To perform a meta-analysis for the detection of cutaneous phosphorylated alpha-synuclein (P-syn) in the α-synucleinopathies.

P-syn is a key protein in the pathogenesis of the α-synucleinopathies, a family of neurodegenerative diseases encompassing Parkinson’s disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and some patients with REM sleep behavioral disorder (RBD). Detection of pathological P-syn aggregates in cutaneous nerve fibers using dual immunohistochemical staining has substantially evolved and improved over the past few years.

A systematic review and meta-analysis were planned in accordance with PRISMA guidelines. A literature search of the MEDLINE/EMBASE databases and a manual bibliography search of relevant articles were used to extract abstracts up to October 2019. Four reviewers assessed studies and performed a quality and risk of bias assessment. Data was extracted to calculate overall sensitivity and specificity of skin biopsy to detect P-syn deposition.

101 publications were identified. After exclusion of duplicates and applying our selection criteria, 41 full-text articles were assessed for eligibility. A total of 10 studies conducted between 2014-2019 were chosen for quantitative meta-analysis. In PD, 8 studies were included (175 patients, 259 controls), sensitivity=0.789, specificity=1.0; MSA, 2 studies were included (24 patients, 64 controls), sensitivity=0.667, specificity=1.0; DLB, 4 studies were included (30 patients, 58 controls), sensitivity=1.0, specificity=1.0; PAF, 2 studies were included (19 patients, 25 controls), sensitivity=1.0, specificity=1.0; RBD, 3 studies were included (60 patients, 92 controls), sensitivity=0.75, specificity=1.0. 

Skin biopsy for the detection of P-syn is a reliable tool to discriminate α-synucleinopathies from controls. These findings represent a significant step towards the use of skin P-syn for the diagnosis of the α-synucleinopathies.  Most excluded studies were from centers without prior experience using dual immunostaining methodology for P-syn staining and contained methodological errors, suggesting significant technical challenges with the technique.