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1. Integrated Management of Atypical Parkinsonism: A Home-based Patient-Centered Healthcare Delivery Based on Telenursing (IMPACT Study)

Author: Fondazione IRCCS Istituto Neurologico Nazionale Casmiro Mondino, Neuromed IRCCS, and Azienda Ospedaliera Universitaria Gaetano Martino, Messina
Published: 2024

2. Validation of the I-UDS Neuropsychological Battery

Author: IRCCS Associazione Oasi Maria SS. ONLUS, Troina, Italy, IRCCS Istituto Auxologico Italiano, Milano, Italy, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy, IRCCS Ospedale San Raffaele, Milano, Italy, Fondazione IRCCS Santa Lucia, Roma, Italy, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, Milano, Italy, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy, IRCCS Don Gnocchi, Milano, Italy, IRCCS Ospedale Maggiore Policlinico, Milano, Italy, IRCCS AOU San Martino, Genova, Italy, IRCCS SDN, Napoli, Italy, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy, IRCCS Istituto delle Scienze Neurologiche di Bologna, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy, and IRCCS Humanitas Mirasole, Rozzano -Milano, Italy
Published: 2023

3. Olfactory discrimination in disorders of consciousness: A new sniff protocol

Author: Davide Sattin, Maria Grazia Bruzzone, Stefania Ferraro, Anna Nigri, Matilde Leonardi, Davide Guido, and Coma Research Center, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
Subjects: Bayesian approach, disorders of consciousness, neuroimaging, olfactory test, vegetative state, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Abstract Background The identification of salient stimuli useful for rehabilitation purposes is important in patients with disorders of consciousness (DOC): among these, olfactory stimuli might play an important role due to the functional coupling between olfactory and emotional processing. However, a high percentage of post brain injury patients present anosmia. Aims of the Study The aim of this pilot research is to present an innovative approach to test olfactory functions at the bedside using four selected odors in patients with DOC. Methods Sixteen patients with DOC were tested with two assessment techniques the new olfactory discrimination protocol (ODP) and a functional magnetic resonance imaging paradigm to evaluate olfactory neural process. The Frequentist and Bayesian methods were used to analyze reliability properties of the new tool. Results Analysis showed a good agreement between assessment techniques and a substantial test‐retest reliability of the ODP. Cohen's Ks were equal to 0.814 (95% CI = 0.471, 1) and 0.607 (0.118; 1) respectively, using the Frequentist approach, while they were 0.762 (95% HPD = 0.470; 0.966) and 0.650 (0.320; 0.913) with the Bayesian approach in the 11 patients analyzed. Conclusions Despite the limits of this preliminary research, the ODP can be useful for clinicians for the preliminary assessment of the olfactory discrimination in patients with DOC.
Published: 2019
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4. Olfactory discrimination in disorders of consciousness: A new sniff protocol

Author: Davide Sattin, Maria Grazia Bruzzone, Stefania Ferraro, Anna Nigri, Matilde Leonardi, Davide Guido, and Coma Research Center, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, Bayesian probability, Anosmia, Disorders of consciousness, Audiology, 050105 experimental psychology, vegetative state, lcsh:RC321-571, 03 medical and health sciences, Behavioral Neuroscience, Olfaction Disorders, 0302 clinical medicine, Neuroimaging, Frequentist inference, medicine, Humans, 0501 psychology and cognitive sciences, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Reliability (statistics), disorders of consciousness, Original Research, Rehabilitation, neuroimaging, medicine.diagnostic_test, business.industry, Functional Neuroimaging, 05 social sciences, Bayesian approach, Reproducibility of Results, Bayes Theorem, Middle Aged, medicine.disease, Olfactory Perception, Magnetic Resonance Imaging, Point-of-Care Testing, Brain Injuries, olfactory test, Consciousness Disorders, Female, medicine.symptom, Functional magnetic resonance imaging, business, 030217 neurology & neurosurgery
Abstract: Background The identification of salient stimuli useful for rehabilitation purposes is important in patients with disorders of consciousness (DOC): among these, olfactory stimuli might play an important role due to the functional coupling between olfactory and emotional processing. However, a high percentage of post brain injury patients present anosmia. Aims of the Study The aim of this pilot research is to present an innovative approach to test olfactory functions at the bedside using four selected odors in patients with DOC. Methods Sixteen patients with DOC were tested with two assessment techniques the new olfactory discrimination protocol (ODP) and a functional magnetic resonance imaging paradigm to evaluate olfactory neural process. The Frequentist and Bayesian methods were used to analyze reliability properties of the new tool. Results Analysis showed a good agreement between assessment techniques and a substantial test‐retest reliability of the ODP. Cohen's Ks were equal to 0.814 (95% CI = 0.471, 1) and 0.607 (0.118; 1) respectively, using the Frequentist approach, while they were 0.762 (95% HPD = 0.470; 0.966) and 0.650 (0.320; 0.913) with the Bayesian approach in the 11 patients analyzed. Conclusions Despite the limits of this preliminary research, the ODP can be useful for clinicians for the preliminary assessment of the olfactory discrimination in patients with DOC.
Published: 2018

5. Multicenter Validation of a Deep Learning Detection Algorithm for Focal Cortical Dysplasia

Author: Hyo Min Lee, Fernando Cendes, Ravnoor S. Gill, Mira Semmelroch, R. Edward Hogan, Benoit Caldairou, Neda Bernasconi, Andrea Bernasconi, Maxime Guye, Andreas Schulze-Bonhage, Graeme D. Jackson, Matteo Lenge, Vanessa Cristina Mendes Coelho, Francesco Deleo, Kyoo Ho Cho, Renzo Guerrini, Dewi V. Schrader, Carmen Barba, Ludovico D'Incerti, Fabrice Bartolomei, Seok-Jun Hong, Horst Urbach, Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute, McGill University, Montreal, Pediatric Neurology Unit and Laboratories Children's Hospital A. Meyer-University of Florence, Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Department of Neurology University of Campinas, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Department of Pediatrics British Columbia Children's Hospital, Vancouver, Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Service de neurophysiologie clinique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Freiburg Epilepsy Center Universitätsklinikum Freiburg, Freiburg Epilpesy Center Universitätsklinikum Freiburg, Yonsei University College of Medicine [Seoul, Republic of Korea], Department of Neurology Washington University School of Medicine, St. Louis, Università degli Studi di Firenze = University of Florence (UniFI), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Adolescent, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Neuroimaging, Temporal lobe, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, Text mining, Deep Learning, Imaging, Three-Dimensional, Image Interpretation, Computer-Assisted, False positive paradox, Medicine, Humans, Generalizability theory, Child, 030304 developmental biology, 0303 health sciences, business.industry, Deep learning, Cortical dysplasia, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Malformations of Cortical Development, Child, Preschool, Cohort, Female, Neurology (clinical), Artificial intelligence, business, Algorithm, 030217 neurology & neurosurgery, Research Article
Abstract: Background and ObjectiveTo test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD).MethodsWe used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2–55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity.ResultsOverall sensitivity was 93% (137 of 148 FCD detected) using a leave-one-site-out cross-validation, with an average of 6 false positives per patient. Sensitivity in MRI-negative FCD was 85%. In 73% of patients, the FCD was among the clusters with the highest confidence; in half, it ranked the highest. Sensitivity in the independent cohort was 83% (19 of 23; average of 5 false positives per patient). Specificity was 89% in healthy and disease controls.DiscussionThis first multicenter-validated deep learning detection algorithm yields the highest sensitivity to date in MRI-negative FCD. By pairing predictions with risk stratification, this classifier may assist clinicians in adjusting hypotheses relative to other tests, increasing diagnostic confidence. Moreover, generalizability across age and MRI hardware makes this approach ideal for presurgical evaluation of MRI-negative epilepsy.Classification of EvidenceThis study provides Class III evidence that deep learning on multimodal MRI accurately identifies FCD in patients with epilepsy initially diagnosed as MRI negative.
Published: 2021
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6. Diagnosis and treatment of Chiari malformation type 1 in children : the International Consensus Document

Author: Massimi, Luca, Peretta, Paola, Erbetta, Alessandra, Solari, Alessandra, Farinotti, Mariangela, Ciaramitaro, Palma, Saletti, Veronica, Caldarelli, Massimo, Canheu, Alexandre Casagrande, Celada, Carlo, Chiapparini, Luisa, Chieffo, Daniela, Cinalli, Giuseppe, Di Rocco, Federico, Furlanetto, Marika, Giordano, Flavio, Jallo, George, James, Syril, Lanteri, Paola, Lemarchand, Christian, Messing-Jünger, Martina, Parazzini, Cecilia, Paternoster, Giovanna, Piatelli, Gianluca, Poca Pastor, María Antonia, Prabahkar, Prab, Ricci, Federica, Righini, Andrea, Sala, Francesco, Sahuquillo Barris, Juan, Stoodley, Marcus, Talamonti, Giuseppe, Thompson, Dominic, Triulzi, Fabio, Zucchelli, Mino, Valentini, Laura, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Massimi L] Pediatric Neurosurgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy. [Peretta P] Pediatric Neurosurgery, AOU Citta’ della Salute e della Scienza di Torino, Torino, Italy. [Erbetta A] Department of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. [Solari A, Farinotti M] Neuroepidemiology Unit – Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. [Ciaramitaro P] Department of Neuroscience, AOU Citta’ della Salute e della Scienza di Torino, Torino, Italy. [Poca MA, Sahuquillo J] Unitat de Recerca en Neurotrauma i Neurocirurgia, Servei de Neurocirurgia i Neurocirurgia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: medicine.medical_specialty, Consensus, Delphi Technique, Statement (logic), Craniovertebral decompression, education, Delphi method, personas::Grupos de Edad::niño [DENOMINACIONES DE GRUPOS], Dermatology, Nervous System Diseases::Nervous System Malformations::Neural Tube Defects::Arnold-Chiari Malformation [DISEASES], Malalties - Presa de decisions, Likert scale, 03 medical and health sciences, 0302 clinical medicine, Diagnòstic, enfermedades del sistema nervioso::malformaciones del sistema nervioso::defectos del tubo neural::malformación de Arnold-Chiari [ENFERMEDADES], medicine, Humans, Chiari 1 malformation, Child, Children, Otros calificadores::/terapia [Otros calificadores], Chiari malformation, International network, Consensus conference, Other subheadings::/therapy [Other subheadings], General Medicine, Persons::Age Groups::Child [NAMED GROUPS], medicine.disease, Syringomyelia, Arnold-Chiari Malformation, Management, Psychiatry and Mental health, Patient population, Ciencias de la información::análisis de sistemas::técnica Delfos [CIENCIA DE LA INFORMACIÓN], Italy, Tub neural - Malformacions, 030220 oncology & carcinogenesis, Family medicine, Information Science::Systems Analysis::Delphi Technique [INFORMATION SCIENCE], Original Article, Neurology (clinical), Psychology, Delphi round, 030217 neurology & neurosurgery
Abstract: Background Chiari malformation type 1 (CM1) is a rare condition where agreed classification and treatment are still missing. The goal of this study is to achieve a consensus on the diagnosis and treatment of CM1 in children. Methods A multidisciplinary panel formulated 57 provisional statements based on a review of the literature. Thirty-four international experts (IE) participated in a Delphi study by independently rating each statement on a 4-point Likert scale (“strongly disagree,” “disagree,” “agree,” “strongly agree”). Statements that were endorsed (“agree” or “strongly agree”) by < 75% of raters were re-formulated, or new statements were added, and another Delphi round followed (up to a maximum of three). Results Thirty-five IE were contacted and 34 agreed to participate. A consensus was reached on 30/57 statements (52.6%) after round 1. Three statements were added, and one removed. After round 2, agreement was reached on 56/59 statements (94.9%). Finally, after round 3, which took place during the 2019 Chiari Consensus Conference (Milan, Italy), agreement was reached on 58/59 statements (98.3%) about four main sections (Definition and Classification, Planning, Surgery, Isolated Syringomyelia). Only one statement did not gain a consensus, which is the “definition of radiological failure 24 month post-surgery.” Conclusions The consensus document consists of 58 statements (24 on diagnosis, 34 on treatment), serving clinicians and researchers following children with CM1. There is a clear need for establishing an international network and registry and to promote collaborative studies to increase the evidence base and optimize the long-term care of this patient population.
Published: 2021

7. Cross-Country Adaptation of a Psychological Flexibility Measure: The Comprehensive Assessment of Acceptance and Commitment Therapy Processes

Author: Ambra Giovannetti, Jana Pöttgen, Elisenda Anglada, Rebeca Menéndez, Jürgen Hoyer, Andrea Giordano, Kenneth Pakenham, Ingrid Galán, Alessandra Solari, Institut Català de la Salut, [Giovannetti AM] Unit of Neuroepidemiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. [Pöttgen J] Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [Anglada E, Menéndez R, Galán I] Centre d’Esclerosi Múltiple de Catalunya (CEMCAT), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Hoyer J] Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany. [Giordano A] Unit of Neuroepidemiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. Department of Psychology, University of Turin, Turin, Italy, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Investigative Techniques::Epidemiologic Methods::Data Collection::Surveys and Questionnaires [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Adult, Multiple Sclerosis, Psychometrics, disciplinas y actividades conductuales::psicoterapia::terapia conductista::terapia cognitivo-conductual::tratamiento de aceptación y responsabilidad [PSIQUIATRÍA Y PSICOLOGÍA], Health, Toxicology and Mutagenesis, Public Health, Environmental and Occupational Health, Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [DISEASES], Behavioral Disciplines and Activities::Psychotherapy::Behavior Therapy::Cognitive Behavioral Therapy::Acceptance and Commitment Therapy [PSYCHIATRY AND PSYCHOLOGY], Reproducibility of Results, técnicas de investigación::métodos epidemiológicos::recopilación de datos::encuestas y cuestionarios [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Qüestionaris, Other subheadings::/therapy [Other subheadings], Translating, Surveys and Questionnaires, enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes desmielinizantes del SNC::esclerosis múltiple [ENFERMEDADES], Teràpia d'acceptació i compromís, Humans, Translations, Acceptance and Commitment Therapy, cultural adaptation, linguistic validation, outcome measures, CompACT, psychological flexibility, Esclerosi múltiple - Tractament, Otros calificadores::/terapia [Otros calificadores], Language
Abstract: Cultural adaptation; Linguistic validation; Psychological flexibility Adaptación cultural; Validación lingüística; Flexibilidad psicológica Adaptació cultural; Validació lingüística; Flexibilitat psicològica Purpose: The Comprehensive assessment of Acceptance and Commitment Therapy (ACT) processes (CompACT) is a 23-item self-report questionnaire assessing psychological flexibility, which is the overarching construct underpinning the ACT framework. We conducted a two-phase project to develop validated versions of the CompACT in three languages: phase 1—cross-cultural adaptation; and phase 2—psychometric validation of the questionnaire for use in Italy, Germany and Spain. This article focuses on the first phase. Methods: We translated and culturally adapted the CompACT in the three target languages, following the ISPOR TCA Task Force guidelines. The process was overseen by a translation panel (three translators, at least two multiple sclerosis (MS) researchers and a lay person), ACT experts and clinicians from the research team of each country and the original CompACT developers. We debriefed the new questionnaire versions via face-to-face interviews with a minimum of four adults from the general population (GP) and four adults with MS in each country. Results: The translation-adaptation process went smoothly in the three countries, with some items (7 in Italy, 4 in Germany, 6 in Spain) revised after feedback from ACT experts. Cognitive debriefing showed that the CompACT was deemed easy to understand and score in each target country by both GP and MS adults. Conclusions: The Italian, German and Spanish versions of the CompACT have semantic, conceptual and normative equivalence to the original scale and good content validity. Our findings are informative for researchers adapting the CompACT and other self-reported outcome measures into multiple languages and cultures. This study is supported by the “REHABILITATION IN MULTIPLE SCLEROSIS-RIMS European network for best practice and resource” (RIMS GRANT PROGRAM 2018 to AMG). The funding source had no role in study design, data collection, data analysis, data interpretation or report writing.
Published: 2022
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8. A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies

Author: Romain Goutagny, Hélène Marie, Ingrid Bethus, Martine Eugie, Andrew Escayg, Ana Rita Salgueiro-Pereira, Paula A. Pousinha, Marion I. Stunault, Vincent Douchamps, Alexandre J.C. Loucif, Vadym Gnatkovsky, Marion Ayrault, Fabrice Duprat, Massimo Mantegazza, Carolina Frassoni, Cristina Regondi, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Physio-pathologie des réseaux neuronaux du cycle veille-sommeil, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department Experimental Neurophysiology, Istituto Nazionale Neurologico C. Besta, Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Laboratoire d'Innovation pour les Technologies des Energies Nouvelles et les nanomatériaux (LITEN), Institut National de L'Energie Solaire (INES), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, GEFS+, Autism, medicine.disease_cause, Hippocampus, Epileptogenesis, Asymptomatic, lcsh:RC321-571, Mice, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Cognition, Dravet syndrome, Seizures, Animals, Medicine, Gene Knock-In Techniques, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Pathological, Mutation, business.industry, Sodium channel, Precision medicine, medicine.disease, Phenotype, Remodeling, 3. Good health, NAV1.1 Voltage-Gated Sodium Channel, 030104 developmental biology, Neurology, Immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; SCN1A (NaV1.1 sodium channel) mutations cause Dravet syndrome (DS) and GEFS+ (which is in general milder), and are risk factors in other epilepsies. Phenotypic variability limits precision medicine in epilepsy, and it is important to identify factors that set phenotype severity and their mechanisms. It is not yet clear whether SCN1A mutations are necessary for the development of severe phenotypes or just for promoting seizures. A relevant example is the pleiotropic R1648H mutation that can cause either mild GEFS+ or severe DS. We used a R1648H knock-in mouse model (Scn1aRH/+) with mild/asymptomatic phenotype to dissociate the effects of seizures and of the mutation per se. The induction of short repeated seizures, at the age of disease onset for Scn1a mouse models (P21), had no effect in WT mice, but transformed the mild/asymptomatic phenotype of Scn1aRH/+ mice into a severe DS-like phenotype, including frequent spontaneous seizures and cognitive/behavioral deficits. In these mice, we found no major modifications in cytoarchitecture or neuronal death, but increased excitability of hippocampal granule cells, consistent with a pathological remodeling. Therefore, we demonstrate for our model that an SCN1A mutation is a prerequisite for a long term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling. Applied to humans, this result suggests that genetic alterations, even if mild per se, may increase the risk of second hits to develop severe phenotypes.
Published: 2019
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9. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study

Author: Eléonore Tollard, Christel Depienne, Carola G.M. van Berkel, Graziella Uziel, Céline Dupuits, Maarten Kamermans, Truus E.M. Abbink, Suzanna G.M. Frints, Nienke L. Postma, Alexis Brice, Adeline Vanderver, Christine E. M. de Die-Smulders, Emiel Polder, Marjo S. van der Knaap, Nicole I. Wolf, Frédéric Sedel, Marianna Bugiani, Damien Galanaud, J. S. H. Vles, Vera M. Kalscheuer, Valerie Touitou, Jan Klooster, Frédéric Darios, Cengiz Yalcinkaya, 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), Service de Génétique Cytogénétique et Embryologie [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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathology Department, VU University Medical Center [Amsterdam], Child Neurology Department, Fondazione IRCCS Istituto Neurologico, Service de Neuroradiologie [CHU Pitié-Salpêtrière], Neurologie, Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Radiologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of Clinical Genetics [Maastricht], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], Department of Child Neurology [Maastricht], Department of Neurology, Children's National Medical Center, Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Division of Child Neurology, Istanbul University -Cerrahpasa Medical School, Department Human Molecular Genetics [MPIMG Berlin], Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Department of Retinal Signal Processing, Netherlands Institute for Neuroscience-KNAW, Department of Neurogenetics, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), ELA, APHP, INSERM, Pathology, Pediatric surgery, NCA - Brain mechanisms in health and disease, Cerrahpasa Medical School-Istanbul University, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), Genetica & Celbiologie, RS: MHeNs School for Mental Health and Neuroscience, RS: GROW - School for Oncology and Reproduction, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service d'ophtalmologie [CHU Pitié-Salpêtrière], Maastricht University [Maastricht], Cerrahpasa Faculty of Medicine, Istanbul University, Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), University of Amsterdam [Amsterdam] (UvA), Service de neurologie 1 [CHU Pitié-Salpétrière], Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Depienne, Christel, Other departments, ANS - Amsterdam Neuroscience, and Genome Analysis
Subjects: Male, Pathology, Candidate gene, Brain Edema, [SDV.GEN] Life Sciences [q-bio]/Genetics, Polymerase Chain Reaction, Leukoencephalopathy, 0302 clinical medicine, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, Leukoencephalopathies, Image Processing, Computer-Assisted, Exome, Age of Onset, 10. No inequality, Child, Exome sequencing, Myelin Sheath, media_common, Neurologic Examination, 0303 health sciences, education.field_of_study, biology, Homozygote, Brain, Genetic Diseases, X-Linked, SDG 10 - Reduced Inequalities, Middle Aged, Immunohistochemistry, Magnetic Resonance Imaging, 3. Good health, medicine.anatomical_structure, Connexin 32, Female, medicine.symptom, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Signal Transduction, Adult, medicine.medical_specialty, Adolescent, Cerebellar Ataxia, White matter, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Chloride Channels, medicine, media_common.cataloged_instance, Humans, RNA, Messenger, European union, education, 030304 developmental biology, Aged, CLCN2, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cerebellar ataxia, Fibroblasts, medicine.disease, CLC-2 Chloride Channels, biology.protein, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: Mutant mouse models suggest that the chloride channel ClC-2 has functions in ion and water homoeostasis, but this has not been confirmed in human beings. We aimed to define novel disorders characterised by distinct patterns of MRI abnormalities in patients with leukoencephalopathies of unknown origin, and to identify the genes mutated in these disorders. We were specifically interested in leukoencephalopathies characterised by white matter oedema, suggesting a defect in ion and water homoeostasis. METHODS: In this observational analytical study, we recruited patients with leukoencephalopathies characterised by MRI signal abnormalities in the posterior limbs of the internal capsules, midbrain cerebral peduncles, and middle cerebellar peduncles from our databases of patients with leukoencephalopathies of unknown origin. We used exome sequencing to identify the gene involved. We screened the candidate gene in additional patients by Sanger sequencing and mRNA analysis, and investigated the functional effects of the mutations. We assessed the localisation of ClC-2 with immunohistochemistry and electron microscopy in post-mortem human brains of individuals without neurological disorders. FINDINGS: Seven patients met our inclusion criteria, three with adult-onset disease and four with childhood-onset disease. We identified homozygous or compound-heterozygous mutations in CLCN2 in three adult and three paediatric patients. We found evidence that the CLCN2 mutations result in loss of function of ClC-2. The remaining paediatric patient had an X-linked family history and a mutation in GJB1, encoding connexin 32. Clinical features were variable and included cerebellar ataxia, spasticity, chorioretinopathy with visual field defects, optic neuropathy, cognitive defects, and headaches. MRI showed restricted diffusion suggesting myelin vacuolation that was confined to the specified white matter structures in adult patients, and more diffusely involved the brain white matter in paediatric patients. We detected ClC-2 in all components of the panglial syncytium, enriched in astrocytic endfeet at the perivascular basal lamina, in the glia limitans, and in ependymal cells. INTERPRETATION: Our observations substantiate the concept that ClC-2 is involved in brain ion and water homoeostasis. Autosomal-recessive CLCN2 mutations cause a leukoencephalopathy that belongs to an emerging group of disorders affecting brain ion and water homoeostasis and characterised by intramyelinic oedema. FUNDING: European Leukodystrophies Association, INSERM and Assistance Publique-Hôpitaux de Paris, Dutch Organisation for Scientific Research (ZonMw), E-Rare, Hersenstichting, Optimix Foundation for Scientific Research, Myelin Disorders Bioregistry Project, National Institute of Neurological Disorders and Stroke, and Genetic and Epigenetic Networks in Cognitive Dysfunction (GENCODYS) Project (funded by the European Union Framework Programme 7).
Published: 2013
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10. TI-VAMP/VAMP7 is the SNARE of secretory lysosomes contributing to ATP secretion from astrocytes

Author: Alessio Colombo, Maura Francolini, Thierry Galli, Loredana Riganti, Michela Matteoli, Claire Wilhelm, Matteo Bergami, Cinzia Cagnoli, Ursula Schenk, Marco Canossa, Emanuela Zuccaro, Carolina Frassoni, Lydia Danglot, Claudia Verderio, Verderio C, Cagnoli C, Bergami M, Francolini M, Schenk U, Colombo A, Riganti L, Frassoni C, Zuccaro E, Danglot L, Wilhelm C, Galli T, Canossa M, Matteoli M., Department of Medical Pharmacology and Consiglio Nazionale delle Ricerche - Istitute of Neuroscience, University of Milano, Consiglio Nazionale delle Ricerche [Roma] (CNR), Fondazione Filarete, Dpt of Neuroscience and Brain Technologies [Genova], NeuroEngineering & bio-arTificial Synergic SystemS Laboratory [Genova] (NetS3 Lab), Istituto Italiano di Tecnologia (IIT)-Istituto Italiano di Tecnologia (IIT), Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Istituto Di Ricovero e Cura a Carattere Scientifico Fondazione Don C. Gnocchi, Istituto Di Ricovero e Cura a Carattere Scientifico Fondazione Fon C. Gnocchi, and Cariplo 2008-3104, FISM 2010/R/39, Progetto CIPE/Limonte, INSERM (Avenir Program), European Commission 'Signalling and Traffic' [STREP 503229], Association pour la Recherche sur le Cancer, Agence Nationale pour la Recherche 'Astrex', Mairie de Paris Medical Research and Health Program, Fondation pour la Recherche Médicale, Association pour la Recherche sur le Cancer, Agence Nationale pour la Recherche
Subjects: Primary Cell Culture, chemistry.chemical_element, TI-VAMP/VAMP7, Down-Regulation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Calcium, Transfection, Hippocampus, Membrane Fusion, Cathepsin B, Exocytosis, R-SNARE Proteins, 03 medical and health sciences, 0302 clinical medicine, Adenosine Triphosphate, Secretory lysosomes, Downregulation and upregulation, Lysosome, medicine, Animals, Humans, Secretion, RNA, Small Interfering, 030304 developmental biology, Cerebral Cortex, 0303 health sciences, Vesicle, Cell Biology, General Medicine, Glioma, Secretory lysosome, Embryo, Mammalian, Cell biology, Rats, ATP, medicine.anatomical_structure, Membrane protein, chemistry, Astrocytes, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Lysosomes, Neuroglia, 030217 neurology & neurosurgery, Protein Binding, Signal Transduction
Abstract: International audience; BACKGROUND INFORMATION: ATP is the main transmitter stored and released from astrocytes under physiological and pathological conditions. Morphological and functional evidence suggest that besides secretory granules, secretory lysosomes release ATP. However, the molecular mechanisms involved in astrocytic lysosome fusion remain still unknown. RESULTS: In the present study, we identify tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP, also called VAMP7) as the vesicular SNARE which mediates secretory lysosome exocytosis, contributing to release of both ATP and cathepsin B from glial cells. We also demonstrate that fusion of secretory lysosomes is triggered by slow and locally restricted calcium elevations, distinct from calcium spikes which induce the fusion of glutamate-containing clear vesicles. Downregulation of TI-VAMP/VAMP7 expression inhibited the fusion of ATP-storing vesicles and ATP-mediated calcium wave propagation. TI-VAMP/VAMP7 downregulation also significantly reduced secretion of cathepsin B from glioma. CONCLUSIONS: Given that sustained ATP release from glia upon injury greatly contributes to secondary brain damage and cathepsin B plays a critical role in glioma dissemination, TI-VAMP silencing can represent a novel strategy to control lysosome fusion in pathological conditions.
Published: 2011
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11. Inhibitory control dysfunction in parkinsonian impulse control disorders

Author: Gianni Pezzoli, Garance M. Meyer, Roberto Cilia, Charlotte Spay, Gabriel Gaugain, Philippe Boulinguez, Alina Beliakova, Bénédicte Ballanger, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centro Parkinson/Parkinson Institute, ASST ‘‘Gaetano Pini/CTO,’, and Fondazione IRCCS Istituto Neurologico 'Carlo Besta'
Subjects: Male, Impulse control disorder, Precuneus, impulsivity, Neuropsychological Tests, Electroencephalography, Impulsivity, Choice Behavior, 050105 experimental psychology, Executive Function, 03 medical and health sciences, precuneus, 0302 clinical medicine, Parkinsonian Disorders, Dopamine, Parietal Lobe, medicine, Humans, 0501 psychology and cognitive sciences, Parkinson, Aged, Brain Mapping, Supplementary motor area, medicine.diagnostic_test, business.industry, 05 social sciences, Middle Aged, medicine.disease, Executive functions, Anticipation, Disruptive, Impulse Control, and Conduct Disorders, inhibitory control, Inhibition, Psychological, medicine.anatomical_structure, Impulsive Behavior, Female, beta, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Nerve Net, medicine.symptom, Beta Rhythm, business, Neuroscience, Psychomotor Performance, 030217 neurology & neurosurgery, medicine.drug
Abstract: Impulse control disorders (ICDs) in Parkinson’s disease have been associated with dysfunctions in the control of value- or reward-based responding (choice impulsivity) and abnormalities in mesocorticolimbic circuits. The hypothesis that dysfunctions in the control of response inhibition (action impulsivity) also play a role in Parkinson’s disease ICDs has recently been raised, but the underlying neural mechanisms have not been probed directly. We used high-resolution EEG recordings from 41 patients with Parkinson’s disease with and without ICDs to track the spectral and dynamical signatures of different mechanisms involved in inhibitory control in a simple visuomotor task involving no selection between competing responses and no reward to avoid potential confounds with reward-based decision. Behaviourally, patients with Parkinson’s disease with ICDs proved to be more impulsive than those without ICDs. This was associated with decreased beta activity in the precuneus and in a region of the medial frontal cortex centred on the supplementary motor area. The underlying dynamical patterns pinpointed dysfunction of proactive inhibitory control, an executive mechanism intended to gate motor responses in anticipation of stimulation in uncertain contexts. The alteration of the cortical drive of proactive response inhibition in Parkinson’s disease ICDs pinpoints the neglected role the precuneus might play in higher order executive functions in coordination with the supplementary motor area, specifically for switching between executive settings. Clinical perspectives are discussed in the light of the non-dopaminergic basis of this function.
Published: 2020
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12. Halogenation of the N‐Terminus Tyrosine 10 Promotes Supramolecular Stabilization of the Amyloid‐β Sequence 7–12

Author: Giancarlo Terraneo, Pierangelo Metrangolo, Alessandro Genoni, Nicola Demitri, Daniele Maiolo, Andrea Pizzi, Fulvio Baggi, Giuseppe Resnati, Lara Gazzera, Fabio Moda, Alessandro Gori, Francesca Baldelli Bombelli, Politecnico di Milano [Milan] (POLIMI), Istituto di Scienze e Tecnologie Chimiche 'Giulio Natta' (SCITEC), Consiglio Nazionale delle Ricerche (CNR), Elettra Sincrotrone Trieste, Laboratoire de Physique et Chimie Théoriques (LPCT), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), and Fondazione IRCCS Istituto Neurologico 'Carlo Besta'
Subjects: inorganic chemicals, Halogenation, Stereochemistry, bromine, Supramolecular chemistry, Molecular Conformation, Sequence (biology), Peptide, 010402 general chemistry, Crystal engineering, 01 natural sciences, lcsh:Chemistry, [CHIM.CRIS]Chemical Sciences/Cristallography, Amino Acid Sequence, Tyrosine, Amino Acids, chemistry.chemical_classification, Halogen bond, Amyloid beta-Peptides, Full Paper, 010405 organic chemistry, Chemistry, Hydrogen Bonding, General Chemistry, Full Papers, peptide, 0104 chemical sciences, Amino acid, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, lcsh:QD1-999, halogen bonding, crystal engineering, halogen bonding crystal engineering supramolecular bromine peptide, Crystallization, Oxidation-Reduction, supramolecular
Abstract: Here, we demonstrate that introduction of halogen atoms at the tyrosine 10 phenol ring of the DSGYEV sequence derived from the flexible amyloid‐β N‐terminus, promotes its self‐assembly in the solid state. In particular, we report the crystal structures of two halogen‐modified sequences, which we found to be stabilized in the solid state by halogen‐mediated interactions. The structural study is corroborated by Non‐Covalent Interaction (NCI) analysis. Our results prove that selective halogenation of an amino acid enhances the supramolecular organization of otherwise unstructured biologically‐relevant sequences. This method may develop as a general strategy for stabilizing highly polymorphic peptide regions., The power of halogens! The high‐resolution single crystal X‐ray structures of two halogenated derivatives of the amyloid‐β sequence 7–12 demonstrate the role of halogen‐mediated intermolecular interactions in stabilizing the solid‐state supramolecular organization of this otherwise unstructured biologically‐relevant sequence.
Published: 2020
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13. Treatment satisfaction, safety, and tolerability of cladribine tablets in patients with highly active relapsing multiple sclerosis

Author: Konrad Rejdak, Jeannette Lechner-Scott, Krzysztof Selmaj, Alessandra Solari, Eva Havrdova, Martin Vališ, Nektaria Alexandri, Raymond Hupperts, Fredrik Piehl, Bruno Brochet, Xavier Montalban, Birgit Keller, Axel Nolting, Dawn Langdon, Francesco Patti, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Klinische Neurowetenschappen, Institut Català de la Salut, [Brochet B] INSERM U 1215, University of Bordeaux, Bordeaux, France. [Hupperts R] Department of Psychology, Royal Holloway, University of London, Egham, United Kingdom. [Langdon D] Department of Psychology, Royal Holloway, University of London, Egham, United Kingdom. [Solari A] Unit of Neuroepidemiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. [Piehl F] Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. [Lechner-Scott J] University of Newcastle, Newcastle, NSW, Australia. Division of Neurology, John Hunter Hospital, Newcastle, NSW, Australia. [Montalban X] Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (CEMCAT), Barcelona, Spain. Vall d'Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Immunosuppressive Agents/adverse effects, Personal Satisfaction, Relapsing-Remitting, Other subheadings::Other subheadings::/drug therapy [Other subheadings], DISEASE, Quality of life, Cladribine tablets, Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis::Multiple Sclerosis, Relapsing-Remitting [DISEASES], Prospective Studies, Cladribine, education.field_of_study, Cumulative dose, General Medicine, enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes desmielinizantes del SNC::esclerosis múltiple::esclerosis múltiple recurrente-remitente [ENFERMEDADES], Neurology, Tolerability, Local, Patient Satisfaction, Cohort, Female, Immunosuppressive Agents, Qualitat de vida - Avaluació, medicine.drug, Tablets, Adult, medicine.medical_specialty, Multiple Sclerosis, Pacients - Satisfacció, Population, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Multiple Sclerosis, Relapsing-Remitting, Internal medicine, medicine, Humans, education, Adverse effect, Treatment satisfaction, business.industry, Multiple Sclerosis, Relapsing-Remitting/drug therapy, Interim analysis, Cladribine/adverse effects, Neoplasm Recurrence, Relapsing multiple sclerosis, Quality of Life, Neurology (clinical), Neoplasm Recurrence, Local, business, Esclerosi múltiple - Tractament, Relapsing-Remitting/drug therapy
Abstract: Cladribine tablets; Relapsing multiple sclerosis; Treatment satisfaction Comprimidos de cladribina; Esclerosis múltiple recurrente; Satisfacción con el tratamiento Comprimits de cladribina; Esclerosi múltiple recurrent; Satisfacció amb el tractament Background Multiple sclerosis (MS) is a chronic disabling disease that is associated with negative effects on health-related quality of life (HRQoL) due to reduced physical and psychosocial functioning. Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) have been approved for the treatment of adult patients with highly active relapsing multiple sclerosis (RMS). The ongoing CLARIFY-MS study (NCT03369665; EudraCT number: 2017-002632-17) aims to assess the effect of cladribine tablets 3.5 mg/kg on HRQoL of patients with highly active RMS. Objective To report on the design of the CLARIFY-MS study, baseline patient characteristics, and results of a pre-planned interim analysis focusing on treatment satisfaction, safety, and tolerability that includes all data reported till 6 months after start of treatment. Methods The CLARIFY-MS study is a 2-year, open-label, single-arm, prospective, multicenter, phase IV study. Eligible patients with highly active RMS were assigned to receive cladribine tablets 3.5 mg/kg over 2 years. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM, v1.4; scale range from 0 to 100, higher values indicating higher satisfaction). Safety assessments, including occurrence of treatment-emergent adverse events (TEAEs; any adverse event reported after drug administration), serious adverse events (SAEs), and lymphocyte counts, were summarized descriptively. Results A total of 482 patients from 85 sites in Europe were treated with cladribine tablets. Mean patient age was 37.4 years, 338 (70.1%) were women, median EDSS was 2.5, and 345 (71.6%) were prior users of disease-modifying therapy (DMT). During the first 6 months after the start of treatment, and before reaching the full dose of cladribine tablets, mean TSQM global satisfaction score for the overall population was 70.4 (standard deviation, ± 18.48). The side effects score was 91.9 (± 17.68), convenience scored 86.6 (± 13.57), and effectiveness was 65.8 (± 21.14). A total of 275 patients (57.1%) reported at least one TEAE and 9 patients (1.9%) had a SAE. The majority of observed lymphopenia cases were of grade 1 or 2; 33 (6.8%) of the total study cohort had grade 3 lymphopenia, and no grade 4 lymphopenia was reported. Conclusion Patients reported high treatment satisfaction (TSQM) with cladribine tablets in this pre-planned interim analysis at 6 months. Few serious, and no unexpected, adverse events were reported, and there were no instances of grade 4 lymphopenia over the first 6 months. These preliminary data indicate good tolerability and convenience of administration of cladribine tablets in patients with highly active RMS. This study was sponsored by Merck Healthcare KGaA, Darmstadt, Germany
Published: 2022

14. Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort

Author: Peakman, Georgia, Russell, Lucy L., Convery, Rhian S., Nicholas, Jennifer M., van Swieten, John C., Jiskoot, Lize C., Moreno, Fermin, Sanchez-Valle, Raquel, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R., Gerhard, Alex, Ducharme, Simon, Le Ber, Isabelle, Tagliavini, Fabrizio, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Bocchetta, Martina, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, de Arriba, María, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B., Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne M., Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Seelaar, Harro, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L., Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Neurology, Amsterdam Neuroscience - Neurodegeneration, University College of London [London] (UCL), London School of Hygiene and Tropical Medicine (LSHTM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Donostia International Physics Center - DIPC (SPAIN), Donostia International Physics Center (DIPC), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU)-University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Karolinska Institutet [Stockholm], University of Toronto, University of Cambridge [UK] (CAM), University of Brescia, University of Western Ontario (UWO), Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Lusófona University [Lisbon], University of Oxford, University of Manchester [Manchester], McGill University = Université McGill [Montréal, Canada], 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), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), 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), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Coimbra [Portugal] (UC), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ludwig-Maximilians-Universität München (LMU), University of Ulm (UUlm), Università degli Studi di Firenze = University of Florence (UniFI), HAL-SU, Gestionnaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Oxford [Oxford], 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), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), 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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Peakman, Georgia [0000-0002-3319-138X], Convery, Rhian S [0000-0002-9477-1812], Van Swieten, John C [0000-0001-6278-6844], Jiskoot, Lize C [0000-0002-1120-1858], Rowe, James B [0000-0001-7216-8679], Borroni, Barbara [0000-0001-9340-9814], Finger, Elizabeth [0000-0003-4461-7427], Galimberti, Daniela [0000-0002-9284-5953], Gerhard, Alex [0000-0002-8071-6062], Ducharme, Simon [0000-0002-7309-1113], Le Ber, Isabelle [0000-0002-2508-5181], Danek, Adrian [0000-0001-8857-5383], Otto, Markus [0000-0002-6647-5944], Sorbi, Sandro [0000-0002-0380-6670], Rohrer, Jonathan D [0000-0002-6155-8417], Apollo - University of Cambridge Repository, and Genetic FTD Initiative (GENFI)
Subjects: Oncology, Medizin, LANGUAGE, Disease, Genetic FTD Initiative (GENFI), Cohort Studies, 0302 clinical medicine, diagnosis [Frontotemporal Dementia], ddc:150, C9orf72, CRITERIA, 030212 general & internal medicine, frontotemporal dementia, C9orf72 Protein, Cross-Sectional Studies, Disease Progression, Frontotemporal Dementia, Humans, Mutation, tau Proteins, Mental Status and Dementia Tests, VERSION, 11 Medical and Health Sciences, Psychiatry, UTILITY, DDC 150 / Psychology, biology, FTD, 17 Psychology and Cognitive Sciences, Psychiatry and Mental health, Mutation (genetic algorithm), Cohort, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, FTLD, Life Sciences & Biomedicine, Alzheimer’s disease, Frontotemporal dementia, medicine.medical_specialty, Clinical Dementia Rating, Tau protein, Clinical Neurology, Alzheimerkrankheit, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, DIAGNOSIS, Asymptomatic, VALIDATION, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, mental disorders, medicine, ddc:610, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurodegeneration, Science & Technology, Neurology & Neurosurgery, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], business.industry, MUTATIONS, medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Surgery, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery
Abstract: BackgroundTherapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer’s Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD.MethodsThe CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (MAPT), 187 GRN, 193 C9orf72) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 MAPT, 92 GRN, 88 C9orf72) and 145 non-carriers had available longitudinal data at a follow-up time point.ResultsCross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: GRN mutation carriers mean 83.4 (SD 27.0), MAPT mutation carriers 78.2 (28.8), C9orf72 mutation carriers 71.0 (34.0), controls 96.2 (7.7), p, publishedVersion
Published: 2022
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15. Identification of risk loci for primary aldosteronism in genome-wide association studies

Author: Edith Le Floch, Teresa Cosentino, Casper K. Larsen, Felix Beuschlein, Martin Reincke, Laurence Amar, Gian-Paolo Rossi, Kelly De Sousa, Stéphanie Baron, Sophie Chantalat, Benjamin Saintpierre, Livia Lenzini, Arthur Frouin, Isabelle Giscos-Douriez, Matthis Ferey, Alaa B. Abdellatif, Tchao Meatchi, Jean-Philippe Empana, Xavier Jouven, Christian Gieger, Melanie Waldenberger, Annette Peters, Daniele Cusi, Erika Salvi, Pierre Meneton, Mathilde Touvier, Mélanie Deschasaux, Nathalie Druesne-Pecollo, Sheerazed Boulkroun, Fabio L. Fernandes-Rosa, Jean-François Deleuze, Xavier Jeunemaitre, Maria-Christina Zennaro, Fernandes Rosa, Fabio, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ludwig-Maximilians University [Munich] (LMU), Universität Zürich [Zürich] = University of Zurich (UZH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Università degli Studi di Padova = University of Padua (Unipd), Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Helmholtz Zentrum München = German Research Center for Environmental Health, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Consiglio Nazionale delle Ricerche [Milano] (CNR), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and ANR-18-CE93-0003,GenAdEx,Contributeurs génétiques et moléculaires à l'excès d'hormones corticosurrénaliennes(2018)
Subjects: Male, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, General Physics and Astronomy, Adrenalectomy, General Chemistry, Aldosterone, Animals, DNA-Binding Proteins, Genome-Wide Association Study, Humans, Mice, Transcription Factors, Adrenal Cortex Neoplasms, Adrenocortical Adenoma, Hyperaldosteronism, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, General Biochemistry, Genetics and Molecular Biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: Primary aldosteronism affects up to 10% of hypertensive patients and is responsible for treatment resistance and increased cardiovascular risk. Here we perform a genome-wide association study in a discovery cohort of 562 cases and 950 controls and identify three main loci on chromosomes 1, 13 and X; associations on chromosome 1 and 13 are replicated in a second cohort and confirmed by a meta-analysis involving 1162 cases and 3296 controls. The association on chromosome 13 is specific to men and stronger in bilateral adrenal hyperplasia than aldosterone producing adenoma. Candidate genes located within the two loci, CASZ1 and RXFP2, are expressed in human and mouse adrenals in different cell clusters. Their overexpression in adrenocortical cells suppresses mineralocorticoid output under basal and stimulated conditions, without affecting cortisol biosynthesis. Our study identifies the first risk loci for primary aldosteronism and highlights new mechanisms for the development of aldosterone excess.
Published: 2022
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16. Remote synchronization of amplitudes across an experimental ring of non-linear oscillators

Author: Minati, Ludovico [Center for Mind/Brain Science, University of Trento, 38123 Mattarello TN, Italy and Scientific Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (Italy)]
Published: 2015
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17. Dosimetric verification of stereotactic radiosurgery/stereotactic radiotherapy dose distributions using Gafchromic EBT3

Author: De Martin, Elena [Health Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (Italy)]
Published: 2015
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18. Synchronization, non-linear dynamics and low-frequency fluctuations: Analogy between spontaneous brain activity and networked single-transistor chaotic oscillators

Author: D'Incerti, Ludovico [Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (Italy)]
Published: 2015
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19. DNA methylation episignature in Gabriele-de Vries syndrome

Author: Florian Cherik, Jack Reilly, Jennifer Kerkhof, Michael Levy, Haley McConkey, Mouna Barat-Houari, Kameryn M. Butler, Christine Coubes, Jennifer A. Lee, Gwenael Le Guyader, Raymond J. Louie, Wesley G. Patterson, Matthew L. Tedder, Mads Bak, Trine Bjørg Hammer, William Craigen, Florence Démurger, Christèle Dubourg, Mélanie Fradin, Rachel Franciskovich, Eirik Frengen, Jennifer Friedman, Nathalie Ruiz Palares, Maria Iascone, Doriana Misceo, Pauline Monin, Sylvie Odent, Christophe Philippe, Flavien Rouxel, Veronica Saletti, Petter Strømme, Perla Cassayre Thulin, Bekim Sadikovic, David Genevieve, CHU Clermont-Ferrand, University of Western Ontario (UWO), London Health Sciences Center (LHSC), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), The Greenwood Genetic Center, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Baylor College of Medicine (BCM), Baylor University, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Oslo University Hospital [Oslo], University of California [San Diego] (UC San Diego), University of California (UC), Hospital Papa Giovanni XXIII (Hosp P Giovanni XXIII), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', and University of Utah
Subjects: Male, Gabriele-de Vries syndrome, Genome, Phenotype, Neurodevelopmental Disorders, [SDV]Life Sciences [q-bio], Intellectual Disability, Humans, Epigenetics, Syndrome, DNA Methylation, YY1, Genetics (clinical)
Abstract: International audience; PURPOSE: Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features. To refine the phenotype and to better understand the molecular basis of the syndrome, we analyzed clinical data and performed genome-wide DNA methylation analysis of a series of individuals carrying a YY1 variant. METHODS: Clinical data were collected for 13 individuals not yet reported through an international call for collaboration. DNA was collected for 11 of these individuals and 2 previously reported individuals in an attempt to delineate a specific DNA methylation signature in GADEVS. RESULTS: Phenotype in most individuals overlapped with the previously described features. We described 1 individual with atypical phenotype, heterozygous for a missense variant in a domain usually not involved in individuals with YY1 pathogenic missense variations. We also described a specific peripheral blood DNA methylation profile associated with YY1 variants. CONCLUSION: We reported a distinct DNA methylation episignature in GADEVS. We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism. We also highlighted the utility of DNA methylation episignature analysis for classification of variants of unknown clinical significance.
Published: 2021
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20. Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels

Author: Mathieu Desroches, Martin Krupa, Paolo Scalmani, Alexandre Loucif, Sandrine Cestèle, Lara Pizzamiglio, Louisiane Lemaire, Massimo Mantegazza, Isabelle Léna, Sarah Zerimech, Fabrice Duprat, Marion Ayrault, Oana Chever, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria), Laboratoire Jean Alexandre Dieudonné (JAD), Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Mathématiques pour les Neurosciences (MATHNEURO), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Côte d'Azur (UCA), Laboratoire Jean Alexandre Dieudonné (LJAD), and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Migraine Disorders, [SDV]Life Sciences [q-bio], FHM, [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], Sodium channels, Mice, Transgenic, Neocortex, Hm1a, Biology, Neurotransmission, Mice, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, aura, spreading depolarization, Interneurons, medicine, Animals, migraine, SCN1A, GABAergic Neurons, Familial hemiplegic migraine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SCCO.NEUR]Cognitive science/Neuroscience, Cortical Spreading Depression, General Medicine, medicine.disease, Migraine with aura, NAV1.1 Voltage-Gated Sodium Channel, medicine.anatomical_structure, Migraine, Cortical spreading depression, GABAergic, medicine.symptom, Neuroscience, Neurological disorders, 030217 neurology & neurosurgery, Research Article, Genetic diseases
Abstract: International audience; Spreading depolarizations (SDs) are involved in migraine, epilepsy, stroke, traumatic brain injury, and subarachnoid hemorrhage. However, the cellular origin and specific differential mechanisms are not clear. Increased glutamatergic activity is thought to be the key factor for generating cortical spreading depression (CSD), a pathological mechanism of migraine. Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up. Neither GABAergic nor glutamatergic synaptic transmission were required for CSD initiation. CSD was not generated in other brain areas, suggesting that this is a neocortex-specific mechanism of CSD initiation. Gain-of-function mutations of NaV1.1 (SCN1A) cause familial hemiplegic migraine type-3 (FHM3), a subtype of migraine with aura, of which CSD is the neurophysiological correlate. Our results provide the mechanism linking NaV1.1 gain of function to CSD generation in FHM3. Thus, we reveal the key role of hyperactivity of GABAergic interneurons in a mechanism of CSD initiation, which is relevant as a pathological mechanism of Nav1.1 FHM3 mutations, and possibly also for other types of migraine and diseases in which SDs are involved.
Published: 2021
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21. Experimental synchronization of chaos in a large ring of mutually coupled single-transistor oscillators: Phase, amplitude, and clustering effects

Author: Minati, Ludovico [MR-Lab, Center for Mind/Brain Science, University of Trento, Italy and Scientific Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (Italy)]
Published: 2014
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22. Experimental dynamical characterization of five autonomous chaotic oscillators with tunable series resistance

Author: Minati, Ludovico [MR-Lab, Center for Mind/Brain Science, University of Trento, Trento, Italy and Scientific Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (Italy)]
Published: 2014
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23. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author: Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS
Subjects: Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract: The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.
Published: 2021
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24. ESO guideline for the management of extracranial and intracranial artery dissection

Author: Stéphanie Debette, Alessandro Pezzini, Stefan T. Engelter, Mikael Mazighi, Isabella Canavero, Julien Haemmerli, Anna Bersano, Philippe Bijlenga, Avtar Lal, Marcel Arnold, David J. Seiffge, Kaori Miwa, Masatoshi Koga, Hugh S. Markus, Sabrina Schilling, Piotr Tekiela, Janika Kõrv, Jennifer J. Majersik, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), FHU NeuroVasc [Site Sainte-Anne, Paris] (GHU-PPN), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Faculté de médecine [Genève], University of Brescia, National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Tartu, Tartu University Hospital [Tartu, Estonia], University of Utah, University of Bern, University of Cambridge [UK] (CAM), and University of Basel (Unibas)
Subjects: medicine.medical_specialty, Subarachnoid hemorrhage, medicine.medical_treatment, Population, 030204 cardiovascular system & hematology, Guidelines, Extracranial artery dissection, Cervical artery dissection, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, medicine, Endovascular treatment, cardiovascular diseases, Intensive care medicine, education, Stroke, education.field_of_study, Aspirin, business.industry, Anticoagulants, Thrombolysis, Guideline, medicine.disease, 3. Good health, Clinical trial, Intracranial artery dissection, Observational study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Mechanical thrombectomy, 030217 neurology & neurosurgery
Abstract: International audience; The aim of the present European Stroke Organisation guideline is to provide clinically useful evidence-based recommendations on the management of extracranial artery dissection (EAD) and intracranial artery dissection (IAD). EAD and IAD represent leading causes of stroke in the young, but are uncommon in the general population, thus making it challenging to conduct clinical trials and large observational studies. The guidelines were prepared following the Standard Operational Procedure for European Stroke Organisation guidelines and according to GRADE methodology. Our four recommendations result from a thorough analysis of the literature comprising two randomized clinical trials (RCTs) comparing anticoagulants to anti-platelets in the acute phase of ischemic stroke and twenty-six comparative observational studies. In EAD patients with acute ischemic stroke we recommend using intravenous thrombolysis (IVT) with alteplase within 4.5 hours of onset if standard inclusion/exclusion criteria are met, and mechanical thrombectomy in patients with large vessel occlusion of the anterior circulation. We further recommend early endovascular or surgical intervention for IAD patients with subarachnoid hemorrhage (SAH). Based on evidence from two phase 2 RCTs that have shown no difference between the benefits and risks of anticoagulants versus anti-platelets in the acute phase of symptomatic EAD, we strongly recommend that clinicians can prescribe either option. In post-acute EAD patients with residual stenosis or dissecting aneurysms and in symptomatic IAD patients with an intracranial dissecting aneurysm and isolated headache, there is insufficient data to provide a recommendation on the benefits and risks of endovascular/surgical treatment. Finally, nine expert consensus statements, adopted by 8 to 11 of the 11 experts involved, propose guidance for clinicians when the quality of evidence was too low to provide recommendations. Some of these pertain to the management of IAD (use of IVT, endovascular treatment, and antiplatelets versus anticoagulation in IAD with ischemic stroke and use of endovascular or surgical interventions for IAD with headache only). Other expert consensus statements address the use of direct anticoagulants and dual antiplatelet therapy in EAD-related cerebral ischemia, endovascular treatment of the EAD/IAD lesion and multidisciplinary assessment of the best therapeutic approaches in specific situations.
Published: 2021
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25. INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma

Author: Pim J. French, Joana Brilhante, Martin J. van den Bent, P. Ansell, Paul Sanghera, Marion Smits, Enrico Franceschi, Sarah Nuyens, Jyotirmoy Dey, Marica Eoli, Hendrikus J. Dubbink, Juan Manuel Sepúlveda, Corneel Coens, Olivier Chinot, Vassilis Golfinopoulos, Paul Clement, Michael Weller, Annemiek M E Walenkamp, Jim Looman, Jean-Sebastian Frenel, Maarten Spruyt, Thierry Gorlia, Scott Krause, Nicolas Whenham, Filip de Vos, Department of Neurology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Department of Medical Oncology (AUSL di Bologna), Azienda Unità Sanitaria Locale di Bologna (AUSL), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de Neuro-oncologie, Assistance Publique - Hôpitaux de Marseille (APHM), University hospital of Zurich [Zurich], Quality of Life Department, European Organisation for Research and Treatment of Cancer, EORTC, European Organization for Research and Treatment of Cancer DataCenter, Guided Treatment in Optimal Selected Cancer Patients (GUTS), University of Zurich, Van Den Bent, Martin, Neurology, Radiology & Nuclear Medicine, and Pathology
Subjects: Oncology, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MONOTHERAPY, Phases of clinical research, Depatuxizumab mafodotin, 0302 clinical medicine, PROGNOSTIC-FACTORS, Lomustine, Clinical endpoint, 1306 Cancer Research, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Brain Neoplasms, Hazard ratio, GLIOMAS, Corrigenda, 3. Good health, ErbB Receptors, 2728 Neurology (clinical), 030220 oncology & carcinogenesis, TRIAL, 2730 Oncology, TYROSINE KINASE INHIBITOR, MGMT, Adjuvant, Life Sciences & Biomedicine, medicine.drug, medicine.medical_specialty, depatux-m, EGFR, BEVACIZUMAB, Clinical Neurology, Clinical Investigations, 610 Medicine & health, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, recurrent, Antibody drug conjugate, Internal medicine, medicine, Temozolomide, AcademicSubjects/MED00300, Humans, Adverse effect, COMBINATION, Antineoplastic Agents, Alkylating, 030304 developmental biology, Science & Technology, business.industry, glioblastoma, EFFICACY, 10040 Clinic for Neurology, Editor's Choice, AcademicSubjects/MED00310, Neurology (clinical), Neurosciences & Neurology, business
Abstract: Background Depatuxizumab mafodotin (Depatux-M) is a tumor-specific antibody–drug conjugate consisting of an antibody (ABT-806) directed against activated epidermal growth factor receptor (EGFR) and the toxin monomethylauristatin-F. We investigated Depatux-M in combination with temozolomide or as a single agent in a randomized controlled phase II trial in recurrent EGFR amplified glioblastoma. Methods Eligible were patients with centrally confirmed EGFR amplified glioblastoma at first recurrence after chemo-irradiation with temozolomide. Patients were randomized to either Depatux-M 1.25 mg/kg every 2 weeks intravenously, or this treatment combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, or either lomustine or temozolomide. The primary endpoint of the study was overall survival. Results Two hundred sixty patients were randomized. In the primary efficacy analysis with 199 events (median follow-up 15.0 mo), the hazard ratio (HR) for the combination arm compared with the control arm was 0.71 (95% CI = 0.50, 1.02; P = 0.062). The efficacy of Depatux-M monotherapy was comparable to that of the control arm (HR = 1.04, 95% CI = 0.73, 1.48; P = 0.83). The most frequent toxicity in Depatux-M treated patients was a reversible corneal epitheliopathy, occurring as grades 3–4 adverse events in 25–30% of patients. In the long-term follow-up analysis with median follow-up of 28.7 months, the HR for the comparison of the combination arm versus the control arm was 0.66 (95% CI = 0.48, 0.93). Conclusion This trial suggests a possible role for the use of Depatux-M in combination with temozolomide in EGFR amplified recurrent glioblastoma, especially in patients relapsing well after the end of first-line adjuvant temozolomide treatment. (NCT02343406)
Published: 2019
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26. HIST1H1E heterozygous protein‐truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

Author: John M. Graham, Anna Ardissone, Dieter Kotzot, Paul R. Mark, Anna Zachariou, Guillermo Lay-Son, Allyn McConkie-Rosell, John Pappas, Karen Low, Fiona Stewart, Chey Loveday, Brian G. Skotko, Melissa Lees, Helen Stewart, Ho Ming Luk, Cheryl Cytrynbaum, Rachel Horton, Siddharth Banka, Gerard Marion, Deborah J. Shears, Marie T. McDonald, Ricardo A. Verdugo, Christine Coubes, Yuri A. Zarate, Christophe Phillipe, Katrina Tatton-Brown, Clare Allen, Deepika D.Cunha Burkardt, Rosanna Weksberg, I. Karen Temple, Alexia Bourgois, David J. Amor, Frédéric Tran Mau-Them, Laurence Faivre, Case Western Reserve University [Cleveland], The institute of cancer research [London], University College London Hospitals (UCLH), Murdoch Children's Research Institute (MCRI), University of Melbourne, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Manchester [Manchester], Manchester University NHS Foundation Trust (MFT), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), The Hospital for sick children [Toronto] (SickKids), Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), University Hospital Southampton NHS Foundation Trust, Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Pontificia Universidad Católica de Chile (UC), Great Ormond Street Hospital for Children [London] (GOSH), University Hospitals Bristol, Department of Health Clinical Genetic Service Centre, Spectrum Health [Grand Rapids], Department of Molecular Genetics and Microbiology [Durham] (MGM), Duke University [Durham], New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Harvard Medical School [Boston] (HMS), Belfast City Hospital, Oxford University Hospitals NHS Trust, University of Oxford [Oxford], University of Southampton, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Universitad de Chile, Arkansas Children's Hospital, Cedars-Sinai Medical Center, St George’s University Hospitals, and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Heterozygote, Bioinformatics, Corpus callosum, Rahman syndrome, Histones, 03 medical and health sciences, Frontal Bossing, 0302 clinical medicine, HIST1H1E, Gene cluster, Intellectual disability, Genetics, Humans, Learning, Medicine, Epigenetics, Genetics (clinical), 030304 developmental biology, Behavior, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, epigenetic regulator gene, biology, business.industry, Facies, Heterozygote advantage, Syndrome, medicine.disease, Phenotype, Histone, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, Mutation, biology.protein, Growth and Development, business, 030217 neurology & neurosurgery
Abstract: International audience; Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein-truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94-base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep-set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding.
Published: 2019
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27. Spatiotemporal analysis for detection of pre-symptomatic shape changes in neurodegenerative diseases: Initial application to the GENFI cohort

Author: Cury, Claire, Durrleman, Stanley, Cash, David, Lorenzi, Marco, Nicholas, Jennifer, Bocchetta, Martina, Van Swieten, John, Borroni, Barbara, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James, Graff, Caroline, Tagliavini, Fabrizio, Frisoni, Giovanni, Laforce, Robert, Finger, Elizabeth, de Mendonça, Alexandre, Sorbi, Sandro, Ourselin, Sébastien, Rohrer, Jonathan, Modat, Marc, Andersson, Christin, Archetti, Silvana, Arighi, Andrea, Benussi, Luisa, Black, Sandra, Cosseddu, Maura, Fallstrm, Marie, Ferreira, Carlos, Fenoglio, Chiara, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Gazzina, Stefano, Ghidoni, Robert, Grisoli, Marina, Jelic, Vesna, Jiskoot, Lize, Keren, Ron, Lombardi, Gemma, Maruta, Carolina, Meeter, Lieke, van Minkelen, Rick, Nacmias, Benedetta, Ijerstedt, Linn, Padovani, Alessandro, Panman, Jessica, Pievani, Michela, Polito, Cristina, Premi, Enrico, Prioni, Sara, Rademakers, Rosa, Redaelli, Veronica, Rogaeva, Ekaterina, Rossi, Giacomina, Rossor, Martin, Scarpini, Elio, Tang-Wai, David, Thonberg, Hakan, Tiraboschi, Pietro, Verdelho, Ana, Warren, Jason, Department of Medical Physics and Biomedical Engineering (UCL), University College of London [London] (UCL), Dementia Research Centre [London] (DRC), Neuroimagerie: méthodes et applications (Empenn), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), E-Patient : Images, données & mOdèles pour la médeciNe numériquE (EPIONE), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), London School of Hygiene and Tropical Medicine (LSHTM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Brescia, Centro Dino Ferrari [Milano], Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, University of Cambridge [UK] (CAM), Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia = University of Brescia (UniBs), Université Laval [Québec] (ULaval), University of Western Ontario (UWO), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Università degli Studi di Firenze = University of Florence (UniFI), Imaging Sciences and Biomedical Engineering Division [London], Guy's and St Thomas' Hospital [London]-King‘s College London, Civic Hospital of Brescia, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, IRCCS Fatebenefratelli - Brescia, Institut de Recherche en Génie Civil et Mécanique (GeM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), UCL, Institute of Neurology [London], Toronto Western Hospital, Neuroimaging and Telemedicine (LENITEM), Mayo Clinic [Jacksonville], Marco Lorenzi received funding from the EPSRC (EP/J020990/1). Jennifer Nicholas is supported by UK Medical Research Council (grant MR/M023664/1). David Cash is supported by grants from the Alzheimer Society(AS-PG-15-025), Alzheimers Research UK (ARUK-PG2014-1946) and Medical Research Council UK (MR/M023664/1). JBR is supported by the Wellcome Trust (103838). Jonathan D. Rohrer is an MRC Clinician Scientist and has received funding from the NIHR Rare Diseases Translational Research Collaboration. Se361 bastien Ourselin receives funding from the EPSRC (EP/H046410/1, EP/K005278), the MRC (MR/J01107X/1), the NIHR Biomedical Research Unit (Dementia) at UCL and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC UCLH/UCL High Impact Initiative- BW.mn.BRC10269). Marc Modat is supported by the UCL Leonard Wolfson Experimental Neurology Centre, ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), European Project: 601055,EC:FP7:ICT,FP7-ICT-2011-9,VPH-DARE@IT(2013), European Project: 666992,H2020 Pilier Societal Challenges,H2020-PHC-2015-two-stage,EuroPOND(2016), European Project: 678304,H2020 ERC,ERC-2015-STG,LEASP(2016), Cury, Claire, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Idex UCA JEDI - - UCA JEDI2015 - ANR-15-IDEX-0001 - IDEX - VALID, VPH Dementia Research Enabled by IT - VPH-DARE@IT - - EC:FP7:ICT2013-04-01 - 2017-03-31 - 601055 - VALID, Data-driven models for Progression Of Neurological Disease - EuroPOND - - H2020 Pilier Societal Challenges2016-01-01 - 2019-12-31 - 666992 - VALID, Learning spatiotemporal patterns in longitudinal image data sets of the aging brain - LEASP - - H2020 ERC2016-09-01 - 2021-08-31 - 678304 - VALID, Neurology, Empenn, Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Brescia [Brescia], Universidade de Lisboa (ULISBOA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and 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)
Subjects: Male, Prodromal Symptoms, Neuroimaging, Middle Aged, Magnetic Resonance Imaging, Article, Shape analysis, Clustering, Cohort Studies, Computational anatomy, Spatio-Temporal Analysis, Thalamus, Frontotemporal Dementia, ddc:618.97, Parallel transport, Spatiotemporal geodesic regression, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract: Brain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer's disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure. In this paper we propose a spatiotemporal analysis pipeline based on Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects. We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease., Graphical abstract Image 1, Highlights • Clustering shape parametrisation allows local shape analysis. • Thalamic shape changes appear 5 years before onset of fronto temporal dementia. • Shape changes seem to occur before volume changes. • Pre-symptomatic shape changes in thalamus are dorsofrontal, where connecting to temporal lobes.
Published: 2019
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28. Modeling NaV1.1/SCN1A sodium channel mutations in a microcircuit with realistic ion concentration dynamics suggests differential GABAergic mechanisms leading to hyperexcitability in epilepsy and migraine

Author: Lemaire, Louisiane, Desroches, Mathieu, Krupa, Martin, Pizzamiglio, Lara, Scalmani, Paolo, Mantegazza, Massimo, Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Côte d'Azur (UCA), Laboratoire Jean Alexandre Dieudonné (JAD), Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SCCO.NEUR]Cognitive science/Neuroscience, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation
Published: 2021

29. Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy

Author: Gemma Tremolada, Lutz Mueller, Nora Denk, Birgit Jaber, Sabine Fürst-Recktenwald, Ksenija Gorni, Shannon Beres, Emmanuel Barreau, Melissa SantaMaria, Renata S. Scalco, Agnieszka Waskowska, Lorenzo Orazi, Steven Kane, Bjoern Jacobsen, Giulia Maria Amorelli, Stefania Bianchi Marzoli, Stephane Nave, Giovanni Baranello, Diletta Santarsiero, Shigeko Yashiro, Robert C. Sergott, Eugenio Mercuri, Marianne Gerber, Wills Eye Hospital, Jefferson (Philadelphia University + Thomas Jefferson University), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Stanford University, Columbia University Medical Center (CUMC), Columbia University [New York], Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Medical University of Gdańsk, National Center for Global Health and Medicine [Japan] (NCGM), F. Hoffmann-La Roche [Basel], and Pagès, Nathalie
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Visual acuity, Adolescent, genetic structures, [SDV]Life Sciences [q-bio], RG7916 TREATMENT, Retina, Muscular Atrophy, Spinal, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Ophthalmology, EXPLORATORY OUTCOMES, Humans, Medicine, Child, Adverse effect, Research Articles, Clinical Trials as Topic, medicine.diagnostic_test, business.industry, General Neuroscience, Fundus photography, Infant, Retinal, Spinal muscular atrophy, Middle Aged, medicine.disease, SMA, [SDV] Life Sciences [q-bio], Clinical trial, Pyrimidines, 030104 developmental biology, Neuromuscular Agents, chemistry, Child, Preschool, SAFETY, Eye disorder, Female, Neurology (clinical), medicine.symptom, business, Azo Compounds, 030217 neurology & neurosurgery, Research Article
Abstract: International audience; Objective: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU.Methods: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2-6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study.Results: A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment.Interpretation: Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam.
Published: 2021
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30. Modeling NaV1.1/SCN1A sodium channel mutations in a microcircuit with realistic ion concentration dynamics suggests differential GABAergic mechanisms leading to hyperexcitability in epilepsy and hemiplegic migraine

Author: Lemaire, Louisiane, Desroches, Mathieu, Krupa, Martin, Pizzamiglio, Lara, Scalmani, Paolo, Mantegazza, Massimo, Lemaire, Louisiane, Idex UCA JEDI - - UCA JEDI2015 - ANR-15-IDEX-0001 - IDEX - VALID, Laboratoires d'excellence - Canaux ioniques d'intérêt thérapeutique - - ICST2011 - ANR-11-LABX-0015 - LABX - VALID, Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Côte d'Azur (UCA), Laboratoire Jean Alexandre Dieudonné (JAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011), Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Laboratoire Jean Alexandre Dieudonné (LJAD)
Subjects: Male, Patch-Clamp Techniques, Physiology, Mouse models, Mice, Animal Cells, Loss of Function Mutation, Medicine and Health Sciences, GABAergic Neurons, Biology (General), ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Neurons, Headaches, Pyramidal Cells, Cortical Spreading Depression, Animal Models, Voltage-Gated Sodium Channel beta-1 Subunit, Electrophysiology, Chemistry, Neurology, Experimental Organism Systems, Gain of Function Mutation, Physical Sciences, Female, [INFO.INFO-MO] Computer Science [cs]/Modeling and Simulation, Cellular Types, Intracellular membranes, Ion Channel Gating, Research Article, Chemical Elements, QH301-705.5, Migraine Disorders, Models, Neurological, Neurophysiology, Research and Analysis Methods, Signs and Symptoms, Model Organisms, Interneurons, Animals, Humans, Migraine, Membrane potential, Epilepsy, [SCCO.NEUR]Cognitive science/Neuroscience, Sodium, [SCCO.NEUR] Cognitive science/Neuroscience, Biology and Life Sciences, Computational Biology, Cell Biology, Mathematical Concepts, Somatosensory Cortex, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Mice, Inbred C57BL, NAV1.1 Voltage-Gated Sodium Channel, Disease Models, Animal, Cellular Neuroscience, Mutation, Animal Studies, Depolarization, Action potentials, Clinical Medicine, Neuroscience
Abstract: Loss of function mutations of SCN1A, the gene coding for the voltage-gated sodium channel NaV1.1, cause different types of epilepsy, whereas gain of function mutations cause sporadic and familial hemiplegic migraine type 3 (FHM-3). However, it is not clear yet how these opposite effects can induce paroxysmal pathological activities involving neuronal networks’ hyperexcitability that are specific of epilepsy (seizures) or migraine (cortical spreading depolarization, CSD). To better understand differential mechanisms leading to the initiation of these pathological activities, we used a two-neuron conductance-based model of interconnected GABAergic and pyramidal glutamatergic neurons, in which we incorporated ionic concentration dynamics in both neurons. We modeled FHM-3 mutations by increasing the persistent sodium current in the interneuron and epileptogenic mutations by decreasing the sodium conductance in the interneuron. Therefore, we studied both FHM-3 and epileptogenic mutations within the same framework, modifying only two parameters. In our model, the key effect of gain of function FHM-3 mutations is ion fluxes modification at each action potential (in particular the larger activation of voltage-gated potassium channels induced by the NaV1.1 gain of function), and the resulting CSD-triggering extracellular potassium accumulation, which is not caused only by modifications of firing frequency. Loss of function epileptogenic mutations, on the other hand, increase GABAergic neurons’ susceptibility to depolarization block, without major modifications of firing frequency before it. Our modeling results connect qualitatively to experimental data: potassium accumulation in the case of FHM-3 mutations and facilitated depolarization block of the GABAergic neuron in the case of epileptogenic mutations. Both these effects can lead to pyramidal neuron hyperexcitability, inducing in the migraine condition depolarization block of both the GABAergic and the pyramidal neuron. Overall, our findings suggest different mechanisms of network hyperexcitability for migraine and epileptogenic NaV1.1 mutations, implying that the modifications of firing frequency may not be the only relevant pathological mechanism., Author summary The voltage-gated sodium channel NaV1.1 is a major target of human mutations implicated in different pathologies. In particular, mutations identified in certain types of epilepsy cause loss of function of the channel, whereas mutations identified in certain types of migraine (in which spreading depolarizations of the cortical circuits of the brain are involved) cause instead gain of function. Here, we study dysfunctions induced by these differential effects in a two-neuron (GABAergic and pyramidal) conductance-based model with dynamic ion concentrations. We obtain results that can be related to experimental findings in both situations. Namely, extracellular potassium accumulation induced by the activity of the GABAergic neuron in the case of CSD, and higher propensity of the GABAergic neuron to depolarization block in the epileptogenic scenario, without significant modifications of its firing frequency prior to it. Both scenarios can induce hyperexcitability of the pyramidal neuron, leading in the migraine condition to depolarization block of both the GABAergic and the pyramidal neuron. Our results are successfully confronted to experimental data and suggest that modification of firing frequency is not the only key mechanism in these pathologies of neuronal excitability.
Published: 2021
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31. NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients

Author: Laurence Perrin, Silvia Cappello, Francesco Neri, Arthur Sorlin, Philippe Khau Van Kien, Ludovico D'Incerti, Françoise Devillard, Rossella Di Giaimo, Paul Kuentz, Agnès Loubat, Marjolaine Willems, Laurence Faivre, Frédéric Tran Mau-Them, Salvatore Oliviero, Michèle Studer, Anna Lisa Romano, Christophe Philippe, Michele Bertacchi, Carolina Frassoni, Aurore Garde, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Robert Debré Paris, Hôpital Robert Debré, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique biologique histologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Leibniz Association, Université de Naples, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Bertacchi, Michele, Romano, Anna Lisa, Loubat, Agnè, Tran Mau-Them, Frederic, Willems, Marjolaine, Faivre, Laurence, Khau van Kien, Philippe, Perrin, Laurence, Devillard, Françoise, Sorlin, Arthur, Kuentz, Paul, Philippe, Christophe, Garde, Aurore, Neri, Francesco, Di Giaimo, Rossella, Oliviero, Salvatore, Cappello, Silvia, D'Incerti, Ludovico, Frassoni, Carolina, and Studer, Michèle
Subjects: cell cycle dynamics, PAX6 Transcription Factor, [SDV]Life Sciences [q-bio], cell cycle dynamic, Neocortex, Biology, Regenerative Medicine, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Neural Stem Cells, Optic Atrophies, Hereditary, Parietal Lobe, Cortex (anatomy), BBSOAS, medicine, Animals, Humans, Molecular Biology, Gyrification, 030304 developmental biology, 0303 health sciences, COUP Transcription Factor I, General Immunology and Microbiology, General Neuroscience, Neurogenesis, Articles, Human brain, NR2F1/COUP-TFI, cortical folding, medicine.disease, Disease Models, Animal, neurodevelopmental disease, medicine.anatomical_structure, NR2F1/COUP‐TFI, Occipital Lobe, PAX6, Haploinsufficiency, Development & Differentiation, Neuroscience, 030217 neurology & neurosurgery
Abstract: The relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra‐Bosch‐Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss‐of‐function mutations of the transcriptional regulator NR2F1. Young patients with NR2F1 haploinsufficiency display mild to moderate intellectual disability and show reproducible polymicrogyria‐like brain malformations in the parietal and occipital cortex. Using a recently established BBSOAS mouse model, we found that Nr2f1 regionally controls long‐term self‐renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6. In the human fetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We propose NR2F1 as an area‐specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification., Reduced levels of the neuronal differentiation factor NR2F1/COUP‐TFI impairs brain cortex folding in humans, and disrupts regional neural progenitor dynamics in the neocortex of a BBSOAS disease mouse model.
Published: 2020
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32. Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes

Author: Nicola Carboni, Chiara Lanzuolo, Elisa Schena, Lucio Santoro, Tiziana Mongini, Elena Biagini, Lucia Morandi, Gisèle Bonne, Giovanna Lattanzi, Lorenzo Maggi, Patrizia Sabatelli, Giulia Ricci, Lucia Ruggiero, Cristina Cappelletti, Marta Columbaro, Luisa Politano, Antoine Muchir, Giuseppe Boriani, Camilla Evangelisti, Sabino Prencipe, Gabriele Siciliano, Elena Pegoraro, Pia Bernasconi, Paola Cavalcante, Liliana Vercelli, Carmelo Rodolico, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Pisa - Università di Pisa, Second University of Naples-Caserta, University of Naples Federico II, University of Turin, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Università degli Studi di Modena e Reggio Emilia, Universita degli Studi di Padova, Istituto Nazionale Genetica Molecolare [Milano] (INGM), Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Bernasconi, Pia, Carboni, Nicola, Ricci, Giulia, Siciliano, Gabriele, Politano, Luisa, Maggi, Lorenzo, Mongini, Tiziana, Vercelli, Liliana, Rodolico, Carmelo, Biagini, Elena, Boriani, Giuseppe, Ruggiero, Lucia, Santoro, Lucio, Schena, Elisa, Prencipe, Sabino, Evangelisti, Camilla, Pegoraro, Elena, Morandi, Lucia, Columbaro, Marta, Lanzuolo, Chiara, Sabatelli, Patrizia, Cavalcante, Paola, Cappelletti, Cristina, Bonne, Gisèle, Muchir, Antoine, Lattanzi, Giovanna, Bernasconi P., Carboni N., Ricci G., Siciliano G., Politano L., Maggi L., Mongini T., Vercelli L., Rodolico C., Biagini E., Boriani G., Ruggiero L., Santoro L., Schena E., Prencipe S., Evangelisti C., Pegoraro E., Morandi L., Columbaro M., Lanzuolo C., Sabatelli P., Cavalcante P., Cappelletti C., Bonne G., Muchir A., and Lattanzi G.
Subjects: 0301 basic medicine, Male, Basic fibroblast growth factor, LMNA, chemistry.chemical_compound, Mice, Transforming growth factor beta 2 (TGF b2), Medicine, Muscular Dystrophy, Muscular dystrophy, Emery–Dreifuss muscular dystrophy, LMNA gene, Cells, Cultured, lamin A/C, muscle fibrosis, Mice, Knockout, Cultured, tendon fibrosis, biology, Myogenesis, Emery-Dreifuss, Cell Differentiation, Middle Aged, Muscular Dystrophy, Emery-Dreifuss, 3. Good health, Laminopathie, Transforming growth factor beta 2 (TGF β2), Fibroblast, Female, Interleukin 17, Human, musculoskeletal diseases, Adult, Cells, Knockout, Muscle Cell, Dilated Cardiomyopathy (CMD1A), Emery-Dreifuss Muscular Dystrophy type 2 (EDMD2), Laminopathies, Limb-Girdle muscular Dystrophy 1B (LGMD1B), muscular differentiation, 03 medical and health sciences, Transforming Growth Factor beta2, Young Adult, Lamin A/C, Muscle fibrosis, Muscular differentiation, Tendon fibrosis, Animals, Fibroblasts, Humans, Muscle Cells, Tenocytes, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Interleukin 6, Animal, Muscular Dystrophy, Emery-Dreifu, business.industry, muscle fibrosi, Cell Biology, Transforming growth factor beta, Tenocyte, medicine.disease, 030104 developmental biology, chemistry, biology.protein, Cancer research, business, Tendon fibrosi, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF β2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF β2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF β2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF β2-dependent mechanisms were also determined in laminopathic cells, where TGF β2 activated AKT/mTOR phosphorylation. These data show that TGF β2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF β2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.
Published: 2018
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33. Dimethyl fumarate and monomethyl fumarate attenuate oxidative stress and mitochondrial alterations leading to oxiapoptophagy in 158N murine oligodendrocytes treated with 7β-hydroxycholesterol

Author: Amira Zarrouk, Gérard Lizard, Thibault Moreau, Khalifa Limem, Ahmed Masmoudi, Jean-Paul Pais de Barros, Thomas Nury, Mohammad Samadi, Anne Vejux, Claudio Caccia, Valerio Leoni, Randa Sghaier, Ameur Cherif, John J. Mackrill, Laboratoire Bio-PeroxIL. Biochimie du peroxysome, inflammation et métabolisme lipidique [Dijon] (BIO-PEROXIL), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de Biochimie, Faculté de Médecine de Sousse, 4002 Sousse, Tunisia, Faculté de médecine de Sousse [Ibn EL Jazzar], Univ. Monastir, LR12ES05, Lab-NAFS 'Nutrition - Functional Food & Vascular Health', Monastir, Tunisia., Laboratoire Biotechnologie et Valorisation des Bio-Géo Ressources [Tunisie] (LR11ES31 (BVBGR)), Université de la Manouba [Tunisie] (UMA), Hospital of Varese, Milan, Italy, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Université de Bourgogne (UB), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Chimie et Physique - Approche Multi-échelle des Milieux Complexes (LCP-A2MC), Université de Lorraine (UL), Biosciences Institute (BSI), University College Cork (UCC), Sghaier, R, Nury, T, Leoni, V, Caccia, C, Pais De Barros, J, Cherif, A, Vejux, A, Moreau, T, Limem, K, Samadi, M, Mackrill, J, Masmoudi, A, Lizard, G, Zarrouk, A, and CCSD, Accord Elsevier
Subjects: Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, monomethyl fumarate, Mitochondrion, medicine.disease_cause, Biochemistry, Lipid peroxidation, Mice, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Fumarates, peroxisome, chemistry.chemical_classification, 0303 health sciences, biology, Dimethyl fumarate, Chemistry, Succinate dehydrogenase, 7β-hydroxycholesterol, apoptosis, Malondialdehyde, 3. Good health, [SDV] Life Sciences [q-bio], mitochondria, Oligodendroglia, lipid profile, Cholesterol, Neuroprotective Agents, Molecular Medicine, autophagy, 158N cell, oxiapoptophagy, Cell Line, Superoxide dismutase, 03 medical and health sciences, medicine, Animals, Molecular Biology, 030304 developmental biology, Reactive oxygen species, oxidative58 stress, Maleates, Apoptosi, Cell Biology, Molecular biology, Hydroxycholesterols, 158N cells, Oxidative Stress, biology.protein, Oxidative stre, Lipid Peroxidation, 030217 neurology & neurosurgery, Oxidative stress
Abstract: International audience; Oxidative stress and mitochondrial dysfunction contribute to the pathogenesis of neurodegenerative diseases and favor lipid peroxidation, leading to increased levels of 7β-hydroxycholesterol (7β-OHC) which induces oxiapoptophagy (OXIdative stress, APOPTOsis, autoPHAGY). The cytoprotective effects of dimethylfumarate (DMF), used in the treatment of relapsing remitting multiple sclerosis and of monomethylfumarate (MMF), its main metabolite, were evaluated on murine oligodendrocytes 158 N exposed to 7β-OHC (50 μM, 24 h) with or without DMF or MMF (25 μM). The activity of 7β-OHC in the presence or absence DMF or MMF was evaluated on several parameters: cell adhesion; plasma membrane integrity measured with propidium iodide (PI), trypan blue and fluoresceine diacetate (FDA) assays; LDH activity; antioxidant enzyme activities (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)); generation of lipid peroxidation products (malondialdehyde (MDA), conjugated dienes (CDs)) and protein oxidation products (carbonylated proteins (CPs)); reactive oxygen species (ROS) overproduction conducted with DHE and DHR123. The effect on mitochondria was determined with complementary criteria: measurement of succinate dehydrogenase activity, evaluation of mitochondrial potential (ΔΨm) and mitochondrial superoxide anions (O2●−) production using DiOC6(3) and MitoSOX, respectively; quantification of mitochondrial mass with Mitotracker Red, and of cardiolipins and organic acids. The effects on mitochondrial and peroxisomal ultrastructure were determined by transmission electron microscopy. Intracellular sterol and fatty acid profiles were determined. Apoptosis and autophagy were characterized by staining with Hoechst 33,342, Giemsa and acridine orange, and with antibodies raised against caspase-3 and LC3. DMF and MMF attenuate 7β-OHC-induced cytotoxicity: cell growth inhibition; decreased cell viability; mitochondrial dysfunction (decrease of succinate dehydrogenase activity, loss of ΔΨm, increase of mitochondrial O2●− production, alteration of the tricarboxilic acid (TCA) cycle, and cardiolipins content); oxidative stress induction (ROS overproduction, alteration of GPx, CAT, and SOD activities, increased levels of MDA, CDs, and CPs); changes in fatty acid and cholesterol metabolism; and cell death induction (caspase-3 cleavage, activation of LC3-I in LC3-II). Ultrastructural alterations of mitochondria and peroxisomes were prevented. These results demonstrate that DMF and MMF prevent major dysfunctions associated with neurodegenerative diseases: oxidative stress, mitochondrial dysfunction, apoptosis and autophagy.
Published: 2019
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34. Managing Parkinson's disease: moving ON with NOP

Author: Daniela Mercatelli, Roberto Eleopra, Michele Morari, Nurulain T. Zaveri, Erwan Bezard, Università degli Studi di Ferrara (UniFE), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', and Department of Medical Sciences
Subjects: 0301 basic medicine, Parkinson's disease, Dopamine, NOP, Substantia nigra, Striatum, Opioid, Nociceptin Receptor, NO, Antiparkinson Agents, Levodopa, 03 medical and health sciences, [SCCO]Cognitive science, 0302 clinical medicine, Dopamine receptor D1, Receptors, Medicine, Animals, Humans, Review Articles, ComputingMilieux_MISCELLANEOUS, Pharmacology, Clinical Trials as Topic, business.industry, Pars compacta, Dopaminergic Neurons, [SCCO.NEUR]Cognitive science/Neuroscience, Parkinson Disease, medicine.disease, 3. Good health, Substantia Nigra, Nociceptin receptor, 030104 developmental biology, Opioid Peptides, Receptors, Opioid, nervous system, business, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract: The opioid‐like neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP receptor) contribute to Parkinson's disease (PD) and motor complications associated with levodopa therapy. The N/OFQ–NOP receptor system is expressed in cortical and subcortical motor areas and, notably, in dopaminergic neurons of the substantia nigra compacta. Dopamine depletion, as in rodent models of PD results in up‐regulation of N/OFQ transmission in the substantia nigra and down‐regulation of N/OFQ transmission in the striatum. Consistent with this, NOP receptor antagonists relieve motor deficits in PD models by reinstating the physiological balance between excitatory and inhibitory inputs impinging on nigro‐thalamic GABAergic neurons. NOP receptor antagonists also counteract the degeneration of nigrostriatal dopaminergic neurons, possibly by attenuating the excitotoxicity or modulating the immune response. Conversely, NOP receptor agonists attenuate levodopa‐induced dyskinesia by attenuating the hyperactivation of striatal D(1) receptor signalling in neurons of the direct striatonigral pathway. The N/OFQ–NOP receptor system might represent a novel target in the therapy of PD.
Published: 2019
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35. Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls

Author: Caterina Terrile, Juliette Bouchereau, Valeria Tiranti, Marina Paviolo, Paule Bénit, Manuel Schiff, Malgorzata Rak, Allan G. Rasmusson, Holger Prokisch, Arcangela Iuso, Thomas Schwarzmayr, Pierre Rustin, Alessia Catania, Laura S. Kremer, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Medical Genetics and Neurogenetics [Milan, Italy], Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Institute of Human Genetics [Neuherberg] (IHG), Helmholtz-Zentrum München (HZM), Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Centre de référence pour les erreurs innées du métabolisme [Hôpital Robert Debré - APHP], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Biology [Lund, Sweden] (Biology building A), Lund University [Lund, Sweden], Department of Pediatrics [Munich, Germany] (Dr. von Hauner Children’s Hospital), Ludwig-Maximilians-Universität München (LMU), This study was supported by the German BMBF and Horizon2020 through E-Rare project GENOMIT (01GM1603 and 01GM1906B to H.P.), Horizon2020 Project SOUND (633974 to H.P.), German Network for Mitochondrial Disorders (mitoNET 01GM1113C to H.P.), AMMi (Association contre les Maladies Mitochondriales) grants to M.P., P.R., P.B. and M.S., E-Rare project GENOMIT (ANR-15-RAR3–0012 to P.R., A.C. and M.S.), Italian Ministry of Health (RF-2016-02361495 to A.C.), Mitocon (Grant no. 2018–01 to V.T.), Mariani Foundation (V.T.)., ANR-15-RAR3-0012,GENOMIT,Mitochondrial Disorders- from a pan-European Registry to medical genetics, toward molecular mechanisms and new therapeutic options(2015), European Project: 633974,H2020,H2020-PHC-2014-two-stage,SOUND(2015), Helmholtz Zentrum München = German Research Center for Environmental Health, Lund University [Lund], Rak, Malgorzata, Mitochondrial Disorders- from a pan-European Registry to medical genetics, toward molecular mechanisms and new therapeutic options - - GENOMIT2015 - ANR-15-RAR3-0012 - E-Rare-3 - VALID, and Statistical multi-Omics UNDerstanding of Patient Samples - SOUND - - H20202015-09-01 - 2018-08-31 - 633974 - VALID
Subjects: 0301 basic medicine, Arabidopsis thaliana, [SDV]Life Sciences [q-bio], Arabidopsis, lcsh:Medicine, Mitochondrion, medicine.disease_cause, 0302 clinical medicine, NADH, NADPH Oxidoreductases, Pharmacology (medical), [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cells, Cultured, Genetics (clinical), chemistry.chemical_classification, biology, Chemistry, NADH dehydrogenase, Mitochondria, Mitochondrial Diseases, Complex I, Alternative Dehydrogenases, Arabidopsis Thaliana, Atnda2, General Medicine, AtNDA2, ddc, [SDV] Life Sciences [q-bio], Mitochondrial respiratory chain, Biochemistry, Saccharomyces cerevisiae Proteins, Saccharomyces cerevisiae, Mitochondrial diseases, Transfection, 03 medical and health sciences, Oxidoreductase, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Alternative dehydrogenases, Electron Transport Complex I, Arabidopsis Proteins, Superoxide Dismutase, Research, lcsh:R, NADPH Dehydrogenase, Fibroblasts, biology.organism_classification, Yeast, 030104 developmental biology, biology.protein, 030217 neurology & neurosurgery, Oxidative stress
Abstract: Background Complex I (CI or NADH:ubiquinone oxidoreductase) deficiency is the most frequent cause of mitochondrial respiratory chain defect. Successful attempts to rescue CI function by introducing an exogenous NADH dehydrogenase, such as the NDI1 from Saccharomyces cerevisiae (ScNDI1), have been reported although with drawbacks related to competition with CI. In contrast to ScNDI1, which is permanently active in yeast naturally devoid of CI, plant alternative NADH dehydrogenases (NDH-2) support the oxidation of NADH only when the CI is metabolically inactive and conceivably when the concentration of matrix NADH exceeds a certain threshold. We therefore explored the feasibility of CI rescue by NDH-2 from Arabidopsis thaliana (At) in human CI defective fibroblasts. Results We showed that, other than ScNDI1, two different NDH-2 (AtNDA2 and AtNDB4) targeted to the mitochondria were able to rescue CI deficiency and decrease oxidative stress as indicated by a normalization of SOD activity in human CI-defective fibroblasts. We further demonstrated that when expressed in human control fibroblasts, AtNDA2 shows an affinity for NADH oxidation similar to that of CI, thus competing with CI for the oxidation of NADH as opposed to our initial hypothesis. This competition reduced the amount of ATP produced per oxygen atom reduced to water by half in control cells. Conclusions In conclusion, despite their promising potential to rescue CI defects, due to a possible competition with remaining CI activity, plant NDH-2 should be regarded with caution as potential therapeutic tools for human mitochondrial diseases.
Published: 2019
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36. Hyperexcitability in Cultured Cortical Neuron Networks from the G93A-SOD1 Amyotrophic Lateral Sclerosis Model Mouse and its Molecular Correlates

Author: Giulia Regalia, Paola Cavalcante, Marco Rasponi, Benedetta Terragni, Ludovico Minati, Giovanni Stefano Ugolini, Giulia Bechi, Stefania Marcuzzo, Massimo Mantegazza, Pia Bernasconi, Natsue Yoshimura, Davide Isaia, Silvia Bonanno, Ambra Rizzo, Renato Mantegazza, Emilio Ciusani, Cristina Cappelletti, Department of Neurophysiopathology, Besta Neurological Institute, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and University of Trento [Trento]
Subjects: 0301 basic medicine, amyotrophic lateral sclerosis, Dendritic spine, [SDV]Life Sciences [q-bio], SOD1, Mice, Transgenic, Biology, Receptors, N-Methyl-D-Aspartate, 03 medical and health sciences, Bursting, 0302 clinical medicine, medicine, Animals, Amyotrophic lateral sclerosis, multi-electrode array (MEA), Motor Neurons, Cell Death, Superoxide Dismutase, cortical neurons, General Neuroscience, hyperexcitability, Neurodegeneration, Motor Cortex, APAF1 apoptosis-related gene, G93A-SOD1 mice, Neurodegenerative Diseases, Motor neuron, medicine.disease, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Corticospinal tract, Neuroscience, 030217 neurology & neurosurgery, Motor cortex
Abstract: International audience; Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the corticospinal tract and leading to motor neuron death. According to a recent study, magnetic resonance imaging-visible changes suggestive of neurodegeneration seem absent in the motor cortex of G93A-SOD1 ALS mice. However, it has not yet been ascertained whether the cortical neural activity is intact, or alterations are present, perhaps even from an early stage. Here, cortical neurons from this model were isolated at post-natal day 1 and cultured on multielectrode arrays. Their activity was studied with a comprehensive pool of neurophysiological analyses probing excitability, criticality and network architecture, alongside immunocytochemistry and molecular investigations. Significant hyperexcitability was visible through increased network firing rate and bursting, whereas topological changes in the synchronization patterns were apparently absent. The number of dendritic spines was increased, accompanied by elevated transcriptional levels of the DLG4 gene, NMDA receptor 1 and the early pro-apoptotic APAF1 gene. The extracellular Na+, Ca2+, K+ and Cl- concentrations were elevated, pointing to perturbations in the culture micro-environment. Our findings highlight remarkable early changes in ALS cortical neuron activity and physiology. These changes suggest that the causative factors of hyperexcitability and associated toxicity could become established much earlier than the appearance of disease symptoms, with implications for the discovery of new hypothetical therapeutic targets.
Published: 2019
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37. Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC 16A2 mutations

Author: Remerand, Ganaelle, Boespflug‐Tanguy, Odile, Tonduti, Davide, Touraine, Renaud, Rodriguez, Diana, Curie, Aurore, Perreton, Nathalie, Des Portes, Vincent, Sarret, Catherine, Afenjar, Alexandra, Burglen, Lydie, Castellotti, Barbara, Cuntz, Danielle, Desguerre, Isabelle, Doummar, Diane, Estienne, Margherita, Freri, Elena, Heron, Delphine, Moutard, Marie‐Laure, Novara, Francesca, Orcesi, Simona, Saletti, Veronica, Zibordi, Federica, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), CIC CHU Lyon (inserm), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire sur le langage, le cerveau et la cognition (L2C2), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service: neuropédiatrie pathologie du développement, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cytogenetics, Fondation 'Neurological Institute C. Mondino ', Fondazione IRCCS Istituto Neurologico 'Carlo Besta', CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: 030506 rehabilitation, Pediatrics, medicine.medical_specialty, Muscle Hypotonia, [SDV]Life Sciences [q-bio], Choreoathetosis, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Developmental Neuroscience, Intellectual disability, medicine, Kyphoscoliosis, ComputingMilieux_MISCELLANEOUS, Dystonia, Allan–Herndon–Dudley syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Hypotonia, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Pediatrics, Perinatology and Child Health, Neurology (clinical), medicine.symptom, 0305 other medical science, business, 030217 neurology & neurosurgery
Abstract: The aim of the study was to redefine the phenotype of Allan-Herndon-Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty-four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro-orthopaedic, pulmonary, and epileptic complications. WHAT THIS PAPER ADDS: Mild intellectual disability is associated with SLC16A2 mutations. A thyroid hormone profile with a free T3 /T4 ratio higher than 0.75 can help diagnose patients. Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders. Axial hypotonia is a consistent feature of Allan-Herndon-Dudley syndrome and leads to specific complications.
Published: 2019
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38. Hsp22 overexpression induces myocardial hypertrophy, senescence and reduced life span through enhanced oxidative stress

Author: Dorothy E. Vatner, Stephen F. Vatner, Didier Morin, Sandrine Pons, Cindy Gueguen, Hongyu Qiu, Alain Berdeaux, Bijan Ghaleh, Christophe Depre, Mathieu Panel, Valerio Leoni, Romain Long, Adela Taranu, Lydie Laure, Claudio Caccia, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire Kastler Brossel (LKB (Lhomond)), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Team Depression and Antidepressants (INSERM UMR 1178), Santé mentale et santé publique (SMSP - U1178), Université Paris-Sud - Paris 11 (UP11)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Department of cell biology and molecular medicine, Cardiovascular Research Institute-University of Medicine and Dentistry-Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers)-Rutgers University System (Rutgers), morin, didier, Morin, D, Long, R, Panel, M, Laure, L, Taranu, A, Gueguen, C, Pons, S, Leoni, V, Caccia, C, Vatner, S, Vatner, D, Qiu, H, Depre, C, Berdeaux, A, Ghaleh, B, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Rutgers New Jersey Medical School (NJMS), and Rutgers University System (Rutgers)-Rutgers University System (Rutgers)-Cardiovascular Research Institute-University of Medicine and Dentistry
Subjects: Male, 0301 basic medicine, Antioxidant, senescence, myocardial hypertrophy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], medicine.disease_cause, Biochemistry, Antioxidants, Muscle hypertrophy, Mice, chemistry.chemical_compound, 0302 clinical medicine, oxidative stress, Phosphorylation, Cells, Cultured, Cellular Senescence, Heat-Shock Proteins, chemistry.chemical_classification, Mitochondria, [SDV] Life Sciences [q-bio], Hypertrophy, Left Ventricular, life span, Senescence, medicine.medical_specialty, Longevity, Mice, Transgenic, Oxidative phosphorylation, Cyclic N-Oxides, 03 medical and health sciences, Physiology (medical), Internal medicine, Heat shock protein, medicine, Animals, Hsp22 overexpression, Reactive oxygen species, Myocardium, Glutathione, 030104 developmental biology, Endocrinology, chemistry, Oxidative stre, Spin Labels, Reactive Oxygen Species, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery, Oxidative stress, Molecular Chaperones
Abstract: International audience; H11 kinase/Hsp22 (Hsp22) is a small heat shock protein, which, when overexpressed cardiac specifically in transgenic (TG) mice, induces stable left ventricular (LV) hypertrophy. Hsp22 also increases oxidative phosphorylation and mitochondrial reactive oxygen species (ROS) production, mechanisms mediating LV hypertrophy, senescence and reduced lifespan. Therefore, we investigated whether ROS production mediates LV hypertrophy, senescence and reduced life span in Hsp22 TG mice. Survival curves revealed that TG mice had a 48% reduction in their mean life span compared to wild type (WT) mice. This was associated with a significant increase in senescence markers, such as p16, p19 mRNA levels as well as the percentage of β-galactosidase positive cells and telomerase activity. Oxidized (GSSG)/reduced (GSH) glutathione ratio, an indicator of oxidative stress, and ROS production from 3 major cellular sources was measured in cardiac tissue. Hearts from TG mice exhibited a decrease in GSH/GSSG ratio together with increased ROS production from all sources. To study the role of ROS, mice were treated with the antioxidant Tempol from weaning to their sacrifice. Chronic Tempol treatment abolished oxidative stress and overproduction of ROS, and reduced myocardial hypertrophy and Akt phosphorylation in TG mice. Tempol also significantly extended life span and prevented aging markers in TG mice. Taken together these results show that overexpression of Hsp22 increases oxidative stress responsible for the induction of hypertrophy and senescence and ultimately reduction in life span.
Published: 2019
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39. Expanding the importance of HMERF titinopathy: new mutations and clinical aspects

Author: Tanya Stojkovic, José C. Milisenda, Ana Maria Cobo, Monika Raimondi, Fernando Silveira, Sarah Leonard-Louis, Marco Savarese, Ricardo Reisin, Lorenzo Maggi, Farzad Fatehi, Wolfram Kress, Sabrina Sacconi, Johanna Palmio, Sini Penttilä, Sergei Nikitin, Tahseen Mozaffar, Shahram Attarian, Bjarne Udd, Peter Hackman, Andrés Berardo, Sergei Kurbatov, Anna Lena Semmler, Tim Lai, Kristl G. Claeys, Andoni Urtizberea, Tampere University Hospital, University of Tampere [Finland], Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, RWTH Aachen University, University Hospital of Würzburg, University of California [Irvine] (UCI), University of California, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital de la Timone [CHU - APHM] (TIMONE), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', CIBER de Enfermedades Raras (CIBERER), Tehran University of Medical Sciences (TUMS), Hospital de São João [Porto], University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), University of California [Irvine] (UC Irvine), University of California (UC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, Medicum, Department of Medical and Clinical Genetics, and University of Helsinki
Subjects: Male, INVOLVEMENT, Neurology, Titin, Respiratory failure, Bioinformatics, 3124 Neurology and psychiatry, Exon, 0302 clinical medicine, Connectin, 030212 general & internal medicine, Family history, Age of Onset, Sanger sequencing, Original Communication, biology, Hereditary myopathy, Skeletal, Middle Aged, 3. Good health, Pedigree, Genetic Diseases, symbols, Muscle, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, Respiratory Insufficiency, Respiratory insufficiency, Life Sciences & Biomedicine, Neurotieteet - Neurosciences, Adult, Distròfia muscular, medicine.medical_specialty, Proximal muscle weakness, Clinical Sciences, Clinical Neurology, Titinopathy, mutations, DISEASE ALLELE, Titinopathy, 03 medical and health sciences, symbols.namesake, Young Adult, Muscular Diseases, medicine, Humans, Myopathy, Muscle, Skeletal, Malalties musculars, Neurology & Neurosurgery, Science & Technology, EARLY RESPIRATORY-FAILURE, business.industry, 3112 Neurosciences, Genetic Diseases, Inborn, Neurosciences, mutations, Muscular dystrophy, Inborn, Insuficiència respiratòria, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, biology.protein, BODIES, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery
Abstract: Journal of neurology 266(3), 680-690 (2019). doi:10.1007/s00415-019-09187-2, Published by Springer, Berlin ; Heidelberg
Published: 2019
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40. Spinal cord involvement in adult-onset metabolic and genetic diseases

Author: Cecilia Marelli, Pierre Labauge, Ettore Salsano, Letterio S. Politi, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Department of Neurology, Children's Hospital [Boston], Boston Children's Hospital, Département de neurologie [Montpellier], and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM)
Subjects: Adult, Mitochondrial Diseases, Hereditary spastic paraplegia, Genetic counseling, [SDV]Life Sciences [q-bio], Neurogenetics, Bioinformatics, Spinal Cord Diseases, Leukoencephalopathy, 03 medical and health sciences, Myelopathy, 0302 clinical medicine, Metabolic Diseases, myelopathy, Leukoencephalopathies, Humans, Medicine, Age of Onset, hereditary spastic paraplegia, neurogenetics, business.industry, Leukodystrophy, Autosomal dominant trait, medicine.disease, Spinal cord, metabolic disease, 3. Good health, Psychiatry and Mental health, medicine.anatomical_structure, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, MRI
Abstract: International audience; In adulthood, spinal cord MRI abnormalities such as T2-weighted hyperintensities and atrophy are commonly associated with a large variety of causes (inflammation, infections, neoplasms, vascular and spondylotic diseases). Occasionally, they can be due to rare metabolic or genetic diseases, in which the spinal cord involvement can be a prominent or even predominant feature, or a secondary one. This review focuses on these rare diseases and associated spinal cord abnormalities, which can provide important but over-ridden clues for the diagnosis. The review was based on a PubMed search (search terms: 'spinal cord' AND 'leukoencephalopathy' OR 'leukodystrophy'; 'spinal cord' AND 'vitamin'), further integrated according to the authors' personal experience and knowledge. The genetic and metabolic diseases of adulthood causing spinal cord signal alterations were identified and classified into four groups: (1) leukodystrophies; (2) deficiency-related metabolic diseases; (3) genetic and acquired toxic/metabolic causes; and (4) mitochondrial diseases. A number of genetic and metabolic diseases of adulthood causing spinal cord atrophy without signal alterations were also identified. Finally, a classification based on spinal MRI findings is presented, as well as indications about the diagnostic work-up and differential diagnosis. Some of these diseases are potentially treatable (especially if promptly recognised), while others are inherited as autosomal dominant trait. Therefore, a timely diagnosis is needed for a timely therapy and genetic counselling. In addition, spinal cord may be the main site of pathology in many of these diseases, suggesting a tempting role for spinal cord abnormalities as surrogate MRI biomarkers.
Published: 2019
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41. Serum magnesium and calcium levels in relation to ischemic stroke Mendelian randomization study

Author: Susanna C. Larsson, Matthew Traylor, Stephen Burgess, Giorgio B. Boncoraglio, Christina Jern, Karl Michaëlsson, Hugh S. Markus, Rainer Malik, Ganesh Chauhan, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne-Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, raci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Daniel I Chasman, Wei-Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Jeffrey Haessler, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Susan R Heckbert, Elizabeth G Holliday, George Howard, Fang-Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez-Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Charles Kooperberg, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin-Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei-Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O'Donnell, Bruce M Psaty, Sara L Pulit, Kristiina Rannikmäe, Alexander P Reiner, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Paul M Ridker, Natalia S Rost, Peter M Rothwell, Jerome I Rotter, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Stella Trompet, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil-Smoller, James G Wilson, Kerri L Wiggins, Qiong Yang, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu-Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean-François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez-Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller-Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba-Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti-Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano-Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres-Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Daniel Strbian, Israel Fernandez-Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, Berr, Claudine, Unit of Cardiovascular and Nutritional Epidemiology [Stockholm, Sweden], Karolinska Institutet [Stockholm]-Institute of Environmental Medicine [Stockholm, Sweden], Stroke Research Group [London, UK] (Department of Brain Repair and Rehabilitation), University of London - UCL [London, UK], MRC Biostatistics Unit [Cambridge, UK], University of Cambridge [UK] (CAM), Department of Public Health and Primary Care [Cambridge, UK] (Institute of Public Health), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Section of Clinical Immunology [Uppsala, Sweden] (Department of Immunology, Genetics and Pathology), Uppsala University, Department of Surgical Sciences [Uppsala, Sweden], This work was supported by the Swedish Research Council for Health, Working Life and Welfare (Forte) and the Swedish Research Council. Hugh Markus is supported by an NIHR Senior Investigator award. His and Matthew Traylor’s work is supported by infrastructural support from the Cambridge University Hospitals Trust NIHR Biomedical Research Centre., MEGASTROKE project of the International Stroke Genetics Consortium : Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HH, Ago T, Almgren P, Amouyel P, Ay H, Bartz RM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD Jr, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PI, DeStefano AL, Hoed MD, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CL, Tanislav C, Tatlisumak T, Taylor KD, Thijs VN, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, Amin N, Aparicio HS, Arnett DK, Attia J, Beiser AS, Berr C, Buring JE, Bustamante M, Caso V, Cheng YC, Choi SH, Chowhan A, Cullell N, Dartigues JF, Delavaran H, Delgado P, Dörr M, Engström G, Ford I, Gurpreet WS, Hamsten A, Heitsch L, Hozawa A, Ibanez L, Ilinca A, Ingelsson M, Iwasaki M, Jackson RD, Jood K, Jousilahti P, Kaffashian S, Kalra L, Kamouchi M, Kitazono T, Kjartansson O, Kloss M, Koudstaal PJ, Krupinski J, Labovitz DL, Laurie CC, Levi CR, Li L, Lind L, Lindgren CM, Lioutas V, Liu YM, Lopez OL, Makoto H, Martinez-Majander N, Matsuda K, Minegishi N, Montaner J, Morris AP, Muiño E, Müller-Nurasyid M, Norrving B, Ogishima S, Parati EA, Peddareddygari LR, Pedersen NL, Pera J, Perola M, Pezzini A, Pileggi S, Rabionet R, Riba-Llena I, Ribasés M, Romero JR, Roquer J, Rudd AG, Sarin AP, Sarju R, Sarnowski C, Sasaki M, Satizabal CL, Satoh M, Sattar N, Sawada N, Sibolt G, Sigurdsson Á, Smith A, Sobue K, Soriano-Tárraga C, Stanne T, Stine OC, Stott DJ, Strauch K, Takai T, Tanaka H, Tanno K, Teumer A, Tomppo L, Torres-Aguila NP, Touze E, Tsugane S, Uitterlinden AG, Valdimarsson EM, van der Lee SJ, Völzke H, Wakai K, Weir D, Williams SR, Wolfe CD, Wong Q, Xu H, Yamaji T, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT Jr, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JM, Kamatani Y, Debette S, Dichgans M., Larsson, Susanna C [0000-0003-0118-0341], Apollo - University of Cambridge Repository, and Neurology
Subjects: medicine.medical_specialty, Neurology, Heredity, Neurologi, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Calcium, Polymorphism, Single Nucleotide, Gastroenterology, Article, Brain Ischemia, Brain ischemia, 03 medical and health sciences, 0302 clinical medicine, Human genetics, Internal medicine, Mendelian randomization, Medicine, Humans, Magnesium, 030212 general & internal medicine, Stroke, Herència (Biologia), Genètica humana, business.industry, Neurosciences, Mendelian Randomization Analysis, Odds ratio, medicine.disease, Confidence interval, 3. Good health, [SDV] Life Sciences [q-bio], Intracranial Embolism, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, 030217 neurology & neurosurgery, Neurovetenskaper
Abstract: Comment inThe yin and yang of magnesium and calcium: New genetic insights for stroke? [Neurology. 2019]; International audience; Objective To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10 −4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10 −4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. Conclusions This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
Published: 2019
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42. Individual Comparison of Cholesterol Metabolism in Normal and Tumour Areas in Radical Prostatectomy Specimens from Patients with Prostate Cancer: Results of the CHOMECAP Study

Author: Jean-Marc A. Lobaccaro, Claudio Caccia, Olivier Celhay, Laura Bousset, Amalia Trousson, Cyrille de Joussineau, Jean-Louis Kemeny, Christelle Damon-Soubeyrant, Laurent Guy, Laurent Morel, Angélique De Haze, Silvère Baron, Valerio Leoni, Bruno Pereira, Laura Sabourin, Catherine Godfraind, Celhay, O, Bousset, L, Guy, L, Kemeny, J, Leoni, V, Caccia, C, Trousson, A, Damon-Soubeyrant, C, De Haze, A, Sabourin, L, Godfraind, C, de Joussineau, C, Pereira, B, Morel, L, Lobaccaro, J, Baron, S, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Resistance Exploring and Targeting (CREaT), Université d'Auvergne - Clermont-Ferrand I (UdA), Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Groningen [Groningen], CHU Clermont-Ferrand, service de Biostatistiques, DRCI, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: Apolipoprotein E, Male, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Prostate cancer, chemistry.chemical_compound, 0302 clinical medicine, Prostate, Gene Regulatory Networks, Ester, Acetyl-CoA C-Acetyltransferase, Principal Component Analysis, Esters, Oxysterols, Middle Aged, Scavenger Receptors, Class B, 3. Good health, Gene Expression Regulation, Neoplastic, Sterols, medicine.anatomical_structure, Cholesterol, Oncology, 030220 oncology & carcinogenesis, Immunohistochemistry, lipids (amino acids, peptides, and proteins), Sterol Regulatory Element Binding Protein 2, medicine.medical_specialty, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Deregulation, 03 medical and health sciences, Apolipoproteins E, Oxysterol, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Aged, Prostatectomy, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, business.industry, Gene Expression Profiling, Prostatic Neoplasms, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Sterol, SCARB1, Endocrinology, chemistry, Surgery, business, Lipoprotein
Abstract: International audience; BACKGROUND: Deregulation of cholesterol metabolism represents a hallmark of prostate cancer (PCa) and promotes its development. OBJECTIVE: To compare cholesterol metabolism on individual paired normal and tumour prostate tissues obtained from patients with PCa. DESIGN, SETTING, AND PARTICIPANTS: Between 2008 and 2012, normal and tumour paired tissue samples were collected from radical prostatectomy specimens from a cohort of 69 patients treated for localised PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tumour and normal tissues were subjected to gene analysis, sterol measurement, and immunohistochemistry. The Wilcoxon paired test and Spearman test were applied for comparison and correlation analyses, respectively. Principal component analysis was also carried out to investigate relationships between quantitative variables. RESULTS AND LIMITATIONS: Overall, cholesterol concentrations were not significantly different between tissue pairs. However, tumour samples were significantly associated with downregulated de novo cholesterol synthesis, but exhibited 54.7% overexpression of SCARB1 that could increase high-density lipoprotein uptake in PCa. Tumour tissues showed different trafficking of available cholesterol, with significantly lower ACAT1, and an altered efflux via APOE. Furthermore, cholesterol metabolism in tumour tissues was characterised by higher accumulation of 7alpha-hydroxycholesterol (OHC), 7betaOHC, and 7-ketosterol, and a lower level of 27OHC. CONCLUSIONS: Focusing on individually paired prostate tissues, our results highlighted several differences between normal and tumour samples linked to a metabolic shift in cholesterol flux. PCa samples exhibited a specific tissue signature characterised by higher SCARB1 expression, higher accumulation of OHC species, and clear downregulation of de novo cholesterol synthesis. PATIENT SUMMARY: Comparing normal and tumour tissues from the same prostates, our study identified a set of alterations in prostate cancer samples in terms of their use of cholesterol. These included higher cholesterol uptake, accumulation of oxidised cholesterol derivatives, and autonomous cellular production of cholesterol. Together, these data provide promising clinical targets to fight prostate cancer.
Published: 2019
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43. First international descriptive and interventional survey for cholesterol and non-cholesterol sterol determination by gas- and liquid-chromatography–Urgent need for harmonisation of analytical methods

Author: Richard E. Ostlund, Bianca Barriuso, Peter B. Jones, Isabel Andrade, Semone B. Myrie, Richard W. Browne, Leena Kaipiainen, Helena Gylling, Christin Helmschrodt, Robert Ahrends, Peter J. Crick, Silke Matysik, Scott V Harding, Luigi Iuliano, Claudio Caccia, Robert Gray, Valéria S. Nunes, Chiara Zerbinati, Valerio Leoni, Dieter Lütjohann, William J. Griffiths, Iciar Astiasarán, Ana Maria Lottenberg, Ulf Diczfalusy, Hans-Gerd Janssen, Silvia Friedrichs, Gerd Schmitz, Lucía Baila-Rueda, Jeff McDonald, Lionel Bretillon, Wolf Jochen Geilenkeuser, Günter Fauler, Ana Cenarro, Guadalupe Garcia-Llatas, Ernst J. Schaefer, María Menéndez-Carreño, Ingemar Björkhem, Todd C Rideout, Anita Lövgren-Sandblom, Yuqin Wang, Anja Kerksiek, Susen Becker, Fernando Ramos, Eliana Polisecki, Frank Kannenberg, Dylan S. MacKay, Diana Ansorena, María Jesús Lagarda, Hans Frieder Schött, Uta Ceglarek, University of Helsinki, HUS Abdominal Center, Gastroenterologian yksikkö, Department of Medicine, Lutjohann, D, Bjorkhem, I, Friedrichs, S, Kerksiek, A, Lovgren-Sandblom, A, Geilenkeuser, W, Ahrends, R, Andrade, I, Ansorena, D, Astiasaran, I, Baila-Rueda, L, Barriuso, B, Becker, S, Bretillon, L, Browne, R, Caccia, C, Ceglarek, U, Cenarro, A, Crick, P, Fauler, G, Garcia-Llatas, G, Gray, R, Griffiths, W, Gylling, H, Harding, S, Helmschrodt, C, Iuliano, L, Janssen, H, Jones, P, Kaipiainen, L, Kannenberg, F, Lagarda, M, Leoni, V, Lottenberg, A, Mackay, D, Matysik, S, Mcdonald, J, Menendez-Carreno, M, Myrie, S, Sutti Nunes, V, Ostlund, R, Polisecki, E, Ramos, F, Rideout, T, Schaefer, E, Schmitz, G, Wang, Y, Zerbinati, C, Diczfalusy, U, Schott, H, Rheinische Friedrich-Wilhelms-Universität Bonn, Karolinska University Hospital-Huddinge, Karolinska Institute, German Reference Institute for Bioanalytics, Partenaires INRAE, Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., College of Health Technology of Coimbra (ESTeSC), Universidad de Navarra [Pamplona] (UNAV), Hospital Universitario Miguel Servet, Laboratoire LTEE, Leipzig University, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Université Bourgogne Franche-Comté [COMUE] (UBFC), State University of New York (SUNY), Hospital of Varese, Milan, Italy, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Swansea University, Medical University Graz, Universitat de València (UV), King‘s College London, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Unilever Research and Development, University of Manitoba [Winnipeg], University of Münster, Universidade de São Paulo (USP), University Hospital Regensburg, University of Texas at Dallas, Boston Heart Diagnostics, Universidade de Coimbra, The work in University of Valencia was financed by CICYT-FEDER (AGL2008−02591-C02-01) and MINECO-FEDER (AGL2012−39503-C02-01). The work at Universitario Miguel Servet, Zaragoza, Spain was funded by Fondo de Investigación Sanitaria (FIS, and PI15/01983). Work in Swansea was supported by the UK Biotechnology and Biological Sciences Research Council (BBSRC, grant numbers BB/I001735/1 and BB/L001942/1).
Subjects: 0301 basic medicine, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Biochemistry, Cholesterol balance, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Surveys and Questionnaires, Phytosterol, ABSORPTION, Medicine, Cholesterol absorption, PRECURSORS, Normal laboratory, Phytosterols, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, SERUM PLANT STEROLS, Sitosterol, 3. Good health, Cholestanol, Cholesterol, Atherosclerosi, 030220 oncology & carcinogenesis, Cholesterol synthesis, Molecular Medicine, lipids (amino acids, peptides, and proteins), Human, Chromatography, Gas, Cholesterol synthesi, Campesterol, atherosclerosis, cholesterol absorption, cholesterol balance, cholesterol synthesis, phytosterols, surrogate marker, Lathosterol, Deuterium labelled, Article, 03 medical and health sciences, Humans, Molecular Biology, Chromatography, business.industry, Cell Biology, Atherosclerosis, Sitosterols, Sterol, 030104 developmental biology, chemistry, Chromatography, Ga, 3121 General medicine, internal medicine and other clinical medicine, 1182 Biochemistry, cell and molecular biology, Gas chromatography, Surrogate marker, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Chromatography, Liquid
Abstract: International audience; Serum concentrations of lathosterol, the plant sterols campesterol and sitosterol and the cholesterol metabolite 5alpha-cholestanol are widely used as surrogate markers of cholesterol synthesis and absorption, respectively. Increasing numbers of laboratories utilize a broad spectrum of well-established and recently developed methods for the determination of cholesterol and non-cholesterol sterols (NCS). In order to evaluate the quality of these measurements and to identify possible sources of analytical errors our group initiated the first international survey for cholesterol and NCS. The cholesterol and NCS survey was structured as a two-part survey which took place in the years 2013 and 2014. The first survey part was designed as descriptive, providing information about the variation of reported results from different laboratories. A set of two lyophilized pooled sera (A and B) was sent to twenty laboratories specialized in chromatographic lipid analysis. The different sterols were quantified either by gas chromatography-flame ionization detection, gas chromatography- or liquid chromatography-mass selective detection. The participants were requested to determine cholesterol and NCS concentrations in the provided samples as part of their normal laboratory routine. The second part was designed as interventional survey. Twenty-two laboratories agreed to participate and received again two different lyophilized pooled sera (C and D). In contrast to the first international survey, each participant received standard stock solutions with defined concentrations of cholesterol and NCS. The participants were requested to use diluted calibration solutions from the provided standard stock solutions for quantification of cholesterol and NCS. In both surveys, each laboratory used its own internal standard (5alpha-cholestane, epicoprostanol or deuterium labelled sterols). Main outcome of the survey was, that unacceptably high interlaboratory variations for cholesterol and NCS concentrations are reported, even when the individual laboratories used the same calibration material. We discuss different sources of errors and recommend all laboratories analysing cholesterol and NCS to participate in regular quality control programs.
Published: 2019
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44. Population structure of modern-day Italians reveals patterns of ancient and archaic ancestries in Southern Europe

Author: Simona Barlera, Giovanni Birolo, Simon Myers, Viola Grugni, Vincenzo Lorenzo Pascali, Andrea Angius, Mait Metspalu, Francesca Brisighelli, Antonio Torroni, Francesco Montinaro, Hovirag Lancioni, Luísa Pereira, Antonella Mulas, Mohammed Melhaoui, Alessandro Achilli, Serena Aneli, Mohammed Cherkaoui, Peristera Paschou, M. Peyret-Guzzon, Pilar Galan, Giorgio B. Boncoraglio, A. M. Di Blasio, Stéphane Mazières, C. Di Gaetano, Garrett Hellenthal, Giuseppe Matullo, George Stamatoyannopoulos, Joanna Giemza, J. Di Cristofaro, Magdalena Zoledziewska, Irene Cardinali, Georgios Athanasiadis, Cristian Capelli, François-Xavier Ricaut, Jacques Chiaroni, Anna Olivieri, Alessandro Raveane, Luca Pagani, Toomas Kivisild, Abdellatif Baali, Nicolas Brucato, Christian Dina, Jean-Michel Dugoujon, Clare Bycroft, Alberto Piazza, Silvia Parolo, Francesco Cucca, Ornella Semino, Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, University of Oxford [Oxford], Aarhus University [Aarhus], Istituto di Ricerche Farmacologiche Mario Negri, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino'-Fondazione 'Istituto Neurologico Nazionale C. Mondino', University of Turin, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Dipartimento di Genetica, Biologica e Biochimica, Università degli studi di Torino (UNITO), Laboratoire d'Etude du Rayonnement et de la Matière en Astrophysique (LERMA), École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS), Georgia Tech - CNRS [Metz] (UMI2958), Ecole Nationale Supérieure des Arts et Metiers Metz-SUPELEC-Georgia Institute of Technology [Atlanta]-Georgia Institute of Technology [Lorraine, France]-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Centre National de la Recherche Scientifique (CNRS), Dipartimento di Genetica e Microbiologica, Università di Pavia, Dipartimento di Genetica e Microbiologia, Instituto de Investigação e Inovação em Saúde, Raveane, A, Aneli, S, Montinaro, F, Athanasiadis, G, Barlera, S, Birolo, G, Boncoraglio, G, Di Blasio, A, Di Gaetano, C, Pagani, L, Parolo, S, Paschou, P, Piazza, A, Stamatoyannopoulos, G, Angius, A, Brucato, N, Cucca, F, Hellenthal, G, Mulas, A, Peyret-Guzzon, M, Zoledziewska, M, Baali, A, Bycroft, C, Cherkaoui, M, Chiaroni, J, Di Cristofaro, J, Dina, C, Dugoujon, J, Galan, P, Giemza, J, Kivisild, T, Mazieres, S, Melhaoui, M, Metspalu, M, Myers, S, Pereira, L, Ricaut, F, Brisighelli, F, Cardinali, I, Grugni, V, Lancioni, H, Pascali, V, Torroni, A, Semino, O, Matullo, G, Achilli, A, Olivieri, A, Capelli, C, Mazières, Stéphane, Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani' = Department of Biology and Biotechnology [Univ di Pavia] (DBB UNIPV), Università degli Studi di Pavia = University of Pavia (UNIPV), University of Oxford, Università degli studi di Torino = University of Turin (UNITO), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université de Cergy Pontoise (UCP), Georgia Tech Lorraine [Metz], Ecole Nationale Supérieure des Arts et Metiers Metz-Georgia Institute of Technology [Atlanta]-Ecole Supérieure d'Electricité - SUPELEC (FRANCE)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS Paris), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Institut National de la Recherche Agronomique (INRA), HESAM Université (HESAM)-HESAM Université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Università degli Studi di Pavia, Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Paris 13 (UP13)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), and Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: SELECTION, [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Distribution (economics), Population genetics, Neanderthal genome project, 0302 clinical medicine, Peninsula, HISTORY, Databases, Genetic, ADAPTATION, Research Articles, History, Ancient, media_common, Neanderthals, MODERN HUMANS, 0303 health sciences, Multidisciplinary, geography.geographical_feature_category, POPULATION GENETICS, GENOMICS, EUROPE, Population Genetic, SciAdv r-articles, ASSOCIATION, [SHS.ANTHRO-BIO] Humanities and Social Sciences/Biological anthropology, Multidisciplinary Sciences, ADMIXTURE, Geography, Italy, Ethnology, Science & Technology - Other Topics, Neanderthals / genetics, Research Article, EUROPE, MIGRATION, media_common.quotation_subject, Pastoralism, Human Genetic, Settore BIO/08 - ANTROPOLOGIA, GENETIC-STRUCTURE, SEQUENCE, White People, 03 medical and health sciences, Bronze Age, POPULATION GENETICS, Genetic variation, Animals, Humans, DNA, Ancient, European Continental Ancestry Group / genetics, 030304 developmental biology, Science & Technology, business.industry, Genome, Human, Genetic Drift, Human Genetics, Anthropology, GENOME-WIDE PATTERNS, business, GENOMICS, 030217 neurology & neurosurgery, Diversity (politics), Genome-Wide Association Study
Abstract: A population in a natural crossroad within Europe reveals multiple ancient contributions and substantial population structure., European populations display low genetic differentiation as the result of long-term blending of their ancient founding ancestries. However, it is unclear how the combination of ancient ancestries related to early foragers, Neolithic farmers, and Bronze Age nomadic pastoralists can explain the distribution of genetic variation across Europe. Populations in natural crossroads like the Italian peninsula are expected to recapitulate the continental diversity, but have been systematically understudied. Here, we characterize the ancestry profiles of Italian populations using a genome-wide dataset representative of modern and ancient samples from across Italy, Europe, and the rest of the world. Italian genomes capture several ancient signatures, including a non–steppe contribution derived ultimately from the Caucasus. Differences in ancestry composition, as the result of migration and admixture, have generated in Italy the largest degree of population structure detected so far in the continent, as well as shaping the amount of Neanderthal DNA in modern-day populations.
Published: 2019
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45. Cholinergic modulation inhibits cortical spreading depression in mouse neocortex through activation of muscarinic receptors and decreased excitatory/inhibitory drive

Author: Fabrice Duprat, Lara Pizzamiglio, Oana Chever, Massimo Mantegazza, Sarah Zerimech, Paolo Scalmani, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Carbachol, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cholinergic Agents, Neocortex, Muscarinic Antagonists, Cholinergic Agonists, Inhibitory postsynaptic potential, Muscarinic agonist, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, aura, spreading depolarization, medicine, Animals, migraine, Pharmacology, Chemistry, Cortical Spreading Depression, Excitatory Postsynaptic Potentials, excitation, Muscarinic antagonist, UP-DOWN states, Receptors, Muscarinic, acetylcholine, inhibition, carbachol, Mice, Inbred C57BL, 030104 developmental biology, Inhibitory Postsynaptic Potentials, Telenzepine, Cortical spreading depression, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cholinergic, Female, Neuroscience, 030217 neurology & neurosurgery, Acetylcholine, medicine.drug
Abstract: International audience; Cortical spreading depression (CSD) is a wave of transient network hyperexcitability leading to long lasting depolarization and block of firing, which initiates focally and slowly propagates in the cerebral cortex. It causes migraine aura and it has been implicated in the generation of migraine headache. Cortical excitability can be modulated by cholinergic actions, leading in neocortical slices to the generation of rhythmic synchronous activities (UP/DOWN states).We investigated the effect of cholinergic activation with the cholinomimetic agonist carbachol on CSD triggered with 130 mM KCl pulse injections in acute mouse neocortical brain slices, hypothesizing that the cholinergic-induced increase of cortical network excitability during UP states could facilitate CSD. We observed instead an inhibitory effect of cholinergic activation on both initiation and propagation of CSD, through the action of muscarinic receptors. In fact, carbachol-induced CSD inhibition was blocked by atropine or by the preferential M1 muscarinic antagonist telenzepine; the preferential M1 muscarinic agonist McN-A-343 inhibited CSD similarly to carbachol, and its effect was blocked by telenzepine. Recordings of spontaneous excitatory and inhibitory post-synaptic currents in pyramidal neurons showed that McN-A-343 induced overall a decrease of the excitatory/inhibitory ratio. This inhibitory action may be targeted for novel pharmacological approaches in the treatment of migraine with muscarinic agonists.
Published: 2020
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46. Primary brain calcification: an international study reporting novel variants and associated phenotypes

Author: Ramos, Eliana Marisa, Carecchio, Miryam, Lemos, Roberta, Ferreira, Joana, Legati, Andrea, Sears, Renee Louise, Hsu, Sandy Chan, Panteghini, Celeste, Magistrelli, Luca, Salsano, Ettore, Esposito, Silvia, Taroni, Franco, Richard, Anne-Claire, Tranchant, Christine, Anheim, Mathieu, Ayrignac, Xavier, Goizet, Cyril, Vidailhet, Marie, Maltete, David, Wallon, David, Frebourg, Thierry, Pimentel, Lylyan, Geschwind, Daniel H, Vanakker, Olivier, Galasko, Douglas, Fogel, Brent L, Innes, A Micheil, Ross, Alison, Dobyns, William B, Alcantara, Diana, O'Driscoll, Mark, Hannequin, Didier, Campion, Dominique, French PFBC study group, Oliveira, João R, Garavaglia, Barbara, Coppola, Giovanni, Nicolas, Gaël, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Universidade Federal de Pernambuco [Recife] (UFPE), Interdisciplinary Institute for Neuroscience (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Università del Piemonte Orientale - Dipartimento DISIT Italy, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Center for Medical Genetics [Ghent], Ghent University Hospital, University of California [San Diego] (UC San Diego), University of California, University of Calgary, Department of Clinical Genetics, Ashgrove House, Foresterhill, Aberdeen, UK, Center for Integrative Brain Research, University of Washington [Seattle], Tecnológico de Monterrey (ITESM), Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Università degli Studi di Salermo, Università degli Studi di Salerno (UNISA), and UNIROUEN - UFR Santé (UNIROUEN UFR Santé)
Subjects: 0301 basic medicine, Proband, Male, Adolescent, Adult, Aged, Aged, 80 and over, Brain Diseases, Calcinosis, Child, Cognitive Dysfunction, Female, Genetic Variation, Heterozygote, Humans, Middle Aged, Mutation, Pedigree, Phenotype, Proto-Oncogene Proteins c-sis, Receptor, Platelet-Derived Growth Factor beta, Receptors, G-Protein-Coupled, Receptors, Virus, Sodium-Phosphate Cotransporter Proteins, Type III, Young Adult, QP0551, [SDV]Life Sciences [q-bio], RB024, Type III, INORGANIC-PHOSPHATE, 0302 clinical medicine, Receptors, Medicine and Health Sciences, 80 and over, 2.1 Biological and endogenous factors, HETEROGENEITY, Family history, Aetiology, Genetics (clinical), Genetics & Heredity, PDGFB, French PFBC study group, Parkinsonism, Platelet-Derived Growth Factor beta, 3. Good health, Virus, Mental Health, Neurological, Medical genetics, QP0624, SLC20A2 MUTATIONS, Receptor, medicine.medical_specialty, Genetic counseling, Clinical Sciences, PDGFRB, and over, MAJOR CAUSE, RB127, Article, 03 medical and health sciences, G-Protein-Coupled, Rare Diseases, Clinical Research, Internal medicine, medicine, INFANTILE MYOFIBROMATOSIS, Genetics, Genetic Testing, SPECTRUM, business.industry, Neurosciences, Biology and Life Sciences, Sodium-Phosphate Cotransporter Proteins, QP0361, medicine.disease, BASAL GANGLIA CALCIFICATION, PDGFRB MUTATION, GENE, Brain Disorders, 030104 developmental biology, business, Xenotropic and Polytropic Retrovirus Receptor, 030217 neurology & neurosurgery, Calcification
Abstract: International audience; Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.
Published: 2018
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47. A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma

Author: Gaetano Finocchiaro, Rodica Anghel, Hans Joerg Urban, George Fountzilas, Warren Mason, Martina Makrutzki, O. L. Chinot, Dana Cernea, François Ghiringhelli, Alba A. Brandes, Miguel Gil-Gil, Enrico Franceschi, Giuseppe Lombardi, Patrick Beauchesne, Chiedzo Mpofu, Josef Pichler, Antoine F. Carpentier, François Dubois, Vittorina Zagonel, Frank Saran, Anna K. Nowak, Department of Medical Oncology (AUSL di Bologna), Azienda Unità Sanitaria Locale di Bologna (AUSL), Institut Català d' Oncologia, IDIBELL, Royal Marsden NHS Foundation Trust, Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), School of medecine (University of Western Australia), The University of Western Australia (UWA), Cancer Clinical Research Unit (CCRU), University of Toronto, Princess Margaret Cancer Centre, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Aristotle University of Thessaloniki, The Oncology Institute 'Prof. Dr. Ion Chiricuta', Assistance Publique - Hôpitaux de Marseille (APHM), Institute of Oncology Prof. Dr. Alexandru Trestioreanu (IOB), University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Service de Neuro-Oncologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), F. Hoffmann-La Roche [Basel], Konsiliardienstes Innere Medizin mit Neuroonkologie, and Johannes Kepler Universität
Subjects: 0301 basic medicine, Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Randomization, Bevacizumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Placebo, Continuous bevacizumab, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Double-Blind Method, Internal medicine, Multicenter trial, Clinical endpoint, Recurrent glioblastoma, Medicine, Humans, Overall survival, Neuro‐Oncology, Aged, Temozolomide, business.industry, Brain Neoplasms, Hazard ratio, Lomustine, Middle Aged, Prognosis, 3. Good health, Clinical trial, Survival Rate, 030104 developmental biology, 030220 oncology & carcinogenesis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Neoplasm Recurrence, Local, business, Glioblastoma, medicine.drug, Follow-Up Studies
Abstract: Background We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. Patients and Methods TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Results Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69–1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48–1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37–1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52–1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). Conclusion There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Implications for Practice Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.
Published: 2018
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48. Spatiotemporal analysis for detection of pre-symptomatic shape changes in neurodegenerative diseases: applied to GENFI study

Author: John C. van Swieten, Maria Carmela Tartaglia, Sandro Sorbi, Marc Modat, Elizabeth Finger, Fabrizio Tagliavini, Mario Masellis, Stanley Durrleman, David M. Cash, Alexandre de Mendonça, James B. Rowe, Martina Bocchetta, Sebastien Ourselin, Jonathan D. Rohrer, Barbara Borroni, Robert Laforce, Jennifer M. Nicholas, Claire Cury, Daniela Galimberti, Giovanni B. Frisoni, Marco Lorenzi, Caroline Graff, Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Dementia Research Centre [London] (DRC), University College of London [London] (UCL), Department of Medical Physics and Biomedical Engineering (UCL), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), E-Patient : Images, données & mOdèles pour la médeciNe numériquE (EPIONE), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), London School of Hygiene and Tropical Medicine (LSHTM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Università degli Studi di Brescia = University of Brescia (UniBs), Centro Dino Ferrari [Milano], Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Cognition and Brain Sciences Unit (MRC CBU), University of Cambridge [UK] (CAM), Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Neuroimaging and Telemedicine (LENITEM), IRCCS Fatebenefratelli - Brescia, Université Laval [Québec] (ULaval), University of Western Ontario (UWO), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Università degli Studi di Firenze = University of Florence (UniFI), Imaging Sciences and Biomedical Engineering Division [London], Guy's and St Thomas' Hospital [London]-King‘s College London, Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Brescia [Brescia], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Universidade de Lisboa (ULISBOA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Thalamus, 02 engineering and technology, Disease, Genfi, 03 medical and health sciences, 0302 clinical medicine, Atrophy, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, 0202 electrical engineering, electronic engineering, information engineering, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Medicine, Shape Analysis, business.industry, Spatiotemporal Analysis, Morphometry, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, Spatio temporal analysis, Frontal lobe, [MATH.MATH-DG]Mathematics [math]/Differential Geometry [math.DG], Frontotemporal Dementia, Cohort, 020201 artificial intelligence & image processing, business, Neuroscience, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, 030217 neurology & neurosurgery, LDDMM, Shape analysis (digital geometry), Frontotemporal dementia
Abstract: Brain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer’s disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure.In this paper we propose a spatiotemporal analysis pipeline based Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects.We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease.
Published: 2018

49. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author: Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, 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), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.
Subjects: 0301 basic medicine, GAMMA-2-SUBUNIT, [SDV]Life Sciences [q-bio], GABRA5, Clinical Neurology, 15Q13.3 MICRODELETIONS, ABSENCE EPILEPSY, SEQUENCE DATA, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic variation, medicine, EPILEPTIC ENCEPHALOPATHIES, Exome, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetic association, Genetics, RISK, Science & Technology, FEBRILE SEIZURES, Neurology & Neurosurgery, biology, 3112 Neurosciences, 1103 Clinical Sciences, MOUSE MODEL, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, DE-NOVO MUTATIONS, Cohort, biology.protein, Neurology (clinical), Human medicine, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Cohort study
Abstract: BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).
Published: 2018
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50. Analysis of shared heritability in common disorders of the brain

Author: Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nicholas, Kurth, Tobias, Ligthart, Lannie, Terwindt, Gisela M, Freilinger, Tobias, Ran, Caroline, Gordon, Scott D, Borck, Guntram, Adams, Hieab HH, Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E, Schürks, Markus, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G, Montgomery, Grant W, Kurki, Mitja I, Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfons, Pozo-Rosich, Patricia, Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Metspalu, Andres, Kubisch, Christian, Ferrari, Michel D, Belin, Andrea C, Van Den Maagdenberg, Arn MJM, Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nicholas, Olesen, Jes, Chasman, Daniel I, Nyholt, Dale R, Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell J, Catarino, Claudia B, Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Dennis, Ferraro, Thomas N, French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S, Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S, Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thomas, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M, Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Thomas, G Neil, Visscher, Frank, Whelan, Christopher D, Zara, Federico, Heinzen, Erin L, Marson, Anthony, Becker, Felicitas, Stroink, Hans, Zimprich, Fritz, Gasser, Thomas, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R, Sharma, Manu, Ryten, Mina, Mok, Kin Y, Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thomas, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Boraska Perica, Vesna, Thornton, Laura M, Huckins, Laura M, William Rayner, N, Lewis, Cathryn M, Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I, Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andreas, Mannik, Katrin, Baker, Jessica H, O'Toole, Julie K, Trace, Sara E, Davis, Oliver SP, Helder, Sietske G, Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N, Van Elburg, Annemarie A, Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julià, Antonio, Rabionet, Raquel, Dick, Danielle M, Ripatti, Samuli, Andreassen, Ole A, Espeseth, Thomas, Lundervold, Astri J, Steen, Vidar M, Pinto, Dalila, Scherer, Stephen W, Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lars, Padyukov, Leonid, Halmi, Katherine A, Mitchell, James, Strober, Michael, Bergen, Andrew W, Kaye, Walter, Szatkiewicz, Jin Peng, 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Sabine M, Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, De-Luca, Daniel Moreno, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thomas, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Rogé, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G, Thompson, Robert C, Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Douglas, McIntosh, Andrew, Bergen, Sarah E, Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B, Reinbold, Céline S, Fullerton, Janice M, Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R, Cichon, Sven, Mühleisen, Thomas W, Degenhardt, Franziska, Schumacher, Johannes, Bauer, Michael, Mitchell, Philip B, Gershon, Elliot S, Rice, John, Potash, James B, Zandi, Peter P, Craddock, Nick, Ferrier, I Nicol, Alda, Martin, Rouleau, Guy A, Turecki, Gustavo, Ophoff, Roel, Pato, Carlos, Anjorin, Adebayo, Stahl, Eli, Leber, Markus, Czerski, Piotr M, Cruceanu, Cristiana, Jones, Ian R, Posthuma, Danielle, Andlauer, Till FM, Forstner, Andreas J, Streit, Fabian, Baune, Bernhard T, Air, Tracy, Sinnamon, Grant, Wray, Naomi R, MacIntyre, Donald J, Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M, Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H, Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S, Nauck, Matthias, Schoevers, Robert A, Beekman, Aartjan Tf, Knowles, James A, Viktorin, Alexander, Arnold, Paul, Barr, Cathy L, Bedoya-Berrio, Gabriel, Bienvenu, O Joseph, Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M, Dietrich, Andrea, Fernandez, Thomas, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L, Hartmann, Andreas, Hirschtritt, Matthew E, Hoekstra, Pieter J, Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J, Macciardi, Fabio, Madruga-Garrido, Marcos, Malaty, Irene A, Maras, Athanasios, McGrath, Lauren, Miguel, Eurípedes C, Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S, Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M, Reus, Victor, Richter, Margaret A, Riddle, Mark A, Robertson, Mary M, Roessner, Veit, Rosário, Maria, Samuels, Jack F, Sandor, Paul, Stein, Dan J, Tsetsos, Fotis, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R, Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S, McLaughlin, Nicole, Nestadt, Paul S, Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A, Cohen, David, Crespo-Facorro, Benedicto, Crowley, James, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Janis, Kučinskas, Vaidutis, Lee Chee Keong, Jimmy, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C, Nenadic, Igor, Van Os, Jim, Pantelis, Christos, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Panos, Sanders, Alan R, Schall, Ulrich, Schwab, Sibylle G, Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, James, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V, Henskens, Frans, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M, Daly, Mark, Dichgans, Martin, Faraone, Stephen V, Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S, Koeleman, Bobby, Mathews, Carol A, Price, Alkes, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W, Cotsapas, Chris, Palotie, Aarno, Smoller, Jordan W, Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M, Schott, Jonathan M, Anney, Richard, Elia, Josephine, Grigoroiu-Serbanescu, Maria, Edenberg, Howard J, Murray, Robin, Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), School of Psychology [Cardiff University], Cardiff University, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), New Jersey Institute of Technology [Newark] (NJIT), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), 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), Laboratoire de Biotechnologie et Microbiologie Appliquée (LBMA), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Gériatrie générale et aigüe [Paris], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Columbia University [New York], Dpt of Neuroscience [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Washington [Seattle], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Children’s Hospital of Philadelphia (CHOP ), University of Kentucky (UK), School of medicine, Duke University [Durham], College of medicine, Brigham Young University (BYU), Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Department of Neurology, Emory University [Atlanta, GA], Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Health sciences center, The University of New Mexico [Albuquerque], Institute for Memory Impairments and Neurological Disorders [Irvine], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Keck School of Medicine [Los Angeles], University of Southern California (USC), University of South Florida [Tampa] (USF), University of Utah School of Medicine [Salt Lake City], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Perelman School of Medicine, University of Pennsylvania, Dublin City University [Dublin] (DCU), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Aristotle University of Thessaloniki, Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Dementia Research Centre [London] (DRC), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, MRC Prion Unit [London], Queen's University [Belfast] (QUB), School of Life Sciences, University of Nottingham, UK (UON), Rheinische Friedrich-Wilhelms-Universität Bonn, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), School of Medicine [Dublin], Trinity College Dublin, Department of Medicine, University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Columbia University Medical Center (CUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Saarland University [Saarbrücken], Universität Leipzig, School of Medicine [Los Angeles], Johannes Kepler Universität Linz - Johannes Kepler University Linz [Autriche] (JKU), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], School of Medecine, Washington University in Saint Louis (WUSTL), Oslo University Hospital [Oslo], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, 23andMe Inc., Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biological Psychology [Amsterdam], Vrije Universiteit Amsterdam [Amsterdam] (VU), Leiden University Medical Center (LUMC), Universiteit Leiden, University-Hospital Munich-Großhadern [München], Karolinska Institutet [Stockholm], Universität Ulm - Ulm University [Ulm, Allemagne], Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Landspitali National University Hospital of Iceland, VU University Medical Center [Amsterdam], Boston VA Research Institute (BVARI), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Christian-Albrechts-Universität zu Kiel (CAU), Institute of Clinical Molecular Biology, Kiel University, National Institute for Health and Welfare [Helsinki], Harvard T.H. Chan School of Public Health, Universitat Autònoma de Barcelona (UAB), Vall d'Hebron University Hospital [Barcelona], University of Tartu, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Human and Clinical Genetics, Universiteit Leiden-Universiteit Leiden, University of Copenhagen = Københavns Universitet (UCPH), Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology [Brisbane] (QUT), Discipline of Psychiatry [Dublin], Trinity College Dublin-Trinity College Dublin, Institute of Neurology [London], The University of Hong Kong (HKU), University of Melbourne, Cooper Medical School of Rowan University [Camden] (CMSRU), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), University of Eastern Finland, Universitätsklinikum Bonn (UKB), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, University Medical Center [Utrecht], Ohio State University [Columbus] (OSU), University of California [San Francisco] (UC San Francisco), University of California (UC), Royal College of Surgeons in Ireland (RCSI), University of Southern Denmark (SDU), United Christian Hospital [Hong Kong] (UCH), University of Cincinnati (UC), University of Cologne, Inselspital Bern, University of Wales, Jefferson University Hospitals, University of Liverpool, Medizinische Universität Wien = Medical University of Vienna, National Institutes of Health [Bethesda] (NIH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Lincoln, University of Newcastle [Callaghan, Australia] (UoN), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Virginia, University of Maryland [Baltimore County] (UMBC), University of Maryland System, Royal Holloway [University of London] (RHUL), University of Edinburgh, Universidade de Lisboa = University of Lisbon (ULISBOA), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University of Split, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), McLean Hospital [Belmont, Ma.], Norwegian Institute of Public Health [Oslo] (NIPH), Università degli Studi di Salerno = University of Salerno (UNISA), University of Bristol [Bristol], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Utrecht University [Utrecht], Azienda Ospedaliera di Padova, Université de Liège, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Università degli Studi di Perugia = University of Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, National and Kapodistrian University of Athens (NKUA), Charles University [Prague] (CU), SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Flinders University [Adelaide, Australia], Virginia Commonwealth University (VCU), University of Oslo (UiO), University of Bergen (UiB), Weill Medical College of Cornell University [New York], University of North Dakota [Grand Forks] (UND), Oregon Research Institute (ORI), University of California [San Diego] (UC San Diego), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Hospital Universitario Mutua de Terrassa, School of Computer Science and Communication [Stockholm], Royal Institute of Technology [Stockholm] (KTH ), Jefferson (Philadelphia University + Thomas Jefferson University), University Medical Center Göttingen (UMG), Universität Heidelberg [Heidelberg] = Heidelberg University, Radboud University Medical Center [Nijmegen], Universitätsklinikum Frankfurt, Maastricht University [Maastricht], Institute of Psychological Medicine and Clinical Neurosciences, Aarhus University [Aarhus], University of Iowa [Iowa City], Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), The Hospital for sick children [Toronto] (SickKids), Hospital de Clínicas de Porto Alegre (HCPA), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of British Columbia (UBC), IRCCS Fondazione Stella Maris [Pisa], Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade de Coimbra [Coimbra], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Our Lady's Children's Hospital Crumlin (OLCHC), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Children’s Hospital Los Angeles [Los Angeles], Yale University [New Haven], Brown University, Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Department of Medical Epidemiology and Biostatistics (MEB), Division of Medical Genetics [Seattle], University of Illinois [Chicago] (UIC), University of Illinois System, Maine Medical Center Research Institute (MMCRI), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Johns Hopkins University School of Medicine [Baltimore], Ludwig Maximilian University [Munich] (LMU), University of Michigan System, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, University of Dundee, National University of Ireland [Galway] (NUI Galway), University Hospital Basel [Basel], Neuroscience Research Australia (NeuRA), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW), University of Chicago, Johns Hopkins University (JHU), Johns Hopkins Bloomberg School of Public Health [Baltimore], Dalhousie University [Halifax], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], State University of New York (SUNY), University Hospital of Cologne [Cologne], University of Adelaide, James Cook University (JCU), Institute for Molecular Bioscience, University of Queensland [Brisbane], Greifswald University Hospital, The University of Sydney, University Medical Center Groningen [Groningen] (UMCG), University of Calgary, University Health Network, Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidade de São Paulo = University of São Paulo (USP), Ospedale San Raffaele, University of Amsterdam [Amsterdam] (UvA), University of Groningen [Groningen], Yale School of Medicine [New Haven, Connecticut] (YSM), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Cape Town, Cold Spring Harbor Laboratory (CSHL), Universidad de Sevilla / University of Sevilla, University of Florida [Gainesville] (UF), University of Denver, Purdue University [West Lafayette], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Moscow Institute of Physics and Technology [Moscow] (MIPT), Sunnybrook Health Sciences Centre, Federal Institute of São Paulo (IFSP), Democritus University of Thrace (DUTH), Universiteit Gent = Ghent University (UGENT), Medical University of Warsaw - Poland, Sorbonne Université - Faculté de Médecine - Département d'Enseignement et de Recherche en Médecine Générale, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institute of Mental Health [Singapore], Universidad de Cantabria [Santander], Tel Aviv University (TAU), University College Cork (UCC), University of Rochester [USA], Statens Serum Institut [Copenhagen], Софийски университет = Sofia University, Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], Nanyang Technological University [Singapour], Department of Life Sciences, Imperial College London, Jena University Hospital [Jena], Oxford University Hospitals NHS Trust, Schizophrenia Research Institute [Sydney], Faculty of Science, Medicine and Health [Wollongong], University of Wollongong [Australia], City University of Hong Kong [Hong Kong] (CUHK), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), This work was supported by grants 1R01MH10764901 and 5U01MH09443203 from the National Institute of Mental Health, as well as the Orion Farmos Research Foundation (V.A.) and the Fannie and John Hertz Foundation (H.K.F.). Consortium specific funding is detailed in the supplementary materials ('Study-specific acknowledgments')., Brainstorm Consortium, University of Kentucky, University of California [Irvine] (UCI), University of California-University of California, University of Pennsylvania [Philadelphia], Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Leipzig [Leipzig], Johannes Kepler University Linz [Linz] (JKU), University of Helsinki-University of Helsinki, University of Helsinki, University of Oxford [Oxford], University of Copenhagen = Københavns Universitet (KU), University of California [San Francisco] (UCSF), University of California, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Newcastle [Australia] (UoN), University of Virginia [Charlottesville], Universidade de Lisboa (ULISBOA), Università degli Studi di Salerno (UNISA), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Università degli Studi di Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli', Universität Heidelberg [Heidelberg], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, VU University Amsterdam, Universidade de São Paulo (USP), Yale University School of Medicine, Universidad de Sevilla, Universiteit Gent = Ghent University [Belgium] (UGENT), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Tel Aviv University [Tel Aviv], University of Sofia, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-Françoi, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Ilyas Kamboh, M., Larson, Eric B., Rogaeva, Ekaterina, George-Hyslop, Peter St, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Yesim Demirci, F., Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S.K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Quinn, Joseph F., Saykin, Andrew J., Schneider, Lon S., Smith, Amanda G., Sonnen, Joshua A., Stern, Robert A., Van Deerlin, Vivianna M., Van Eldik, Linda J., Harold, Denise, Russo, Giancarlo, Rubinsztein, David C., Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C., Hampel, Harald, Owen, Michael J., Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M., Rossor, Martin, Lupton, Michelle K., Hoffmann, Per, Kornhuber, Johanne, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C., Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J., De Jager, Philip L., Geschwind, Daniel H., Riemenschneider, Matthia, Riedel-Heller, Steffi, Rotter, Jerome I., Ransmayr, Gerhard, Hyman, Bradley T., Cruchaga, Carlo, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nichola, Kurth, Tobia, Ligthart, Lannie, Terwindt, Gisela M., Freilinger, Tobia, Ran, Caroline, Gordon, Scott D., Borck, Guntram, Adams, Hieab H.H., Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E., Schürks, Marku, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja I., Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfon, Pozo-Rosich, Patricia, Hansen, Thoma, Werge, Thoma, Kaprio, Jaakko, Metspalu, Andre, Kubisch, Christian, Ferrari, Michel D., Belin, Andrea C., Van Den Maagdenberg, Arn M. J. M., Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nichola, Olesen, Je, Chasman, Daniel I., Nyholt, Dale R., Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell, Catarino, Claudia B., Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Denni, Ferraro, Thomas N., French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S., Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S., Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thoma, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M., Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Neil Thomas, G., Visscher, Frank, Whelan, Christopher D., Zara, Federico, Heinzen, Erin L., Marson, Anthony, Becker, Felicita, Stroink, Han, Zimprich, Fritz, Gasser, Thoma, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R., Sharma, Manu, Ryten, Mina, Mok, Kin Y., Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thoma, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Perica, Vesna Boraska, Thornton, Laura M., Huckins, Laura M., William Rayner, N., Lewis, Cathryn M., Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I., Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andrea, Mannik, Katrin, Baker, Jessica H., O'Toole, Julie K., Trace, Sara E., Davis, Oliver S. P., Helder, Sietske G., Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N., Van Elburg, Annemarie A., Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragisko, Tziouvas, Konstantino, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julia, Antonio, Rabionet, Raquel, Dick, Danielle M., Ripatti, Samuli, Andreassen, Ole A., Espeseth, Thoma, Lundervold, Astri J., Steen, Vidar M., Pinto, Dalila, Scherer, Stephen W., Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lar, Padyukov, Leonid, Halmi, Katherine A., Mitchell, Jame, Strober, Michael, Bergen, Andrew W., Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesú, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D., Banaschewski, Tobia, Franke, Barbara, Buitelaar, Jan K., Vasquez, Alejandro Aria, Doyle, Alysa E., Reif, Andrea, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H., Dalsgaard, Soeren, Børglum, Anders D., Waldman, Irwin, Wilmot, Beth, Molly, Nikola, Bau, Claiton H.D., Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K., McGough, James J., Grevet, Eugenio H., Medland, Sarah E., Robinson, Elise, Weiss, Lauren A., Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M., Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, Moreno-De-Luca, Daniel, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thoma, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Roge, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G., Thompson, Robert C., Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Dougla, McIntosh, Andrew, Bergen, Sarah E., Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B., Reinbold, Céline S., Fullerton, Janice M., Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R., Cichon, Sven, Mühleisen, Thomas W., Degenhardt, Franziska, Schumacher, Johanne, Bauer, Michael, Mitchell, Philip B., Gershon, Elliot S., Rice, John, Potash, James B., Zandi, Peter P., Craddock, Nick, Nicol Ferrier, I., Alda, Martin, Rouleau, Guy A., Turecki, Gustavo, Ophoff, Roel, Pato, Carlo, Anjorin, Adebayo, Stahl, Eli, Leber, Marku, Czerski, Piotr M., Cruceanu, Cristiana, Jones, Ian R., Posthuma, Danielle, Andlauer, Till F.M., Forstner, Andreas J., Streit, Fabian, Baune, Bernhard T., Air, Tracy, Sinnamon, Grant, Wray, Naomi R., MacIntyre, Donald J., Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M., Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H., Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S., Nauck, Matthia, Schoevers, Robert A., Beekman, Aartjan TF, Knowles, James A., Viktorin, Alexander, Arnold, Paul, Barr, Cathy L., Bedoya-Berrio, Gabriel, Joseph Bienvenu, O., Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M., Dietrich, Andrea, Fernandez, Thoma, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L., Hartmann, Andrea, Hirschtritt, Matthew E., Hoekstra, Pieter J., Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J., Macciardi, Fabio, Madruga-Garrido, Marco, Malaty, Irene A., Maras, Athanasio, McGrath, Lauren, Miguel, Eurípedes C., Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S., Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M., Reus, Victor, Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Roessner, Veit, Rosário, Maria, Samuels, Jack F., Sandor, Paul, Stein, Dan J., Tsetsos, Foti, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R., Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S., McLaughlin, Nicole, Nestadt, Paul S., Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A., Cohen, David, Crespo-Facorro, Benedicto, Crowley, Jame, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Jani, Kučinskas, Vaiduti, Keong, Jimmy Lee Chee, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C., Nenadic, Igor, Van Os, Jim, Pantelis, Christo, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Pano, Sanders, Alan R., Schall, Ulrich, Schwab, Sibylle G., Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, Jame, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V., Henskens, Fran, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M., Daly, Mark, Dichgans, Martin, Faraone, Stephen V., Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S., Koeleman, Bobby, Mathews, Carol A., Price, Alke, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W., Cotsapas, Chri, Palotie, Aarno, Smoller, Jordan W., Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M., Epidemiology, Radiology & Nuclear Medicine, Anttila, V, Bulik-Sullivan, B, Finucane, H, Walters, R, Bras, J, Duncan, L, Escott-Price, V, Falcone, G, Gormley, P, Malik, R, Patsopoulos, N, Ripke, S, Wei, Z, Yu, D, Lee, P, Turley, P, Grenier-Boley, B, Chouraki, V, Kamatani, Y, Berr, C, Letenneur, L, Hannequin, D, Amouyel, P, Boland, A, Deleuze, J, Duron, E, Vardarajan, B, Reitz, C, Goate, A, Huentelman, M, Ilyas Kamboh, M, Larson, E, Rogaeva, E, George-Hyslop, P, Hakonarson, H, Kukull, W, Farrer, L, Barnes, L, Beach, T, Yesim Demirci, F, Head, E, Hulette, C, Jicha, G, Kauwe, J, Kaye, J, Leverenz, J, Levey, A, Lieberman, A, Pankratz, V, Poon, W, Quinn, J, Saykin, A, Schneider, L, Smith, A, Sonnen, J, Stern, R, Van Deerlin, V, Van Eldik, L, Harold, D, Russo, G, Rubinsztein, D, Bayer, A, Tsolaki, M, Proitsi, P, Fox, N, Hampel, H, Owen, M, Mead, S, Passmore, P, Morgan, K, Nöthen, M, Rossor, M, Lupton, M, Hoffmann, P, Kornhuber, J, Lawlor, B, Mcquillin, A, Al-Chalabi, A, Bis, J, Ruiz, A, Boada, M, Seshadri, S, Beiser, A, Rice, K, Van Der Lee, S, De Jager, P, Geschwind, D, Riemenschneider, M, Riedel-Heller, S, Rotter, J, Ransmayr, G, Hyman, B, Cruchaga, C, Alegret, M, Winsvold, B, Palta, P, Farh, K, Cuenca-Leon, E, Furlotte, N, Kurth, T, Ligthart, L, Terwindt, G, Freilinger, T, Ran, C, Gordon, S, Borck, G, Adams, H, Lehtimäki, T, Wedenoja, J, Buring, J, Schürks, M, Hrafnsdottir, M, Hottenga, J, Penninx, B, Artto, V, Kaunisto, M, Vepsäläinen, S, Martin, N, Montgomery, G, Kurki, M, Hämäläinen, E, Huang, H, Huang, J, Sandor, C, Webber, C, Muller-Myhsok, B, Schreiber, S, Salomaa, V, Loehrer, E, Göbel, H, Macaya, A, Pozo-Rosich, P, Hansen, T, Werge, T, Kaprio, J, Metspalu, A, Kubisch, C, Ferrari, M, Belin, A, Van Den Maagdenberg, A, Zwart, J, Boomsma, D, Eriksson, N, Olesen, J, Chasman, D, Nyholt, D, Avbersek, A, Baum, L, Berkovic, S, Bradfield, J, Buono, R, Catarino, C, Cossette, P, De Jonghe, P, Depondt, C, Dlugos, D, Ferraro, T, French, J, Hjalgrim, H, Jamnadas-Khoda, J, Kälviäinen, R, Kunz, W, Lerche, H, Leu, C, Lindhout, D, Lo, W, Lowenstein, D, Mccormack, M, Møller, R, Molloy, A, Ng, P, Oliver, K, Privitera, M, Radtke, R, Ruppert, A, Sander, T, Schachter, S, Schankin, C, Scheffer, I, Schoch, S, Sisodiya, S, Smith, P, Sperling, M, Striano, P, Surges, R, Neil Thomas, G, Visscher, F, Whelan, C, Zara, F, Heinzen, E, Marson, A, Becker, F, Stroink, H, Zimprich, F, Gasser, T, Gibbs, R, Heutink, P, Martinez, M, Morris, H, Sharma, M, Ryten, M, Mok, K, Pulit, S, Bevan, S, Holliday, E, Attia, J, Battey, T, Boncoraglio, G, Thijs, V, Chen, W, Mitchell, B, Rothwell, P, Sharma, P, Sudlow, C, Vicente, A, Markus, H, Kourkoulis, C, Pera, J, Raffeld, M, Silliman, S, Perica, V, Thornton, L, Huckins, L, William Rayner, N, Lewis, C, Gratacos, M, Rybakowski, F, Keski-Rahkonen, A, Raevuori, A, Hudson, J, Reichborn-Kjennerud, T, Monteleone, P, Karwautz, A, Mannik, K, Baker, J, O'Toole, J, Trace, S, Davis, O, Helder, S, Ehrlich, S, Herpertz-Dahlmann, B, Danner, U, Van Elburg, A, Clementi, M, Forzan, M, Docampo, E, Lissowska, J, Hauser, J, Tortorella, A, Maj, M, Gonidakis, F, Tziouvas, K, Papezova, H, Yilmaz, Z, Wagner, G, Cohen-Woods, S, Herms, S, Julia, A, Rabionet, R, Dick, D, Ripatti, S, Andreassen, O, Espeseth, T, Lundervold, A, Steen, V, Pinto, D, Scherer, S, Aschauer, H, Schosser, A, Alfredsson, L, Padyukov, L, Halmi, K, Mitchell, J, Strober, M, Bergen, A, Kaye, W, Szatkiewicz, J, Cormand, B, Ramos-Quiroga, J, Sánchez-Mora, C, Ribasés, M, Casas, M, Hervas, A, Arranz, M, Haavik, J, Zayats, T, Johansson, S, Williams, N, Dempfle, A, Rothenberger, A, Kuntsi, J, Oades, R, Banaschewski, T, Franke, B, Buitelaar, J, Vasquez, A, Doyle, A, Reif, A, Lesch, K, Freitag, C, Rivero, O, Palmason, H, Romanos, M, Langley, K, Rietschel, M, Witt, S, Dalsgaard, S, Børglum, A, Waldman, I, Wilmot, B, Molly, N, Bau, C, Crosbie, J, Schachar, R, Loo, S, Mcgough, J, Grevet, E, Medland, S, Robinson, E, Weiss, L, Bacchelli, E, Bailey, A, Bal, V, Battaglia, A, Betancur, C, Bolton, P, Cantor, R, Celestino-Soper, P, Dawson, G, De Rubeis, S, Duque, F, Green, A, Klauck, S, Leboyer, M, Levitt, P, Maestrini, E, Mane, S, Moreno-De-Luca, D, Parr, J, Regan, R, Reichenberg, A, Sandin, S, Vorstman, J, Wassink, T, Wijsman, E, Cook, E, Santangelo, S, Delorme, R, Roge, B, Magalhaes, T, Arking, D, Schulze, T, Thompson, R, Strohmaier, J, Matthews, K, Melle, I, Morris, D, Blackwood, D, Mcintosh, A, Bergen, S, Schalling, M, Jamain, S, Maaser, A, Fischer, S, Reinbold, C, Fullerton, J, Guzman-Parra, J, Mayoral, F, Schofield, P, Cichon, S, Mühleisen, T, Degenhardt, F, Schumacher, J, Bauer, M, Mitchell, P, Gershon, E, Rice, J, Potash, J, Zandi, P, Craddock, N, Nicol Ferrier, I, Alda, M, Rouleau, G, Turecki, G, Ophoff, R, Pato, C, Anjorin, A, Stahl, E, Leber, M, Czerski, P, Cruceanu, C, Jones, I, Posthuma, D, Andlauer, T, Forstner, A, Streit, F, Baune, B, Air, T, Sinnamon, G, Wray, N, Macintyre, D, Porteous, D, Homuth, G, Rivera, M, Grove, J, Middeldorp, C, Hickie, I, Pergadia, M, Mehta, D, Smit, J, Jansen, R, De Geus, E, Dunn, E, Li, Q, Nauck, M, Schoevers, R, Beekman, A, Knowles, J, Viktorin, A, Arnold, P, Barr, C, Bedoya-Berrio, G, Joseph Bienvenu, O, Brentani, H, Burton, C, Camarena, B, Cappi, C, Cath, D, Cavallini, M, Cusi, D, Darrow, S, Denys, D, Derks, E, Dietrich, A, Fernandez, T, Figee, M, Freimer, N, Gerber, G, Grados, M, Greenberg, E, Hanna, G, Hartmann, A, Hirschtritt, M, Hoekstra, P, Huang, A, Huyser, C, Illmann, C, Jenike, M, Kuperman, S, Leventhal, B, Lochner, C, Lyon, G, Macciardi, F, Madruga-Garrido, M, Malaty, I, Maras, A, Mcgrath, L, Miguel, E, Mir, P, Nestadt, G, Nicolini, H, Okun, M, Pakstis, A, Paschou, P, Piacentini, J, Pittenger, C, Plessen, K, Ramensky, V, Ramos, E, Reus, V, Richter, M, Riddle, M, Robertson, M, Roessner, V, Rosário, M, Samuels, J, Sandor, P, Stein, D, Tsetsos, F, Van Nieuwerburgh, F, Weatherall, S, Wendland, J, Wolanczyk, T, Worbe, Y, Zai, G, Goes, F, Mclaughlin, N, Nestadt, P, Grabe, H, Depienne, C, Konkashbaev, A, Lanzagorta, N, Valencia-Duarte, A, Bramon, E, Buccola, N, Cahn, W, Cairns, M, Chong, S, Cohen, D, Crespo-Facorro, B, Crowley, J, Davidson, M, Delisi, L, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Haan, L, Hougaard, D, Karachanak-Yankova, S, Khrunin, A, Klovins, J, Kučinskas, V, Keong, J, Limborska, S, Loughland, C, Lönnqvist, J, Maher, B, Mattheisen, M, Mcdonald, C, Murphy, K, Nenadic, I, Van Os, J, Pantelis, C, Pato, M, Petryshen, T, Quested, D, Roussos, P, Sanders, A, Schall, U, Schwab, S, Sim, K, So, H, Stögmann, E, Subramaniam, M, Toncheva, D, Waddington, J, Walters, J, Weiser, M, Cheng, W, Cloninger, R, Curtis, D, Gejman, P, Henskens, F, Mattingsdal, M, Oh, S, Scott, R, Webb, B, Breen, G, Churchhouse, C, Bulik, C, Daly, M, Dichgans, M, Faraone, S, Guerreiro, R, Holmans, P, Kendler, K, Koeleman, B, Mathews, C, Price, A, Scharf, J, Sklar, P, Williams, J, Wood, N, Cotsapas, C, Palotie, A, Smoller, J, Sullivan, P, Rosand, J, Corvin, A, Neale, B, Kauwe, John S. K., Mcquillin, Andrew, Adams, Hieab H. H., Mccormack, Mark, Bau, Claiton H. D., Mcgough, James J., Mcintosh, Andrew, Andlauer, Till F. M., Macintyre, Donald J., Mcgrath, Lauren, Mclaughlin, Nicole, Delisi, Lynn, Mcdonald, Colm, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), RIKEN Center for Integrative Medical Science, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), University of South Florida (USF), University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Cardiff University-Medical Research Council, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Johannes Kepler University Linz [linz] (JKU), Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Universitat Autònoma de Barcelona [Barcelona] (UAB), Hôpital Erasme (Bruxelles), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Jagiellonian University [Krakow] (UJ), Technische Universität Dresden (TUD), National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Charles University [Prague], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), University Medicine Goettingen, Università di Bologna [Bologna] (UNIBO), Forschungszentrum Jülich GmbH, UNSW Medicine [Sydney], McGill University, Universidad de Antioquia, University of Florida [Gainesville], Universiteit Gent [Ghent], Service Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], University of Wollongong, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Anttila, Verneri [0000-0002-0073-4675], Finucane, Hilary K [0000-0003-3864-9828], Walters, Raymond K [0000-0001-8422-6530], Duncan, Laramie [0000-0003-1131-661X], Escott-Price, Valentina [0000-0003-1784-5483], Falcone, Guido J [0000-0002-6407-0302], Gormley, Padhraig [0000-0002-8908-6968], Malik, Rainer [0000-0001-9212-2520], Ripke, Stephan [0000-0003-3622-835X], Wei, Zhi [0000-0001-6059-4267], Yu, Dongmei [0000-0001-7901-4365], Lee, Phil H [0000-0003-1770-3100], Breen, Gerome [0000-0003-2053-1792], Bulik, Cynthia M [0000-0001-7772-3264], Daly, Mark [0000-0002-0949-8752], Dichgans, Martin [0000-0002-0654-387X], Faraone, Stephen V [0000-0002-9217-3982], Holmans, Peter [0000-0003-0870-9412], Koeleman, Bobby [0000-0001-7749-182X], Mathews, Carol A [0000-0003-2208-7058], Sklar, Pamela [0000-0001-9715-4943], Williams, Julie [0000-0002-4069-0259], Wood, Nicholas W [0000-0002-9500-3348], Cotsapas, Chris [0000-0002-7772-5910], Smoller, Jordan W [0000-0002-0381-6334], Sullivan, Patrick [0000-0002-6619-873X], Rosand, Jonathan [0000-0002-1014-9138], Corvin, Aiden [0000-0001-6717-4089], Neale, Benjamin M [0000-0003-1513-6077], and Apollo - University of Cambridge Repository
Subjects: Etiology, [SDV]Life Sciences [q-bio], MESH: Brain Diseases, body-mass index, genetics [Mental Disorders], Disorders of the Brain, Risks factors, classification [Mental Disorders], MESH: Quantitative Trait, Heritable, MESH: Risk Factors, Risk Factors, MESH: Genetic Variation, alzheimers-disease, 610 Medicine & health, bipolar disorder, Brain Diseases, deficit hyperactivity disorder, Multidisciplinary, Mental Disorders, genetics [Brain Diseases], Brain Disease, Brain, Genetic Variation, Genome-Wide Association Study, Humans, Phenotype, Quantitative Trait, Heritable, Psychiatric Disorders, anorexia-nervosa, Mental Disorder, Psychiatric Genomics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], long-term survival, Engineering sciences. Technology, Human, General Science & Technology, population-based twin, diagnosis [Mental Disorders], MESH: Phenotype, Neurological Disorders, Quantitative Trait, MD Multidisciplinary, MESH: Mental Disorders, diagnosis [Brain Diseases], Heritable, genetic correlations, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, major depressive disorder, Risk Factor, Brain Diseases/classification, Brain Diseases/diagnosis, Brain Diseases/genetics, Mental Disorders/classification, Mental Disorders/diagnosis, Mental Disorders/genetics, classification [Brain Diseases], Perturbações do Desenvolvimento Infantil e Saúde Mental, ddc:320, MESH: Genome-Wide Association Study, genome-wide association, Brainstorm Consortium, Genetic Factors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders.
Published: 2018
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