biomarker for underlying Lewy body disease and their detection in CSF is the current gold standard since comparisons with brain pathology have shown exceptional agreement. Skin has emerged as a less invasive sample matrix than CSF, but studies have shown that 3 to 6 biopsies are needed, thus there is interest in the implementation of optimized synSAA methods to use a single skin biopsy. In addition, the biological and clinical implications of detecting syn-seeds in skin are not clear, and correlations between disease progression and the distribution of seeds between CSF and skin have not been established.

Method: CSF and skin homogenate (SH) from a single 3mm punch (located at C7) in PPMI participants were analyzed in triplicate at Amprion using previously described synSAA conditions (Ma et al., 2024). Participants (89) included 29 sporadic PD (19 early; <2y from diagnosis, 10 late; >5y from diagnosis), 30 hyposmia prodromal, 15 RBD prodromal (PSG confirmed), and 15 healthy control (HC). All participants had extensive characterization, including CSF_synSAA, DAT-SPECT, UPSIT and clinical scales including UPDRS and the RBDSQ.

Results: All participants with CSF_synSAA- results were also skin_synSAA-, regardless of presentation (including HC). Among the CSF_synSAA+ cases: 1) Early PD and late PD cases were 42% and 80% skin_synSAA+, which respectively increased to 75% and 100% when selecting for participants with RBDSQ>6; 2) Hyposmia prodromal cases were 50% skin_synSAA+, which increased to 60% when selecting for participants endorsing dream enactment on a screening questionnaire; 3) RBD defined as PSG positive were 80% skin_synSAA+.

Conclusion: Although this study is cross-sectional, results suggest that skin_synSAA positivity appears to be secondary to CSF_synSAA positivity. It is possible that skin_synSAA could serve as a progression biomarker test anchor given the increasing positivity rate with longer disease duration. Skin_synSAA strongly correlates with evidence of RBD, particularly in prodromal and early PD, suggesting a novel biological process connecting RBD and deposition of syn-seeds in skin. Longitudinal studies are needed to confirm these findings.

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-and-csf-samples-from-ppmi-participants/