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

Ronald B. Postuma (1) , Alex Iranzo , Michele Hu , Birgit Högl (2) , Bradley Boeve (3) , Raffaele Manni , Wolfgang Oertel (4) , Isabelle Arnulf (5) , Luigi Ferini-Strambi (6) , Monica Puligheddu , Elena Antelmi (7) , Valérie Cochen de Cock (8) , Dario Arnaldi (9) , Brit Mollenhauer (10) , Aleksandar Videnovic , Karel Sonka (11) , Ki-Young Jung (12) , Dieter Kunz , Yves M Dauvilliers (13, 14) , Federica Provini , Simon Lewis , Jitka Buskova , Milena Pavlova , Anna Heidbreder (15) , Jacques Montplaisir (16) , Joan Santamaria (8) , Thomas Barber (17) , Ambra Stefani (2) , Erik St Louis , Michele Terzaghi , Annette Janzen , Smandra Leu-Semenescu (5) , Guiseppe Plazzi , Flavio Nobili (9) , Friederike Sixel-Doering , Petr Dusek , Frederik Bes , Pietro Cortelli (18) , Kaylena Ehgoetz Martens , Jean-François Gagnon (19) , Carles Gaig , Marco Zucconi (6) , Claudia Trenkwalder (9) , Ziv Gan-Or (1) , Christine Lo , Michal Rolinski (17) , Philip Mahlknecht , Evi Holzknecht , Angel Boeve , Luke Teigen , Gianpaolo Toscano , Geert Mayer , Silvia Morbelli (9) , Benjamin Dawson , Amélie Pelletier (16) , Erik St.Louis

1 McGill University = Université McGill [Montréal, Canada]
2 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
3 Mayo Clinic [Rochester]
4 Philipps Universität Marburg = Philipps University of Marburg
5 CHU Pitié-Salpêtrière [AP-HP]
6 UniSR - Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie]
7 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna
8 EuroMov - Euromov
9 UniGe - Università degli studi di Genova = University of Genoa
10 UMG - University Medical Center Göttingen
11 1. LF UK / 1st Faculty of Medicine - 1. lékařská fakulta, Univerzita Karlova [Praha, Česká republika] = First Faculty of Medicine, Charles University [Prague, Czech Republic]
12 Seoul National University Hospital
13 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
14 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
15 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
16 Hôpital du Sacré-Coeur de Montréal
17 University of Oxford
18 Ospedale Bellaria [Bologna, Italy]
19 UQAM - Université du Québec à Montréal = University of Québec in Montréal

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.

Keywords: Parkinson’s disease; REM sleep behaviour disorder; dementia with Lewy bodies; multiple system atrophy

Domains: Neurons and Cognition [q-bio.NC]; Human health and pathology

Ronald B. Postuma, Alex Iranzo, Michele Hu, Birgit Högl, Bradley Boeve, et al.. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain - A Journal of Neurology , 2019, 142 (3), pp.744-759. ⟨10.1093/brain/awz030⟩. ⟨hal-02886582⟩