TY - JOUR
T1 - Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder
T2 - a multicentre study
AU - International REM Sleep Behavior Disorder Study Group
AU - Postuma, Ronald B
AU - Iranzo, Alex
AU - Hu, Michele
AU - Högl, Birgit
AU - Boeve, Bradley F
AU - Manni, Raffaele
AU - Oertel, Wolfgang H
AU - Arnulf, Isabelle
AU - Ferini-Strambi, Luigi
AU - Puligheddu, Monica
AU - Antelmi, Elena
AU - Cochen De Cock, Valerie
AU - Arnaldi, Dario
AU - Mollenhauer, Brit
AU - Videnovic, Aleksandar
AU - Sonka, Karel
AU - Jung, Ki-Young
AU - Kunz, Dieter
AU - Dauvilliers, Yves
AU - Provini, Federica
AU - Lewis, Simon J
AU - Buskova, Jitka
AU - Pavlova, Milena
AU - Heidbreder, Anna
AU - Montplaisir, Jacques Y
AU - Santamaria, Joan
AU - Barber, Thomas R
AU - Stefani, Ambra
AU - St Louis, Erik K
AU - Terzaghi, Michele
AU - Janzen, Annette
AU - Leu-Semenescu, Smandra
AU - Plazzi, Guiseppe
AU - Nobili, Flavio
AU - Sixel-Doering, Friederike
AU - Dusek, Petr
AU - Bes, Frederik
AU - Cortelli, Pietro
AU - Ehgoetz Martens, Kaylena
AU - Gagnon, Jean-Francois
AU - Gaig, Carles
AU - Zucconi, Marco
AU - Trenkwalder, Claudia
AU - Gan-Or, Ziv
AU - Lo, Christine
AU - Rolinski, Michal
AU - Mahlknecht, Philip
AU - Holzknecht, Evi
AU - Boeve, Angel R
AU - Teigen, Luke N
N1 - © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
U2 - 10.1093/brain/awz030
DO - 10.1093/brain/awz030
M3 - Article (Academic Journal)
C2 - 30789229
SN - 0006-8950
VL - 142
SP - 744
EP - 759
JO - Brain
JF - Brain
IS - 3
ER -