Objective: To report differences in the amount, localization and topographic distribution of cutaneous P-SYN deposition between cerebellar and parkinsonian variants of MSA.

Background: MSA is a neurodegenerative disease classically associated with the central deposition of P-SYN within glial cytoplasmic inclusions. Recent studies report peripheral deposition of P-SYN within cutaneous nerves.

Method: After consent, participants with MSA completed neurologic examinations, medical history, cognitive evaluation, orthostatic vitals and neurodegenerative disease questionnaires. All participants underwent blinded clinical review by a panel of experts to confirm a diagnosis of MSA. Skin biopsies at the distal leg, distal thigh and posterior cervical sites were performed on all participants with quantitation of P-SYN.

Results: 69 MSA participants were enrolled and 55 were confirmed by the expert panel.  Of the 55 confirmed MSA cases, 31 were MSA-P and 24 were MSA-C. Patients with MSA-C were younger (64.9±6.8 vs. 69.2±9.9, P=0.06), although disease severity was similar (by MDS-UPDRS, Hoehn and Yahr scores, orthostatic hypotension). The Parkinson’s disease 39-point questionnaire was greater in MSA-C (73±26 vs 54±33 in MSA-P: P<0.05). P-SYN was detected in 54/55 (98% of cases: one MSA-P case was negative). There were no differences in P-SYN quantity or topographic distribution of P-SYN deposition between MSA-P and MSA-C. P-SYN was present 75% of the biopsies from the posterior cervical region, in 76% of the distal thigh biopsies and in 64% of the distal leg biopsies. The deposition of P-SYN within nerve fibers was preferentially located within somatic nerve fibers (including the subepidermal plexus and nerve fiber bundles) in the individuals with MSA. Only rare deposition was observed in autonomic nerve fibers innervating autonomic structures such as sweat glands, piloarrector muscles and blood vessels. Two patients with MSA-P, both P-SYN positive, went to autopsy and had glial cytoplasmic inclusions with confirmation of MSA diagnosis.

Conclusion: With 3 biopsies, the sensitivity of detection of P-SYN in patients with MSA is 98%. Despite major differences in clinical presentation, patients with MSA-C and MSA-P have similar cutaneous pathologic synuclein profiles. Longitudinal follow up of patients with MSA is necessary to determine if changes in P-SYN accumulation support a role of skin biopsy assessment of P-SYN as a surrogate outcome biomarker.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cutaneous-phosphorylated-alpha-synuclein-deposition-in-multiple-system-atrophy/