Objective: To evaluate the performance of a skin α-synuclein seed amplification assay (skin_synSAA) as a screening test using samples from movement disorder subjects with uncertain diagnosis (UnDx).

Background: CSF_synSAA has been established as a sensitive biomarker test to detect α-synuclein seeds (syn-seeds) which are found in subjects with Lewy body diseases and multiple system atrophy. Although it remains challenging to find less invasive biological matrices reaching the same sensitivity as CSF in the assay, screening with a highly specific test using an alternative matrix could significantly reduce the number of lumbar punctures needed to assist clinical diagnosis if syn-seeds are detected.

Method: Skin homogenates (SH) were generated using 3mm biopsy samples (neck C7) from four neurologically healthy control (HC) subjects and 11 UnDx subjects for movement disorders at Paracelsus-Elena-Klinik. The SH were analyzed in triplicates at Amprion using skin_synSAA that was modified from the previously reported CSF_synSAA (Ma et al., 2024). Ten out of the 11 UnDx subjects also had CSF collected on the same visit or on a previous visit to the skin collection, they were analyzed in triplicates using the CSF_synSAA.

Results: Of the ten UnDx subjects tested with the CSF_synSAA, four were CSF_synSAA+, five were CSF_synSAA-, and one was inconclusive. All CSF_synSAA+ cases displayed amplification patterns associated with type1 syn-seeds. The skin_synSAA was able to detect two of the four CSF_synSAA+ subjects, both with type1 syn-seeds, while all five CSF_synSAA- subjects remained negative in the skin_synSAA as well as the inconclusive case. In addition, all HC subjects were negative in the skin_synSAA.

Conclusion: The results suggest that in addition to HC subjects, the skin_synSAA is highly specific even for challenging cases with ambiguous clinical presentations. These subjects often either meet most of the diagnostic criteria but not able to be assigned to a certain diagnosis due to a single exclusion criterium, or they meet the diagnostic criteria for multiple diseases. Given the excellent specificity of the skin_synSAA, it could serve as a screening biomarker test prior to CSF collection.

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/a-highly-specific-skin-%ce%b1-synuclein-seed-amplification-assay-for-screening-of-synucleionpathies/