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11 results on '"Sixel-Doring, F."'

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

2. Severe contractions in parkinson's disease caused by immobilization and lack of dopaminergic treatment

Author

Sixel-Doring, F., Rausch-Hertel, M., and Trenkwalder, C.

Subjects
Contracture -- Risk factors, Contracture -- Drug therapy, Contracture -- Research, Dopa -- Dosage and administration, Dopa -- Research, Parkinson's disease -- Complications and side effects, Parkinson's disease -- Research, Health
Abstract

Four patients in advanced stages of Parkinson's disease developed irreversible limb contractures in the course of acute comorbidity. The most likely reasons for such severe conditions are exacerbation of severe rigidity, dystonic posturing and loss of physiologic movement range following the reduction of dopaminergic medication.. A movement disorder specialist should therefore be consulted for tailoring an adequate treatment plan and appropriate administration of oral levodopa preparations via gastric tube. Further, high frequency physiotherapy should be provided during immobilization periods. Keywords: Parkinson's disease, limb contractures, comorbidity with immobilization dopaminergic deficit, Table of Contents Abstract Introduction Discussion References Introduction Immobilization is a frequent condition in elderly patients with PD due to surgery after hip fractures, other operations or any acute comorbidity. [...]

Published
2008

4. 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

5. Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients

Author

Baldelli, Luca, Schade, Sebastian, Jesús, Silvia, Schreglmann, Sebastian R., Sambati, Luisa, Gómez-Garre, Pilar, Halsband, Claire, Calandra-Buonaura, Giovanna, Adarmes-Gómez, Astrid Daniela, Sixel-Döring, Friederike, Zenesini, Corrado, Pirazzini, Chiara, Garagnani, Paolo, Bacalini, Maria Giulia, Bhatia, Kailash P., Cortelli, Pietro, Mollenhauer, Brit, Franceschi, Claudio, Houlden, Henry, Liò, Pietro, Luchinat, Claudio, Delledonne, Massimo, Mills, Kevin, Pedersen, Nancy L., Azevedo, Tiago, Bartoletti-Stella, Anna, Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Capellari, Sabina, Carriòn-Claro, Mario, Clayton, Robert, Dal Molin, Alessandra, Dimitri, Giovanna Maria, Doykov, Ivan, Giuliani, Cristina, Hägg, Sara, Hällqvist, Jenny, Heywood, Wendy, Huertas, Ismael, Jylhävä, Juulia, Labrador-Espinosa, Miguel A., Licari, Cristina, Macias, Daniel, Magrinelli, Francesca, Rodríguez, Juan Francisco Martín, Maturo, Maria Giovanna, Mengozzi, Giacomo, Meoni, Gaia, Milazzo, Maddalena, Nardini, Christine, Periñán-Tocino, Maria Teresa, Ravaioli, Francesco, Sala, Claudia, Spasov, Simeon, Tejera-Parrado, Cristina, Tenori, Leonardo, Paola, Turano, Williams, Dylan, Xumerle, Luciano, Zago, Elisa, Broli, Marcella, De Massis, Patrizia, Escuela-Martin, Rocio, Fabbri, Giovanni, Gabellini, Anna, Guaraldi, Pietro, Macrì, Stefania, Nassetti, Stefania Alessandra, Scaglione, Cesa Lorella Maria, Valzania, Franco, Rosaria, Cilea, Mignani, Francesco, Ortega, Rosario Vigo, Boninsegna, Claudia, De Luca, Silvia, Mir, Pablo, Trenkwalder, Claudia, Provini, Federica, European Commission, Schade, Sebastian [0000-0002-6316-6804], Gómez-Garre, Pilar [0000-0002-0437-6182], Mir, Pablo [0000-0003-1656-302X], Provini, Federica [0000-0001-9063-2658], Apollo - University of Cambridge Repository, Baldelli L., Schade S., Jesus S., Schreglmann S.R., Sambati L., Gomez-Garre P., Halsband C., Calandra Buonaura G., Adarmes-Gomez A.D., Sixel-Doring F., Zenesini C., Pirazzini C., Garagnani P., Bacalini M.G., Bhatia K.P., Cortelli P., Mollenhauer B., Franceschi C., Houlden H., Lio P., Luchinat C., Delledonne M., Mills K., Pedersen N.L., Azevedo T., Bartoletti-Stella A., Bonilla-Toribio M., Buiza-Rueda D., Capellari S., Carrion-Claro M., Clayton R., Dal Molin A., Dimitri G.M., Doykov I., Giuliani C., Hagg S., Hallqvist J., Heywood W., Huertas I., Jylhava J., Labrador-Espinosa M.A., Licari C., Macias D., Magrinelli F., Rodriguez J.F.M., Maturo M.G., Mengozzi G., Meoni G., Milazzo M., Nardini C., Perinan-Tocino M.T., Ravaioli F., Sala C., Spasov S., Tejera-Parrado C., Tenori L., Paola T., Williams D., Xumerle L., Zago E., Broli M., De Massis P., Escuela-Martin R., Fabbri G., Gabellini A., Guaraldi P., Macri S., Nassetti S.A., Scaglione C.L.M., Valzania F., Rosaria C., Mignani F., Ortega R.V., Boninsegna C., De Luca S., Mir P., Trenkwalder C., and Provini F.

Subjects
Pediatrics, medicine.medical_specialty, Parkinson's disease, MathematicsofComputing_GENERAL, Disease, prodromal symptom, Predictive markers, REM sleep behavior disorder, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Orthostatic vital signs, 0302 clinical medicine, 030225 pediatrics, Medicine, Motor Manifestations, Disease markers, RC346-429, siblings, business.industry, TheoryofComputation_GENERAL, Cognition, Parkinson Disease, medicine.disease, 3. Good health, metabolomics, parkinson disease, Neurology, Risk factors, Cohort, PD, Neurology. Diseases of the nervous system, Neurology (clinical), PROPAG-AGEING consortium, business, 030217 neurology & neurosurgery
Abstract

PROPAG-AGEING consortium., A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had, This project has received funding from the European Union’s Horizon 2020 research and innovation program Propag‐Ageing under grant agreement no. 634821.

Published
2021

6. 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

7. 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

8. 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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9. 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

10. NPC1 variants are not associated with Parkinson's disease, REM-sleep behavior disorder or dementia with Lewy bodies in European cohorts.

Author

Somerville EN, Krohn L, Yu E, Rudakou U, Senkevich K, Ruskey JA, Asayesh F, Ahmad J, Spiegelman D, Dauvilliers Y, Arnulf I, Hu MTM, Montplaisir JY, Gagnon JF, Desautels A, Ibrahim A, Stefani A, Högl B, Gigli GL, Valente M, Janes F, Bernardini A, Dusek P, Sonka K, Kemlink D, Plazzi G, Antelmi E, Biscarini F, Mollenhauer B, Trenkwalder C, Sixel-Doring F, Figorilli M, Puligheddu M, De Cock VC, Oertel W, Janzen A, Ferini-Strambi L, Heibreder A, Monaca CC, Abril B, Dijkstra F, Viaene M, Boeve BF, Postuma RB, Rouleau GA, and Gan-Or Z

Subjects
Humans, Sleep, Niemann-Pick C1 Protein, Parkinson Disease genetics, Synucleinopathies, Lewy Body Disease genetics, REM Sleep Behavior Disorder genetics
Abstract

NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Niemann-Pick disease type C (NPC), a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association of NPC1 variants with the synucleinopathies Parkinson's disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement-sleep behavior disorder (RBD). We analyzed common and rare variants from 3 cohorts of European descent: 1084 RBD cases and 2945 controls, 2852 PD cases and 1686 controls, and 2610 DLB cases and 1920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests were used to assess rare variants, both adjusted for sex, age, and principal components. No variants were associated with any of the synucleinopathies, supporting that common and rare NPC1 variants do not play an important role in alpha synucleinopathies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2023
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11. A Clinically Applicable Interactive Micro and Macro-Sleep Staging Algorithm for Elderly and Patients with Neurodegeneration.

Author

Cesari M, Christensen JAE, Sixel-Doring F, Muntean ML, Mollenhauer B, Trenkwalder C, Jennum P, and Sorensen HBD

Subjects
Aged, Case-Control Studies, Humans, Polysomnography, Algorithms, Neurodegenerative Diseases complications, Parkinson Disease complications, REM Sleep Behavior Disorder diagnosis, Sleep Stages
Abstract

Elderly and patients with neurodegenerative diseases (NDD) often complain about sleep problems and show altered sleep structure. Automated algorithms for efficient and specific sleep staging are needed. We propose a new algorithm using only one electroencephalographic and two electrooculographic channels to score wakefulness, rapid eye movement (REM) sleep and non-REM sleep in a cohort of elderly healthy controls (HC), patients with Parkinson's disease (PD), isolated REM sleep behavior disorder (iRBD), considered the prodromal stage of PD, and patients with PD and RBD (PD+RBD). The proposed method scores both standard 30-s epochs (macro-staging) and 5-s mini-epochs (micro-staging), whose evaluation may help to better understand sleep micro-structure. Moreover, the algorithm is interactive, as it labels the classified sleep epochs as either certain or uncertain, so that experts can manually review the uncertain ones. The algorithm performances were evaluated for macro-sleep staging, where it achieved overall accuracies of 0.87±0.05 in 41 HC, 0.86±0.10 in 57 PD, 0.76±0.10 in 31 iRBD and 0.77±0.10 in 30 PD+RBD patients when all 30-s epochs were considered. The accuracies increased to 0.91±0.05, 0.90±0.08, 0.85±0.09, 0.88±0.08 respectively when considering only the certain ones. The epochs labeled as uncertain were 9.95±4.15%, 11.13±7.86%, 18.39±7.38% and 18.90±8.00% in HC, PD, iRBD and PD+RBD respectively. The proposed interactive micro and macro sleep staging algorithm can be used in clinics to reduce the burden of manual sleep staging in elderly and patients with NDD.

Published
2019
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