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Clinical Trial
. 2019 Mar 1;142(3):744-759.
doi: 10.1093/brain/awz030.

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

Ronald B Postuma  1   2 , Alex Iranzo  3 , Michele Hu  4 , Birgit Högl  5 , Bradley F Boeve  6 , Raffaele Manni  7 , Wolfgang H Oertel  8 , Isabelle Arnulf  9 , Luigi Ferini-Strambi  10 , Monica Puligheddu  11 , Elena Antelmi  12   13 , Valerie Cochen De Cock  14 , Dario Arnaldi  15 , Brit Mollenhauer  16 , Aleksandar Videnovic  17 , Karel Sonka  18 , Ki-Young Jung  19 , Dieter Kunz  20 , Yves Dauvilliers  21 , Federica Provini  22   23 , Simon J Lewis  24 , Jitka Buskova  25 , Milena Pavlova  26 , Anna Heidbreder  27 , Jacques Y Montplaisir  2 , Joan Santamaria  14 , Thomas R Barber  4 , Ambra Stefani  5 , Erik K St Louis  6 , Michele Terzaghi  7 , Annette Janzen  8 , Smandra Leu-Semenescu  9 , Guiseppe Plazzi  12   13 , Flavio Nobili  15 , Friederike Sixel-Doering  16 , Petr Dusek  18 , Frederik Bes  20 , Pietro Cortelli  22   23 , Kaylena Ehgoetz Martens  24 , Jean-Francois Gagnon  28 , Carles Gaig  3 , Marco Zucconi  10 , Claudia Trenkwalder  15 , Ziv Gan-Or  29   30 , Christine Lo  4 , Michal Rolinski  4 , Philip Mahlknecht  5 , Evi Holzknecht  5 , Angel R Boeve  6 , Luke N Teigen  6 , Gianpaolo Toscano  7 , Geert Mayer  31 , Silvia Morbelli  32 , Benjamin Dawson  1 , Amelie Pelletier  1   2
Affiliations
Clinical Trial

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

Ronald B Postuma et al. Brain. .

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.

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

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Figures

Figure 1
Figure 1
Kaplan-Meier plot of disease-free survival (i.e. free of parkinsonism or dementia) among patients with iRBD..
Figure 2
Figure 2
Kaplan-Meier plot of disease-free survival of patients with iRBD stratified according to presence of motor and cognitive markers. Results are presented according to baseline assessment (i.e. patients who develop a de novo marker abnormality over the course of the follow-up remain in the ‘marker-free’ group). Solid line indicates patients with normal values, dashed line abnormal values. Hazard ratios (HRs) are with Cox proportional hazards, adjusting for age, sex, and centre, with 95% confidence intervals in parentheses.
Figure 3
Figure 3
Kaplan-Meier plot of disease-free survival of patients with iRBD stratified according to presence of sleep and psychiatric markers. Solid line indicates patients with normal values, dashed line abnormal values. Hazard ratios (HRs) are with Cox proportional hazards, adjusting for age, sex, and centre, with 95% confidence intervals in parentheses.
Figure 4
Figure 4
Kaplan-Meier plot of disease-free survival of patients with iRBD stratified according to presence of special sensory and autonomic markers. Solid line indicates patients with normal values, dashed line abnormal values. Hazard ratios (HRs) are with Cox proportional hazards, adjusting for age, sex, and centre, with 95% confidence intervals in parentheses.
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