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1. Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

Author

Krohn, L., Heilbron, K., Blauwendraat, C., Reynolds, R. H., Yu, E., Senkevich, K., Rudakou, U., Estiar, M. A., Gustavsson, E. K., Brolin, K., Ruskey, J. A., Freeman, K., Asayesh, F., Chia, R., Arnulf, I., M. T. M., Hu, Montplaisir, J. Y., Gagnon, J. -F., Desautels, A., Dauvilliers, Y., Gigli, G. L., Valente, M., Janes, F., Bernardini, A., Hogl, B., Stefani, A., Ibrahim, A., Sonka, K., Kemlink, D., Oertel, W., Janzen, A., Plazzi, G., Biscarini, F., Antelmi, E., Figorilli, M., Puligheddu, M., Mollenhauer, B., Trenkwalder, C., Sixel-Doring, F., Cochen De Cock, V., Monaca, C. C., Heidbreder, A., Ferini-Strambi, L., Dijkstra, F., Viaene, M., Abril, B., Boeve, B. F., Aslibekyan, S., Auton, A., Babalola, E., Bell, R. K., Bielenberg, J., Bryc, K., Bullis, E., Coker, D., Partida, G. C., Dhamija, D., Das, S., Elson, S. L., Filshtein, T., Fletez-Brant, K., Fontanillas, P., Freyman, W., Gandhi, P. M., Hicks, B., Hinds, D. A., Jewett, E. M., Jiang, Y., Kukar, K., Lin, K. -H., Lowe, M., Mccreight, J. C., Mcintyre, M. H., Micheletti, S. J., Moreno, M. E., Mountain, J. L., Nandakumar, P., Noblin, E. S., O'Connell, J., Petrakovitz, A. A., Poznik, G. D., Schumacher, M., Shastri, A. J., Shelton, J. F., Shi, J., Shringarpure, S., Tran, V., Tung, J. Y., Wang, X., Wang, W., Weldon, C. H., Wilton, P., Hernandez, A., Wong, C., Tchakoute, C. T., Scholz, S. W., Ryten, M., Bandres-Ciga, S., Noyce, A., Cannon, P., Pihlstrom, L., Nalls, M. A., Singleton, A. B., Rouleau, G. A., Postuma, R. B., Gan-Or, Z., and 23andMe Research Team

Subjects
Multidisciplinary, Risk factors, General Physics and Astronomy, Genomics, General Chemistry, Human medicine, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology
Abstract

Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention. REM-sleep behavior disorder often precedes Parkinson's disease or dementia. Here, the authors perform a genome-wide association study for REM-sleep behavior disorder, and discover how it potentially affects gene expression in the brain.

Published
2022

3. Beneficial effect of 24-month bilateral subthalamic stimulation on quality of sleep in Parkinson's disease

Author

Dafsari, H. S., Ray-Chaudhuri, K., Ashkan, K., Sachse, L., Mahlstedt, P., Silverdale, M., Rizos, A., Strack, M., Jost, S. T., Reker, P., Samuel, M., Visser-Vandewalle, V., Evans, J., Antonini, A., Martinez-Martin, P., Timmermann, L., Schrag, A., Weintraub, D., Barone, P., Brooks, D. J., Brown, R. G., Jenner, P., Jeon, B., Lyons, K., Pavese, N., Politis, M., Postuma, R. B., Schapira, A., Stocchi, F., Tsuboi, Y., Sauerbier, A., Deutsche Forschungsgemeinschaft (Alemania), NIHR - Mental Health Biomedical Research Centre (Reino Unido), Dementia Unit at South London, South London and Maudsley NHS Foundation Trust (Reino Unido), King College London, German Research Foundation, National Institute of Health Research (NIHR) Mental Health Biomedical Research Centre, and Maudsley NHS Foundation Trust and King’s College London

Subjects
0301 basic medicine, Male, Sleep Wake Disorders, Quality of life, medicine.medical_specialty, Deep brain stimulation, Parkinson's disease, Neurology, Activities of daily living, medicine.medical_treatment, Deep Brain Stimulation, Non-motor symptoms, Subthalamic nucleus, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Parkinson’s disease sleep scale, Outcome Assessment, Health Care, medicine, Humans, Prospective Studies, Aged, Original Communication, business.industry, Parkinson Disease, Middle Aged, medicine.disease, nervous system diseases, 030104 developmental biology, surgical procedures, operative, Observational study, Female, Neurology (clinical), Analysis of variance, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and sleep symptoms in Parkinson’s disease (PD). However, the long-term effects of STN-DBS on sleep and its relationship with QoL outcome are unclear. Methods In this prospective, observational, multicenter study including 73 PD patients undergoing bilateral STN-DBS, we examined PDSleep Scale (PDSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD-motor examination, -activities of daily living, and -complications (SCOPA-A, -B, -C), and levodopa-equivalent daily dose (LEDD) preoperatively, at 5 and 24 months follow-up. Longitudinal changes were analyzed with Friedman-tests or repeated-measures ANOVA, when parametric tests were applicable, and Bonferroni-correction for multiple comparisons. Post-hoc, visits were compared with Wilcoxon signed-rank/t-tests. The magnitude of clinical responses was investigated using effect size. Results Significant beneficial effects of STN-DBS were observed for PDSS, PDQ-8, SCOPA-A, -B, and -C. All outcomes improved significantly at 5 months with subsequent decrements in gains at 24 months follow-up which were significant for PDSS, PDQ-8, and SCOPA-B. Comparing baseline and 24 months follow-up, we observed significant improvements of PDSS (small effect), SCOPA-A (moderate effect), -C, and LEDD (large effects). PDSS and PDQ-8 improvements correlated significantly at 5 and 24 months follow-up. Conclusions In this multicenter study with a 24 months follow-up, we report significant sustained improvements after bilateral STN-DBS using a PD-specific sleep scale and a significant relationship between sleep and QoL improvements. This highlights the importance of sleep in holistic assessments of DBS outcomes.

Published
2020
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4. A brain signature of prodromal Lewy body dementia in isolated REM sleep behavior disorder

Author

Rahayel, S., Postuma, R., Montplaisir, J., Misic, B., Tremblay, C., Vo, A., Lewis, S., Matar, E., Martens, K. Ehgoetz, Blanc, F., Yao, C., Pelletier, Amandine, Gaubert, M., Carrier, J., Monchi, O., Chouinard, S., Panisset, M., Dagher, A., Gagnon, J. -F., Université Laval [Québec] (ULaval), The Open University [Milton Keynes] (OU), Institut des Sciences Moléculaires d'Orsay (ISMO), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Service de cardiologie [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], IFP Energies nouvelles (IFPEN), Université de Pau et des Pays de l'Adour (UPPA), Montreal Neurological Institute and Hospital, and McGill University = Université McGill [Montréal, Canada]

Subjects
Cognitive dysfunction, Dementia with Lewy bodies (DLB), [SDV]Life Sciences [q-bio], Magnetic resonance imaging(MRI)
Abstract

25th Congress of the European-Sleep-Research-Society (ESRS), ELECTR NETWORK, SEP 22-24, 2020; International audience

Published
2020

5. Full sequencing and haplotype analysis of MAPT in Parkinson's disease and rapid eye movement sleep behavior disorder

Author

Li, J, Ruskey, J, Arnulf, I, Dauvilliers, Y, Hu, M, Högl, B, Leblond, C, Zhou, S, Ambalavanan, A, Ross, J, Bourassa, C, Spiegelman, D, Laurent, S, Stefani, A, Charley Monaca, C, Cochen De Cock, V, Boivin, M, Ferini-Strambi, L, Plazzi, G, Antelmi, E, Young, P, Heidbreder, A, Labbe, C, Ferman, T, Dion, P, Fan, D, Desautels, A, Gagnon, J, Dupré, N, Fon, E, Montplaisir, J, Boeve, B, Postuma, R, Rouleau, G, Ross, O, Gan-Or, Z, Li, J., Ruskey, J. A., Arnulf, I., Dauvilliers, Y., M. T. M., Hu, Hogl, B., Leblond, C. S., Zhou, S., Ambalavanan, A., Ross, J. P., Bourassa, C. V., Spiegelman, D., Laurent, S. B., Stefani, A., Charley Monaca, C., Cochen De Cock, V., Boivin, M., Ferini-Strambi, L., Plazzi, G., Antelmi, E., Young, P., Heidbreder, A., Labbe, C., Ferman, T. J., Dion, P. A., Fan, D., Desautels, A., Gagnon, J. -F., Dupre, N., Fon, E. A., Montplaisir, J. Y., Boeve, B. F., Postuma, R. B., Rouleau, G. A., Ross, O. A., Gan-Or, Z., Service des Pathologies du sommeil [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Euromov (EuroMov), Université de Montpellier (UM), Clinique Beau Soleil [Montpellier], Li, Jiao, Ruskey, Jennifer A., Arnulf, Isabelle, Dauvilliers, Yve, Hu, Michele T.M., Högl, Birgit, Leblond, Claire S., Zhou, Sirui, Ambalavanan, Amirthagowri, Ross, Jay P., Bourassa, Cynthia V., Spiegelman, Dan, Laurent, Sandra B, Stefani, Ambra, Charley Monaca, Christelle, Cochen De Cock, Valérie, Boivin, Michel, Ferini-Strambi, Luigi, Plazzi, Giuseppe, Antelmi, Elena, Young, Peter, Heidbreder, Anna, Labbe, Catherine, Ferman, Tanis J., Dion, Patrick A., Fan, Dongsheng, Desautels, Alex, Gagnon, Jean-Françoi, Dupré, Nicola, Fon, Edward A., Montplaisir, Jacques Y., Boeve, Bradley F., Postuma, Ronald B., Rouleau, Guy A., Ross, Owen A., and Gan-Or, Ziv

Subjects
Lewy Body Disease, Male, Principal Component Analysis, Genotype, Parkinson's disease, REM sleep behavior disorder, Parkinson Disease, tau Proteins, Middle Aged, Polymorphism, Single Nucleotide, Cohort Studies, Neurology, Gene Frequency, genetics, MAPT, Neurology (clinical), Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Genetic Predisposition to Disease, genetic, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Aged
Abstract

Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT‐associated variants and the entire coding sequence of MAPT were analyzed. Age‐, sex‐, and ethnicity‐adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder. Results: MAPT‐H2 variants were associated with PD (odds ratios: 0.62‐0.65; P = 0.010‐0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12‐2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48‐0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. Conclusions: Our results confirm the protective effect of the MAPT‐H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus.

Published
2018
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7. Day-care versus inpatient pediatric surgery: a comparison of costs incurred by parents

Author

Stanwick, R S, Horne, J M, Peabody, D M, and Postuma, R

Subjects
Male, Inpatients, Hospital Departments, Manitoba, Hospitals, Pediatric, Adenoidectomy, Hospitalization, Strabismus, Ambulatory Surgical Procedures, Outpatients, Costs and Cost Analysis, Humans, Female, Child, Surgery Department, Hospital, Research Article
Abstract

The cost-effectiveness for parents of day-care pediatric surgery was assessed by comparing time and financial costs associated with two surgical procedures, one (squint repair) performed exclusively as a day-care procedure, the other (adenoidectomy) performed exclusively as an inpatient procedure. All but 1 of 165 eligible families participated. The children underwent surgery between February and July 1981. The day-care surgery group (59 families) incurred average total time costs of 16.1 hours, compared with 37.1 hours for the inpatient surgery group (105 families), as parents in the latter group remained with their child during the longer hospital stay. Parents from out of town incurred the greater time and financial costs. In both groups parents of younger children tended to spend more time at the hospital than parents of older children. Type of surgical management was not a significant factor in out-of-pocket expenses. Loss of income was associated with employment of the mother as a professional or a manager and may reflect inequalities in access to compassionate leave between men and women in equivalent positions. Opening day-care surgery facilities on weekends might reduce the financial burden on working mothers. Overall, day-care surgery was found to be cost-effective for families.

Published
1987

8. Herstel van spinnen

Author

Postuma, R.

Subjects
Life Science, Toxicology, Toxicologie
Published
1988

10. Fine-mapping of SNCA variants in REM sleep behavior disorder identifies distinct associations

Author

Krohn, L., Wu, R., Ruskey, J., Laurent, S., Philstrom, L., Arnulf, I., Hu, M., Dauvilliers, Y., Hogl, B., Stefani, A., Holzknecht, E., Monaca, C., Beatriz, A., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Cochen, V., Mollenhauer, B., Sonka, K., MICHELA FIGORILLI, Dijkstra, F., Viaene, M., Oertel, W., Gagnon, J., Nalls, M., Blauwendraat, C., Singleton, A., Desautels, A., Montplaisir, J., Ross, O., Boeve, B., Dupre, N., Fon, E., Postuma, R., Rouleau, G., and Gan-Or, Z.

13. Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Author

Edward A. Fon, Armaghan Alam, Richard Y.J. Wu, Cornelis Blauwendraat, Jennifer A. Ruskey, Luigi Ferini-Strambi, Paul Cannon, Mathias Toft, Mariarosaria Valente, Alex Desautels, Andrew B. Singleton, Valérie Cochen De Cock, Yves Dauvilliers, Elena Antelmi, C. Trenkwalder, Kari Anne Bjørnarå, Abril Beatriz, Christelle Charley Monaca, Jacques Montplaisir, Nicolas Dupré, Mineke Viaene, Peter Young, Birgit Högl, Giuseppe Plazzi, Monica Puligheddu, W. H. Oertel, Marco Toffoli, Bradley F. Boeve, Owen A. Ross, Friederike Sixel-Döring, Lasse Pihlstrøm, Michele T.M. Hu, Isabelle Arnulf, Sandra B. Laurent, Karl Heilbron, Michela Figorilli, Anna Heidbreder, Lynne Krohn, Guy A. Rouleau, Karel Sonka, Ziv Gan-Or, Mike A. Nalls, Jean-François Gagnon, David Kemlink, Evi Holzknecht, Femke Dijkstra, Ambra Stefani, Gian Luigi Gigli, Brit Mollenhauer, Ronald B. Postuma, Krohn L., Wu R.Y.J., Heilbron K., Ruskey J.A., Laurent S.B., Blauwendraat C., Alam A., Arnulf I., Hu M.T.M., Dauvilliers Y., Hogl B., Toft M., Bjornara K.A., Stefani A., Holzknecht E., Monaca C.C., Abril B., Plazzi G., Antelmi E., Ferini-Strambi L., Young P., Heidbreder A., Cochen De Cock V., Mollenhauer B., Sixel-Doring F., Trenkwalder C., Sonka K., Kemlink D., Figorilli M., Puligheddu M., Dijkstra F., Viaene M., Oertel W., Toffoli M., Gigli G.L., Valente M., Gagnon J.-F., Nalls M.A., Singleton A.B., Desautels A., Montplaisir J.Y., Cannon P., Ross O.A., Boeve B.F., Dupre N., Fon E.A., Postuma R.B., Pihlstrom L., Rouleau G.A., Gan-Or Z., Krohn, L., R. Y. J., Wu, Heilbron, K., Ruskey, J. A., Laurent, S. B., Blauwendraat, C., Alam, A., Arnulf, I., M. T. M., Hu, Dauvilliers, Y., Hogl, B., Toft, M., Bjornara, K. A., Stefani, A., Holzknecht, E., Monaca, C. C., Abril, B., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Young, P., Heidbreder, A., Cochen De Cock, V., Mollenhauer, B., Sixel-Doring, F., Trenkwalder, C., Sonka, K., Kemlink, D., Figorilli, M., Puligheddu, M., Dijkstra, F., Viaene, M., Oertel, W., Toffoli, M., Gigli, G. L., Valente, M., Gagnon, J. -F., Nalls, M. A., Singleton, A. B., Desautels, A., Montplaisir, J. Y., Cannon, P., Ross, O. A., Boeve, B. F., Dupre, N., Fon, E. A., Postuma, R. B., Pihlstrom, L., Rouleau, G. A., Gan-Or, Z., McGill University Health Center [Montreal] (MUHC), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Imperial College London, 23andMe Inc., National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Oxford [Oxford], Nuffield Department of Clinical Neurosciences [Oxford], Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Innsbruck Medical University [Austria] (IMU), Oslo University Hospital [Oslo], Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Alma Mater Studiorum University of Bologna (UNIBO), University of Bologna, Department of Biomedical and Neuromotor Sciences [Bologna, Italy], Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Münster, Clinique Beau Soleil [Montpellier], EuroMov - Digital Health in Motion (Euromov DHM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Montpellier (UM), Paracelsus-Elena-Klinik, Kassel, Germany., University Medical Center Göttingen (UMG), First Faculty of Medicine Charles University [Prague], Universita degli Studi di Cagliari [Cagliari], Algemeen Ziekenhuis Sint-Dimpna, Philipps University of Marburg, Università degli Studi di Udine - University of Udine [Italie], University College of London [London] (UCL), Department of Mathematics and Computer Science [Udine], Hôpital du Sacré-Coeur de Montréal, Université du Québec à Montréal = University of Québec in Montréal (UQAM), Data Tecnica International, Centre d'études avancées en Médecine du Sommeil (CEAMS), Université de Montréal (UdeM)-Hôpital du Sacré-Coeur de Montréal, Mayo Clinic [Jacksonville], Mayo Clinic [Rochester], Laval University Medical center, and Université Laval [Québec] (ULaval)

Subjects
Male, 0301 basic medicine, Oncology, Linkage disequilibrium, Synucleinopathies, REM sleep behavior disorder, MESH: Logistic Models, REM Sleep Behavior Disorder, 0302 clinical medicine, synucleinopathy, SNCA, Odds Ratio, RBD-specific risk variants, MESH: Aged, MESH: Middle Aged, Rapid eye movement sleep behavior disorder (RBD), MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Parkinson Disease, Middle Aged, MESH: Case-Control Studies, 3. Good health, Neurology, MESH: Synucleinopathies, alpha-Synuclein, Female, Adult, Lewy Body Disease, medicine.medical_specialty, Prodromal Symptoms, Single-nucleotide polymorphism, Locus (genetics), Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, MESH: alpha-Synuclein, medicine, Humans, Genetic Predisposition to Disease, MESH: Prodromal Symptoms, Allele frequency, MESH: Lewy Body Disease, Aged, MESH: Humans, business.industry, Dementia with Lewy bodies, [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Adult, Odds ratio, medicine.disease, MESH: Odds Ratio, MESH: Male, synucleinopathies, Logistic Models, 030104 developmental biology, MESH: REM Sleep Behavior Disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Synuclein, Neurology (clinical), business, MESH: Female, MESH: Parkinson Disease, 030217 neurology & neurosurgery
Abstract

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598.

Published
2020
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14. Comprehensive Analysis of Familial Parkinsonism Genes in Rapid‐Eye‐Movement Sleep Behavior Disorder

Author

Christelle Charley Monaca, Alex Desautels, Yves Dauvilliers, Beatriz Abril, Elena Antelmi, Ambra Stefani, Giuseppe Plazzi, Karel Sonka, Monica Puligheddu, Brit Mollenhauer, Birgit Högl, Sandra B. Laurent, Eric Yu, Farnaz Asayesh, Luigi Ferini-Strambi, Mariarosaria Valente, Jennifer A. Ruskey, Michela Figorilli, Uladzislau Rudakou, Annette Janzen, Ziv Gan-Or, Francesco Janes, Mineke Viaene, Ronald B. Postuma, Valérie Cochen De Cock, Bradley F. Boeve, David Kemlink, Evi Holzknecht, Dan Spiegelman, Jacques Montplaisir, Anna Heidbreder, Gian Luigi Gigli, Michele T.M. Hu, Friederike Sixel-Döring, Lynne Krohn, Kheireddin Mufti, Guy A. Rouleau, Isabelle Arnulf, Claudia Trenkwalder, Wolfgang H. Oertel, Femke Dijkstra, Jean-François Gagnon, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Clinique Beau Soleil [Montpellier], EuroMov - Digital Health in Motion (Euromov DHM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Montpellier (UM), CHU Lille, Université de Lille, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Mufti, K., Rudakou, U., Yu, E., Krohn, L., Ruskey, J. A., Asayesh, F., Laurent, S. B., Spiegelman, D., Arnulf, I., M. T. M., Hu, Montplaisir, J. Y., Gagnon, J. -F., Desautels, A., Dauvilliers, Y., Gigli, G. L., Valente, M., Janes, F., Hogl, B., Stefani, A., Holzknecht, E., Sonka, K., Kemlink, D., Oertel, W., Janzen, A., Plazzi, G., Antelmi, E., Figorilli, M., Puligheddu, M., Mollenhauer, B., Trenkwalder, C., Sixel-Doring, F., Cochen De Cock, V., Monaca, C. C., Heidbreder, A., Ferini-Strambi, L., Dijkstra, F., Viaene, M., Abril, B., Boeve, B. F., Postuma, R. B., Rouleau, G. A., and Gan-Or, Z.

Subjects
0301 basic medicine, Heterozygote, Parkinson's disease, MESH: Sleep, [SDV]Life Sciences [q-bio], REM sleep behavior disorder, Rapid eye movement sleep, Disease, genetic analysis, Compound heterozygosity, Genetic analysis, 03 medical and health sciences, 0302 clinical medicine, Parkinsonian Disorders, Medicine, Humans, MESH: Heterozygote, Genetics, MESH: Humans, business.industry, MESH: Parkinsonian Disorders, PARK7, Parkinson Disease, medicine.disease, LRRK2, 3. Good health, 030104 developmental biology, Neurology, MESH: REM Sleep Behavior Disorder, Human medicine, Neurology (clinical), business, Sleep, 030217 neurology & neurosurgery, MESH: Parkinson Disease
Abstract

International audience; Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.

Published
2021
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15. Olfaction in patients with isolated REM sleep behavior disorder who eventually develop multiple system atrophy

Author

Gregor K. Wenning, Luigi Ferini-Strambi, Aleksandar Videnovic, Ambra Stefani, Birgit Högl, Ronald B. Postuma, Alex Iranzo, Stefani, A., Ferini-Strambi, L., Postuma, R. B., Iranzo, A., Videnovic, A., Hogl, B., and Wenning, G. K.

Subjects
Atrophy, business.industry, Physiology (medical), Medicine, In patient, Neurology (clinical), Olfaction, business, medicine.disease, REM sleep behavior disorder, Neuroscience
Published
2020

16. LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder

Author

Peter Young, Birgit Högl, Wolfgang H. Oertel, Michele T.M. Hu, Giuseppe Plazzi, Valérie Cochen De Cock, Dan Spiegelman, Yves Dauvilliers, Elena Antelmi, Jacques Montplaisir, Ambra Stefani, Friederike Sixel-Döring, Jennifer A. Ruskey, Christelle Charley Monaca, Brit Mollenhauer, Ziv Gan-Or, Isabelle Arnulf, Guy A. Rouleau, Ronald B. Postuma, Bouchra Ouled Amar Bencheikh, Claudia Trenkwalder, Luigi Ferini-Strambi, Jean-François Gagnon, Anna Heidbreder, Ouled Amar Bencheikh, Bouchra, Ruskey, Jennifer A., Arnulf, Isabelle, Dauvilliers, Yve, Monaca, Christelle Charley, De Cock, Valérie Cochen, Gagnon, Jean-Françoi, Spiegelman, Dan, Hu, Michele T.M., Högl, Birgit, Stefani, Ambra, Ferini-Strambi, Luigi, Plazzi, Giuseppe, Antelmi, Elena, Young, Peter, Heidbreder, Anna, Mollenhauer, Brit, Sixel-Döring, Friederike, Trenkwalder, Claudia, Oertel, Wolfgang, Montplaisir, Jacques Y., Postuma, Ronald B., Rouleau, Guy A., Gan-Or, Ziv, Ouled Amar Bencheikh, B., Ruskey, J. A., Arnulf, I., Dauvilliers, Y., Monaca, C. C., De Cock, V. C., Gagnon, J. -F., Spiegelman, D., M. T. M., Hu, Hogl, B., Stefani, A., Ferini-Strambi, L., Plazzi, G., Antelmi, E., Young, P., Heidbreder, A., Mollenhauer, B., Sixel-Doring, F., Trenkwalder, C., Oertel, W., Montplaisir, J. Y., Postuma, R. B., Rouleau, G. A., Gan-Or, Z., Service des Pathologies du sommeil [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Euromov (EuroMov), Université de Montpellier (UM), and Clinique Beau Soleil [Montpellier]

Subjects
Male, 0301 basic medicine, REM sleep behavior disorder, Disease, Biology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Genetic, Genetics, medicine, LRRK2, Parkinson disease, Neurology, Geriatrics and Gerontology, Neurology (clinical), Humans, Coding region, Dementia, Aged, Synucleinopathies, Haplotype, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Middle Aged, Protective Factors, medicine.disease, 3. Good health, 030104 developmental biology, Haplotypes, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

Background: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear.Methods: The full coding sequence, exon-intron boundaries and 5′ and 3′ untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD.Results: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44–0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% CI 1.05–1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified.Conclusions: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD.

Published
2018
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17. GBA variants in REM sleep behavior disorder: a multicenter study

Author

Jennifer A. Ruskey, Friederike Sixel-Döring, David Kemlink, Michela Figorilli, Giuseppe Plazzi, Gian Luigi Gigli, Christelle Charley Monaca, Alberto J. Espay, Michele T.M. Hu, Monica Puligheddu, Bradley F. Boeve, Abril Beatriz, Lynne Krohn, Wolfgang H. Oertel, Yves Dauvilliers, Elena Antelmi, Marco Toffoli, Ziv Gan-Or, Uladzislau Rudakou, Mariarosaria Valente, Anna Heidbreder, Valérie Cochen De Cock, Etienne Leveille, Mineke Viaene, Ronald B. Postuma, Jean-François Gagnon, Jacques Montplaisir, Ambra Stefani, Claudia Trenkwalder, Birgit Högl, Guy A. Rouleau, Farnaz Asayesh, Luigi Ferini-Strambi, Karel Sonka, Isabelle Arnulf, Brit Mollenhauer, Alex Desautels, Femke Dijkstra, Krohn, L., Ruskey, J. A., Rudakou, U., Leveille, E., Asayesh, F., M. T. M., Hu, Arnulf, I., Dauvilliers, Y., Hogl, B., Stefani, A., Monaca, C. C., Abril, B., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Boeve, B. F., Espay, A. J., De Cock, V. C., Mollenhauer, B., Sixel-Doring, F., Trenkwalder, C., Sonka, K., Kemlink, D., Figorilli, M., Puligheddu, M., Dijkstra, F., Viaene, M., Oertel, W., Toffoli, M., Gigli, G. L., Valente, M., Gagnon, J. -F., Desautels, A., Montplaisir, J. Y., Postuma, R. B., Rouleau, G. A., Gan-Or, Z., McGill University = Université McGill [Montréal, Canada], McGill University Health Center [Montreal] (MUHC), Institut Interdisciplinaire d'Innovation Technologique [Sherbrooke] (3IT), Université de Sherbrooke (UdeS), Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), University of Bologna/Università di Bologna, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Mayo Clinic [Rochester], University of Cincinnati (UC), Euromov (EuroMov), Université de Montpellier (UM), University Medical Center Göttingen (UMG), Philipps Universität Marburg = Philipps University of Marburg, Charles University [Prague] (CU), First Faculty of Medicine Charles University [Prague], University of Cagliari, Università degli Studi di Udine - University of Udine [Italie], University of Alberta, Université de Montréal (UdeM), Hôpital du Sacré-Coeur de Montréal, National Institutes of Health [Bethesda] (NIH), Service de Pathologies du sommeil [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Retiveau, Nolwenn

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], REM Sleep Behavior Disorder, MESH: Glucosylceramidase, Gastroenterology, MESH: Neurodegenerative Diseases, Behavior disorder, 0302 clinical medicine, MESH: Genetic Variation, Age of Onset, MESH: Aged, Sanger sequencing, 0303 health sciences, MESH: Middle Aged, Genetic analysis, MESH: Genetic Predisposition to Disease, Neurodegenerative Diseases, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Disease Progression, symbols, Glucosylceramidase, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], GBA, Female, medicine.medical_specialty, MESH: Age of Onset, REM sleep behavior disorder, 03 medical and health sciences, symbols.namesake, Internal medicine, medicine, Humans, Dementia with Lewy Bodies, Genetic Predisposition to Disease, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, Aged, MESH: Humans, business.industry, Dementia with Lewy bodies, Parkinson’s disease, Genetic Variation, Odds ratio, medicine.disease, MESH: Male, Confidence interval, 030104 developmental biology, MESH: REM Sleep Behavior Disorder, Multicenter study, Neurology (clinical), business, MESH: Female, 030217 neurology & neurosurgery
Abstract

ObjectiveTo study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.MethodsA total of 4,147 individuals were included: 1,061 iRBD patients and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk for iRBD, age at onset (AAO) and conversion rates.ResultsGBA variants were found in 9.5% of iRBD patients compared to 4.1% in controls (odds ratio [OR]=2.45, 95% CI=1.87–3.22, p=1×10−10). The estimated OR for mild p.N370S variant carriers was 3.69, 95% CI=1.90–7.14, p=3.5×10−5, while for severe variant carriers it was 17.55, 95% CI=2.11–145.9, p=0.0015. Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or non-carriers (p=0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% in non-carriers (p=0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be taken with caution.ConclusionsGBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.

Published
2019
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18. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study

Author

Postuma, Ronald, Iranzo, Alex, Hu, Michele, Högl, Birgit, Boeve, Bradley, Manni, Raffaele, Oertel, Wolfgang, Arnulf, Isabelle, Ferini-Strambi, Luigi, Puligheddu, Monica, Antelmi, Elena, Cochen De Cock, Valérie, Arnaldi, Dario, Mollenhauer, Brit, Videnovic, Aleksandar, Sonka, Karel, Jung, Ki-Young, Kunz, Dieter, Dauvilliers, Yves, Provini, Federica, Lewis, Simon, Buskova, Jitka, Pavlova, Milena, Heidbreder, Anna, Montplaisir, Jacques, Santamaria, Joan, Barber, Thomas, Stefani, Ambra, St Louis, Erik, 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-François, Gaig, Carles, Zucconi, Marco, Trenkwalder, Claudia, Gan-Or, Ziv, Lo, Christine, Rolinski, Michal, Mahlknecht, Philip, Holzknecht, Evi, Boeve, Angel, Teigen, Luke, Toscano, Gianpaolo, Mayer, Geert, Morbelli, Silvia, Dawson, Benjamin, Pelletier, Amélie, St.Louis, Erik, Postuma, R. B., Iranzo, A., Hu, M., Hogl, B., Boeve, B. F., Manni, R., Oertel, W. H., 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, S. J., Buskova, J., Pavlova, M., Heidbreder, A., Montplaisir, J. Y., Santamaria, J., Barber, T. R., Stefani, A., Louis, S. E. K., 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, A. R., Teigen, L. N., Toscano, G., Mayer, G., Morbelli, S., Dawson, B., Pelletier, A., Postuma R.B., Iranzo A., Hu M., Hogl B., Boeve B.F., Manni R., Oertel W.H., 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 S.J., Buskova J., Pavlova M., Heidbreder A., Montplaisir J.Y., Santamaria J., Barber T.R., Stefani A., Louis S.E.K., 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 A.R., Teigen L.N., Toscano G., Mayer G., Morbelli S., Dawson B., Pelletier A., McGill University = Université McGill [Montréal, Canada], Innsbruck Medical University [Austria] (IMU), Mayo Clinic [Rochester], Philipps University of Marburg, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Bologna, Euromov (EuroMov), Université de Montpellier (UM), University of Genoa (UNIGE), University Medical Center Göttingen (UMG), First Faculty of Medicine Charles University [Prague], Seoul National University Hospital, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Münster, Hôpital du Sacré-Coeur de Montréal, University of Oxford [Oxford], Ospedale Bellaria [Bologna, Italy], and Université du Québec à Montréal = University of Québec in Montréal (UQAM)

Subjects
0301 basic medicine, Male, Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, REM sleep behaviour disorder, Kaplan-Meier Estimate, REM Sleep Behavior Disorder, Cohort Studies, 0302 clinical medicine, Risk Factors, Restless legs syndrome, Prospective Studies, Depression (differential diagnoses), Parkinsonism, Hazard ratio, Parkinson Disease, Middle Aged, Prognosis, humanities, 3. Good health, Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Parkinson’s disease, Lewy Body Disease, medicine.medical_specialty, Polysomnography, Prodromal Symptoms, Parkinson’s disease, REM sleep behaviour disorder, dementia with Lewy bodies, multiple system atrophy, REM sleep behavior disorder, 03 medical and health sciences, Parkinsonian Disorders, Internal medicine, dementia with Lewy bodie, mental disorders, medicine, Dementia, Humans, Aged, Proportional Hazards Models, business.industry, Dementia with Lewy bodies, Scientific Commentaries, medicine.disease, 030104 developmental biology, Neurology (clinical), business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Forecasting
Abstract

International audience; 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.

Published
2019
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19. SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder

Author

Marco Toffoli, Uladzislau Rudakou, Anna Heidbreder, Michele T.M. Hu, Isabelle Arnulf, Lynne Krohn, Jean-François Gagnon, Femke Dijkstra, Yves Dauvilliers, Beatriz Abril, Elena Antelmi, Brit Mollenhauer, Annette Janzen, Naomi C. Futhey, Ambra Stefani, Jacques Montplaisir, W. H. Oertel, David Kemlink, Evi Holzknecht, Armaghan Alam, Paul Cannon, Luigi Ferini-Strambi, Guy A. Rouleau, Claudia Trenkwalder, Mineke Viaene, Karel Sonka, Birgit Högl, Christelle Charley Monaca, Ronald B. Postuma, Monica Puligheddu, Alex Desautels, Mariarosaria Valente, Bradley F. Boeve, Karl Heilbron, Valérie Cochen De Cock, Michela Figorilli, Friederike Sixel-Döring, Ziv Gan-Or, Gian Luigi Gigli, Jennifer A. Ruskey, Giuseppe Plazzi, Rudakou, U., Futhey, N. C., Krohn, L., Ruskey, J. A., Heilbron, K., Cannon, P., Alam, A., Arnulf, I., M. T. M., Hu, Montplaisir, J. Y., Gagnon, J. -F., Desautels, A., Dauvilliers, Y., Toffoli, M., Gigli, G. L., Valente, M., Hogl, B., Stefani, A., Holzknecht, E., Sonka, K., Kemlink, D., Oertel, W., Janzen, A., Plazzi, G., Antelmi, E., Figorilli, M., Puligheddu, M., Mollenhauer, B., Trenkwalder, C., Sixel-Doring, F., De Cock, V. C., Monaca, C. C., Heidbreder, A., Ferini-Strambi, L., Dijkstra, F., Viaene, M., Abril, B., Boeve, B. F., Postuma, R. B., Rouleau, G. A., Gan-Or, Z., Salvy-Córdoba, Nathalie, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], 23andMe Inc., Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Nuffield Department of Clinical Neurosciences [Oxford], University of Oxford, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Centre d'études avancées en Médecine du Sommeil (CEAMS), Université de Montréal (UdeM)-Hôpital du Sacré-Coeur de Montréal, Université du Québec à Montréal = University of Québec in Montréal (UQAM), Hôpital Gui de Chauliac [Montpellier], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Università degli Studi di Udine - University of Udine [Italie], UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, University of Udine and University Hospital of Udine, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), First Faculty of Medicine Charles University [Prague], Philipps Universität Marburg = Philipps University of Marburg, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institute of Neurological Sciences of Bologna IRCCS, University of Cagliari, Paracelsus-Elena-Klinik, Kassel, Germany., department of neurology, clinical dementia center and DZNE, goettingen, Allemagne., Georg-August-University = Georg-August-Universität Göttingen, Department of Psychiatry and Psychotherapy, University Medical Center Goettingen (UMG), Göttingen, Clinique Beau Soleil [Montpellier], Euromov (EuroMov), Université de Montpellier (UM), CHU Lille, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Algemeen Ziekenhuis Sint-Dimpna, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Mayo Clinic [Rochester], Hôpital du Sacré-Coeur de Montréal, and Department of Human Genetics [Montréal]

Subjects
Male, 0301 basic medicine, Aging, REM sleep behavior disorder, Disease, Bioinformatics, European descent, Behavior disorder, 0302 clinical medicine, Medicine, MESH: Genetic Variation, MESH: High-Throughput Nucleotide Sequencing, MESH: Genetic Association Studies, education.field_of_study, General Neuroscience, sphingomyelin phosphodiesterase 1, High-Throughput Nucleotide Sequencing, MESH: Negative Results, MESH: Sleep Wake Disorders, Association study, Sphingomyelin Phosphodiesterase, Female, Sphingomyelin phosphodiesterase 1, Sleep Wake Disorders, Rapid eye movement sleep, Sleep, REM, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, association study, 03 medical and health sciences, Humans, education, Genetic Association Studies, MESH: Humans, business.industry, Dementia with Lewy bodies, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Genetic Variation, medicine.disease, MESH: Sleep, REM, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Sphingomyelin Phosphodiesterase, Neurology (clinical), Geriatrics and Gerontology, business, MESH: Female, Negative Results, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.

Published
2020
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20. Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies

Author

Uladzislau Rudakou, Edward A. Fon, Petra Oliva, Guy A. Rouleau, Yves Dauvilliers, Elena Antelmi, Birgit Högl, Anna Heidbreder, Jean-François Trempe, Christopher Liong, Bouchra Ouled Amar Bencheikh, Pavlina Wolf, Isabelle Arnulf, Luigi Ferini-Strambi, A. Desautels, Jennifer A. Ruskey, Peter Young, Nicolas Dupré, Valérie Cochen De Cock, Giuseppe Plazzi, Lior Greenbaum, Michele T.M. Hu, Lynne Krohn, Roy N. Alcalay, Guillaume Lamoureux, Ziv Gan-Or, Xiaokui Kate Zhang, Jacques Montplaisir, S. Hassin-Baer, Dan Spiegelman, Ronald B. Postuma, Ambra Stefani, Jean-François Gagnon, Christelle Charley Monaca, Benoît Vanderperre, Sandra B. Laurent, Tugba N. Ozturk, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Montreal Neurological Institute and Hospital, Concordia University [Montreal], Centre for Research in Molecular Modeling and Department of Chemistry & Biochemistry, PROTEO, The Quebec Network for Research on Protein Function, Engineering, and Applications, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)-Université de Sherbrooke (UdeS)-Université Laval [Québec] (ULaval)-McGill University = Université McGill [Montréal, Canada]-University of Ottawa [Ottawa]-Université du Québec à Trois-Rivières (UQTR)-Université de Montréal (UdeM)-TransBiotech, Lévis-Concordia University [Montreal]-Université du Québec à Montréal = University of Québec in Montréal (UQAM), Department of Neurology and Neurosurgery [Montreal], McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford [Oxford], Nuffield Department of Clinical Neurosciences [Oxford], Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universität Innsbruck [Innsbruck], Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Alma Mater Studiorum University of Bologna (UNIBO), Institute of Neurological Sciences of Bologna IRCCS, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Münster, Clinique Beau Soleil [Montpellier], Euromov (EuroMov), Université de Montpellier (UM), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Sanofi Genzyme, The Danek Gertner Institute of Genetics, Chaim Sheba Medical Center, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Columbia University College of Physicians and Surgeons, Center for advanced research in sleep medicine, Montreal, Université de Montréal (UdeM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Axe Neurosciences [CHU Québec], Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Research Center of CIUSSS of the North of Montreal and Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada, Laval University Medical center, Université Laval [Québec] (ULaval), McGill University Health Center [Montreal] (MUHC), Department of Pharmacology and Therapeutics [Montréal], Center for Computational and Integrative Biology [Camden] (CCIB), Rutgers University [Camden], Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Krohn, L., Ozturk, T. N., Vanderperre, B., Ouled Amar Bencheikh, B., Ruskey, J. A., Laurent, S. B., Spiegelman, D., Postuma, R. B., Arnulf, I., M. T. M., Hu, Dauvilliers, Y., Hogl, B., Stefani, A., Monaca, C. C., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Rudakou, U., Cochen De Cock, V., Young, P., Wolf, P., Oliva, P., Zhang, X. K., Greenbaum, L., Liong, C., Gagnon, J. -F., Desautels, A., Hassin-Baer, S., Montplaisir, J. Y., Dupre, N., Rouleau, G. A., Fon, E. A., Trempe, J. -F., Lamoureux, G., Alcalay, R. N., Gan-Or, Z., Krohn L., Ozturk T.N., Vanderperre B., Ouled Amar Bencheikh B., Ruskey J.A., Laurent S.B., Spiegelman D., Postuma R.B., Arnulf I., Hu M.T.M., Dauvilliers Y., Hogl B., Stefani A., Monaca C.C., Plazzi G., Antelmi E., Ferini-Strambi L., Heidbreder A., Rudakou U., Cochen De Cock V., Young P., Wolf P., Oliva P., Zhang X.K., Greenbaum L., Liong C., Gagnon J.-F., Desautels A., Hassin-Baer S., Montplaisir J.Y., Dupre N., Rouleau G.A., Fon E.A., Trempe J.-F., Lamoureux G., Alcalay R.N., and Gan-Or Z.

Subjects
0301 basic medicine, Male, Models, Molecular, Potassium Channels, Synucleinopathies, Genome-wide association study, REM Sleep Behavior Disorder, MESH: Glucosylceramidase, MESH: Genotype, 0302 clinical medicine, TMEM175/GAK/DGKQ, genetics, MESH: Molecular Dynamics Simulation, Parkinson, Genetics, MESH: Aged, MESH: Middle Aged, synucleinopaties, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Parkinson Disease, MESH: Potassium Channels, Middle Aged, MESH: Case-Control Studies, Transmembrane protein, Neurology, MESH: Synucleinopathies, Glucosylceramidase, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, synucleinopathies, MESH: Models, Molecular, Adult, Genotype, Locus (genetics), Single-nucleotide polymorphism, Biology, Molecular Dynamics Simulation, Polymorphism, Single Nucleotide, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Homology modeling, Genetic association, Aged, MESH: Humans, MESH: Adult, MESH: Male, 030104 developmental biology, REM sleep behavior disorder, MESH: REM Sleep Behavior Disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Neurology (clinical), Lysosomes, Glucocerebrosidase, MESH: Female, 030217 neurology & neurosurgery, synucleinopathie, MESH: Parkinson Disease, MESH: Lysosomes
Abstract

Objective The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. Methods Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. Results Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. Interpretation Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.

Published
2018
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21. Environmental risk factors for REM sleep behavior disorder: A multicenter case-control study

Author

V. Cochen De Cock, Marcus M. Unger, Ronald B. Postuma, Yo-El Ju, Jacques Montplaisir, Marco Zucconi, Joan Santamaria, Masayuki Miyamoto, W. H. Oertel, Birgit Högl, Christina Wolfson, Tomoyuki Miyamoto, Birgit Frauscher, Amélie Pelletier, Karel Sonka, Geert Mayer, Smaranda Leu-Semenescu, Monica Puligheddu, Michele Terzaghi, Poul Jennum, Luigi Ferini-Strambi, Maria Livia Fantini, Isabelle Arnulf, Raffaele Manni, A. Iranzo, Karin Stiasny-Kolster, Yves Dauvilliers, Postuma, R. B., Montplaisir, J. Y, Pelletier, A., Dauvilliers, Y, Oertel, W, Iranzo, A., FERINI STRAMBI, Luigi, Arnulf, I., Hogl, B., Manni, R., Miyamoto, T., Mayer, G., Stiasny kolster, K., Puligheddu, M., Ju, Y., Jennum, P., Sonka, K., Santamaria, J., Fantini, M. L., Zucconi, M., Leu semenescu, S., Frauscher, B., Terzaghi, M., Miyamoto, M., Unger, M. M., De Cock, V. C., and Wolfson, C.

Subjects
Male, medicine.medical_specialty, Polysomnography, Poison control, REM Sleep Behavior Disorder, Environment, Coffee, Sensitivity and Specificity, Severity of Illness Index, REM sleep behavior disorder, Risk Factors, Surveys and Questionnaires, Internal medicine, Severity of illness, Confidence Intervals, Odds Ratio, medicine, Humans, Occupations, Life Style, Aged, Tea, medicine.diagnostic_test, business.industry, Parkinsonism, Smoking, Case-control study, Parasomnia, Odds ratio, Middle Aged, medicine.disease, Alcohols, Case-Control Studies, Physical therapy, Educational Status, Female, Neurology (clinical), business
Abstract

Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder.Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors.A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008).Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

Published
2012
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22. Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group

Author

B. F. Boeve, Clifford B. Saper, Yuan-Yang Lai, Luigi Ferini-Strambi, Birgit Högl, E. St. Louis, Marco Zucconi, Markku Partinen, Jean Gagnon, Marcus M. Unger, Jacques Montplaisir, P. Jennum, Anna Heidbreder, P. Schmidt, Milena Pavlova, Yun Kwok Wing, W. H. Oertel, Claudio L. Bassetti, V. Cochen De Cock, J. Santamaria, Carlos Singer, Peter Young, Y. Inoue, Carlos H. Schenck, Raffaele Ferri, Karel Sonka, Birgit Frauscher, Geert Mayer, Jens Carsten Möller, Pierre-Hervé Luppi, Jerome M. Siegel, Yves Dauvilliers, Giuseppe Plazzi, Ronald B. Postuma, Aleksandar Videnovic, Isabelle Arnulf, Claudia Trenkwalder, A. Iranzo, Friederike Sixel-Döring, Schenck, Ch, Montplaisir, Jy, Frauscher, B, Hogl, B, Gagnon, Jf, Postuma, R, Sonka, K, Jennum, P, Partinen, M, Arnulf, I, Cochen de Cock, V, Dauvilliers, Y, Luppi, Ph, Heidbreder, A, Mayer, G, Sixel Döring, F, Trenkwalder, C, Unger, M, Young, P, Wing, Yk, FERINI STRAMBI, Luigi, Ferri, R, Plazzi, G, Zucconi, M, Inoue, Y, Iranzo, A, Santamaria, J, Bassetti, C, Möller, Jc, Boeve, Bf, Lai, Yy, Pavlova, M, Saper, C, Schmidt, P, Siegel, Jm, Singer, C, St Louis, E, Videnovic, A, Oertel, W., C. H. Schenck, J. Y. Montplaisir, B. Frauscher, B. Hogl, J. Gagnon, R. Postuma, K. Sonka, P. Jennum, M. Partinen, I. Arnulf, V. C. de, Y. Dauvillier, P. Luppi, A. Heidbreder, G. Mayer, F. Sixel-Döring, C. Trenkwalder, M. Unger, P. Young, Y. K. Wing, L. Ferini-Strambi, R. Ferri, G. Plazzi, M. Zucconi, Y. Inoue, A. Iranzo, J. Santamaria, C. Bassetti, J. C. Möller, B. F. Boeve, Y. Y. Lai, M. Pavlova, C. Saper, P. Schmidt, J. M. Siegel, C. Singer, E. S. Loui, A. Videnovic, and W. Oertel

Subjects
medicine.medical_specialty, Consensus, REM Sleep Behavior Disorder, Clonazepam, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Risk Factors, medicine, International Classification of Sleep Disorders, Humans, Apathy, Rem behavior disorder, NEURODEGENERATION, GABA Modulators, 030304 developmental biology, Melatonin, 0303 health sciences, Clinical Trials as Topic, Dementia with Lewy bodies, Actigraphy, Parkinson Disease, General Medicine, medicine.disease, 3. Good health, Neuroprotective Agents, Inclusion and exclusion criteria, Physical therapy, Clinical Global Impression, Anxiety, medicine.symptom, Psychology, 030217 neurology & neurosurgery
Abstract

Objectives We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. Methods The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). Results Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1–3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. Conclusions The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

Published
2013

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