Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study

Abstract

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.

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Affiliated Institutions

• Brigham and Women's Hospital US
• Ospedale Bellaria IT
• Harvard University US
• University of Cagliari IT
• Sorbonne Université FR
• Hôpital Gui de Chauliac FR
• University Hospital Münster DE
• Consorci Institut D'Investigacions Biomediques August Pi I Sunyer ES
• Canadian Sleep & Circadian Network CA
• Charité - Universitätsmedizin Berlin DE
• Istituti di Ricovero e Cura a Carattere Scientifico IT
• Innsbruck Medical University AT
• Ospedale Policlinico San Martino IT
• University of Oxford GB
• Centre Hospitalier Universitaire de Montpellier FR
• Université de Montpellier FR
• Biomedical Research Networking Center on Neurodegenerative Diseases ES
• Universitätsmedizin Göttingen DE
• Massachusetts General Hospital US
• University of Bologna IT
• Montreal Neurological Institute and Hospital CA
• Hospital Clínic de Barcelona ES
• IRCCS Ospedale San Raffaele IT
• Inserm FR
• Charles University CZ
• Hôpital du Sacré-Cœur de Montréal CA
• Parkinson's UK GB
• Institute of Neurological Sciences IT
• McGill University CA
• University of Genoa IT
• Pitié-Salpêtrière Hospital FR
• The University of Sydney AU
• Philipps University of Marburg DE
• National Institute of Mental Health CZ
• Mayo Clinic in Arizona US
• Université du Québec à Montréal CA
• Seoul National University Hospital KR
• General University Hospital in Prague CZ
• Montreal General Hospital CA
• Paracelsus Elena Klinik Kassel DE

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