Alpha-synuclein pathology in isolated rapid eye movement sleep behaviour disorder: a meta-analysis

Accumulating evidence indicates that patients with isolated rapid eye movement sleep behaviour disorder (iRBD), a prodromal stage of synucleinopathies, show abnormal deposition of misfolded alpha-synuclein (a-Syn) in peripheral tissues. The clinical utility of testing for a-Syn in iRBD is unclear. This meta-analysis focused on the utility of testing for the abnormal a-Syn phosphorylated at Ser129 (p-syn) and a-Syn seeding activity (a-Syn seed amplification assays [aSyn-SAA]). Following an electronic database search, 15 studies were included that provided at a minimum data on test positivity in participants with iRBD. Test positivity from cerebrospinal fluid (CSF) was 80% (95% confidence interval [CI] 68-88%, I² = 71%) and for skin was 74.8% (95% CI 53.2-88.5%, I² = 64%) for aSyn-SAA and 78.5% (95% CI 70.4-84.9%, I² = 14%) for p-syn. The phenoconversion rate ratio of biopsy-positive versus biopsy-negative iRBD was 1.28 (95% CI 0.68-2.41, I² = 0%). Skin as a source had a specificity of 99% (95% CI 95-100%, I² = 0%; p = 0.01 compared to CSF). As a test, p-syn, had a specificity of 100% (95% CI 93-100%, I² = 0%; p < 0.001) compared to aSyn-SAA. The odds ratio of a-Syn test positivity in iRBD versus other RBDs was 112 (95% CI 20-629, I² = 0%). These results demonstrate clinically significant test positivity in iRBD and favour skin over CSF as the source of a-Syn pathological analysis, and p-syn over aSyn-SAA as the testing method. Overall, these findings indicate that testing for a-Syn could help in differentiating iRBD from RBD secondary to other conditions.