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1. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

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

Author: Bruno Dubois, Audrey Gabelle, François Sellal, Jérémie Pariente, Marie Sarazin, Agnès Camuzat, Raffaella Migliaccio, Frédérique Etcharry-Bouyx, Amandine Geraudie, Sophie Ferrieux, Simona Bottani, Carole Roué-Jagot, Mira Didic, Florence Pasquier, Leila Sellami, Alexis Brice, Olivier Colliot, Fabienne Clot, Marc Teichmann, Didier Hannequin, Christel Thauvin-Robinet, Claire Boutoleau-Bretonnière, Julien Lagarde, Cinzia Coppola, David Wallon, Richard Levy, Marie Noguès-Lassiaille, Dario Saracino, Aurélie Funkiewiez, Maria Luisa Gorno-Tempini, Olivier Martinaud, Isabelle Le Ber, Marion Houot, Stéphane Epelbaum, Sophie Auriacombe, Alexandre Morin, Vincent Deramecourt, Ftd-Als, Philippe Couratier, Daisy Rinaldi, Saracino, Dario, Ferrieux, Sophie, Noguès-Lassiaille, Marie, Houot, Marion, Funkiewiez, Aurélie, Sellami, Leila, Deramecourt, Vincent, Pasquier, Florence, Couratier, Philippe, Pariente, Jérémie, Géraudie, Amandine, Epelbaum, Stéphane, Wallon, David, Hannequin, Didier, Martinaud, Olivier, Clot, Fabienne, Camuzat, Agnè, Bottani, Simona, Rinaldi, Daisy, Auriacombe, Sophie, Sarazin, Marie, Didic, Mira, Boutoleau-Bretonnière, Claire, Thauvin-Robinet, Christel, Lagarde, Julien, Roué-Jagot, Carole, Sellal, Françoi, Gabelle, Audrey, Etcharry-Bouyx, Frédérique, Morin, Alexandre, Coppola, Cinzia, Levy, Richard, Dubois, Bruno, Brice, Alexi, Colliot, Olivier, Luisa Gorno-Tempini, Maria, Teichmann, Marc, Migliaccio, Raffaella, Le Ber, Isabelle, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Lille, CHU Limoges, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychologie et imagerie de la mémoire humaine (NIMH), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Charles Foix [AP-HP], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), GHU AP-HP Centre Université de Paris, Hôpitaux Civils de Colmar, 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), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), University of the Study of Campania Luigi Vanvitelli, University of California [San Francisco] (UC San Francisco), University of California (UC), The research leading to these results received funding from the Investissements davenir 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), PHRC Predict-PGRN (to ILB, promotion by Assistance Publique Hôpitaux de Paris)., ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Admin, Oskar, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, 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), CHU Toulouse [Toulouse], 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), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [San Francisco] (UCSF), University of California, 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)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE)
Subjects: Oncology, medicine.medical_specialty, Apraxia, 050105 experimental psychology, Primary progressive aphasia, 03 medical and health sciences, Dementia aphasia, 0302 clinical medicine, Atrophy, Gyrus, Aphasia, Agrammatism, Internal medicine, medicine, 0501 psychology and cognitive sciences, Prospective cohort study, business.industry, 05 social sciences, respiratory system, medicine.disease, medicine.anatomical_structure, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: ObjectiveTo determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates.MethodsPatients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA.ResultsAmong the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%).ConclusionsThis study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene–specific therapies.
Published: 2021
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3. Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

Author: Fabienne Clot, Florence Pasquier, Didier Hannequin, Olivier Colliot, Armelle Rametti-Lacroux, Sophie Auriacombe, Raffaella Migliaccio, Ludmila Jornea, Marion Houot, Agnès Camuzat, Carole Azuar, Alexis Brice, Mathilde Sauvée, Philippe Martin-Hardy, Richard Levy, Philippe Couratier, Isabelle Le Ber, Jérémie Pariente, Claire Boutoleau-Bretonnière, Karim Dorgham, Dario Saracino, Bruno Dubois, Mira Didic, Daisy Rinaldi, Prev-Demals, David Wallon, Predict-PGRN study groups, Ftd-Als, Sylvie Forlani, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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), Université Lille 2 - Faculté de Médecine, CHU Limoges, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), CIC - Nantes, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), The research leading to these results received funding from the ’Investissements d’avenir’ ANR-11- INBS-0011. This work was partially funded by the Programme Hospitalier de Recherche Clinique (PHRC) Predict- PGRN (to ILB, promotion by Assistance Publique–Hôpitaux de Paris), the PHRC FTLD- exome (to ILB, promotion by Assistance Publique–Hôpitaux de Paris), by the ANR- PRTS PREV- DEMALS project (to ILB, grant number ANR-14- CE15-0016-07, promotion by Assistance Publique–Hôpitaux de Paris) and the Fondation Vaincre Alzheimer (to ILB, grant number FR-17035)., ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Faculté de Médecine Henri Warembourg - Université de Lille, 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), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Saracino, Dario, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), 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 Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Disease progression, Youden's J statistic, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Therapeutic trial, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, C9orf72, Internal medicine, Medicine, Biomarker (medicine), Surgery, Neurology (clinical), Amyotrophic lateral sclerosis, business, Trial registration, 030217 neurology & neurosurgery, 030304 developmental biology, Frontotemporal dementia
Abstract: ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (pGRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276 and NCT04014673.
Published: 2021
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4. Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72 -associated frontotemporal dementia and amyotrophic lateral sclerosis

Author: Noémie Robil, Agnès Camuzat, Vincent Anquetil, Isabelle Le Ber, Ivan Moszer, Florence Pasquier, Philippe Couratier, Emmanuelle Becker, Ludmila Jornea, David Wallon, Olivier Colliot, Dario Saracino, Sylvie Forlani, Thomas Gareau, Daisy Rinaldi, Virgilio Kmetzsch, Pierre de la Grange, Dynamics, Logics and Inference for biological Systems and Sequences (Dyliss), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Service de Neurologie [CHU Limoges], CHU Limoges, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Rouen, Université de Lille, Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), GenoSplice [Paris], FRONTLAB: Fonctions et dysfonctions de systèmes frontaux [ICM Paris] (FRONTlab), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-14-CE15-0016,PREV-DEMALS,Prédire pour prévenir les démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA)(2014), ANR-11-INBS-0013,IFB (ex Renabi-IFB),Institut français de bioinformatique(2011), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), 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), École pratique des hautes études (EPHE), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FRONTlab - Systèmes frontaux : fonctions et dysfonctions (FRONTlab), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Kmetzsch, Virgilio, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Appel à projets générique - Prédire pour prévenir les démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA) - - PREV-DEMALS2014 - ANR-14-CE15-0016 - Appel à projets générique - VALID, Infrastructures - Institut français de bioinformatique - - IFB (ex Renabi-IFB)2011 - ANR-11-INBS-0013 - INBS - VALID, Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), 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 de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), 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: Oncology, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Chromosome 9, Disease, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], C9orf72, Internal medicine, microRNA, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amyotrophic lateral sclerosis, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Mutation, business.industry, medicine.disease, [STAT.ML] Statistics [stat]/Machine Learning [stat.ML], Psychiatry and Mental health, Surgery, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: ObjectiveTo identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72 patients and presymptomatic carriers.MethodsThe PREV-DEMALS study is a prospective study including 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.ResultsFour miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72 mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.ConclusionsWe identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.Trial registration numberNCT02590276.
Published: 2020
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5. Presymptomatic spinal cord pathology in c9orf72 mutation carriers: a longitudinal neuroimaging study

Author: Olivier Colliot, Dario Saracino, Isabelle Le Ber, Agnès Camuzat, Mélanie Pélégrini-Issac, Véronique Marchand-Pauvert, Menghan Li, Daisy Rinaldi, François Salachas, Peter Bede, Mohamed-Mounir El Mendili, Giorgia Querin, Julien Cohen-Adad, Martin Catala, Pierre-François Pradat, 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), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), École Polytechnique de Montréal (EPM), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), This study was supported by the Assistance Publique – Hôpitaux de Paris (Clinical Research and Development Department) grant ANR/DGOS PRTS 2015 -2019 PrevDemAls (to I.L.B.), the 'Investissements d’avenir' ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-Investissements-Avenir Institut-Hospitalo-Universitaire-06), the Centre d’Investigation Clinique (CIC 1422), and the Centre pour l’Acquisition et le Traitement des Images (CATI) platform, at IHU-A-ICM, Paris, France. Peter Bede is supported by the Health Research Board (HRB EIA-2017-019), the Andrew Lydon scholarship, the Irish Institute of Clinical Neuroscience IICN − Novartis Ireland Research Grant, and the Iris O'Brien Foundation., ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Colliot, Olivier, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de 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), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), 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)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Pathology, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, 0302 clinical medicine, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Longitudinal Studies, Prospective Studies, Amyotrophic lateral sclerosis, medicine.diagnostic_test, Middle Aged, 3. Good health, medicine.anatomical_structure, Neurology, Spinal Cord, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], Frontotemporal Dementia, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], medicine.symptom, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Frontotemporal dementia, Adult, medicine.medical_specialty, Heterozygote, Neuroimaging, Asymptomatic, 03 medical and health sciences, Young Adult, Atrophy, Fractional anisotropy, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Aged, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, C9orf72 Protein, business.industry, Amyotrophic Lateral Sclerosis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Magnetic resonance imaging, medicine.disease, Spinal cord, 030104 developmental biology, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Corticospinal tract, Asymptomatic Diseases, Mutation, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: International audience; OBJECTIVE:C9orf72 hexanucleotide repeats expansions account for almost half of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Recent imaging studies in asymptomatic C9orf72 carriers have demonstrated cerebral white (WM) and gray matter (GM) degeneration before the age of 40 years. The objective of this study was to characterize cervical spinal cord (SC) changes in asymptomatic C9orf72 hexanucleotide carriers.METHODS:Seventy-two asymptomatic individuals were enrolled in a prospective study of first-degree relatives of ALS and FTD patients carrying the c9orf72 hexanucleotide expansion. Forty of them carried the pathogenic mutation (C9+ ). Each subject underwent quantitative cervical cord imaging. Structural GM and WM metrics and diffusivity parameters were evaluated at baseline and 18 months later. Data were analyzed in C9+ and C9- subgroups, and C9+ subjects were further stratified by age.RESULTS:At baseline, significant WM atrophy was detected at each cervical vertebral level in C9+ subjects older than 40 years without associated changes in GM and diffusion tensor imaging parameters. At 18-month follow-up, WM atrophy was accompanied by significant corticospinal tract (CST) fractional anisotropy (FA) reductions. Intriguingly, asymptomatic C9+ subjects older than 40 years with family history of ALS (as opposed to FTD) also exhibited significant CST FA reduction at baseline.INTERPRETATION:Cervical SC imaging detects WM atrophy exclusively in C9+ subjects older than 40 years, and progressive CST FA reductions can be identified on 18-month follow-up. Cervical SC magnetic resonance imaging readily captures presymptomatic pathological changes and disease propagation in c9orf72-associated conditions. ANN NEUROL 2019;86:158-167.
Published: 2019
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6. Neurite density is reduced in the presymptomatic phase of C9orf72 disease

Author: Anne Bertrand, Daisy Rinaldi, Olivier Colliot, Hui Zhang, Isabelle Le Ber, Alexandre Routier, Stanley Durrleman, Philippe Couratier, Florence Pasquier, Didier Hannequin, Daniel C. Alexander, Marion Houot, Jiaying Zhang, Junhao Wen, Sorbonne Université (SU), Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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 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 Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Pathology, medicine.medical_specialty, Neurite, business.industry, Frontotemporal lobar degeneration, Grey matter, medicine.disease, White matter, [STAT]Statistics [stat], 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Atrophy, medicine.anatomical_structure, C9orf72, Medicine, Surgery, [INFO]Computer Science [cs], Neurology (clinical), Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery, Diffusion MRI
Abstract: ObjectiveTo assess the added value of neurite orientation dispersion and density imaging (NODDI) compared with conventional diffusion tensor imaging (DTI) and anatomical MRI to detect changes in presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation.MethodsThe PREV-DEMALS (Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis) study is a prospective, multicentre, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Sixty-seven participants (38 presymptomatic C9orf72 mutation carriers (C9+) and 29 non-carriers (C9−)) were included in the present cross-sectional study. Each participant underwent one single-shell, multishell diffusion MRI and three-dimensional T1-weighted MRI. Volumetric measures, DTI and NODDI metrics were calculated within regions of interest. Differences in white matter integrity, grey matter volume and free water fraction between C9+ and C9− individuals were assessed using linear mixed-effects models.ResultsCompared with C9−, C9+ demonstrated white matter abnormalities in 10 tracts with neurite density index and only 5 tracts with DTI metrics. Effect size was significantly higher for the neurite density index than for DTI metrics in two tracts. No tract had a significantly higher effect size for DTI than for NODDI. For grey matter cortical analysis, free water fraction was increased in 13 regions in C9+, whereas 11 regions displayed volumetric atrophy.ConclusionsNODDI provides higher sensitivity and greater tissue specificity compared with conventional DTI for identifying white matter abnormalities in the presymptomatic C9orf72 carriers. Our results encourage the use of neurite density as a biomarker of the preclinical phase.Trial registration numberNCT02590276.
Published: 2019
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7. In vivo neurometabolic profiling in patients with spinocerebellar ataxia types 1, 2, 3, and 7

Author: Alexis Brice, C Jauffret, Dinesh K. Deelchand, Pierre-Gilles Henry, Daisy Rinaldi, Gülin Öz, Alexandra Durr, Tra My Nguyen, Romain Valabregue, Uzay E. Emir, Fanny Mochel, Lynn E. Eberly, and Isaac M. Adanyeguh
Subjects: Cerebellum, Pathology, medicine.medical_specialty, Ataxia, Movement disorders, business.industry, medicine.disease, Pons, Atrophy, medicine.anatomical_structure, Neurology, medicine, Cerebellar vermis, Spinocerebellar ataxia, Neurology (clinical), medicine.symptom, business, Machado–Joseph disease
Abstract: Spinocerebellar ataxias (SCAs) belong to polyglutamine repeat disorders and are characterized by a predominant atrophy of the cerebellum and the pons. Proton magnetic resonance spectroscopy (1H MRS) using an optimized semiadiabatic localization by adiabatic selective refocusing (semi-LASER) protocol was performed at 3 T to determine metabolite concentrations in the cerebellar vermis and pons of a cohort of patients with SCA1 (n = 16), SCA2 (n = 12), SCA3 (n = 21), and SCA7 (n = 12) and healthy controls (n = 33). Compared with controls, patients displayed lower total N-acetylaspartate and, to a lesser extent, lower glutamate, reflecting neuronal loss/dysfunction, whereas the glial marker, myoinositol (myo-Ins), was elevated. Patients also showed higher total creatine as reported in Huntington's disease, another polyglutamine repeat disorder. A strong correlation was found between the Scale for the Assessment and Rating of Ataxia and the neurometabolites in both affected regions of patients. Principal component analyses confirmed that neuronal metabolites (total N-acetylaspartate and glutamate) were inversely correlated in the vermis and the pons to glial (myo-Ins) and energetic (total creatine) metabolites, as well as to disease severity (motor scales). Neurochemical plots with selected metabolites also allowed the separation of SCA2 and SCA3 from controls. The neurometabolic profiles detected in patients underlie cell-specific changes in neuronal and astrocytic compartments that cannot be assessed by other neuroimaging modalities. The inverse correlation between metabolites from these two compartments suggests a metabolic attempt to compensate for neuronal damage in SCAs. Because these biomarkers reflect dynamic aspects of cellular metabolism, they are good candidates for proof-of-concept therapeutic trials. © 2015 International Parkinson and Movement Disorder Society
Published: 2015
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8. A double-blind, placebo-controlled trial of triheptanoin in adult polyglucosan body disease and open-label, long-term outcome

Author: Isabelle Ledoux, Derek M. Blankenship, Raphael Schiffmann, Karine Martin, H. Orhan Akman, Mary E. Wallace, Marie-Pierre Luton, Jacob Turner, Scott Coleman, Daisy Rinaldi, Fanny Mochel, and Jean-Yves Hogrel
Subjects: 0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Placebo-controlled study, Walk Test, Walking, Placebo, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Disability Evaluation, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, Genetics, medicine, Humans, Genetics (clinical), Triglycerides, Aged, Cross-Over Studies, business.industry, Adult polyglucosan body disease, Middle Aged, Glycogen Storage Disease, Crossover study, Confidence interval, Triheptanoin, 030104 developmental biology, Treatment Outcome, chemistry, Cohort, Regression Analysis, Female, Nervous System Diseases, business, 030217 neurology & neurosurgery
Abstract: Adult polyglucosan body disease (APBD) is a progressive neurometabolic disorder caused by a deficiency of glycogen branching enzyme. We tested the efficacy of triheptanoin as a therapy for patients with APBD based on the hypothesis that decreased glycogen degradation leads to brain energy deficit. This was a two-site, randomized crossover trial of 23 patients (age 35–73 years; 63% men) who received triheptanoin or vegetable oil as placebo. The trial took place over 1 year and was followed by a 4-year open-label phase. Generalized linear mixed models were used to analyze this study. At baseline, using the 6-min walk test, patients could walk a mean of 389 ± 164 m (range 95–672; n = 19), highlighting the great clinical heterogeneity of our cohort. The overall mean difference between patients on triheptanoin versus placebo was 6 m; 95% confidence interval (CI) −11 to 22; p = 0.50. Motion capture gait analysis, gait quality, and stair climbing showed no consistent direction of change. All secondary endpoints were statistically nonsignificant after false discovery rate adjustment. Triheptanoin was safe and generally well tolerated. During the open-label phase of the study, the most affected patients at baseline kept deteriorating while mildly disabled patients remained notably stable up to 4 years. We cannot conclude that triheptanoin was effective in the treatment of APBD over a 6-month period, but we found it had a good safety profile. This study also emphasizes the difficulty of conducting trials in very rare diseases presenting with a wide clinical heterogeneity. ClinicalTrials.gov Identifier: NCT00947960.
Published: 2017

9. [P3–364]: ACCELERATED SUBCORTICAL ATROPHY DURING AGING IN PRESYMPTOMATIC CARRIERS OF C9ORF72 MUTATION

Author: Florence Pasquier, Agnès Camuzat, Anne Bertrand, Daisy Rinaldi, Junhao Wen, Alexandre Routier, Sabrina Fontanella, Philippe Couratier, Olivier Colliot, Alexis Brice, Stanley Durrleman, Olivier Martinaud, and Isabelle Le Ber
Subjects: Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Subcortical atrophy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, C9orf72, Mutation (genetic algorithm), medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2017
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10. Low cancer prevalence in polyglutamine expansion diseases

Author: Ouahid Lagha Boukbiza, Daisy Rinaldi, Mathieu Anheim, Alhassane Diallo, Perrine Charles, Alexis Brice, Alina Tataru, Morgane Sonia Thion, Cecilia Marelli, Alexandra Durr, Fabienne Calvas, Sandrine Humbert, Claire Ewenczyk, Fanny Mochel, Giulia Coarelli, Christine Tranchant, Marie-Lorraine Monin, Sophie Tezenas du Montcel, Bertrand Carlander, Maya Tchikviladzé, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (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)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (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)-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), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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), 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 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), 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), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (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)-École normale supérieure - Paris (ENS Paris), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (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), Sorbonne Université (SU)-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)-Centre National de la Recherche Scientifique (CNRS)-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), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Pathology, [SDV]Life Sciences [q-bio], Population, Disease, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Neoplasms, Medicine, Humans, Spinocerebellar Ataxias, Genetic Predisposition to Disease, education, Retrospective Studies, education.field_of_study, business.industry, Neurodegeneration, Retrospective cohort study, Middle Aged, medicine.disease, Confidence interval, 3. Good health, Europe, 030104 developmental biology, Huntington Disease, Spinocerebellar ataxia, Female, Neurology (clinical), Skin cancer, business, Carcinogenesis, Peptides, 030217 neurology & neurosurgery
Abstract: Objective:Polyglutamine (PolyQ) diseases are dominantly transmitted neurologic disorders, caused by coding and expanded CAG trinucleotide repeats. Cancer was reported retrospectively to be rare in patients with PolyQ diseases and we aimed to investigate its prevalence in France.Methods:Consecutive patients with Huntington disease (HD) and spinocerebellar ataxia (SCA) were questioned about cancer, cardiovascular diseases, and related risk factors in 4 university hospitals in Paris, Toulouse, Strasbourg, and Montpellier. Standardized incidence ratios (SIR), based on age- and sex-adjusted rate of the French population, were assessed for different types of cancer.Results:We questioned 372 patients with HD and 134 patients with SCA. SIR showed significantly reduced risk of cancer in HD: 23 observed cases vs 111.05 expected ones (SIR 0.21, 95% confidence interval [CI] 0.13–0.31), as well as in SCA: 7 observed cases vs 34.73 expected (SIR 0.23, 95% CI 0.08–0.42). This was surprising since risk behavior for cancer was increased in these patients, with significantly greater tobacco and alcohol consumption in patients with HD vs patients with SCA (p < 0.0056). There was no association between CAG repeat size and cancer or cardiovascular disease. However, in patients with HD, skin cancers were more frequent than expected (5 vs 0.98, SIR 5.11, 95% CI 1.65–11.95).Conclusions:There was a decreased cancer rate in PolyQ diseases despite high incidence of risk factors. Intriguingly, skin cancer incidence was higher, suggesting a crosstalk between neurodegeneration and skin tumorigenesis.
Published: 2016
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11. Abnormal response to cortical activation in early stages of Huntington disease

Author: Daisy Rinaldi, Tra My Nguyen, Pierre-Gilles Henry, Dinesh K. Deelchand, Fanny Mochel, Alexandra Durr, Pierre G. Carlier, Romain Valabregue, and Claire Wary
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Stimulation, Disease, 3. Good health, Cortex (botany), Phosphocreatine, 03 medical and health sciences, chemistry.chemical_compound, Adenosine diphosphate, 0302 clinical medicine, Inorganic phosphate, Endocrinology, Neurology, chemistry, In vivo, Internal medicine, Medicine, Neurology (clinical), business, Adenosine triphosphate, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Background: We wished to identify noninvasive in vivo biomarkers of brain energy deficit in Huntington disease. Methods: We studied 15 early affected patients (mean motor United Huntington Disease Rating Scale, 18 ± 9) and 15 age- and sex-matched controls. We coupled 31phosphorus nuclear magnetic resonance spectroscopy with activation of the occipital cortex in order to measure the relative concentrations of adenosine triphosphate, phosphocreatine, and inorganic phosphate before, during, and after visual stimulation. Results: In controls, we observed an 11% increase in the inorganic phosphate/phosphocreatine ratio (P = .024) and a 13% increase in the inorganic phosphate/adenosine triphosphate ratio (P = .016) during brain activation, reflecting increased adenosine diphosphate concentrations. Subsequently, controls had a return to baseline levels during recovery (P = .012 and .022, respectively). In contrast, both ratios were unchanged in patients during and after visual stimulation. Conclusions: 31Phosphorus nuclear magnetic resonance spectroscopy could provide functional biomarkers of brain energy deficit to monitor therapeutic efficacy in Huntington disease. © 2012 Movement Disorder Society
Published: 2012
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12. Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency

Author: Laurent Servais, Bénédicte Héron, Sandrine Vuillaumier, Elsa Kaphan, Domitille Gras, Emmanuel Roze, Raphael Schiffmann, Romain Valabregue, Elodie Hainque, Samantha Caillet, Chris Ottolenghi, Isaac M. Adanyeguh, Agathe Roubertie, Fanny Mochel, Jean-Yves Hogrel, Daisy Rinaldi, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neuropédiatrie [Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, CHU Trousseau [APHP], Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie Hormonale et Génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Baylor Research Institute, Baylor College of Medecine, Université Paris Descartes - Paris 5 (UPD5), Laboratoire de Biochimie Métabolique, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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], Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service d'Explorations Fonctionnelles Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Service de diabétologie [CHU Pitié-Salpétrière], Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre de Neuro-Imagerie de Recherche ( CENIR ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université Paris Descartes - Paris 5 ( UPD5 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), 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)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Centre de Neuro-Imagerie de Recherche (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuroradiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Diabétologie [CHU Pitié-Salpétrière], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, 0301 basic medicine, Motor disorder, Magnetic Resonance Spectroscopy, Movement disorders, Phosphocreatine, Pilot Projects, chemistry.chemical_compound, 0302 clinical medicine, Young adult, Child, Glucose Transporter Type 1, Movement Disorders, Middle Aged, 3. Good health, Triheptanoin, Psychiatry and Mental health, METABOLIC DISEASE, Cardiology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Occipital Lobe, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Phosphates, Young Adult, 03 medical and health sciences, Chorea, Internal medicine, medicine, Humans, Triglycerides, business.industry, Functional Neuroimaging, Therapeutic effect, medicine.disease, Surgery, 030104 developmental biology, chemistry, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Energy Metabolism, business, Occipital lobe, 030217 neurology & neurosurgery
Abstract: Objective:On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. Methods:We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7–47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional31P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. Results:Patients with GLUT1-DS experienced a mean of 30.8 (±27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (±2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (±21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when triheptanoin was withdrawn. Conclusions:Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS. Trial registration number:NCT02014883.
Published: 2016
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13. Expanded neurochemical profile in the early stage of Huntington disease using proton magnetic resonance spectroscopy

Author: Pierre-Gilles Henry, Alexandra Durr, Fanny Mochel, Stéphane Lehéricy, Isaac M. Adanyeguh, Leorah Freeman, Daisy Rinaldi, Marie Lorraine Monin, 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), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, 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, medicine.medical_specialty, Movement disorders, Proton Magnetic Resonance Spectroscopy, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Striatum, Neurotransmission, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, Neurochemical, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Spectroscopy, Visual Cortex, 2. Zero hunger, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Glutamate receptor, Middle Aged, Neostriatum, Glutamine, Huntington Disease, Endocrinology, Visual cortex, medicine.anatomical_structure, Metabolome, Molecular Medicine, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; The striatum is a well-known region affected in Huntington disease (HD). However, other regions, including the visual cortex, are implicated. We have identified previously an abnormal energy response in the visual cortex of patients at an early stage of HD using 31P magnetic resonance spectroscopy (31P MRS). We therefore sought to further characterize these metabolic alterations with 1H MRS using a well-validated semi-localized by adiabatic selective refocusing (semi-LASER) sequence that allows the measurement of an expanded number of neurometabolites. Ten early affected patients [Unified Huntington Disease Rating Scale (UHDRS), total motor score = 13.6 ± 10.8] and 10 healthy volunteers of similar age and body mass index (BMI) were recruited for the study. We performed 1H MRS in the striatum – the region that is primarily affected in HD – and the visual cortex. The protocol allowed a reliable quantification of 10 metabolites in the visual cortex and eight in the striatum, compared with three to five metabolites in previous 1H MRS studies performed in HD. We identified higher total creatine (p < 0.05) in the visual cortex and lower glutamate (p < 0.001) and total creatine (p < 0.05) in the striatum of patients with HD compared with controls. Less abundant neurometabolites [glutamine, γ-aminobutyric acid (GABA), glutathione, aspartate] showed similar concentrations in both groups. The protocol allowed the measurement of several additional metabolites compared with standard vendor protocols. Our study points to early changes in metabolites involved in energy metabolism in the visual cortex and striatum of patients with HD. Decreased striatal glutamate could reflect early neuronal dysfunction or impaired glutamatergic neurotransmission.
Published: 2018
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14. G13 Abnormal responses to visual cortex activation in early stage Huntington disease patients using 31P-NMR spectroscopy

Author: Daisy Rinaldi, Fanny Mochel, Claire Wary, T-M Nguyen, Alexandra Durr, P-G Henry, Romain Valabregue, Dinesh K. Deelchand, and Pierre G. Carlier
Subjects: medicine.medical_specialty, Pathology, ATP synthase, biology, Bioenergetics, business.industry, Stimulation, Stimulus (physiology), Phosphocreatine, Psychiatry and Mental health, chemistry.chemical_compound, Visual cortex, medicine.anatomical_structure, Endocrinology, chemistry, In vivo, Internal medicine, biology.protein, Pi, medicine, Surgery, Neurology (clinical), business
Abstract: Objective To test the hypothesis that brain energy metabolism is abnormal in patients at an early stage of Huntington disease (HD). Background Energy metabolism has been a major focus of HD research for many years due to several observations in both patients and models of the disease. However, there are currently no in vivo biomarkers of brain energy metabolism in HD. Methods We coupled noninvasive 31P-NMR spectroscopy with activation of the occipital cortex in order to measure the levels of ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) before, during and after a visual stimulus. We studied 15 HD patients at an early stage of the disease (mean motor UHDRS =18±9) and 15 age- and sex-matched controls. Results In controls, we observed an 11% increase in Pi/PCr ratio (p=0.024) and a 13% increase in Pi/ATP ratio (p=0.016) during brain activation, reflecting increased ATP synthesis and ADP levels. Subsequently, controls had a return to baseline levels during recovery (p=0.012 et 0.022 respectively). In HD patients, both Pi/PCr and Pi/ATP ratios were unchanged during and after visual stimulation, reflecting altered mitochondrial bioenergetics. In addition, in HD patients the ratio of Pi/ATP correlated with the UHDRS score during the activation (p=0.014) and recovery periods (p=0.009), while Pi/PCr ratio correlated with the UHDRS score during recovery (p=0.016), reflecting a correlation between brain energy metabolism and disease severity in HD. Conclusions 31Phosphorus nuclear magnetic resonance spectroscopy could provide functional biomarkers of brain energy deficit to monitor therapeutic efficacy in Huntington disease.
Published: 2012
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15. Abnormal Responses to Visual Cortex Activation in Early Stage Huntington Disease Patients Using 31P-NMR Spectroscopy (P06.033)

Author: Fanny Mochel, Tra-My Nguyen, Claire Wary, Romain Valabregue, Pierre G. Carlier, Dinesh K. Deelchand, Alexandra Durr, Pierre-Gilles Henry, and Daisy Rinaldi
Subjects: medicine.medical_specialty, ATP synthase, biology, Bioenergetics, business.industry, Stimulation, Disease, Phosphocreatine, chemistry.chemical_compound, Endocrinology, chemistry, In vivo, Internal medicine, biology.protein, Pi, medicine, Neurology (clinical), Trinucleotide repeat expansion, business, Neuroscience
Abstract: Objective: To test the hypothesis that brain energy metabolism is abnormal in patients at an early stage of Huntington disease (HD). Background HD is an autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the HTT gene. Energy metabolism has been a major focus of HD research for many years due to several observations in both patients and models of the disease. However, there are currently no in vivo biomarkers of brain energy metabolism in HD. Design/Methods: We coupled noninvasive 31P-nuclear magnetic resonance spectroscopy (NMRS) with activation of the occipital cortex in order to measure the levels of ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) before, during and after a visual stimulus. We studied 15 HD patients at an early stage of the disease (mean motor UHDRS= 18 ±9) and 15 age- and sex-matched controls. Results: In controls, we observed an 11% increase in Pi/PCr ratio (p=0.012) and a 13% increase in Pi/ATP ratio (p=0.008) during brain activation, reflecting increased ATP synthesis and ADP levels. Subsequently, controls had a return to baseline levels during recovery (p=0.006 et 0.011 respectively). In HD patients, both Pi/PCr and Pi/ATP ratios were unchanged during and after visual stimulation, reflecting altered mitochondrial bioenergetics. In addition, in HD patients the ratio of Pi/ATP correlated with the UHDRS score during the activation (p=0.014) and recovery periods (p=0.009), while Pi/PCr ratio correlated with the UHDRS score during recovery (p=0.016), reflecting a correlation between brain energy metabolism and disease severity in HD. Conclusions: We have identified noninvasive functional biomarkers of brain energy deficit to assess therapeutic efficacy in HD. We are now extending our 31P-NMRS studies to presymptomatic individuals. Disclosure: Dr. Mochel has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Deelchand has nothing to disclose. Dr. Rinaldi has nothing to disclose. Dr. Valabregue has nothing to disclose. Dr. Wary has nothing to disclose. Dr. Carlier has nothing to disclose. Dr. Durr has nothing to disclose. Dr. Henry has nothing to disclose.
Published: 2012
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16. Early Cognitive, Structural, and Microstructural Changes in Presymptomatic C9orf72 Carriers Younger Than 40 Years

Author: Isabelle Le Ber, Clémence Fournier, Junhao Wen, Sabrina Sayah, Alexis Brice, Richard Levy, Daisy Rinaldi, Bruno Dubois, Stanley Durrleman, Didier Hannequin, Anne Bertrand, Alexandre Routier, Florence Pasquier, Philippe Couratier, Olivier Colliot, M.-O. Habert, Marion Houot, Paola Caroppo, Sabrina Fontanella, Olivier Martinaud, and Agnès Camuzat
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Population, Neuropsychological Tests, Cohort Studies, White matter, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Internal medicine, Image Processing, Computer-Assisted, medicine, Humans, Amyotrophic lateral sclerosis, education, Aged, education.field_of_study, C9orf72 Protein, medicine.diagnostic_test, business.industry, Neuropsychology, Brain, Magnetic resonance imaging, Frontotemporal lobar degeneration, Middle Aged, medicine.disease, Magnetic Resonance Imaging, White Matter, 030104 developmental biology, medicine.anatomical_structure, Asymptomatic Diseases, Mutation, Female, Neurology (clinical), Cognition Disorders, business, 030217 neurology & neurosurgery, Diffusion MRI
Abstract: Importance Presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation, the most frequent genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. Objectives To assess the occurrence of cognitive, structural, and microstructural changes in presymptomatic C9orf72 carriers. Design, Setting, and Participants The PREV-DEMALS study is a prospective, multicenter, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Eighty-four participants entered the study between October 2015 and April 2017; 80 (95%) were included in cross-sectional analyses of baseline data. All participants underwent neuropsychological testing and magnetic resonance imaging; 63 (79%) underwent diffusion tensor magnetic resonance imaging. Gray matter volumes and diffusion tensor imaging metrics were calculated within regions of interest. Anatomical and microstructural differences between individuals who carried the C9orf72 mutation (C9+) and those who did not carry the C9orf72 mutation (C9−) were assessed using linear mixed-effects models. Data were analyzed from October 2015 to April 2017. Main Outcomes and Measures Differences in neuropsychological scores, gray matter volume, and white matter integrity between C9+ and C9− individuals. Results Of the 80 included participants, there were 41 C9+ individuals (24 [59%] female; mean [SD] age, 39.8 [11.1] years) and 39 C9− individuals (24 [62%] female; mean [SD] age, 45.2 [13.9] years). Compared with C9− individuals, C9+ individuals had lower mean (SD) praxis scores (163.4 [6.1] vs 165.3 [5.9]; P = .01) and intransitive gesture scores (34.9 [1.6] vs 35.7 [1.5]; P = .004), atrophy in 8 cortical regions of interest and in the right thalamus, and white matter alterations in 8 tracts. When restricting the analyses to participants younger than 40 years, compared with C9− individuals, C9+ individuals had lower praxis scores and intransitive gesture scores, atrophy in 4 cortical regions of interest and in the right thalamus, and white matter alterations in 2 tracts. Conclusions and Relevance Cognitive, structural, and microstructural alterations are detectable in young C9+ individuals. Early and subtle praxis alterations, underpinned by focal atrophy of the left supramarginal gyrus, may represent an early and nonevolving phenotype related to neurodevelopmental effects of C9orf72 mutation. White matter alterations reflect the future phenotype of frontotemporal lobar degeneration/amyotrophic lateral sclerosis, while atrophy appears more diffuse. Our results contribute to a better understanding of the preclinical phase of C9orf72 disease and of the respective contribution of magnetic resonance biomarkers. Trial Registration clinicaltrials.gov Identifier: NCT02590276
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16 results on '"Daisy, Rinaldi"'

1. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

2. Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant

3. Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

4. Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72 -associated frontotemporal dementia and amyotrophic lateral sclerosis

5. Presymptomatic spinal cord pathology in c9orf72 mutation carriers: a longitudinal neuroimaging study

6. Neurite density is reduced in the presymptomatic phase of C9orf72 disease

7. In vivo neurometabolic profiling in patients with spinocerebellar ataxia types 1, 2, 3, and 7

8. A double-blind, placebo-controlled trial of triheptanoin in adult polyglucosan body disease and open-label, long-term outcome

9. [P3–364]: ACCELERATED SUBCORTICAL ATROPHY DURING AGING IN PRESYMPTOMATIC CARRIERS OF C9ORF72 MUTATION

10. Low cancer prevalence in polyglutamine expansion diseases

11. Abnormal response to cortical activation in early stages of Huntington disease

12. Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency

13. Expanded neurochemical profile in the early stage of Huntington disease using proton magnetic resonance spectroscopy

14. G13 Abnormal responses to visual cortex activation in early stage Huntington disease patients using 31P-NMR spectroscopy

15. Abnormal Responses to Visual Cortex Activation in Early Stage Huntington Disease Patients Using 31P-NMR Spectroscopy (P06.033)

16. Early Cognitive, Structural, and Microstructural Changes in Presymptomatic C9orf72 Carriers Younger Than 40 Years

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