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

Summary 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%, I 2 = 71%) and for skin was 74.8% (95% CI 53.2–88.5%, I 2 = 64%) for aSyn‐SAA and 78.5% (95% CI 70.4–84.9%, I 2 = 14%) for p‐syn. The phenoconversion rate ratio of biopsy‐positive versus biopsy‐negative iRBD was 1.28 (95% CI 0.68–2.41, I 2 = 0%). Skin as a source had a specificity of 99% (95% CI 95–100%, I 2 = 0%; p = 0.01 compared to CSF). As a test, p‐syn, had a specificity of 100% (95% CI 93–100%, I 2 = 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, I 2 = 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.