Detection of α-synuclein in CSF by RT-QuIC in patients with isolated rapid-eye-movement sleep behaviour disorder: a longitudinal observational study

Background Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the alpha-synucleinopathies Parkinson's disease and dementia with Lewy bodies. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has high sensitivity and specificity for the detection of misfolded alpha-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect alpha-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal alpha-synucleinopathy. Methods In this longitudinal observational study, CSF samples were obtained by lumbar puncture from patients with video polysomnography-confirmed IRBD recruited at a specialised sleep disorders centre in Barcelona, Spain, and from controls free of neurological disease. CSF samples were stored until analysed using RT-QuIC. After lumbar puncture, participants were assessed clinically for neurological status every 3-12 months. Rates of neurological disease-free survival were estimated using the Kaplan-Meier method. Disease-free survival rates were assessed from the date of lumbar puncture to the date of diagnosis of any neurodegenerative disease, or to the last follow-up visit for censored observations. Findings 52 patients with IRBD and 40 healthy controls matched for age (p=0 . 20), sex (p=0.15), and duration of followup (p=0.27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF alpha-synuclein RT-QuIC assay was positive in 47 (90%) patients with IRBD and in four (10%) controls, resulting in a sensitivity of 90.4% (95% CI 79.4-95-8) and a specificity of 90.0% (95% CI 76.9-96.0). Mean follow-up from lumbar puncture until the end of the study (July 31, 2020) was 7.1 years (SD 2.8) in patients with IRBD and 7.7 years (2.9) in controls. During follow-up, 32 (62%) patients were diagnosed with Parkinson's disease or dementia with Lewy bodies a mean 3.4 years (SD 2.6) after linnbar puncture, of whom 31 (97%) were alpha-synudein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were alpha-synuclein negative had lower risk for developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were alpha-synuclein positive (log-rank test p=0.028; hazard ratio 0.143, 95% CI 0.019-1.063). During follow-up, none of the controls developed an alpha-synucleinopathy. Kaplan-Meier analysis showed that participants who were alpha-synuclein negative (ie, five patients with IRBD plus 36 controls) had lower risk of developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8 and 10 years after lumbar puncture than participants who were alpha-synuclein positive (ie, 47 patients with IRBD plus four controls; log-rank test p<0.0001; hazard ratio 0 . 024, 95% CI 0.003-0.177). Interpretation In patients with IRBD, RT-QuIC detects misfolded alpha-synuclein in the CSF with both sensitivity and specificity of 90%, and alpha-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson's disease or dementia with Lewy bodies. Detection of alpha-synuclein in the CSF represents a potential prodromal marker of Parkinson's disease and dementia with Lewy bodies. If these findings are replicated in additional cohorts, detection of CSF alpha-synuclein by RT-QuIC could be used to enrich IRBD cohorts in neuroprotective trials, particularly when assessing interventions that target alpha-synuclein. Copyright (C) 2021 Elsevier Ltd. All rights reserved.