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

Ronald B Postuma, Alex Iranzo, Michele Hu, Birgit Högl, Bradley F Boeve, Raffaele Manni, Wolfgang H Oertel, Isabelle Arnulf, Luigi Ferini-Strambi, Monica Puligheddu, Elena Antelmi, Valerie Cochen De Cock, Dario Arnaldi, Brit Mollenhauer, Aleksandar Videnovic, Karel Sonka, Ki-Young Jung, Dieter Kunz, Yves Dauvilliers, Federica ProviniSimon J Lewis, Jitka Buskova, Milena Pavlova, Anna Heidbreder, Jacques Y Montplaisir, Joan Santamaria, Thomas R Barber, Ambra Stefani, Erik K St Louis, Michele Terzaghi, Annette Janzen, Smandra Leu-Semenescu, Guiseppe Plazzi, Flavio Nobili, Friederike Sixel-Doering, Petr Dusek, Frederik Bes, Pietro Cortelli, Kaylena Ehgoetz Martens, Jean-Francois Gagnon, Carles Gaig, Marco Zucconi, Claudia Trenkwalder, Ziv Gan-Or, Christine Lo, Michal Rolinski, Philip Mahlknecht, Evi Holzknecht, Angel R Boeve, Luke N Teigen, Gianpaolo Toscano, Geert Mayer, Silvia Morbelli, Benjamin Dawson, Amelie Pelletier

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)744-759
Number of pages16
JournalBrain : a journal of neurology
Volume142
Issue number3
DOIs
Publication statusPublished - Mar 1 2019

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REM Sleep Behavior Disorder
Parkinsonian Disorders
Multicenter Studies
Dementia
Sample Size
Prodromal Symptoms
Multiple System Atrophy
Restless Legs Syndrome
Lewy Body Disease
Color Vision
Sleep Apnea Syndromes
Kaplan-Meier Estimate
Sleep Initiation and Maintenance Disorders
Erectile Dysfunction
Substantia Nigra
Constipation
Neurodegenerative Diseases
Parkinson Disease
Sleep
Anxiety

Cite this

Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder : a multicentre study. / Postuma, Ronald B; Iranzo, Alex; Hu, Michele; Högl, Birgit; Boeve, Bradley F; Manni, Raffaele; Oertel, Wolfgang H; Arnulf, Isabelle; Ferini-Strambi, Luigi; Puligheddu, Monica; Antelmi, Elena; Cochen De Cock, Valerie; Arnaldi, Dario; Mollenhauer, Brit; Videnovic, Aleksandar; Sonka, Karel; Jung, Ki-Young; Kunz, Dieter; Dauvilliers, Yves; Provini, Federica; Lewis, Simon J; Buskova, Jitka; Pavlova, Milena; Heidbreder, Anna; Montplaisir, Jacques Y; Santamaria, Joan; Barber, Thomas R; Stefani, Ambra; St Louis, Erik K; Terzaghi, Michele; Janzen, Annette; Leu-Semenescu, Smandra; Plazzi, Guiseppe; Nobili, Flavio; Sixel-Doering, Friederike; Dusek, Petr; Bes, Frederik; Cortelli, Pietro; Ehgoetz Martens, Kaylena; Gagnon, Jean-Francois; Gaig, Carles; Zucconi, Marco; Trenkwalder, Claudia; Gan-Or, Ziv; Lo, Christine; Rolinski, Michal; Mahlknecht, Philip; Holzknecht, Evi; Boeve, Angel R; Teigen, Luke N; Toscano, Gianpaolo; Mayer, Geert; Morbelli, Silvia; Dawson, Benjamin; Pelletier, Amelie.

In: Brain : a journal of neurology, Vol. 142, No. 3, 01.03.2019, p. 744-759.

Research output: Contribution to journalArticle

Postuma, RB, Iranzo, A, Hu, M, Högl, B, Boeve, BF, Manni, R, Oertel, WH, Arnulf, I, Ferini-Strambi, L, Puligheddu, M, Antelmi, E, Cochen De Cock, V, Arnaldi, D, Mollenhauer, B, Videnovic, A, Sonka, K, Jung, K-Y, Kunz, D, Dauvilliers, Y, Provini, F, Lewis, SJ, Buskova, J, Pavlova, M, Heidbreder, A, Montplaisir, JY, Santamaria, J, Barber, TR, Stefani, A, St Louis, EK, Terzaghi, M, Janzen, A, Leu-Semenescu, S, Plazzi, G, Nobili, F, Sixel-Doering, F, Dusek, P, Bes, F, Cortelli, P, Ehgoetz Martens, K, Gagnon, J-F, Gaig, C, Zucconi, M, Trenkwalder, C, Gan-Or, Z, Lo, C, Rolinski, M, Mahlknecht, P, Holzknecht, E, Boeve, AR, Teigen, LN, Toscano, G, Mayer, G, Morbelli, S, Dawson, B & Pelletier, A 2019, 'Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study', Brain : a journal of neurology, vol. 142, no. 3, pp. 744-759. https://doi.org/10.1093/brain/awz030
Postuma, Ronald B ; Iranzo, Alex ; Hu, Michele ; Högl, Birgit ; Boeve, Bradley F ; Manni, Raffaele ; Oertel, Wolfgang H ; Arnulf, Isabelle ; Ferini-Strambi, Luigi ; Puligheddu, Monica ; Antelmi, Elena ; Cochen De Cock, Valerie ; Arnaldi, Dario ; Mollenhauer, Brit ; Videnovic, Aleksandar ; Sonka, Karel ; Jung, Ki-Young ; Kunz, Dieter ; Dauvilliers, Yves ; Provini, Federica ; Lewis, Simon J ; Buskova, Jitka ; Pavlova, Milena ; Heidbreder, Anna ; Montplaisir, Jacques Y ; Santamaria, Joan ; Barber, Thomas R ; Stefani, Ambra ; St Louis, Erik K ; Terzaghi, Michele ; Janzen, Annette ; Leu-Semenescu, Smandra ; Plazzi, Guiseppe ; Nobili, Flavio ; Sixel-Doering, Friederike ; Dusek, Petr ; Bes, Frederik ; Cortelli, Pietro ; Ehgoetz Martens, Kaylena ; Gagnon, Jean-Francois ; Gaig, Carles ; Zucconi, Marco ; Trenkwalder, Claudia ; Gan-Or, Ziv ; Lo, Christine ; Rolinski, Michal ; Mahlknecht, Philip ; Holzknecht, Evi ; Boeve, Angel R ; Teigen, Luke N ; Toscano, Gianpaolo ; Mayer, Geert ; Morbelli, Silvia ; Dawson, Benjamin ; Pelletier, Amelie. / Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder : a multicentre study. In: Brain : a journal of neurology. 2019 ; Vol. 142, No. 3. pp. 744-759.
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title = "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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T1 - Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder

T2 - a multicentre study

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

AU - Toscano, Gianpaolo

AU - Mayer, Geert

AU - Morbelli, Silvia

AU - Dawson, Benjamin

AU - Pelletier, Amelie

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

C2 - 30789229

VL - 142

SP - 744

EP - 759

JO - Brain

JF - Brain

SN - 0006-8950

IS - 3

ER -