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1. Long-term effect of apomorphine infusion in advanced Parkinson’s disease: a real-life study

Author: Bruna Meira, Bertrand Degos, Elise Corsetti, Mohamed Doulazmi, Emeline Berthelot, Clara Virbel-Fleischman, Pauline Dodet, Aurélie Méneret, Louise-Laure Mariani, Cécile Delorme, Florence Cormier-Dequaire, David Bendetowicz, Nicolas Villain, Clément Tarrano, Lise Mantisi, Hélène Letrillart, Céline Louapre, Eavan McGovern, Yulia Worbe, David Grabli, Marie Vidailhet, Elodie Hainque, and Emmanuel Roze
Subjects: Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson’s disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson’s disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.
Published: 2021
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2. Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease

Author: Sabine Prud'hon, Samir Bekadar, Agnès Rastetter, Justine Guégan, Florence Cormier-Dequaire, Lucette Lacomblez, Graziella Mangone, Hana You, Mailys Daniau, Yannick Marie, Hélène Bertrand, Suzanne Lesage, Sophie Tezenas Du Montcel, Mathieu Anheim, Alexis Brice, Fabrice Danjou, and Jean-Christophe Corvol
Subjects: Parkinson's disease (PD), dopamine agonists (DA), impulse control disorders (ICD), pharmacogenetics, exome sequencing, Neurology. Diseases of the nervous system, RC346-429
Abstract: Introduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to account for part of this heritability. We aimed to identify new pathways associated with ICDs in PD.Methods: Thirty-six Parkinsonian patients on DA therapy with (n = 18) and without ICDs (n = 18) matched on age at PD's onset, and gender was selected to represent the most extreme phenotypes of their category. Exome sequencing was performed, and variants with a strong functional impact in brain-expressed genes were selected. Allele frequencies and their distribution in genes and pathways were analyzed with single variant and SKAT-O tests. The 10 most associated variants, genes, and pathways were retained for replication in the Parkinson's progression markers initiative (PPMI) cohort.Results: None of markers tested passed the significance threshold adjusted for multiple comparisons. However, the “Adenylate cyclase activating” pathway, one of the top associated pathways in the discovery data set (p = 1.6 × 10−3) was replicated in the PPMI cohort and was significantly associated with ICDs in a post hoc pooled analysis (combined p-value 3.3 × 10−5). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in RasGRF2, p = 5 × 10−4; rs1877652 in PDE2A, p = 8 × 10−4) although non-significant after Bonferroni correction.Conclusion: Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD.
Published: 2020
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3. Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

Author: Suzanne Lesage, Marion Houot, Graziella Mangone, Christelle Tesson, Hélène Bertrand, Sylvie Forlani, Mathieu Anheim, Christine Brefel-Courbon, Emmanuel Broussolle, Stéphane Thobois, Philippe Damier, Franck Durif, Emmanuel Roze, François Tison, David Grabli, Fabienne Ory-Magne, Bertrand Degos, François Viallet, Florence Cormier-Dequaire, Anne-Marie Ouvrard-Hernandez, Marie Vidailhet, Ebba Lohmann, Andrew Singleton, Jean-Christophe Corvol, Alexis Brice, and for the French Parkinson disease Genetics Study Group(PDG)
Subjects: Parkinson's disease, LRRK2, G2019S, SNCA, VPS35, autosomal dominant inheritance, Neurology. Diseases of the nervous system, RC346-429
Abstract: LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2–2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0–2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤ 50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.
Published: 2020
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4. A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood

Author: Elodie Hainque, Samantha Caillet, Sandrine Leroy, Constance Flamand-Roze, Isaac Adanyeguh, Fanny Charbonnier-Beaupel, Maryvonne Retail, Benjamin Le Toullec, Mariana Atencio, Sophie Rivaud-Péchoux, Vanessa Brochard, Florence Habarou, Chris Ottolenghi, Florence Cormier, Aurélie Méneret, Marta Ruiz, Mohamed Doulazmi, Anne Roubergue, Jean-Christophe Corvol, Marie Vidailhet, Fanny Mochel, and Emmanuel Roze
Subjects: Alternating hemiplegia of childhood, Triheptanoin, Crossover trial, Medicine
Abstract: Abstract Background Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Methods We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects. Results In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated. Conclusions Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting. Trial registration The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.
Published: 2017
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5. Personality Assessment with Temperament and Character Inventory in Parkinson's Disease

Author: Mathilde Boussac, Christophe Arbus, Olivier Colin, Chloé Laurencin, Alexandre Eusebio, Elodie Hainque, Jean Christophe Corvol, Nathalie Versace, Olivier Rascol, Vanessa Rousseau, Estelle Harroch, Fabienne Ory-Magne, Margherita Fabbri, Caroline Moreau, Anne-Sophie Rolland, Béchir Jarraya, David Maltête, Sophie Drapier, Ana-Raquel Marques, Nicolas Auzou, Thomas Wirth, Mylène Meyer, Bruno Giordana, Mélissa Tir, Tiphaine Rouaud, David Devos, Christine Brefel-Courbon, Pr Luc Defebvre, Dr Nicolas Carriere, Dr Guillaume Grolez, Dr Guillaume Baille, Dr Kreisler, Pr Jean-Pierre Pruvo, Pr Leclerc, Dr Renaud Lopes, Dr Romain Viard, Dr Gregory Kuchcinski, Mr Julien Dumont, Pr Kathy Dujardin, Mme M. Delliaux, Mrs M. Brion, Dr Gustavo Touzet, Pr Nicolas Reyns, Pr Arnaud Delval, Mrs Valerie Santraine, Mrs Marie Pleuvret, Mrs Nolwen Dautrevaux, Mr Victor Laugeais, Thavarak Ouk, Camille Potey, Celine Leclercq, Elise Gers, Jean-Christophe Corvol, null Marie-Vidailhet, Marie-Laure Welter, Lucette Lacomblez, David Grabli, Emmanuel Roze, Yulia Worbe, Cécile Delorme, Hana You, Jonas Ihle, Raquel Guimeraes-Costa, Florence Cormier-Dequaire, Aurélie Méneret, Andréas Hartmann, Louise-Laure Mariani, Stéphane Lehericy, Virginie Czernecki, Fanny Pineau, Frédérique Bozon, Camille Huiban, Eve Benchetrit, Carine Karachi, Soledad Navarro, Philippe Cornu, Arlette Welaratne, Carole Dongmo-Kenfack, Lise Mantisi, Nathalie Jarry, Sophie Aix, Carine Lefort, Dr Tiphaine Rouaud, Pr Philippe Damier, Pr Pascal Derkinderen, Dr Anne-Gaelle Corbille, Dr Elisabeth Calvier-Auffray, Mrs Laetitia Rocher, Mrs Anne-Laure Deruet, Dr Raoul Sylvie, Dr Roualdes Vincent, Mrs Le Dily Séverine, Dr Ana Marques, Dr Berangere Debilly, Pr Franck Durif, Dr Philippe Derost, Dr Charlotte Beal, Carine Chassain, Laure Delaby, Tiphaine Vidal, Pr Jean Jacques Lemaire, Isabelle Rieu, Elodie Durand, Pr Alexandre Eusebio, Pr Jean-Philippe Azulay, Dr Tatiana Witjas, Dr Frédérique Fluchère, Dr Stephan Grimaldi, Pr Nadine Girard, Marie Delfini, Dr Romain Carron, Pr Jean Regis, Dr Giorgio Spatola, Camille Magnaudet, Dr Ansquer Solène, Dr Benatru Isabelle, Dr Colin Olivier, Pr Houeto Jl, Pr Guillevin Remy, Mrs Fradet Anne, Mrs Anziza Manssouri, Mrs Blondeau Sophie, Dr Richard Philippe, Dr Cam Philippe, Dr Page Philippe, Pr Bataille Benoit, Mrs Rabois Emilie, Mrs Guillemain Annie, Dr Drapier Sophie, Dr Frédérique Leh, Dr Alexandre Bonnet, Pr Marc Vérin, Dr Jean-Christophe Ferré, Mr Jean François Houvenaghel, Pr Claire Haegelen, Mrs Francoise Kestens, Mrs Solenn Ory, Pr Pierre Burbaud, Dr Nathalie Damon-Perriere, Pr Wassilios Meissner, Pr Francois Tison, Dr Stéphanie Bannier, Dr Elsa Krim, Pr Dominique Guehl, Sandrine Molinier-Blossier, Morgan Ollivier, Marion Lacoste, Marie Bonnet, Pr Emmanuel Cuny, Dr Julien Engelhardt, Olivier Branchard, Clotilde Huet, Julie Blanchard, Pr Rascol Olivier, Dr Christine Brefel Courbon, Dr Fabienne Ory Magne, Dr Marion Simonetta Moreau, Pr Christophe Arbus, Pr Fabrice Bonneville, Dr Jean Albert Lotterie, Marion Sarrail, Charlotte Scotto d’Apollonia, Pr Patrick Chaynes, Pr François Caire, Pr David Maltete, Dr Romain Lefaucheur, Dr Damien Fetter, Dr Nicolas Magne, Mrs Sandrine Bioux, Mrs Maud Loubeyre, Mrs Evangéline Bliaux, Mrs Dorothée Pouliquen, Pr Stéphane Derrey, Mrs Linda Vernon, Dr Frédéric Ziegler, Mathieu Anheim, Ouhaid Lagha-Boukbiza, Christine Tranchant, Odile Gebus, Solveig Montaut, S. Kremer, Nadine Longato, Clélie Phillips, Jimmy Voirin, Marie des Neiges Santin, Dominique Chaussemy, Dr Amaury Mengin, Dr Caroline Giordana, Dr Claire Marsé, Lydiane Mondot, Robin Kardous, Bernadette Bailet, Héloise Joly, Denys Fontaine, Dr Aurélie Leplus, Amélie Faustini, Vanessa Ferrier, Pr Pierre Krystkowiak, Dr Mélissa Tir, Pr Jean-Marc Constans, Sandrine Wannepain, Audrey Seling, Dr Michel Lefranc, Stéphanie Blin, Béatrice Schuler, Pr Stephane Thobois, Dr Teodor Danaila, Dr Chloe Laurencin, Pr Yves Berthezene, Dr Roxana Ameli, Helene Klinger, Dr Gustavo Polo, Patrick Mertens, A. Nunes, Elise Metereau, Dr Lucie Hopes, Dr Solène Frismand, Dr Emmanuelle Schmitt, Mrs Mylène Meyer, Mrs Céline Dillier, Pr Sophie Colnat, Mrs Anne Chatelain, Dr Jean- Philippe Brandel, Dr Cécile Hubsch, Dr Patte Karsenti, Dr Marie Lebouteux, Dr Marc Ziegler, Dr Christine Delmaire, Dr Julien Savatowky, Mrs Juliette Vrillac, Mrs Claire Nakache, Dr Vincent D'Hardemare, Mr Lhaouas Belamri, Dr Valérie Mesnage, Dr Cécilia Bonnet, Dr Jarbas Correa Lino, Dr Camille Decrocq, Dr Anne Boulin, Mrs Inès Barre, Mrs Jordane Manouvrier, Dr Bérénice Gardel, Pr Béchir Jarraya, Mrs Catherine Ziz, Mrs Lydie Prette, Mr Hassen Douzane, David Gay, Robin Bonicel, Fouzia El Mountassir, Clara Fischer, Jean-François Mangin, Marie Chupin, Yann Cointepas, Bertrand Accart, Patrick Gelé, Florine Fievet, Matthieu Chabel, Virginie Derenaucourt, Loïc Facon, Yanick Tchantchou Njosse, Dominique Deplanque, Alain Duhamel, Lynda Djemmane, Florence Duflot, Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), 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), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier de Brive-la-Gaillarde (CH Brive), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (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), Université de Lyon, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), CHU Marseille, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), 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), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Excellence en Maladies Neurodégénératives (NeuroToul), CIC - Biotherapie - Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), 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), CHU Lille, Service NEUROSPIN (NEUROSPIN), 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), Hôpital Foch [Suresnes], Neuroimagerie cognitive - Psychologie cognitive expérimentale (UNICOG-U992), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA), Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), CHU Bordeaux [Bordeaux], Les Hôpitaux Universitaires de Strasbourg (HUS), 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), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by the France Parkinson charity and French Ministry of Health (PHRC national 2012). This is an ancillary study to Protocol ID: 2013-A00193-42, ClinicalTrials.gov: NCT02360683., Centre Hospitalier Brive-la-Gaillarde, and Hôpital P.P.-Riquet
Subjects: Personality Inventory, Temperament and character inventory, Parkinson's disease, Parkinson Disease, Personality Assessment, Antidepressive Agents, Neurology, Anti-Anxiety Agents, Fluctuating PD patients, Quality of Life, Humans, Neurology (clinical), Geriatrics and Gerontology, Temperament, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Personality
Abstract: International audience; INTRODUCTION: There is a growing interest in personality evaluation in Parkinson's disease (PD), following observations of specific temperaments in PD patients. Therefore, our objective was to evaluate personality dimensions from the Temperament and Character Inventory (TCI) in a cohort of fluctuating PD patients considered for deep brain stimulation. METHODS: Fluctuating PD patients from the PREDISTIM cohort were included. Description of TCI dimensions and comparison with a French normative cohort were performed. Pearson correlations between TCI dimensions and motor, behavioral and cognitive variables were investigated. Structural and internal consistency analysis of the TCI were further assessed. RESULTS: The 570 PD patients presented significant higher scores in Harm Avoidance, Reward Dependence, Persistence, Self-Directedness and Cooperativeness and significant lower scores in Self-Transcendence compared to the French normative cohort; only Novelty Seeking scores were not different. Harm Avoidance and Self-directedness scores were correlated with PDQ-39 total, HAMD, HAMA scores, and anxiolytic/antidepressant treatment. Novelty Seeking scores were correlated with impulsivity. Pearson correlations between TCI dimensions, principal component analysis of TCI sub-dimensions and Cronbach's alpha coefficients showed adequate psychometric proprieties. CONCLUSION: The TCI seems to be an adequate tool to evaluate personality dimensions in PD with good structural and internal consistencies. These fluctuating PD patients also have specific personality dimensions compared to normative French population. Moreover, Harm Avoidance and Self-Directedness scores are associated with anxio-depressive state or quality of life and, and Novelty Seeking scores with impulsivity.
Published: 2022
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6. Compensatory Mechanisms Nine Years Before Parkinson's Disease Conversion in a <scp>LRRK2 R1441H</scp> Family

Author: Romain Valabregue, Alexis Brice, Suzanne Lesage, Jean-Christophe Corvol, Sonia Lavisse, Graziella Mangone, Philippe Remy, Stéphane Lehéricy, Sara Sambin, Caroline Decaix, Florence Cormier, Nadya Pyatigorskaya, and Isabelle Arnulf
Subjects: Pediatrics, medicine.medical_specialty, Parkinson's disease, Neurology, business.industry, medicine, MEDLINE, Neurology (clinical), medicine.disease, business, LRRK2
Published: 2021
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7. Comparison of mean diffusivity, R2* relaxation rate and morphometric biomarkers for the clinical differentiation of parkinsonism

Author: Lydia Chougar, François-Xavier Lejeune, Johann Faouzi, Benjamin Morino, Alice Faucher, Nadine Hoyek, David Grabli, Florence Cormier, Marie Vidailhet, Jean-Christophe Corvol, Olivier Colliot, Bertrand Degos, and Stéphane Lehéricy
Subjects: Neurology, Neurology (clinical), Geriatrics and Gerontology
Published: 2023
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8. Regional Selectivity of Neuromelanin Changes in the Substantia Nigra in Atypical Parkinsonism

Author: Lydia Chougar, Emina Arsovic, Rahul Gaurav, Emma Biondetti, Alice Faucher, Romain Valabrègue, Nadya Pyatigorskaya, Gwendoline Dupont, François‐Xavier Lejeune, Florence Cormier, Jean‐Christophe Corvol, Marie Vidailhet, Bertrand Degos, David Grabli, Stéphane Lehéricy, 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), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Bourgogne (UB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), PARK-AI, and Chougar, Lydia
Subjects: Melanins, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Parkinson Disease, Multiple System Atrophy, Magnetic Resonance Imaging, nervous system diseases, Substantia Nigra, Parkinsonian Disorders, Neurology, nervous system, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Supranuclear Palsy, Progressive, Neurology (clinical), [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background: Neurodegeneration in the substantia nigra pars compacta (SNc) in parkinsonian syndromes may affect the nigral territories differently.Objective: The objective of this study was to investigate the regional selectivity of neurodegenerative changes in the SNc in patients with Parkinson's disease (PD) and atypical parkinsonism using neuromelanin-sensitive magnetic resonance imaging (MRI).Methods: A total of 22 healthy controls (HC), 38 patients with PD, 22 patients with progressive supranuclear palsy (PSP), 20 patients with multiple system atrophy (MSA, 13 with the parkinsonian variant, 7 with the cerebellar variant), 7 patients with dementia with Lewy body (DLB), and 4 patients with corticobasal syndrome were analyzed. volume and signal-to-noise ratio (SNR) values of the SNc were derived from neuromelanin-sensitive MRI in the whole SNc. Analysis of signal changes was performed in the sensorimotor, associative, and limbic territories of the SNc.Results: SNc volume and corrected volume were significantly reduced in PD, PSP, and MSA versus HC. Patients with PSP had lower volume, corrected volume, SNR, and contrast-to-noise ratio than HC and patients with PD and MSA. Patients with PSP had greater SNR reduction in the associative region than HC and patients with PD and MSA. Patients with PD had reduced SNR in the sensorimotor territory, unlike patients with PSP. Patients with MSA did not differ from patients with PD.Conclusions: This study provides the first MRI comparison of the topography of neuromelanin changes in parkinsonism. The spatial pattern of changes differed between PSP and synucleinopathies. These nigral topographical differences are consistent with the topography of the extranigral involvement in parkinsonian syndromes.
Published: 2022
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9. Long-term effect of apomorphine infusion in advanced Parkinson’s disease: a real-life study

Author: Nicolas Villain, Hélène Letrillart, Clara Virbel-Fleischman, Eavan McGovern, Pauline Dodet, Lise Mantisi, Emeline Berthelot, Elise Corsetti, Cécile Delorme, David Grabli, Emmanuel Roze, Elodie Hainque, Céline Louapre, Clément Tarrano, Mohamed Doulazmi, Florence Cormier-Dequaire, Yulia Worbe, Bertrand Degos, David Bendetowicz, Marie Vidailhet, Louise-Laure Mariani, Bruna Meira, Aurélie Méneret, Universidade de Lisboa = University of Lisbon (ULISBOA), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut 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), Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France], 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), Service de Pathologies du sommeil [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Gestionnaire, HAL Sorbonne Université 5, Universidade de Lisboa (ULISBOA), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Service des Pathologies du sommeil [CHU Pitié-Salpêtrière], 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Quality of life, 0301 basic medicine, medicine.medical_specialty, Parkinson's disease, Disease, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, medicine, Term effect, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], RC346-429, business.industry, medicine.disease, humanities, 3. Good health, Discontinuation, Apomorphine, 030104 developmental biology, Neurology, Tolerability, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology. Diseases of the nervous system, Neurology (clinical), Life study, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson’s disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson’s disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.
Published: 2021
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10. Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease

Author: Roger A. Barker, Claudia Trenkwalder, Sami S. Amr, Anne-Marie Wills, Christine Klein, Meike Kasten, Florence Cormier-Dequaire, Thomas G. Beach, Todd M. Herrington, Ganqiang Liu, Suzanne Lesage, Ole-Bjørn Tysnes, Clemens R. Scherzer, Jacobus J. van Hilten, Michael A. Schwarzschild, Meghan C. Campbell, Jodi Maple-Grødem, Albert Y. Hung, Zhixiang Liao, Michael T. Hayes, Jean-Christophe Corvol, Alexis Elbaz, Guido Alves, Frank Zhu, John H. Growdon, Pille Taba, Peter Heutink, Johan Marinus, Brit Mollenhauer, Joseph J. Locascio, Caroline H. Williams-Gray, Xianjun Dong, Joel S. Perlmutter, Bernard Ravina, Graziella Mangone, Alexis Brice, Ira Shoulson, Sulev Kõks, Jiajie Peng, Liu, Ganqiang [0000-0002-1921-9542], Dong, Xianjun [0000-0002-8052-9320], Maple-Grødem, Jodi [0000-0001-7142-0078], Elbaz, Alexis [0000-0001-9724-5490], Hung, Albert Y [0000-0003-3658-571X], Kõks, Sulev [0000-0001-6087-6643], Alves, Guido [0000-0003-0630-2870], Heutink, Peter [0000-0001-5218-1737], Scherzer, Clemens R [0000-0002-0567-9193], and Apollo - University of Cambridge Repository
Subjects: Oncology, Multifactorial Inheritance, Parkinson's disease, Apolipoprotein E4, Genome-wide association study, Disease, genetics [Cognition Disorders], genetics [Glucosylceramidase], Cognition, 0302 clinical medicine, genetics [Parkinson Disease], Risk Factors, Longitudinal Studies, GBA protein, human, genetics [Multifactorial Inheritance], genetics [Apolipoprotein E4], 0303 health sciences, education.field_of_study, Hazard ratio, Parkinson Disease, genetics [Synapses], Disease Progression, Glucosylceramidase, physiopathology [Parkinson Disease], medicine.medical_specialty, Population, genetics [Mutation], Biology, Article, 03 medical and health sciences, ddc:570, Internal medicine, Genetics, medicine, Humans, Dementia, Genetic Predisposition to Disease, education, Survival analysis, Proportional Hazards Models, 030304 developmental biology, Proportional hazards model, medicine.disease, Survival Analysis, pathology [Parkinson Disease], Genetic Loci, Mutation, Synapses, Cognition Disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 x 10(-11)), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 x 10(-8)) and WWOX (HR = 2.12, P = 2.37 x 10(-8)) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.A genome-wide survival study identifies variants at RIMS2 associated with progression of Parkinson's disease to dementia and highlights divergence in the genetic architecture of disease onset and progression.
Published: 2021
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11. Automated Categorization of Parkinsonian Syndromes Using Magnetic Resonance Imaging in a Clinical Setting

Author: Louise-Laure Mariani, Marie Villotte, Alexis Brice, Lydia Yahia-Cherif, Lydia Chougar, Romain Valabregue, Christine Payan, David Grabli, Emma Biondetti, Rahul Gaurav, Olivier Colliot, Johann Faouzi, Nadya Pyatigorskaya, Gwendoline Dupont, Stéphane Lehéricy, Ines Piot, Jean-Christophe Corvol, Florence Cormier, M. Vidailhet, Bertrand Degos, 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-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neuroradiologie [CHU Pitié-Salpêtrière], 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, Centre de Neuro-Imagerie de Recherche (CENIR), Université de Paris - Faculté de Médecine Paris Centre (UP Médecine Paris Centre), Université de Paris (UP), Service des Maladies du Système Nerveux [CHU Pitié-Salpêtrière], Service de neurochirurgie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), BESPIM, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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], Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Université Paris Cité - UFR Médecine Paris Centre [Santé] (UPC Médecine Paris Centre), Université Paris Cité (UPC), Pôle des Maladies du Système Nerveux [CHU Pitié-Salpêtrière] (Pôle MSN), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), PARK-AI, 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), 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)-Sorbonne Université (SU), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), 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)-Sorbonne Université (SU), 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)-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), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Service de neurochirurgie [CHU Dijon], and ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019)
Subjects: 0301 basic medicine, medicine.medical_specialty, Parkinson's disease, multiple system atrophy, Progressive supranuclear palsy, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Parkinsonian Disorders, medicine, Humans, multimodal magnetic resonance imaging, Receiver operating characteristic, medicine.diagnostic_test, business.industry, Parkinsonism, Magnetic resonance imaging, progressive supranuclear palsy, medicine.disease, Magnetic Resonance Imaging, 3. Good health, nervous system diseases, machine learning algorithm, 030104 developmental biology, Diffusion Tensor Imaging, Neurology, Categorization, nervous system, Cohort, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Supranuclear Palsy, Progressive, business, 030217 neurology & neurosurgery, Diffusion MRI
Abstract: Background Machine learning algorithms using magnetic resonance imaging (MRI) data can accurately discriminate parkinsonian syndromes. Validation in patients recruited in routine clinical practice is missing. Objective The aim of this study was to assess the accuracy of a machine learning algorithm trained on a research cohort and tested on an independent clinical replication cohort for the categorization of parkinsonian syndromes. Methods Three hundred twenty-two subjects, including 94 healthy control subjects, 119 patients with Parkinson's disease (PD), 51 patients with progressive supranuclear palsy (PSP) with Richardson's syndrome, 35 with multiple system atrophy (MSA) of the parkinsonian variant (MSA-P), and 23 with MSA of the cerebellar variant (MSA-C), were recruited. They were divided into a training cohort (n = 179) scanned in a research environment and a replication cohort (n = 143) examined in clinical practice on different MRI systems. Volumes and diffusion tensor imaging (DTI) metrics in 13 brain regions were used as input for a supervised machine learning algorithm. To harmonize data across scanners and reduce scanner-dependent effects, we tested two types of normalizations using patient data or healthy control data. Results In the replication cohort, high accuracies were achieved using volumetry in the classification of PD-PSP, PD-MSA-C, PSP-MSA-C, and PD-atypical parkinsonism (balanced accuracies: 0.840-0.983, area under the receiver operating characteristic curves: 0.907-0.995). Performances were lower for the classification of PD-MSA-P, MSA-C-MSA-P (balanced accuracies: 0.765-0.784, area under the receiver operating characteristic curve: 0.839-0.871) and PD-PSP-MSA (balanced accuracies: 0.773). Performance using DTI was improved when normalizing by controls, but remained lower than that using volumetry alone or combined with DTI. Conclusions A machine learning approach based on volumetry enabled accurate classification of subjects with early-stage parkinsonism, examined on different MRI systems, as part of their clinical assessment. © 2020 International Parkinson and Movement Disorder Society.
Published: 2020
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12. Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations Authors

Author: Florence Cormier, Timothée Lenglet, Alexis Brice, Jean-Christophe Corvol, Fabienne Clot, Vincent Deramecourt, Karl Mondon, Dario Saracino, Stéphane Thobois, Vincent Huin, Aurélie Méneret, Emilie Beaufils, Cécile Delorme, Audrey Gabelle, Fábio Carneiro, Marie Vidailhet, Isabelle Le Ber, Mélissa Tir, Marie-Odile Habert, Daniela Andriuta, 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), 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 et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), 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), Université de Tours (UT), Service de neurologie [Amiens], CHU Amiens-Picardie, Excellence Laboratory LabEx DISTALZ, The research leading to these results received funding from the 'Investissements d'avenir' ANR-11-INBS-0011. This work was funded by the Programme Hospitalier de Recherche Clinique (PHRC) FTLD-exome (to ILB, promotion by Assistance Publique – Hôpitaux de Paris) and by PHRC Predict-PGRN (to ILB, promotion by Assistance Publique – Hôpitaux de Paris)., 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 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)-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), Lille Neurosciences & Cognition - U 1172 (LilNCog), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), ANR-16-IDEX-0006,MUSE,MUSE(2016), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Gestionnaire, HAL Sorbonne Université 5, Service de neurologie 1 [CHU Pitié-Salpétrière], Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Tours
Subjects: Male, 0301 basic medicine, Parkinson's disease, TDP-43, Disease, Bioinformatics, Progranulins, 0302 clinical medicine, C9orf72, Age of Onset, Family history, PSP, Parkinsonism, Parkinson Disease, FTD, Middle Aged, Pedigree, 3. Good health, Neurology, Frontotemporal Dementia, Neurons and Cognition (q-bio.NC), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], FTLD, GRN, Frontotemporal dementia, CBS, 03 medical and health sciences, Parkinsonian Disorders, medicine, Humans, Dementia, Cognitive Dysfunction, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Aged, C9orf72 Protein, business.industry, medicine.disease, nervous system diseases, 030104 developmental biology, Quantitative Biology - Neurons and Cognition, FOS: Biological sciences, Mutation, Etiology, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract: Introduction A phenotype of isolated parkinsonism mimicking Idiopathic Parkinson's Disease (IPD) is a rare clinical presentation of GRN and C9orf72 mutations, the major genetic causes of frontotemporal dementia (FTD). It still remains controversial if this association is fortuitous or not, and which clinical clues could reliably suggest a genetic FTD etiology in IPD patients. This study aims to describe the clinical characteristics of FTD mutation carriers presenting with IPD phenotype, provide neuropathological evidence of the mutation's causality, and specifically address their “red flags” according to current IPD criteria. Methods Seven GRN and C9orf72 carriers with isolated parkinsonism at onset, and three patients from the literature were included in this study. To allow better delineation of their phenotype, the presence of supportive, exclusion and “red flag” features from MDS criteria were analyzed for each case. Results Amongst the ten patients (5 GRN, 5 C9orf72), seven fulfilled probable IPD criteria during all the disease course, while behavioral/language or motoneuron dysfunctions occurred later in three. Disease duration was longer and dopa-responsiveness was more sustained in C9orf72 than in GRN carriers. Subtle motor features, cognitive/behavioral changes, family history of dementia/ALS were suggestive clues for a genetic diagnosis. Importantly, neuropathological examination in one patient revealed typical TDP-43-inclusions without alpha-synucleinopathy, thus demonstrating the causal link between FTD mutations, TDP-43-pathology and PD phenotype. Conclusion We showed that, altogether, family history of early-onset dementia/ALS, the presence of cognitive/behavioral dysfunction and subtle motor characteristics are atypical features frequently present in the parkinsonian presentations of GRN and C9orf72 mutations.
Published: 2020
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13. Analyse génétique et phénotypique des formes autosomiques dominantes dans une large cohorte multi-centrique

Author: Suzanne, Lesage, Marion, Houot, Graziella, Mangone, Christelle, Tesson, Hélène, Bertrand, Sylvie, Forlani, Mathieu, Anheim, Christine, Brefel-Courbon, Emmanuel, Broussolle, Stéphane, Thobois, Philippe, Damier, Franck, Durif, Emmanuel, Roze, François, Tison, David, Grabli, Fabienne, Ory-Magne, Bertrand, Degos, François, Viallet, Florence, Cormier-Dequaire, Anne-Marie, Ouvrard-Hernandez, Marie, Vidailhet, Ebba, Lohmann, Andrew, Singleton, Jean-Christophe, Corvol, Alexis, Brice, 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), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), 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), Les Hôpitaux Universitaires de Strasbourg (HUS), 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), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), CHU Toulouse [Toulouse], Hôpital Pierre-Paul Riquet [Toulouse], Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Clermont-Ferrand, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dynamique et physiopathologie des réseaux neuronaux, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, National Institutes of Health [Bethesda] (NIH), 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), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), 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), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), and Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: genotype-phenotype correlations, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV]Life Sciences [q-bio], Parkinson's disease, LRRK2, Brief Research Report, autosomal dominant inheritance, [SCCO]Cognitive science, Neurology, Parkinson’s disease, G2019S, SNCA, MESH: Parkinson’s disease, SNCA, VPS35, VPS35
Abstract: International audience; LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2-2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤ 50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.
Published: 2020
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14. Automated classification of neurodegenerative parkinsonian syndromes using multimodal magnetic resonance imaging in a clinical setting

Author: Emma Biondetti, Louise-Laure Mariani, Johann Faouzi, Bertrand Degos, Alexis Brice, M. Vidailhet, Jean-Christophe Corvol, Lydia Chougar, Marie Villotte, Olivier Colliot, Gwendoline Dupont, Nadya Pyatigorskaya, Romain Valabregue, David Grabli, Florence Cormier, Stéphane Lehéricy, Christine Payan, Ines Piot, and Rahul Gaurav
Subjects: medicine.medical_specialty, medicine.diagnostic_test, business.industry, Parkinsonism, Magnetic resonance imaging, medicine.disease, Training cohort, nervous system diseases, 030218 nuclear medicine & medical imaging, Parkinsonian syndromes, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, stomatognathic system, nervous system, Categorization, mental disorders, Replication (statistics), Research environment, Cohort, medicine, business, 030217 neurology & neurosurgery
Abstract: BackgroundSeveral studies have shown that machine learning algorithms using MRI data can accurately discriminate parkinsonian syndromes. Validation under clinical conditions is missing.ObjectivesTo evaluate the accuracy for the categorization of parkinsonian syndromes of a machine learning algorithm trained with a research cohort and tested on an independent clinical replication cohort.Methods361 subjects, including 94 healthy controls, 139 patients with PD, 60 with PSP with Richardson’s syndrome, 41 with MSA of the parkinsonian variant (MSA-P) and 27 with MSA of the cerebellar variant (MSA-P), were recruited. They were divided into a training cohort (n=179) scanned in a research environment, and a replication cohort (n=182), scanned in clinical conditions on different MRI systems. Volumes and DTI metrics in 13 brain regions were used as input for a supervised machine learning algorithm.ResultHigh accuracy was achieved using volumetry in the classification of PD versus PSP, PD versus MSA-P, PD versus MSA-C, PD versus atypical parkinsonian syndromes and PSP versus MSA-C in both cohorts, although slightly lower in the replication cohort (balanced accuracy: 0.800 to 0.915 in the training cohort; 0.741 to 0.928 in the replication cohort). Performance was lower in the classification of PSP versus MSA-P and MSA-P versus MSA-C. When adding DTI metrics, the performance tended to increase in the training cohort, but not in the replication cohort.ConclusionsA machine learning approach based on volumetric and DTI data can accurately classify subjects with early-stage parkinsonism, scanned on different MRI systems, in the setting of their clinical workup.
Published: 2020
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15. Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease

Author: Mathieu Anheim, Ouhaid Lagha-Boukbiza, Emmanuel Roze, Florence Cormier-Dequaire, Paul Krack, Alexis Brice, Lucette Lacomblez, Jean-Christophe Corvol, Solène Ansquer, Samir Bekadar, Sophie Tezenas du Montcel, Isabelle Benatru, Bénédicte Lebrun-Vignes, Pierre-Michel Llorca, Olivier Rascol, Graziella Mangone, Luc Defebvre, David Maltête, Ana Marques‐Raquel, Fabienne Ory-Magne, Anna Castrioto, Marie Vidailhet, Franck Durif, Said Lebbah, Eugénie Lhommée, Jean-Philippe Azulay, Fanny Charbonnier-Beaupel, Alexandre Kreisler, Suzanne Lesage, Antoine Pelissolo, Christine Tranchant, David Grabli, Christine Brefel-Courbon, Mélissa Tir, and Pierre Krystkowiak
Subjects: 0301 basic medicine, Oncology, Candidate gene, medicine.medical_specialty, Parkinson's disease, Population, Disease, Logistic regression, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Internal medicine, Medicine, Family history, education, education.field_of_study, business.industry, medicine.disease, 3. Good health, Impulse control, 030104 developmental biology, Bonferroni correction, Neurology, symbols, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: BACKGROUND Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. METHODS We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. RESULTS The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P
Published: 2018
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16. Parkinson's disease polygenic risk score is not associated with impulse control disorders: A longitudinal study

Author: Vanessa Brochard, Fanny Artaud, Frédéric Bourdain, S. Sambin, Valérie Mesnage, O. Rascol, Clemens R. Scherzer, Fabienne Ory-Magne, Isabelle Rieu, Jean-Christophe Corvol, Fanny Pineau, Merry Mazmanian, Louise-Laure Mariani, Monica Roy, Hélène Bertrand, Marie Vidailhet, Graziella Mangone, Tiphaine Vidal, Benjamin Le Toullec, Bérangère Debilly, Sara Leder, Emmanuel Roze, Bertrand Degos, Samir Bekadar, Cecilia Bonnet, Genetic core: Alexis Brice, Jean-Philippe Brandel, Antoine Faurie-Grepon, Hana You, Monique Galitsky, Stephan Klebe, Julia Kraemmer, J. Ihle, Mostafa Hajji, Virginie Bayet, David Grabli, Richard Levy, P. Derkinderen, Hakima Manseur, Ll Mariani, Julie Socha, Suzanne Lesage, Florence Cormier-Dequaire, Statistical analyses, A. Marques, Fernando Pico, Khadija Tahiri, Andreas Hartmann, Stéphane Bernard, Olivier Rascol, Eve Benchetrit, Alexis Brice, Julia Muellner, F. Durif, Violaine Plante-Bordeneuve, Sponsor activities, J-C Corvol, Alain Mallet, Co-investigators, Coralie Villeret, Pascal Derkinderen, Franck Durif, Anne-Marie Bonnet, Neuropsychologists, Christine Brefel-Courbon, Mélissa Tir, A. Elbaz, Lucette Lacomblez, Alexis Elbaz, Elsa Pomies, F. Artaud, Principal investigators for sites, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), NS-Park/FCRIN Network, UMS 015, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Foch [Suresnes], Fondation A. Rothschild, Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Clermont-Ferrand, CHU Saint-Antoine [AP-HP], Centre Hospitalier de Versailles André Mignot (CHV), Hôpital Henri Mondor, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANR-10-IAIHU-06 MinistÃ¨re des Affaires Sociales et de la SantÃ©: AOR0810 Agence Nationale de SÃ©curitÃ© du MÃ©dicament et des Produits de SantÃ©, ANSM: ANSM-2013, This project was funded by grants from the French Ministry of Health (Programme Hospitalier de Recherche Clinique, AOR0810 ) and from the French Drug Agency (Agence Nationale de Sécurité et des Médicaments, ANSM-2013 ). The research leading to these results has received funding from the program ' Investissements d’Avenir ' ANR-10-IAIHU-06 . We want to express our gratitude to all the participants who made this study possible., ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Longitudinal study, Multifactorial Inheritance, Parkinson's disease, Movement disorders, Genome-wide association study, Disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Genetic predisposition, Humans, Longitudinal Studies, Age of Onset, Adverse effect, Generalized estimating equation, Aged, business.industry, Parkinson Disease, Middle Aged, medicine.disease, 3. Good health, Disruptive, Impulse Control, and Conduct Disorders, 030104 developmental biology, Neurology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), France, Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; Objective: To examine the relationship between a Parkinson's disease (PD) polygenic risk score (PRS) and impulse control disorders (ICDs) in PD. Background: Genome wide association studies (GWAS) have brought forth a PRS associated with increased risk of PD and younger disease onset. ICDs are frequent adverse effects of dopaminergic drugs and are also more frequent in patients with younger disease onset. It is unknown whether ICDs and PD share genetic susceptibility. Methods: We used data from a multicenter longitudinal cohort of PD patients with annual visits up to 6 years (DIG-PD). At each visit ICDs, defined as compulsive gambling, buying, eating, or sexual behavior were evaluated by movement disorders specialists. We genotyped DNAs using the Megachip assay (Illumina) and calculated a weighted PRS based on 90 SNPs associated with PD. We estimated the association between PRS and prevalence of ICDs at each visit using Poisson generalized estimating equations, adjusted for dopaminergic treatment and other known risk factors for ICDs. Results: Of 403 patients, 185 developed ICDs. Patients with younger age at onset had a higher prevalence of ICDs (p < 0.001) as well as higher PRS values (p = 0.06). At baseline, there was no association between the PRS and ICDs (overall, p = 0.84). The prevalence of ICDs increased over time similarly across the quartiles of the PRS (overall, p = 0.88; DA users, p = 0.99). Conclusion: Despite younger disease onset being associated with both higher PRS and ICD prevalence, our findings are not in favor of common susceptibility genes for PD and ICDs.
Published: 2020
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17. Examining the Reserve Hypothesis in Parkinson's Disease: A Longitudinal Study

Author: Lucette Lacomblez, Alexis Elbaz, Florence Cormier-Dequaire, David Grabli, Frédéric Bourdain, Jean-Philippe Brandel, Fabienne Ory-Magne, Franck Durif, Cecilia Bonnet, Pei-Chen Lee, Hana You, Pascal Derkinderen, Marie Vidailhet, Olivier Rascol, Jean-Christophe Corvol, Alexis Brice, A. Marques, Graziella Mangone, Fernando Pico, Christine Brefel-Courbon, Fanny Artaud, Valérie Mesnage, Stephan Klebe, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacologie Clinique et Neurosciences, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Excellence en Maladies Neurodégénératives (NeuroToul), CHU Toulouse [Toulouse], Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie, Hôpital Foch [Suresnes], Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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), Department of neurology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), 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), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Epidemiology and Public Health, University College of London [London] (UCL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Julius-Maximilians-Universität Würzburg (JMU), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (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), 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), and 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)
Subjects: 0301 basic medicine, Male, Longitudinal study, medicine.medical_specialty, Parkinson's disease, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medizin, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Cognition, Quality of life, medicine, Dementia, Humans, Cognitive Dysfunction, Longitudinal Studies, ComputingMilieux_MISCELLANEOUS, Aged, Depressive Disorder, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Proportional hazards model, business.industry, Depression, 4. Education, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Parkinson Disease, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Neurology, Quality of Life, Anxiety, Female, Neurology (clinical), medicine.symptom, business, Cognition Disorders, 030217 neurology & neurosurgery, Cohort study
Abstract: BACKGROUND Whether reserve plays a role in Parkinson's disease (PD) patients has received less attention than in dementia and has been mainly examined in relation with cognitive function. OBJECTIVE To investigate whether reserve plays a role in the severity and progression of motor, cognitive, and nonmotor PD symptoms by examining whether education level (proxy of reserve) is associated with baseline performance and rate of progression. METHODS We used data from a longitudinal cohort of PD patients (≤5-year disease duration at baseline) annually followed up to 5 years (n = 393; 41% women; mean age = 62.3 years, standard deviation = 10.0; mean disease duration = 2.6 years, standard deviation = 1.5). We examined the relationship of education with time to reach Hoehn and Yahr stage ≥3 using Cox regression and with baseline severity and progression of motor (Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts II and III, gait speed), cognitive (Mini-Mental State Examination), and nonmotor (depression, anxiety, nonmotor symptoms scale, quality of life) symptoms using mixed models. RESULTS Education level was not associated with age at onset or diagnosis. Compared with the low-education group, the incidence of Hoehn and Yahr ≥3.0 was 0.42 times lower (95% confidence interval, 0.22-0.82, P = 0.012) in the high-education group. Higher education was associated with better baseline motor function (P 0.15). Similar results were observed for cognition. Education was not associated with nonmotor symptoms. CONCLUSIONS Higher education is associated with better baseline motor/cognitive function in PD, but not with rate of decline, and with a lower risk of reaching Hoehn and Yahr ≥3 during the follow-up. Our observations are consistent with a passive reserve hypothesis for motor/cognitive symptoms. © 2019 International Parkinson and Movement Disorder Society.
Published: 2019
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18. French validation of the questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease–Rating Scale (QUIP-RS)

Author: Bruno Pereira, Hana You, Julie Socha, Jean-Christophe Corvol, Eve Benchetrit, Franck Durif, Alexis Elbaz, Ana Marques, Fanny Pineau, Elsa Pomies, Pascal Derkinderen, Tiphaine Vidal, Graziella Mangone, Florence Cormier, Monique Galitstky, Olivier Rascol, Daniel Weintraub, Fanny Artaud, Groupe de sociologie politique et morale (GSPM), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Délégation à la Recherche Clinique et à l'Innovation (DRCI), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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), 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)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Excellence en Maladies Neurodégénératives (NeuroToul), CHU Toulouse [Toulouse], Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neurology, University of Pennsylvania [Philadelphia], Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Pennsylvania, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Male, Parkinson's disease, Impulse control disorder, Psychometrics, Concordance, media_common.quotation_subject, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, 03 medical and health sciences, 0302 clinical medicine, Cronbach's alpha, Rating scale, Medicine, Humans, ComputingMilieux_MISCELLANEOUS, media_common, Aged, Language, Psychiatric Status Rating Scales, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, business.industry, Addiction, [SCCO.NEUR]Cognitive science/Neuroscience, Reproducibility of Results, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Parkinson Disease, Middle Aged, Translating, medicine.disease, 3. Good health, Disruptive, Impulse Control, and Conduct Disorders, 030104 developmental biology, Cross-Sectional Studies, Neurology, Cohort, Observational study, Female, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract: The management of impulse control disorders (ICDs) in Parkinson's disease (PD) relies on their early identification, allowing adjustment of antiparkinsonian treatment before these manifestations lead to major social, financial or legal consequences. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) is an English-developed and -validated PD-specific rating scale constructed to support the rating of ICDs and related disorders and the assessment of changes in symptom severity over time, but it has not to date been validated in French.We conducted an observational, multicenter, cross-sectional study among a subset of patients (n = 280) from the Drug Interacting with Genes in PD (DIG-PD) cohort, aiming to assess psychometric properties of the French version of QUIP-RS: acceptability, internal consistency, factor analysis, reproductibility and hypotheses testing. In addition to this scale, the following measures were applied: MDS-Unified Parkinson's Disease Rating Scale, Mini-Mental State Examination, Frontal Assessment Behavior, and Ardouin Scale of Behavior in Parkinson's Disease (ASBPD).Cronbach's alpha coefficient was 0.72 and ranged from 0.25 to 0.55. Regarding test-retest reliability and inter-rater reliability, the Lin concordance coefficient for items was higher than 0.58. The correlations between QUIP-RS and ASBPD were moderate to high except for dopaminergic addiction and hobbyism (r = 0.41 and 0.40 respectively, p 0.001). No clinically significant correlation was found between QUIP-RS total score (and items) and other scales.The French version of the QUIP-RS appears to be a valid, reliable, and precise instrument for the assessment of ICDs and related disorders in PD. REGISTRATION NUMBER: clinicaltrials.gov number NCT01564992.
Published: 2019
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19. 'De-novo' consultation: Evaluation of an outpatient's clinic dedicated to early diagnosis of parkinsonian syndromes

Author: Andreas Hartmann, Cécile Hubsch, David Grabli, Louise-Laure Mariani, Pauline Dodet, Jean-Christophe Corvol, Marie Vidailhet, Yulia Worbe, S. Aix, J. Ruggeri, Florence Cormier, A. M. Bonnet, Emmanuel Roze, Marie-Laure Welter, Bertrand Degos, Lucette Lacomblez, Service de Neuroradiologie [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), Centre expert inter-régional de coordination de la maladie de Parkinson [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), and HAL-UPMC, Gestionnaire
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Parkinson's disease, Referral, Disease, Ambulatory Care Facilities, Parkinsonian syndrome, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Parkinsonian Disorders, Outpatients, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Expert center, Young adult, Medical diagnosis, Disease management (health), Referral and Consultation, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Retrospective cohort study, Middle Aged, Early diagnosis, medicine.disease, 3. Good health, Patient care management, Neurology, 030220 oncology & carcinogenesis, Physical therapy, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, Neurology (clinical), Differential diagnosis, business, 030217 neurology & neurosurgery
Abstract: International audience; In the absence of specific clinical signs, imaging or biomarkers, the differential diagnosis of degenerative parkinsonian syndromes may be difficult at early stages of the disease. To reduce the risk of misdiagnosis or delayed diagnosis and referral to multiple medical centers at disease onset, easier access to expert centers should be available. To improve the initial care of parkinsonian patients, the Parkinson's disease Expert Center (PEC) at Pitié-Salpêtrière Academic Hospital has set up a specific outpatients clinic with short waiting times dedicated to the diagnosis of early Parkinson's disease and related disorders.MethodsThe PEC setup first identifies requests for diagnostic confirmation of parkinsonian syndromes, then specific outpatients clinic visits are scheduled weekly, with examinations carried out by neurologists at the PEC on a rotating schedule. Data from the first year of the new procedure were analyzed retrospectively through self-administered questionnaires sent to patients seen during this period. The main outcomes were to confirm the ability to keep to short delays for patients’ examinations and to assess patients’ satisfaction with the setup.ResultsBoth study outcomes were achieved. The creation of an outpatients clinic dedicated to the early diagnosis of parkinsonian syndromes allowed shorter delays before the first examination of 5 weeks instead of several months. Keeping to the weekly schedule and limited time taken for each visit was also achieved. Following this initial outpatients visit, diagnosis of a parkinsonian syndrome was clinically confirmed or further specified in 80% of cases. A survey of patients’ satisfaction showed a rate of over 91% in terms of the timing and course of clinical examinations at our PEC.Discussion/ConclusionThis study of our quality-improvement program for Parkinson's disease management has shown that specific consultations with shorter waiting times aiming to allow early specialized assessment of parkinsonian syndromes is beneficial for patients and reduces the risk of delayed diagnoses.
Published: 2017
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20. The 'Neurological Hat Game': A fun way to learn the neurological semiology

Author: M.-C. Renaud, M Mongin, L.L. Mariani, Emmanuel Roze, Béatrice Garcin, Aurélie Méneret, Florence Cormier, Bertrand Degos, C Delorme, 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Pleasure, medicine.medical_specialty, Students, Medical, Teaching method, [SDV]Life Sciences [q-bio], Personal Satisfaction, Memorization, law.invention, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Games, Recreational, law, Terminology as Topic, Neural Pathways, medicine, Limbic System, Humans, Learning, 030212 general & internal medicine, Memory Consolidation, Medical education, 4. Education, Teaching, ComputingMilieux_PERSONALCOMPUTING, Sign (semiotics), Semiology, Standard 52-card deck, Neurology, Female, Neurology (clinical), Educational Measurement, Psychology, 030217 neurology & neurosurgery, Preliminary Data
Abstract: In-class courses are deserted by medical students who tend to find it more beneficial to study in books and through online material. New interactive teaching methods, such as serious games increase both performance and motivation. We developed and assessed a new teaching method for neurological semiology using the "Hat Game" as a basis.In this game, two teams of second-year medical students are playing against one another. The game is played with a deck of cards. A neurological symptom or sign is written on each card. Each team gets a predefined period of time to guess as many words as possible. One member is the clue-giver and the others are the guessers. There are three rounds: during the first round, the clue-giver uses any descriptive term he wants and as many as he wants to make his team guess the maximum number of words within the allocated time. During the second round, the clue-giver can only choose one clue-word and, during the third round, he mimes the symptom or sign. The team that has guessed the most cards wins the game. To assess the efficacy of this learning procedure, multiple choices questions (MCQs) were asked before and after the game. Exam results of second-year students on their final university Neurology exam were analyzed. A satisfaction survey was proposed to all participating students.Among 373 students, 121 volunteers (32.4%) were enrolled in the "Neurology Hat Game" and 112 attended the game. One hundred and seven of the 112 students completed the MCQs with a significant improvement in their responses after the game (P0.001). The 112 students who completed the satisfaction self-administered questionnaire were very satisfied with this funny new teaching method.Teaching neurological semiology via the "Hat Game" is an interesting method because it is student-centered, playful and complementary to the lecturer-centered courses. A randomized controlled study would be necessary to confirm these preliminary results.
Published: 2018
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21. Clinical and anatomical predictors for freezing of gait and falls after subthalamic deep brain stimulation in Parkinson's disease patients

Author: Eric Bardinet, Brian Lau, Florence Cormier-Dequaire, Soledad Navarro, Hayat Belaid, Marie-Laure Welter, Marie Vidailhet, S. Fernandez-Vidal, David Grabli, Carine Karachi, 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), 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), Service de neurophysiologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Parkinson's disease, Deep brain stimulation, genetic structures, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Deep Brain Stimulation, Dopamine, Grey matter, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Atrophy, Subthalamic Nucleus, medicine, Humans, Effects of sleep deprivation on cognitive performance, Gait, Gait Disorders, Neurologic, Aged, business.industry, Putamen, Parkinson Disease, Middle Aged, medicine.disease, nervous system diseases, 3. Good health, Subthalamic nucleus, surgical procedures, operative, 030104 developmental biology, medicine.anatomical_structure, nervous system, Neurology, Accidental Falls, Female, Neurology (clinical), Geriatrics and Gerontology, business, therapeutics, 030217 neurology & neurosurgery
Abstract: Introduction Freezing of gait (FOG) and falls are the most disabling motor symptoms in Parkinson's disease (PD) patients. The effects of subthalamic deep-brain-stimulation (STN-DBS) on FOG and falls are still a matter of controversy, and factors contributing to their outcome have yet to be defined. Methods We examined the relationship between FOG and falls after STN-DBS and preoperative clinical features, MRI voxel-based-morphometry (VBM) analysis and statistical mapping of electrode locations. Results 331 patients (age at surgery = 57.7 ± 8.4 years; disease duration = 12.5 ± 5 years) were included in the final analysis, with VBM analysis in 151 patients. After surgery, FOG was aggravated in 93 patients and falls in 75 patients. After surgery, FOG severity was related to its level before surgery without dopaminergic treatment, the dopaminergic treatment dosage and severity of motor fluctuations after surgery; and falls severity to lower postoperative cognitive performance. VBM analyses revealed that, relative to other patient groups, patients with FOG worsening had putamen grey matter density decrease, and fallers patients a left postcentral gyrus atrophy. The best effects of STN-DBS on FOG and falls were associated with the location of contacts within the STN, but no specific location related to aggravation. Conclusions FOG and falls are reduced after STN-DBS in about 1/3 of patients, with the best effects obtained for electrodes located within the STN. Clinicians should be aware that, after STN-DBS, FOG severity is related to preoperative FOG severity whatever its dopa-sensitivity; and falls to lower postoperative cognitive performance; and atrophy of cortico-subcortical brain areas.
Published: 2018
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22. Sleep aspects on video-polysomnography in LRRK2 mutation carriers

Author: Smaranda Leu-Semenescu, Alexis Brice, Jean-Christophe Corvol, Mickael Ehrminger, Eden Debellemaniere, Isabelle Arnulf, Marie Vidailhet, and Florence Cormier
Subjects: 0303 health sciences, medicine.medical_specialty, Parkinson's disease, medicine.diagnostic_test, business.industry, Rapid eye movement sleep, Disease, Polysomnography, Electroencephalography, medicine.disease, LRRK2, REM sleep behavior disorder, Sleep in non-human animals, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Neurology, Internal medicine, Cardiology, Medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Background Rapid eye movement sleep behavior disorder and sleepiness precede or accompany idiopathic Parkinson's disease (PD), but their presence in subjects with leucine-rich repeat kinase 2 mutations is unknown. Methods Ten patients with leucine-rich repeat kinase 2-associated PD, four healthy leucine-rich repeat kinase 2 mutation carriers, 20 patients with idiopathic PD, and 12 healthy controls underwent clinical assessments and a nighttime video-polysomnography. Results No sleep changes, no rapid eye movement sleep behavior disorder, or rapid eye movement sleep without atonia was found in the 14 subjects with leucine-rich repeat kinase 2mutations compared with controls, whereas 41% of patients with idiopathic PD had rapid eye movement sleep behavior disorder. Eventually, 20% of patients with leucine-rich repeat kinase 2–associated PD had abnormal periodic leg movements, a frequency similar to the idiopathic PD group frequency. Conclusions The sleep phenotype in leucine-rich repeat kinase 2 mutations parallels that of idiopathic PD, except for absent rapid eye movement sleep behavior disorder here in the presymptomatic and symptomatic stages. © 2015 International Parkinson and Movement Disorder Society
Published: 2015
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23. High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry

Author: Jean-Christophe Corvol, Lydia Yahia-Cherif, Romain Valabregue, Hartwig R. Siebner, Nadya Pyatigorskaya, Fabrice Poupon, Marie Vidailhet, Stéphane Lehéricy, Stephan Klebe, Alexis Brice, M Sharman, and Florence Cormier-Dequaire
Subjects: medicine.medical_specialty, Relaxometry, Pathology, Parkinson's disease, business.industry, Substantia nigra, medicine.disease, LRRK2, Asymptomatic, Gastroenterology, Parkin, nervous system diseases, Globus pallidus, Neurology, Internal medicine, Basal ganglia, medicine, Neurology (clinical), medicine.symptom, business
Abstract: Objectives The goal of this work was to investigate iron deposition in the basal ganglia and thalamus in symptomatic and asymptomatic leucine-rich repeat kinase 2 (LRRK2) and Parkin-associated Parkinson's disease (PD), using R2* relaxometry rate. Methods Twenty subjects with genetic PD (four symptomatic and two asymptomatic Parkin subjects, nine symptomatic and five asymptomatic LRRK2 subjects) were compared with 20 patients with idiopathic PD (IPD) and 20 healthy subjects. Images were obtained at 3 teslas, using multi-echo T2 and T2* sequences. R2 and R2* values were calculated in the substantia nigra (SN), the striatum, the globus pallidus, and the thalamus. Results The R2* values in the SN were increased in IPD and mutation-carrying patients as compared with controls and in mutation-carrying patients as compared with IPD. Asymptomatic mutation carriers showed higher R2* values than controls and did not differ from IPD patients. No changes were seen in the other structures or in R2 values. Conclusion These results are consistent with increased iron load in LRRK2- and Parkin-mutation carriers. The increased R2* in asymptomatic PD-mutation carriers suggests that iron deposition occurs early during the preclinical phase of the disease. R2* measurements may be used as markers for investigating nigrostriatal damage in preclinical mutation-carrying patients. © 2015 International Parkinson and Movement Disorder Society
Published: 2015
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24. Sleep and REM sleep behaviour disorder in Parkinson’s disease with impulse control disorder

Author: Franck Durif, Alessandro Cicolin, Michela Figorilli, Leonardo Lopiano, Maria Livia Fantini, Jean-Christophe Corvol, Eve Benchetrit, Monica Puligheddu, P. Beudin, Bruno Pereira, Maurizio Zibetti, Florence Cormier-Dequaire, Ana Marques, Isabelle Arnulf, Lucette Lacomblez, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service des Pathologies du sommeil [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Délégation à la Recherche Clinique et à l’Innovation, CHU Clermont-Ferrand, 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)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-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, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Levodopa, Parkinson's disease, Movement disorders, Impulse control disorder, Polysomnography, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Video Recording, REM Sleep Behavior Disorder, REM sleep behavior disorder, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Aged, medicine.diagnostic_test, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SCCO.NEUR]Cognitive science/Neuroscience, Case-control study, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Parkinson Disease, Middle Aged, medicine.disease, Antidepressive Agents, 3. Good health, Disruptive, Impulse Control, and Conduct Disorders, Psychiatry and Mental health, 030104 developmental biology, Case-Control Studies, Dopamine Agonists, Physical therapy, Female, Surgery, Neurology (clinical), Age of onset, medicine.symptom, Sleep, Psychology, 030217 neurology & neurosurgery, medicine.drug
Abstract: IntroductionBecause the association between rapid eye movement sleep behaviour disorder (RBD) and impulse control disorders (ICDs) in Parkinson’s disease (PD) has been debated, we assessed the sleep characteristics and the frequency of RBD using video-polysomnography (v-PSG) in patients with PD with versus without ICDs.MethodsEighty non-demented patients with PD consecutively identified during routine evaluation at three movement disorders centres were enrolled in a case–control study. Forty patients (22 men; mean age: 62.6±9.7 years, Hoehn & Yahr: 2.1±0.6) with one or more current ICDs were age-matched and sex-matched with 40 patients with no history of ICDs (22 men, mean age: 64.9±7.8 years, Hoehn & Yahr: 2.2±0.6). They underwent a detailed sleep interview followed by a full-night in-lab v-PSG. Sleep was scored blindly to ICDs condition and RBD diagnosis included a clinical complaint of enacted dreams and/or documented behaviour during rapid eye movement (REM) sleep, with the presence of quantified REM sleep without atonia (RSWA).ResultsPatients with ICDs had a higher arousal index and higher RSWA than those without ICDs (51.9%±28.2%vs 32.2±27.1%, p=0.004). In addition, RBD was more frequent in the ICD group (85%vs53%, p=0.0001). RBD was still associated with ICDs in a multivariate regression analysis including age of onset, PD duration and severity, treatment duration, levodopa-equivalent and dopamine agonist-equivalent daily doses and antidepressant use (OR: 4.9 (95% CI 1.3 to 18.5), p=0.02).ConclusionsThis large, controlled series of patients with PD with ICDs assessed by v-PSG confirms the association between ICDs and RBD. Increased surveillance of symptoms of ICDs should be recommended in patients with PD with RBD.
Published: 2018
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25. Longitudinal analysis of impulse control disorders in Parkinson disease

Author: Jean-Christophe, Corvol, Fanny, Artaud, Florence, Cormier-Dequaire, Olivier, Rascol, Franck, Durif, Pascal, Derkinderen, Ana-Raquel, Marques, Frédéric, Bourdain, Jean-Philippe, Brandel, Fernando, Pico, Lucette, Lacomblez, Cecilia, Bonnet, Christine, Brefel-Courbon, Fabienne, Ory-Magne, David, Grabli, Stephan, Klebe, Graziella, Mangone, Hana, You, Valérie, Mesnage, Pei-Chen, Lee, Alexis, Brice, Marie, Vidailhet, Alexis, Elbaz, Antoine, Faurie-Grepon, Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), 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 de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), 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], 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), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], 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), National Taiwan University [Taiwan] (NTU), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherches épidémiologiques en neurologie et psychopathologie, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [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], 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), INSERM UMR_S975, CIC AP-HP (pitie-Salpetriere)/inserm, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Department of Neurology, University Hospital of Würzburg-University Hospital of Würzburg, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Department of Neurology, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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 de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM)
Subjects: 0301 basic medicine, Male, Levodopa, Pediatrics, medicine.medical_specialty, Longitudinal study, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medizin, Disease, Antiparkinson Agents, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, Cumulative incidence, Longitudinal Studies, Generalized estimating equation, ComputingMilieux_MISCELLANEOUS, Aged, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Parkinson Disease, Middle Aged, Confidence interval, 3. Good health, Discontinuation, Disruptive, Impulse Control, and Conduct Disorders, 030104 developmental biology, Dopamine Agonists, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug, Cohort study, Follow-Up Studies
Abstract: ObjectiveTo investigate the longitudinal dose-effect relationship between dopamine replacement therapy and impulse control disorders (ICDs) in Parkinson disease (PD).MethodsWe used data from a multicenter longitudinal cohort of consecutive patients with PD with ≤5 years' disease duration at baseline followed up annually up to 5 years. ICDs were evaluated during face-to-face semistructured interviews with movement disorder specialists. Generalized estimating equations and Poisson models with robust variance were used to study the association between several time-dependent definitions of dopamine agonist (DA) use, taking dose and duration of treatment into account, and ICDs at each visit. Other antiparkinsonian drugs were also examined.ResultsAmong 411 patients (40.6% women, mean age 62.3 years, average follow-up 3.3 years, SD 1.7 years), 356 (86.6%) took a DA at least once since disease onset. In 306 patients without ICDs at baseline, the 5-year cumulative incidence of ICDs was 46.1% (95% confidence interval [CI] 37.4–55.7, DA ever users 51.5% [95% CI 41.8–62.1], DA never users 12.4% [95% CI 4.8–30.0]). ICD prevalence increased from 19.7% at baseline to 32.8% after 5 years. ICDs were associated with ever DA use (prevalence ratio 4.23, 95% CI 1.78–10.09). Lifetime average daily dose and duration of treatment were independently associated with ICDs with significant dose-effect relationships. Similar analyses for levodopa were not in favor of a strong association. ICDs progressively resolved after DA discontinuation.ConclusionIn this longitudinal study of patients with PD characterized by a high prevalence of DA treatment, the 5-year cumulative incidence of ICDs was ≈46%. ICDs were strongly associated with DA use with a dose-effect relationship; both increasing duration and dose were associated with ICDs. ICDs progressively resolved after DA discontinuation.ClinicalTrials.gov identifier:NCT01564992.
Published: 2017
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26. Haematopoietic stem cell transplantation in CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

Author: Pierre Labauge, Florence Cormier, Stephanie Nguyen, Cécile Delorme, Jerome Froger, Nathalie Fegueux, Serge Lumbroso, Virginie Czernecki, Emmanuel Ellie, Raphael Schiffmann, Emmanuel Roze, Stéphane Lehéricy, Fanny Mochel, and Patrick Aubourg
Subjects: Pathology, medicine.medical_specialty, business.industry, Multiple sclerosis, Context (language use), Neurological disorder, Fluid-attenuated inversion recovery, medicine.disease, Hyperintensity, Leukoencephalopathy, Transplantation, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, medicine, Surgery, Neurology (clinical), Cognitive decline, business, 030217 neurology & neurosurgery
Abstract: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a severe neurodegenerative disease leading to death usually within a few years after symptoms onset.1 Patients present with cognitive decline, behavioural changes and pyramidal signs in the context of patchy white matter lesions. ALSP is a primary microgliopathy caused by haploinsufficiency of the colony-stimulating factor 1 receptor (CSF1R). CSF1R is critical for the development, maintenance and activation of microglia. We hypothesised that haematopoietic stem cell transplantation (HSCT) can be relevant in ALSP by correcting CSF1R loss-of-function in microglia. We provide the first prospective report of a patient with ALSP with a 30-month follow-up after a successful HSCT. We present in parallel the clinical outcome of a consecutive patient with similar age, sex and disease course who did not undergo HSCT. Patient 1 was in her early 30s when she developed leg stiffness after a mild head trauma. Her mother died of a rapidly progressive neurological disorder before age 40. Brain MRI revealed patchy and asymmetrical T2/FLAIR white matter hyperintensities (online supplementary file 1A) and T1 hypointensities. She was first misdiagnosed with multiple sclerosis. ALSP was then suspected because of the family history and hyperintense white matter lesions on diffusion weighted imaging (DWI). CSF1R - targeted analysis revealed a c.2498C>A, p.Thr833Lys mutation. ### Supplementary data [jnnp-2019-320701supp001.pdf] A repeat brain MRI showed progression of T2/FLAIR (online supplementary file 1A) and DWI white matter lesions. Neuropsychological testing revealed mild alterations in executive and working memory …
Published: 2019
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27. Le jeu du chapeau : une manière amusante d’apprendre la neurologie

Author: Louise-Laure Mariani, Delorme Cécile, Bertrand Degos, Béatrice Garcin, Emmanuel Flamand-Roze, Florence Cormier, Marie Mongin, Marie-Christine Renaud, and Aurélie Méneret
Subjects: Neurology, Neurology (clinical)
Abstract: Introduction En medecine, les cours facultaires sont desertes par les etudiants, qui preferent apprendre dans les livres. De nouvelles methodes d’enseignement interactives sont necessaires pour ameliorer les performances et la motivation. Objectifs Nous avons developpe et evalue une methode d’apprentissage de la semiologie neurologique basee sur le principe du jeu du chapeau. Patients et methodes Deux equipes d’etudiants jouent l’une contre l’autre. Un signe ou symptome est ecrit sur chaque carte d’une pile. Chaque equipe dispose d’un temps pre-defini pour faire deviner un maximum de mots a l’equipe adverse au cours de 3 manches : 1. par une description en utilisant tous les termes souhaites 2, avec un seul mot 3, en mimant le signe/symptome. Nous avons evalue l’efficacite de cette methode grâce a des QCM avant et apres l’enseignement, et par l’analyse des resultats aux examens de neurologie. Resultats Parmi 373 etudiants en 2e annee de medecine, 112 volontaires (32,4 %) ont participe au jeu du chapeau. Cent sept sur 112 etudiants ont complete les QCMs avant et apres l’enseignement avec une amelioration significative de leurs performances (p Discussion L’enseignement de la semiologie neurologique par le jeu du chapeau est une methode interessante car centree sur l’etudiant, amusante, et complementaire par rapport aux enseignements classiques. Notre etude presente de possibles biais de selection, et une etude controlee et randomisee serait interessante pour confirmer ces resultats preliminaires. Conclusion Le jeu du chapeau est une nouvelle methode d’enseignement efficace et amusante, qui peut etre utilisee pour l’apprentissage de la semiologie neurologique, mais qui peut egalement etre proposees pour l’enseignement d’autres specialites medicales.
Published: 2019
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28. Differences in MDS-UPDRS Scores Based on Hoehn and Yahr Stage and Disease Duration

Author: Barbara C. Tilley, Eva Reiter, Klaus Seppi, Thomas Foltynie, Carlos Singer, Iciar Aviles-Olmos, Carmen Rodriguez-Blazquez, Michal Minár, Milan Grofik, Pille Taba, Vladimir Han, Henry Moore, Peter Valkovič, Alberto Bergareche-Yarza, Christopher G. Goetz, Eve Benchetrit, Matej Skorvanek, Graziella Mangone, Pablo Martinez-Martin, Anabel Chade, Anette Schrag, Werner Poewe, Norbert Kovács, Veronika Datieva, Amin Cervantes-Arriaga, Zuzana Gdovinova, Mario Alvarez-Sanchez, Nelida Garretto, Bernadette Pinter, Florence Cormier, Mari Muldmaa, Amelia Mendoza-Rodriguez, Juan Carlos Martínez-Castrillo, Oleg Levin, Jean-Christophe Corvol, Charline Benoit, Liis Kadastik-Eerme, David A. Gallagher, Tomoko Arakaki, Glenn T. Stebbins, Mayela Rodríguez-Violante, Monica M. Kurtis, Jing Huang, Karin Rallmann, Oscar S. Gershanik, Zsuzsanna Aschermann, and Christoph Mueller
Subjects: 0301 basic medicine, Gerontology, medicine.medical_specialty, Parkinson's disease, Mds updrs, Disease duration, Hoehn and Yahr, Part iii, scale, 03 medical and health sciences, 0302 clinical medicine, Rating scale, Internal medicine, medicine, Stage (cooking), Motor assessment, Research Articles, Mean age, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), medicine.disease, nervous system diseases, 030104 developmental biology, Neurology, Neurology (clinical), disease duration, Psychology, 030217 neurology & neurosurgery
Abstract: BACKGROUND: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) is a newly developed tool to assess Parkinson's disease (PD). Changes in scores on the scale over the course of PD, including increasing disease duration and Hoehn and Yahr (HY) stages, have not been described. The objectives of this study were to analyze MDS‐UPDRS scores on Parts I through IV and their differences based on HY stage and disease duration in a large cohort of patients with PD. METHODS: For this cross‐sectional study, demographic data and MDS‐UPDRS scores were collected, including HY stage. Subscores on MDS‐UPDRS Parts I through IV were analyzed using 1‐way analyses of variance for each HY stage and in 5‐year increments of disease duration. Part III (motor assessment) scores were analyzed separately for on and off states. RESULTS: The mean age of the 3206 patients was 65.8 ± 10.6 years, 53.3% were men, the mean disease duration was 11.5 ± 4.6 years, and the median HY stage was 2 (range, 0–5); 2156 patients were examined in an on state and 987 were examined in an off state. Scores for all MDS‐UPDRS parts increased significantly through HY stages 1 through 5, with an average increase of 3.8, 7.7, 14.6, and 2.0 points consecutively for parts I through IV, respectively. For the 5‐year increments of disease duration, MDS‐UPDRS subscores increased by an average of 1.6, 3.3, 4.2, and 1.4 points consecutively for parts I through IV, respectively. This increase was significant only during the first 15 years of disease for all 4 parts, including part III scores evaluated in both on and off states. CONCLUSIONS: MDS‐UPDRS scores for all 4 parts increase significantly with every HY stage and also with 5‐year increments of disease duration in the first 15 years of the disease.
Published: 2017

29. Inflammatory profile discriminates clinical subtypes in LRRK2-associated Parkinson's disease

Author: Thomas O. Joos, Jean-Christophe Corvol, Thomas Knorpp, Nicole Schneiderhan-Marra, Connie Marras, T. Gasser, Tatiana Foroud, Daniela Berg, Birgitt Schüle, Kathrin Brockmann, Walter Maetzler, Alexis Brice, Florence Cormier, Eduard Tolosa, Javier Ruiz-Martínez, Dolores Vilas, Claudia Schulte, Jose-Felix Marti-Masso, Jan O. Aasly, Markus Langkamp, Claustre Pont-Sunyer, Anne-Marie Bernard, and Anja Apel
Subjects: 0301 basic medicine, Male, Parkinson's disease, BDNF protein, human, blood [Cytokines], Disease, Cohort Studies, CCL4 protein, human, 0302 clinical medicine, Neurotrophic factors, genetics [Parkinson Disease], blood [Chemokine CCL4], Age of Onset, Chemokine CCL4, Macrophage inflammatory protein, Chemokine CCL2, Aged, 80 and over, blood [Biomarkers], Parkinson Disease, Middle Aged, LRRK2, Neurology, etiology [Inflammation], Disease Progression, Biomarker (medicine), Cytokines, Female, medicine.symptom, Adult, Inflammation, Context (language use), blood [Brain-Derived Neurotrophic Factor], Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, 03 medical and health sciences, genetics [Inflammation], blood [Chemokine CCL2], medicine, Humans, ddc:610, LRRK2 protein, human, Aged, pathology [Inflammation], business.industry, Brain-Derived Neurotrophic Factor, medicine.disease, pathology [Parkinson Disease], 030104 developmental biology, Immunology, Mutation, CCL2 protein, human, genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2], Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers
Abstract: Background and purpose The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PDLRRK2) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes. Methods An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PDLRRK2 patients from the MJFF LRRK2 Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor. Results Patients classified as diffuse/malignant presented with the highest levels of the pro-inflammatory proteins interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein 1-β (MIP-1-β) paralleled by high levels of the neurotrophic protein brain-derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis. Conclusions Inflammation seems to be associated with the presence of a specific clinical subtype in PDLRRK2 that is characterized by a broad and more severely affected spectrum of motor and non-motor symptoms. The pro-inflammatory metabolites IL-8, MCP-1 and MIP-1-β as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PDLRRK2 and predict progression.
Published: 2017
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30. Clinical-genetic model predicts incident impulse control disorders in Parkinson's disease

Author: Alexis Brice, Daniel Weintraub, Vincent Guillemot, Julia Kraemmer, Ivan Moszer, Florence Cormier-Dequaire, Jean-Christophe Corvol, Mike A. Nalls, Kara M. Smith, Andrew B. Singleton, 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 (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Medizinische Universität Wien = Medical University of Vienna, Department of Neurology, University of Pennsylvania [Philadelphia], Dpt of Psychiatry [Philadelphia], Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Corporal Michael J Crescenz Department of Veterans Affairs Medical Center (VAMC), Laboratory of Neurogenetics, National Institutes of Health [Bethesda] (NIH), HAL-UPMC, Gestionnaire, 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), University of Pennsylvania, and University of Pennsylvania-University of Pennsylvania
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Parkinson's disease, Multivariate analysis, Genotype, Dopamine Agents, Disease, Polymorphism, Single Nucleotide, Article, Antiparkinson Agents, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Exome, Genetic Predisposition to Disease, Longitudinal Studies, Genetic Association Studies, Exome sequencing, Aged, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Models, Genetic, Receiver operating characteristic, business.industry, Area under the curve, Parkinson Disease, Sequence Analysis, DNA, Middle Aged, Heritability, medicine.disease, 3. Good health, Disruptive, Impulse Control, and Conduct Disorders, Psychiatry and Mental health, 030104 developmental biology, Multivariate Analysis, Cohort, Physical therapy, Female, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Objectives Impulse control disorders (ICD) are commonly associated with dopamine replacement therapy (DRT) in patients with Parkinson's disease (PD). Our aims were to estimate ICD heritability and to predict ICD by a candidate genetic multivariable panel in patients with PD.Methods Data from de novo patients with PD, drug-naïve and free of ICD behaviour at baseline, were obtained from the Parkinson's Progression Markers Initiative cohort. Incident ICD behaviour was defined as positive score on the Questionnaire for Impulsive-Compulsive Disorders in PD. ICD heritability was estimated by restricted maximum likelihood analysis on whole exome sequencing data. 13 candidate variants were selected from the DRD2, DRD3, DAT1, COMT, DDC, GRIN2B, ADRA2C, SERT, TPH2, HTR2A, OPRK1 and OPRM1 genes. ICD prediction was evaluated by the area under the curve (AUC) of receiver operating characteristic (ROC) curves.Results Among 276 patients with PD included in the analysis, 86% started DRT, 40% were on dopamine agonists (DA), 19% reported incident ICD behaviour during follow-up. We found heritability of this symptom to be 57%. Adding genotypes from the 13 candidate variants significantly increased ICD predictability (AUC=76%, 95% CI (70% to 83%)) compared to prediction based on clinical variables only (AUC=65%, 95% CI (58% to 73%), p=0.002). The clinical-genetic prediction model reached highest accuracy in patients initiating DA therapy (AUC=87%, 95% CI (80% to 93%)). OPRK1, HTR2A and DDC genotypes were the strongest genetic predictive factors.Conclusions Our results show that adding a candidate genetic panel increases ICD predictability, suggesting potential for developing clinical-genetic models to identify patients with PD at increased risk of ICD development and guide DRT management.
Published: 2016
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31. Inflammatory profile in LRRK2-associated prodromal and clinical PD

Author: Kathrin, Brockmann, Anja, Apel, Claudia, Schulte, Nicole, Schneiderhan-Marra, Claustre, Pont-Sunyer, Dolores, Vilas, Javier, Ruiz-Martinez, Markus, Langkamp, Jean-Christophe, Corvol, Florence, Cormier, Thomas, Knorpp, Thomas O, Joos, Thomas, Gasser, Birgitt, Schüle, Jan O, Aasly, Tatiana, Foroud, Jose Felix, Marti-Masso, Alexis, Brice, Eduardo, Tolosa, Connie, Marras, Daniela, Berg, and Walter, Maetzler
Subjects: Male, International Cooperation, blood [Cytokines], Biocompatible Materials, genetics [Gene Expression Regulation], Faculty of Medicine, Cohort Studies, Medizinische Fakultät, genetics [Parkinson Disease], blood [Parkinson Disease], Parkinson, Aged, 80 and over, Sex Characteristics, metabolism [Interleukin-12], article, Parkinson Disease, LRRK2, Middle Aged, Intercellular Adhesion Molecule-1, Interleukin-12, Interleukin-10, Neurology, Cytokines, Female, Adult, Adolescent, Immunology, genetics [Mutation], Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Cellular and Molecular Neuroscience, Young Adult, Immune, Inflammation, ddc:6, Humans, metabolism [Biocompatible Materials], ddc:610, LRRK2 protein, human, blood [Intercellular Adhesion Molecule-1], Aged, Retrospective Studies, metabolism [Interleukin-10], Research, metabolism [Cytokines], nervous system diseases, Gene Expression Regulation, Mutation, Linear Models, genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2]
Abstract: Background There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients. Methods We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium. Results A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles. Conclusions Concomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0588-5) contains supplementary material, which is available to authorized users.
Published: 2016
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32. A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood

Author: A Roubergue, Mariana Atencio, Marta Ruiz, Aurélie Méneret, Vanessa Brochard, Maryvonne Retail, Samantha Caillet, Sandrine Leroy, Jean-Christophe Corvol, Emmanuel Roze, Elodie Hainque, Florence Habarou, Isaac Adanyeguh, Sophie Rivaud-Péchoux, Benjamin Le Toullec, Chris Ottolenghi, Constance Flamand-Roze, Fanny Mochel, Mohamed Doulazmi, Fanny Charbonnier-Beaupel, Marie Vidailhet, Florence Cormier, BMC, BMC, 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], 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), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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 d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), EpiScience [London, UK], Service de Neurologie et Unité Neurovasculaire [Centre Hospitalier Sud-Francilien], Université Paris-Sud - Paris 11 (UP11)-Centre Hospitalier Sud Francilien, IFPPC - Institut de formation et de recherche pour les professionnels de la santé & Centre de santé et de thérapies Psycho Corporelles [Paris], CAMKeys [Paris], Service de biochimie métabolique [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), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Groupe de Recherche Clinique Neurométabolique [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CH Evry-Corbeil-CH Evry-Corbeil, 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)-Institut de Biologie Paris Seine (IBPS), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Département de Neurologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-IFR70-Hôpital de la Salpétrière, CIC Pitié Neurosciences, Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Service de Diététique [AP-HP Hôpital Pitié-Salpêtrière], AP-HP Hôpital Pitié-Salpétrière, Université Paris-Sud - Paris 11 ( UP11 ) -Centre Hospitalier Sud Francilien, Pharmacie [AP-HP Hôpital Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing ( B2A ), 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 ), Sorbonne Universités, Département de Neurologie [AP-HP Hôpital Saint-Antoine], AP-HP - Hôpital Saint-Antoine, Département de Génétique [AP-HP Hôpital Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-IFR70-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], lcsh:Medicine, Hemiplegia, Placebo, Double blind, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, ATP1A3, Humans, Medicine, Pharmacology (medical), Ictal, In patient, Triglycerides, Genetics (clinical), Cross-Over Studies, [ SDV ] Life Sciences [q-bio], business.industry, Research, Alternating hemiplegia of childhood, lcsh:R, General Medicine, Triheptanoin, medicine.disease, Crossover trial, Crossover study, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, chemistry, Dietary Supplements, Female, business, 030217 neurology & neurosurgery
Abstract: International audience; AbstractBackgroundBased on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations.MethodsWe conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects.ResultsIn an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated.ConclusionsTriheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting.Trial registrationThe study has been registered with clinicaltrials.gov (NCT002408354) the 03/24/2015.
Published: 2016
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33. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

Author: Suzanne Lesage, Valérie Drouet, Elisa Majounie, Vincent Deramecourt, Maxime Jacoupy, Aude Nicolas, Florence Cormier-Dequaire, Sidi Mohamed Hassoun, Claire Pujol, Sorana Ciura, Zoi Erpapazoglou, Tatiana Usenko, Claude-Alain Maurage, Mourad Sahbatou, Stefan Liebau, Jinhui Ding, Basar Bilgic, Murat Emre, Nihan Erginel-Unaltuna, Gamze Guven, François Tison, Christine Tranchant, Marie Vidailhet, Jean-Christophe Corvol, Paul Krack, Anne-Louise Leutenegger, Michael A. Nalls, Dena G. Hernandez, Peter Heutink, J. Raphael Gibbs, John Hardy, Nicholas W. Wood, Thomas Gasser, Alexandra Durr, Jean-François Deleuze, Meriem Tazir, Alain Destée, Ebba Lohmann, Edor Kabashi, Andrew Singleton, Olga Corti, Alexis Brice, Yves Agid, Mathieu Anheim, Anne-Marie Bonnet, Michel Borg, Emmanuel Broussolle, Philippe Damier, Alexandra Dürr, Franck Durif, Stephan Klebe, Maria Martinez, Pierre Pollak, Olivier Rascol, Marc Vérin, François Viallet, Jean Christophe Corvol, Sampath Arepalli, Roger A. Barker, Yoav Ben-Shlomo, Daniela Berg, Francesco Bettella, Kailash Bhatia, Rob M.A. de Bie, Alessandro Biffi, Bastiaan R. Bloem, Zoltan Bochdanovits, Michael Bonin, Jose M. Bras, Kathrin Brockmann, Janet Brooks, David J. Burn, Gavin Charlesworth, Honglei Chen, Patrick F. Chinnery, Sean Chong, Carl E. Clarke, Mark R. Cookson, Carl Counsell, Jean-François Dartigues, Panos Deloukas, Günther Deuschl, David T. Dexter, Karin D. van Dijk, Allissa Dillman, Jing Dong, Frank Durif, Sarah Edkins, Valentina Escott-Price, Jonathan R. Evans, Thomas Foltynie, Jianjun Gao, Michelle Gardner, Alison Goate, Emma Gray, Rita Guerreiro, Clare Harris, Jacobus J. van Hilten, Albert Hofman, Albert Hollenbeck, Peter Holmans, Janice Holton, Michèle Hu, Xuemei Huang, Heiko Huber, Gavin Hudson, Sarah E. Hunt, Johanna Huttenlocher, Thomas Illig, Pálmi V. Jónsson, Laura L. Kilarski, Iris E. Jansen, Jean-Charles Lambert, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Steven Lubbe, Codrin Lungu, María Martinez, Walter Mätzler, Alisdair McNeill, Catriona Moorby, Matthew Moore, Karen E. Morrison, Ese Mudanohwo, Sean S. O’Sullivan, Michael J. Owen, Justin Pearson, Joel S. Perlmutter, Hjörvar Pétursson, Vincent Plagnol, Bart Post, Simon Potter, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Mohamad Saad, Javier Simón-Sánchez, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Claudia Schulte, Manu Sharma, Karen Shaw, Una-Marie Sheerin, Ira Shoulson, Joshua Shulman, Ellen Sidransky, Chris C.A. Spencer, Hreinn Stefánsson, Kári Stefánsson, Joanna D. Stockton, Amy Strange, Kevin Talbot, Carlie M. Tanner, Avazeh Tashakkori-Ghanbaria, Daniah Trabzuni, Bryan J. Traynor, André G. Uitterlinden, Daan Velseboer, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Caroline H. Williams-Gray, Sophie Winder-Rhodes, Isabel Wurster, Nigel Williams, Huw R. Morris, Andrew B. Singleton, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Complex Trait Genetics, Neurology, Graduate School, ANS - Cellular & Molecular Mechanisms, Krack, Paul, 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)-Centre National de la Recherche Scientifique (CNRS)-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), Department of Neurodegenerative Diseases, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Laboratory of Neurogenetics, National Institute of Aging, Département d'histologie et de pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), CHU Pitié-Salpêtrière [AP-HP], Fondation Jean Dausset CEPH, Institute of Neuroanatomy, Department of Neurology, Behavioural Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Department of Genetics, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Pôle Tête-Cou-CETD, Les Hôpitaux Universitaires de Strasbourg (HUS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, Department of Molecular Neuroscience, University College of London [London] (UCL)-Institute of Neurology, Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Commissariat à l'Energie Atomique Saclay, Service de Neurologie, CHU Mustapha, Movement Disorders Unit, HAL-UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), 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)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, Turkey, parkin protein, Mitochondrion, Compound heterozygosity, Parkin, Proteins/*genetics/metabolism, Consanguinity, 0302 clinical medicine, diagnosis [Parkinsonian Disorders], Mitophagy, Genetics(clinical), metabolism [Protein Kinases], Cognitive decline, Genetics (clinical), Exome sequencing, genetics [Ubiquitin-Protein Ligases], Genetics, Parkinsonism, genetics [Protein Kinases], Homozygote, metabolism [Proteins], Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Pedigree, Phenotype, genetics [Parkinsonian Disorders], COS Cells, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Parkinsonian Disorders/diagnosis/*genetics, Protein Kinases/*genetics/metabolism, PTEN-induced putative kinase, Adult, Heterozygote, Mitochondrial Degradation/*genetics, Ubiquitin-Protein Ligases, PINK1, Biology, VPS13C protein, human, 03 medical and health sciences, Genetic Heterogeneity, metabolism [Ubiquitin-Protein Ligases], Parkinsonian Disorders, ddc:570, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Gene Silencing, Aged, Proteins, Reproducibility of Results, medicine.disease, genetics [Proteins], ddc:616.8, Ubiquitin-Protein Ligases/*genetics/metabolism, 030104 developmental biology, HEK293 Cells, Case-Control Studies, Protein Kinases, 030217 neurology & neurosurgery, genetics [Mitophagy]
Abstract: Contains fulltext : 167923.pdf (Publisher’s version ) (Open Access) Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.
Published: 2016
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34. High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry

Author: Nadya, Pyatigorskaya, Michael, Sharman, Jean-Christophe, Corvol, Romain, Valabregue, Lydia, Yahia-Cherif, Fabrice, Poupon, Florence, Cormier-Dequaire, Hartwig, Siebner, Stephan, Klebe, Marie, Vidailhet, Alexis, Brice, and Stephane, Lehéricy
Subjects: Adult, Male, Heterozygote, Iron, Ubiquitin-Protein Ligases, Parkinson Disease, Middle Aged, Protein Serine-Threonine Kinases, Globus Pallidus, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Magnetic Resonance Imaging, Neostriatum, Substantia Nigra, Thalamus, Mutation, Humans, Female, Aged
Abstract: The goal of this work was to investigate iron deposition in the basal ganglia and thalamus in symptomatic and asymptomatic leucine-rich repeat kinase 2 (LRRK2) and Parkin-associated Parkinson's disease (PD), using R2* relaxometry rate.Twenty subjects with genetic PD (four symptomatic and two asymptomatic Parkin subjects, nine symptomatic and five asymptomatic LRRK2 subjects) were compared with 20 patients with idiopathic PD (IPD) and 20 healthy subjects. Images were obtained at 3 teslas, using multi-echo T2 and T2* sequences. R2 and R2* values were calculated in the substantia nigra (SN), the striatum, the globus pallidus, and the thalamus.The R2* values in the SN were increased in IPD and mutation-carrying patients as compared with controls and in mutation-carrying patients as compared with IPD. Asymptomatic mutation carriers showed higher R2* values than controls and did not differ from IPD patients. No changes were seen in the other structures or in R2 values.These results are consistent with increased iron load in LRRK2- and Parkin-mutation carriers. The increased R2* in asymptomatic PD-mutation carriers suggests that iron deposition occurs early during the preclinical phase of the disease. R2* measurements may be used as markers for investigating nigrostriatal damage in preclinical mutation-carrying patients.
Published: 2015

35. Sleep aspects on video-polysomnography in LRRK2 mutation carriers

Author: Mickael, Ehrminger, Smaranda, Leu-Semenescu, Florence, Cormier, Jean-Christophe, Corvol, Marie, Vidailhet, Eden, Debellemaniere, Alexis, Brice, and Isabelle, Arnulf
Subjects: Adult, Male, Polysomnography, Video Recording, Electroencephalography, Parkinson Disease, REM Sleep Behavior Disorder, Middle Aged, Protein Serine-Threonine Kinases, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Mutation, Humans, Female, Aged
Abstract: Rapid eye movement sleep behavior disorder and sleepiness precede or accompany idiopathic Parkinson's disease (PD), but their presence in subjects with leucine-rich repeat kinase 2 mutations is unknown.Ten patients with leucine-rich repeat kinase 2-associated PD, four healthy leucine-rich repeat kinase 2 mutation carriers, 20 patients with idiopathic PD, and 12 healthy controls underwent clinical assessments and a nighttime video-polysomnography.No sleep changes, no rapid eye movement sleep behavior disorder, or rapid eye movement sleep without atonia was found in the 14 subjects with leucine-rich repeat kinase 2mutations compared with controls, whereas 41% of patients with idiopathic PD had rapid eye movement sleep behavior disorder. Eventually, 20% of patients with leucine-rich repeat kinase 2-associated PD had abnormal periodic leg movements, a frequency similar to the idiopathic PD group frequency.The sleep phenotype in leucine-rich repeat kinase 2 mutations parallels that of idiopathic PD, except for absent rapid eye movement sleep behavior disorder here in the presymptomatic and symptomatic stages.
Published: 2015

36. Séquençage d’exomes et troubles du contrôle des impulsions dans la maladie de Parkinson

Author: Justine Guéguan, Jean-Christophe Corvol, Florence Cormier, Khadija Tahiri, Fabrice Danjou, Bekadar Samir, and Sabine Prud’hon
Subjects: Neurology, Neurology (clinical)
Abstract: Introduction Dans la maladie de Parkinson (MP), les troubles du controle des impulsions (TCI) sont frequents chez les patients traites par agonistes dopaminergiques (AD). Une heritabilite forte de ces troubles a ete suggeree dans la population generale et dans la MP. Objectifs Notre objectif etait d’identifier les genes associes aux TCI dans la MP en comparant les sequences d’exomes chez les patients avec et sans TCI. Patients et methodes Nous avons compare 36 patients parkinsoniens avec (n = 18) ou sans (n = 18) TCI apparies sur le sexe et l’âge de debut de la MP. Le sequencage a ete realise avec le kit MedExome SeqCap EZ (Roche) et le sequenceur NexSeq 500 (Illumina). Les variants avec impact fonctionnel eleve (caddscore≥12,37) ont ete selectionnes. Leur frequence allelique et leur distribution dans les pathways et les genes ont ete analysees par single et skat-O tests, puis repliquees dans la cohorte Parkinson's Progression Markers Initiative (PPMI). Resultats L’analyse de la distribution des 6953 variants selectionnes a permis d’identifier une liste de 5 pathways associes aux TCI (p Discussion Nos resultats sont coherents avec l’importance des voies de transduction dependantes de l’AMPc et de ERK demontree dans les modeles animaux d’addiction et de plasticite induite par la dopamine. La limite essentielle de cette analyse tient au faible nombre de sujets etudies, aucun des variants identifie ne passant les seuils de significativite apres correction pour comparaisons multiples. Conclusion Nos resultats suggerent que les genes impliques dans les voies de transduction en aval des recepteurs couples aux proteines G participent a la susceptibilite genetique des TCI dans la MP.Informations complementaires Michael J Fox foundation, IHU-A-ICM.
Published: 2017
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37. Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinson's disease

Author: Jean-Baptiste Martini, Jean-Christophe Corvol, Julia Muellner, Florence Cormier-Dequaire, Marie-Odile Habert, Niklaus Meier, Andreas Hartmann, Aurélie Kas, Iman Gharrad, Alexis Brice, Marie Vidailhet, Khadija Tahiri, Alain Mallet, Michael Schuepbach, 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of neurology, Inselspital Bern, Laboratoire d'Imagerie Biomédicale (LIB), 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 Neurologie [CHU Pitié-Salpêtrière], IFR70-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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Administateur, HAL Sorbonne Université, Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Parkinson's disease, Caudate nucleus, Striatum, 0302 clinical medicine, Methionine, 610 Medicine & health, Denervation, Aged, 80 and over, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Putamen, Dopaminergic, Parkinson Disease, Valine, motor symptoms, Middle Aged, Neurology, compensatory mechanism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Psychology, rs4680, Adult, medicine.medical_specialty, Catechol O-Methyltransferase, behavioral disciplines and activities, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, Spect imaging, mental disorders, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, Aged, Tomography, Emission-Computed, Single-Photon, Dopaminergic Neurons, fungi, dopaminergic denervation, medicine.disease, COMT, Corpus Striatum, Endocrinology, nervous system, Parkinson’s disease, Neurology (clinical), Geriatrics and Gerontology, Neuroscience, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background : Catecholamine-O-methyl-tranferase (COMT) initiates dopamine degradation. Its activity is mainly determined by a single nucleotide polymorphism in the COMT gene (Val158Met, rs4680) separating high (Val/Val, COMTHH), intermediate (Val/Met, COMTHL) and low metabolizers (Met/Met, COMTLL). We investigated dopaminergic denervation in the striatum in PD patients according to COMT rs4680 genotype.Methods : Patients with idiopathic PD were assessed for motor severity (UPDRS-III rating scale in OFF-state), dopaminergic denervation using [123I]-FP-CIT SPECT imaging, and genotyped for the COMT rs4680 enzyme. [123I]-FP-CIT binding potential (BP) for each voxel was defined by the ratio of tracer-binding in the region of interest (striatum, caudate nucleus and putamen) to that in a region of non-specific activity. Genotyping was performed using TaqMan® SNP genotyping assay. We used a regression model to evaluate the effect of COMT genotype on the BP in the striatum and its sub-regions.Results : Genotype distribution was: 11 (27.5%) COMTHH, 26 (65%) COMTHL and 3 (7.5%) COMTLL. There were no significant differences in disease severity, treatments, or motor scores between genotypes. When adjusted to clinical severity, gender and age, low and intermediate metabolizers showed significantly higher rates of striatal denervation (COMTHL+LL BP=1.32 +/- 0.04) than high metabolizers (COMTHH, BP=1.6 +/- 0.08; F(1.34)=9.0, p=0.005). Striatal sub-regions showed similar results. BP and UPDRS-III motor scores (r=0.44, p=0.04) (p
Published: 2014
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38. Parkinson's disease in GTP cyclohydrolase 1 mutation carriers

Author: Niccolò E, Mencacci, Ioannis U, Isaias, Martin M, Reich, Christos, Ganos, Vincent, Plagnol, James M, Polke, Jose, Bras, Joshua, Hersheson, Maria, Stamelou, Alan M, Pittman, Alastair J, Noyce, Kin Y, Mok, Thomas, Opladen, Erdmute, Kunstmann, Sybille, Hodecker, Alexander, Münchau, Jens, Volkmann, Samuel, Samnick, Katie, Sidle, Tina, Nanji, Mary G, Sweeney, Henry, Houlden, Amit, Batla, Anna L, Zecchinelli, Gianni, Pezzoli, Giorgio, Marotta, Andrew, Lees, Paulo, Alegria, Paul, Krack, Florence, Cormier-Dequaire, Suzanne, Lesage, Alexis, Brice, Peter, Heutink, Thomas, Gasser, Steven J, Lubbe, Huw R, Morris, Pille, Taba, Sulev, Koks, Elisa, Majounie, J, Raphael Gibbs, Andrew, Singleton, John, Hardy, Stephan, Klebe, Kailash P, Bhatia, and Nicholas W, Wood
Subjects: Adult, Aged, 80 and over, Male, Risk, Heterozygote, Adolescent, Genetic Variation, Parkinson Disease, Middle Aged, United States, Pedigree, Europe, Young Adult, Databases, Genetic, Mutation, Humans, Female, Child, GTP Cyclohydrolase, Aged
Abstract: GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
Published: 2014

39. Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in Parkinson's disease

Author: Alain Duhamel, Jean-Christophe Corvol, Stéphanie Lejeune, Fanny Charbonnier-Beaupel, Florence Cormier-Dequaire, Noël Zahr, Bernard Sablonnière, Anne-Marie Bonnet, Jean Costentin, Cecilia Bonnet, David Devos, Nathalie Rouaix, Marie Vidailhet, and Khadija Tahiri
Subjects: Male, medicine.medical_specialty, Levodopa, Parkinson's disease, Genotype, Drug Resistance, Biology, Polymorphism, Single Nucleotide, Antiparkinson Agents, Pharmacokinetics, Double-Blind Method, Dopamine, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Promoter Regions, Genetic, Aged, Aromatic L-amino acid decarboxylase, Benserazide, Cross-Over Studies, Area under the curve, Parkinson Disease, Middle Aged, medicine.disease, Crossover study, nervous system diseases, Endocrinology, Neurology, ROC Curve, Area Under Curve, Dopa Decarboxylase, Female, Neurology (clinical), Geriatrics and Gerontology, medicine.drug
Abstract: Background In Parkinson's disease (PD), the response to l -dopa is highly variable and unpredictable. The major pathway for dopamine synthesis from l -dopa is decarboxylation by aromatic l -amino acid decarboxylase (AAAD, encoded by the DDC gene). Objective To determine the motor response to l -dopa in PD patients as a function of the DDC gene promoter polymorphisms (rs921451 T > C polymorphism (DDCT/C) and rs3837091 AGAG del (DDCAGAG/−)). Methods Thirty-three Caucasian PD patients underwent an acute l -dopa challenge together with the peripheral AAAD inhibitor benserazide and were genotyped for rs921451 and rs3837091. The primary efficacy criterion was the motor response to l -dopa, as estimated by the area under the curve for the change in the Unified Parkinson's Disease Rating Scale part III (UPDRS) score relative to baseline (AUCΔUPDRS) in the 4 h following l -dopa administration. Secondary endpoints were pharmacokinetic parameters for plasma levels of l -dopa and dopamine. Investigators and patients were blinded to genotypes data throughout the study. Results When adjusted for the l -dopa dose, the AUCΔUPDRS was significantly lower in DDCCC/CT patients (n = 14) than in DDCTT patients (n = 19) and significantly lower in DDC−/− or AGAG/− patients (n = 8) than in DDCAGAG/AGAG patients (n = 25). There were no significant intergroup differences in plasma pharmacokinetic parameters for l -dopa and dopamine. Discussion The rs921451 and rs3837091 polymorphisms of the DDC gene promoter influence the motor response to l -dopa but do not significantly change peripheral pharmacokinetic parameters for l -dopa and dopamine. Our results suggest that DDC may be a genetic modifier of the l -dopa response in Parkinson's disease.
Published: 2013

40. The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in mice

Author: Muriel Priault, Wilfred F. A. den Dunnen, Jean-Christophe Corvol, Alexis Brice, Khalid Hamid El Hachimi, Merle Ruberg, Martine Barkats, Fanny Charbonnier-Beaupel, Annie Sittler, Marie-Paule Muriel, Thibaut Marais, Florence Cormier-Dequaire, Khadija Tahiri, Alexandra Durr, Florian Beaumatin, Danielle Seilhean, Giovanni Stevanin, Martina Marinello, Sandro Alves, and Molecular Neuroscience and Ageing Research (MOLAR)
Subjects: Autophagosome, Male, Mice, Trinucleotide Repeats, NEURODEGENERATIVE DISEASE, GENETIC MOUSE MODELS, Cell Line, Transformed, LAMP2, MACHADO-JOSEPH-DISEASE, TOR Serine-Threonine Kinases, Microfilament Proteins, Brain, Polyglutamine tract, Lysosome, SCA7 knock-in mouse, Cell biology, ALZHEIMERS-DISEASE, medicine.anatomical_structure, HUNTINGTONS-DISEASE, Small Ubiquitin-Related Modifier Proteins, Beclin-1, Female, Signal Transduction, Programmed cell death, Patients, Mice, Transgenic, Nerve Tissue Proteins, Biology, Pathology and Forensic Medicine, ATG12, Cellular and Molecular Neuroscience, medicine, Autophagy, Animals, Humans, Spinocerebellar Ataxias, BECLIN 1, PI3K/AKT/mTOR pathway, POLYGLUTAMINE, Ataxin-7, Membrane Proteins, MUTANT ATAXIN-7, Phosphate-Binding Proteins, Gene Expression Regulation, AGGREGATE-PRONE PROTEINS, Case-Control Studies, Leukocytes, Mononuclear, Ataxia, Neurology (clinical), Transcriptome, Apoptosis Regulatory Proteins, Carrier Proteins, Lysosomes
Abstract: There is still no treatment for polyglutamine disorders, but clearance of mutant proteins might represent a potential therapeutic strategy. Autophagy, the major pathway for organelle and protein turnover, has been implicated in these diseases. To determine whether the autophagy/lysosome system contributes to the pathogenesis of spinocerebellar ataxia type 7 (SCA7), caused by expansion of a polyglutamine tract in the ataxin-7 protein, we looked for biochemical, histological and transcriptomic abnormalities in components of the autophagy/lysosome pathway in a knock-in mouse model of the disease, postmortem brain and peripheral blood mononuclear cells (PBMC) from patients. In the mouse model, mutant ataxin-7 accumulated in inclusions immunoreactive for the autophagy-associated proteins mTOR, beclin-1, p62 and ubiquitin. Atypical accumulations of the autophagosome/lysosome markers LC3, LAMP-1, LAMP2 and cathepsin-D were also found in the cerebellum of the SCA7 knock-in mice. In patients, abnormal accumulations of autophagy markers were detected in the cerebellum and cerebral cortex of patients, but not in the striatum that is spared in SCA7, suggesting that autophagy might be impaired by the selective accumulation of mutant ataxin-7. In vitro studies demonstrated that the autophagic flux was impaired in cells overexpressing full-length mutant ataxin-7. Interestingly, the expression of the early autophagy-associated gene ATG12 was increased in PBMC from SCA7 patients in correlation with disease severity. These results provide evidence that the autophagy/lysosome pathway is impaired in neurons undergoing degeneration in SCA7. Autophagy/lysosome-associated molecules might, therefore, be useful markers for monitoring the effects of potential therapeutic approaches using modulators of autophagy in SCA7 and other autophagy/lysosome-associated neurodegenerative disorders.
Published: 2013

41. Genetics of impulse control disorders in Parkinson's disease

Author: Florence Cormier, Julia Muellner, and Jean-Christophe Corvol
Subjects: Parkinson's disease, Dopamine Plasma Membrane Transport Proteins, Pharmacology, Catechol O-Methyltransferase, Receptors, Dopamine, Gene Frequency, Dopamine, medicine, Humans, Biological Psychiatry, 5-HT receptor, Serotonin Plasma Membrane Transport Proteins, Catechol-O-methyl transferase, Polymorphism, Genetic, biology, Dopaminergic, Parkinson Disease, medicine.disease, Disruptive, Impulse Control, and Conduct Disorders, Psychiatry and Mental health, Neurology, Dopamine receptor, Receptors, Serotonin, biology.protein, GRIN2B, Neurology (clinical), Psychology, medicine.drug
Abstract: Impulse control disorders (ICD) have been recognised in Parkinson's disease (PD) as adverse effects of dopamine replacement therapy, particularly with dopamine agonists. Although virtually all PD patients are treated with dopaminergic drugs, only a minority will develop hyperdopaminergic states, suggesting predisposing and/or protecting factors. The age at onset, the sex and the dose or type of dopaminergic drugs have been identified as clinical predictive factors. Recent genetic studies have investigated associations between ICD and polymorphisms of genes involved in the dopamine metabolism pathway (COMT, DAT), dopamine receptors (DRD1, DRD2, DRD3, DRD4), serotonin receptors and its transporter (HTR2A, 5HTT), and glutamate receptors (GRIN2B). Although validation in larger and independent cohorts is needed, the results from these studies give us some insights into the pathophysiology of hyperdopaminergic states and may be useful, at term, in personalising antiparkinsonian treatment in clinical practice.
Published: 2012

42. Michael J. Fox Foundation LRRK2 Consortium: geographical differences in returning genetic research data to study participants

Author: Nir Giladi, Karen Marder, Helen Mejia-Santana, Alexandra Durr, Jean-Christophe Corvol, Thomas Gasser, Alison Urkowitz, Roy N. Alcalay, Matthew J. Farrer, Alexis Brice, Caroline M. Tanner, Javier Ruiz Martínez, Dolores Vilas, Jan O. Aasly, Eduardo Tolosa, Maurizio Facheris, J. William Langston, Cheryl A. Halter, Daniela Berg, Kathrin Brockmann, Avi Orr-Urtreger, Anat Mirelman, Rachel Saunders-Pullman, Connie Marras, Birgitt Schüle, Susan Bressman, Tatiana Foroud, Deborah Raymond, Adina Wise, Piu Chan, Anthony E. Lang, Claustre Pont-Sunyer, Lorraine N. Clark, Florence Cormier, and Jose-Felix Marti-Masso
Subjects: business.industry, education, parasitic diseases, MEDLINE, Medicine, Library science, Foundation (evidence), business, behavioral disciplines and activities, humanities, Genetics (clinical), nervous system diseases, Research data
Abstract: Michael J. Fox Foundation LRRK2 Consortium: geographical differences in returning genetic research data to study participants
Published: 2014
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43. Le trouble comportemental en sommeil paradoxal est-il un marqueur pré-symptomatique chez les sujets mutés LRRK2 (syndrome parkinsonien juvénile) ?

Author: Mickael Ehrminger, Florence Cormier, Isabelle Arnulf, Smaranda Leu, Alexis Brice, and Jean-Christophe Corvol
Subjects: Behavioral Neuroscience, Neuropsychology and Physiological Psychology, Neurology, Cognitive Neuroscience, Neurology (clinical)
Abstract: Objectif Le trouble comportemental en sommeil paradoxal (TCSP) est fortement associe a la maladie de Parkinson idiopathique (MPi) : il la precede dans 30 % des cas et l’accompagne dans 60 % des cas. Les mutations du gene LRRK2 sont rares et induisent un syndrome parkinsonien juvenile dont l’association avec la synucleine n’est pas encore claire. Ces mutations induisent-elles un TCSP chez les sujets mutes pre-symptomatiques ou symptomatiques ? Methodes Nous avons inclus 15 sujets mutes sur LRRK2 (11 parkinsoniens, 4 porteurs sains), 22 parkinsoniens idiopathiques, et 17 temoins sains apparies en âge et en sexe. Ils ont beneficie d’une videopolysomnographie, avec mesure du pourcentage de sommeil paradoxal sans atonie, et d’echelles motrices (UPDRS motrice OFF). Resultats Il n’y avait pas de TCSP ou de pourcentage de sommeil paradoxal sans atonie superieur a 15 % ni chez les porteurs sains et ni chez les porteurs symptomatiques d’une mutation du gene LRRK2, alors que les patients MPi avaient un TCSP dans 41 % des cas, et presentaient plus d’activite tonique en sommeil paradoxal que les parkinsoniens LRRK2 (p Conclusion Sur cet echantillon, le controle de l’atonie musculaire en sommeil paradoxal ne semble pas associe aux lesions induites par les mutations du gene LRRK2.
Published: 2015
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44. The endoplasmic reticulum-mitochondria interface is perturbed in PARK2 knockout mice and patients with PARK2 mutations

Author: StÃ©phanie Bigou, Zoi Erpapazoglou, ClÃ©ment A. Gautier, Vania Broccoli, Alexis Brice, Benjamin Foret, FranÃ§ois Mouton-Liger, Carine Dalle, Delphine Bohl, Mathilde Girard, Sophie Duffaure, Florence Cormier, Jean-Christophe Corvol, Marie Paule Muriel, Olga Corti, Angelo Iannielli, Patrick P. Michel, 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], 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), Institute of Stem Cell Therapy and Exploration of Monogenic Diseases, CNR Institute of Neuroscience, National Research Council [Italy] (CNR), San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and CHU Pitié-Salpêtrière [AP-HP]
Subjects: 0301 basic medicine, Ubiquitin-Protein Ligases, Induced Pluripotent Stem Cells, MFN2, Mitochondrion, Biology, Endoplasmic Reticulum, medicine.disease_cause, Parkin, fibroblast, mfn2 gene, GTP Phosphohydrolases, Mice, 03 medical and health sciences, Cytosol, Mitophagy, Genetics, medicine, Animals, Humans, Calcium Signaling, Molecular Biology, Genetics (clinical), Mice, Knockout, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Endoplasmic reticulum, park2 gene, E3 Ubiquitin-Protein Ligase Parkin, Parkinson Disease, General Medicine, Fibroblasts, Molecular biology, nervous system diseases, mitochondria, 030104 developmental biology, Gene Expression Regulation, Mitochondrial biogenesis, mutation
Abstract: International audience; Mutations in PARK2, encoding the E3 ubiquitin protein ligase Parkin, are a common cause of autosomal recessive Parkinson’s disease (PD). Loss of PARK2 function compromises mitochondrial quality by affecting mitochondrial biogenesis, bioenergetics, dynamics, transport and turnover. We investigated the impact of PARK2 dysfunction on the endoplasmic reticulum (ER)-mitochondria interface, which mediates calcium (Ca2+) exchange between the two compartments and is essential for Parkin-dependent mitophagy. Confocal and electron microscopy analyses showed the ER and mitochondria to be in closer proximity in primary fibroblasts from PARK2 knockout (KO) mice and PD patients with PARK2 mutations than in controls. Ca2+ flux to the cytosol was also modified, due to enhanced ER-to-mitochondria Ca2+ transfers, a change that was also observed in neurons derived from induced pluripotent stem cells of a patient with PARK2 mutations. Subcellular fractionation showed the abundance of the Parkin substrate mitofusin 2 (Mfn2), which is known to modulate the ER-mitochondria interface, to be specifically higher in the mitochondrion-associated ER membrane compartment in PARK2 KO tissue. Mfn2 downregulation or the exogenous expression of normal Parkin restored cytosolic Ca2+ transients in fibroblasts from patients with PARK2 mutations. In contrast, a catalytically inactive PD-related Parkin variant had no effect. Overall, our data suggest that Parkin is directly involved in regulating ER-mitochondria contacts and provide new insight into the role of the loss of Parkin function in PD development.
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