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

• Published in: Lancet neurology 2021-03, Vol.20 (3), p.203-212
• Main Authors: Iranzo, Alex, Fairfoul, Graham, Ayudhaya, Anutra Chumbala Na, Serradell, Monica, Gelpi, Ellen, Vilaseca, Isabel, Sanchez-Valle, Raquel, Gaig, Carles, Santamaria, Joan, Tolosa, Eduard, Riha, Renata L, Green, Alison J E
• Format: Article
• Language: English
• Subjects: Aged; alpha-Synuclein - cerebrospinal fluid; Alzheimer's disease; Biomarkers; Brain research; Cerebrospinal fluid; Clinical trials; Cognitive ability; Computer Systems; Dementia; Dementia disorders; Diagnosis; Disease Progression; Disease-Free Survival; Eye movements; Female; Humans; Kaplan-Meier Estimate; Lewy bodies; Lewy Body Disease - etiology; Longitudinal Studies; Male; Middle Aged; Movement disorders; Neurodegenerative diseases; Neurological diseases; Neuroprotection; Observational studies; Parkinson Disease - etiology; Parkinson's disease; Polysomnography; Prodromal Symptoms; REM sleep; REM Sleep Behavior Disorder - cerebrospinal fluid; REM Sleep Behavior Disorder - complications; Risk Assessment; Sensitivity and Specificity; Sleep; Sleep disorders; Spinal Puncture; Survival; Synuclein
• ISSN: 1474-4422; 1474-4465
• DOI: 10.1016/S1474-4422(20)30449-X

Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the α-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 α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect α-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal α-synucleinopathy. 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. 52 patients with IRBD and 40 healthy controls matched for age (p=0·20), sex (p=0·15), and duration of follow-up (p=0·27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF α-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 lumbar puncture, of whom 31 (97%) were α-synuclein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were α-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 α-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 α-synucleinopathy. Kaplan-Meier analysis showed that participants who were α-synuclein negative (ie, five patients with