Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

Brain and Mind Centre University of Sydney Camperdown Australia

Centre d'Études Avancées en Médecine du Sommeil Hôpital du Sacré Cœur de Montréal Montréal Canada

Clinical Neurology Dept of Neuroscience University of Genoa and Polyclinic San Martino Hospital Genoa Italy

Department of Biomedical and Neuromotor Sciences Bellaria Hospital University of Bologna Bologna Italy

Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Department of Human Genetics McGill University Montreal Canada

Department of Neurology and Centre of Clinical Neurosciences of the 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Neurology and Neurosurgery Montreal Neurological Institute McGill University Montreal Canada

Department of Neurology Brigham and Women's Hospital Boston; Harvard Medical School Boston USA

Department of Neurology Hephata Klinik Schwalmstadt Treysa Germany

Department of Neurology Innsbruck Medical University Innsbruck Austria

Department of Neurology McGill University Montreal General Hospital Montreal Canada

Department of Neurology Philipps Universität Marburg Germany

Department of Neurosurgery Kassel Germany

Department of Psychology Université du Québec à Montréal Montreal Quebec Canada

Institute for Sleep Medicine and Neuromuscular Disorders University Hospital Muenster Muenster Germany

Institute of Physiology Charité Universitätsmedizin Berlin Germany

IRCCS Institute of Neurological Sciences of Bologna Bellaria Hospital Bologna Italy

IRCCS Institute of the Neurological Sciences Ospedale Bellaria ASL di Bologna Bologna Italy

Mayo Clinic Rochester MN USA

Movement Disorders Unit and Division of Sleep Medicine Massachusetts General Hospital Harvard Medical School Boston USA

National Institute of Mental Health Klecany 3rd Faculty of Medicine Charles Unviersity Prague Czech Republic

Neurology Service Hospital Clinic de Barcelona IDIBAPS CIBERNED Barcelona Spain

Neuroscience Research Institute Seoul National University College of Medicine Department of Neurology Seoul National University Hospital Seoul Korea

Nuclear Medicine Department of Health Sciences University of Genoa and Polyclinic San Martino Hospital Genoa Italy

Oxford Parkinson's Disease Centre and Oxford University Oxford UK

Sleep and Neurology Unit Beau Soleil Clinic Montpellier France; EuroMov University of Montpellier Montpellier France

Sleep Center Department of Cardiovascular and Neurological Sciences University of Cagliari Italy

Sleep Disorders Center Department of Neurology Scientific Institute Ospedale San Raffaele Vita Salute University Milan Italy

Sleep disorders unit Pitie Salpetriere Hospital and Sorbonne University Paris France

Sleep Unit Department of Neurology Hôpital Gui de Chauliac Montpellier INSERM U1061 Montpellier F 34093 Cedex 5 France

Unit of Sleep Medicine and Epilepsy IRCCS C Mondino Foundation Pavia Italy

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Brain. 2019 Mar 1;142(3):498-501. doi: 10.1093/brain/awz014. PubMed

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