An Analysis of the Number of Skin Biopsies Needed in the Detection of Phosphorylated Alpha-Synuclein
Todd Levine1, Bailey Bellaire2, Roy Freeman3, Christopher Gibbons4
1Honor Health, 2CND Life Sciences, 3Beth Israel Deaconess Hosp, 4Beth Israel Deaconess Medical Center
Objective:
To determine the optimal number of skin biopsies necessary for accurate detection of phosphorylated alpha-synuclein (PSYN) and peripheral nerve degeneration.
Background:
Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF) are neurodegenerative disease characterized by deposition of PSYN. Detection of cutaneous PSYN has resulted in substantive changes to the clinical diagnostic pathway.
Design/Methods:
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 skin biopsies taken at the posterior cervical, distal thigh and distal leg regions.
Results:
In the Syn-One study cohort (using clinically confirmed diagnostic criteria), cutaneous PSYN was missed in up to 62% of cases with 1 biopsy and missed in up to 34% with 2 biopsies. In the ICD-10 cohort, cutaneous P-SYN was missed in up to 58% of cases with 1 biopsy and 37% with 2 biopsies. Proximal biopsies had a higher yield for P-SYN but missed the majority of cases of peripheral nerve degeneration.
Conclusions:
While proximal skin biopsies may provide a high diagnostic yield in some synucleinopathy subtypes with clinically confirmed disease, limiting skin biopsy protocols to fewer than three biopsies will result in a clinically significant percent of false negative tests that will increase as diagnostic certainty decreases. Furthermore, the diagnostic discrimination of synuclein subtyping provided by deposition pattern and distribution is lost with fewer than 3 biopsies.
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