Objective: To review two independent data sets to define the test performance of skin biopsies for the detection of P-SYN and peripheral nerve degeneration in patients with clinically diagnosed synucleinopathies.

Background: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF) are neurodegenerative diseases collectively known as synucleinopathies characterized by deposition of phosphorylated alpha-synuclein (P-SYN). Diagnosing synucleinopathies remains difficult, particularly in the early stages. The Syn-One Test is an established tool for the diagnosis of synucleinopathies.

Method: We studied 2 groups of patients.  The first group included 432 participants from the Syn-One study (JAMA 2024, PMID:38506839) which included healthy controls, PD, MSA, DLB, and PAF confirmed by an expert panel of physicians.  A second cohort included 6966 patients with clinical testing performed at CND Life Sciences for evaluation of possible synucleinopathy.  Suspected diagnosis was established using ICD-10 codes and included 5127 with PD,143 with MSA, 824 with DLB, 199 with PAF and 673 unknown diagnoses. All subjects had 3 skin biopsies (3mm) taken at the posterior cervical, distal thigh and distal leg regions with immunostaining for P-SYN and for the pan-axonal marker PGP 9.5.

Results: In the Syn-One study cohort (using confirmed clinical diagnostic criteria), cutaneous P-SYN was detected in up to 60% (range 38-84%) of cases with 1 biopsy and 82% (range 66-98%) with 2 biopsies.  In the ICD-10 cohort, cutaneous P-SYN was detected in 58% (range 42-75%) of cases with 1 biopsy and 75% (range 63-91%) with 2 biopsies. Proximal biopsies had a higher yield for P-SYN in patients with clinically confirmed PD, but was lower in MSA, PAF and DLB.  The distal leg biopsy was most effective at detecting cases of peripheral nerve degeneration.

Conclusion: The combination of three skin biopsies is necessary for adequate test performance in detecting P-SYN, particularly in clinical settings where diagnostic certainty is lower.  Proximal and distal skin biopsies provide additional clinical information about peripheral nerve fiber degeneration. Limiting skin biopsy protocols to fewer than three biopsies will result in a clinically significant percentage of false negative tests. Future studies are necessary to determine whether additional biopsies will enhance test performance.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/three-biopsies-optimizes-test-performance-for-the-detection-of-cutaneous-phosphorylated-alpha-synuclein/