Author: "Didier Hannequin" / Topic: neurology (clinical) - Searchworks@Jio Institute Digital Library Search Results

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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

2. Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers

Author: Isabelle Le Ber, Marie Sarazin, Olivier Quenez, Florence Clavaguera, Catherine Schramm, Anne Rovelet-Lecrux, Camille Heitz, Mathieu Mula, Stéphane Epelbaum, Susana Boluda, Charles Duyckaerts, Manon Thierry, Didier Hannequin, Magalie Lecourtois, Serge Marty, Michel Bottlaender, Julien Lagarde, David Wallon, Natsuko Nakamura, François Sellal, Antoine Bonnevalle, Laetitia Miguel, Gaël Nicolas, Stéphane Rousseau, Dominique Campion, Thérèse Rivasseau Jonveaux, Aline Zarea, Eloi Magnin, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurologie de la mémoire et du langage [CHU Ste Anne], Université Paris Descartes - Paris 5 (UPD5), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité BioMaps (BIOMAPS), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Proband, Adult, Male, Pathology, medicine.medical_specialty, Heterozygote, [SDV]Life Sciences [q-bio], Tau protein, tau Proteins, Pathology and Forensic Medicine, Progressive supranuclear palsy, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Extrapyramidal symptoms, Alzheimer Disease, Basal ganglia, medicine, Humans, Cognitive Dysfunction, Age of Onset, ComputingMilieux_MISCELLANEOUS, Inclusion Bodies, biology, business.industry, Brain, Middle Aged, medicine.disease, 030104 developmental biology, Tauopathies, Chromosomal region, biology.protein, Female, Neurology (clinical), Tauopathy, Alzheimer's disease, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.
Published: 2021

3. Comparison of Pittsburgh compound B and florbetapir in cross‐sectional and longitudinal studies

Author: William S. Brooks, Ivonne Jimenez-Velazques, Jérémie Pariente, Andrei G. Vlassenko, William E. Klunk, Robert A. Koeppe, Serge Gauthier, Smiljana Milosavljevic-Ristic, Guoqiao Wang, Michel Bottlaender, Roger Clarnette, Shauna H. Yuan, Raquel Sánchez-Valle, Russ C. Hornbeck, Ging-Yuek Robin Hsiung, Gregory Klein, Clifford R. Jack, Colin L. Masters, Nelly Joseph-Mathurin, Bruno Dubois, Barbara J. Snider, Shaney Flores, Douglas Galasko, David Wallon, Chengjie Xiong, Tammie L.S. Benzinger, Stephen Salloway, Christopher H. van Dyck, Sarah B. Berman, Brian A. Gordon, Catherine J. Mummery, Michael J. Fulham, John C. Morris, Yi Su, John M. Ringman, Randall J. Bateman, Jared R. Brosch, Martin R. Farlow, Benjamin Speidel, Suman Jayadev, Erik D. Roberson, Didier Hannequin, Lawrence S. Honig, Eric McDade, and Mario Masellis
Subjects: Positron emission tomography, Multivariate statistics, Amyloid, PiB, Amyloid pet, Neuroimaging, lcsh:Geriatrics, Imaging data, lcsh:RC346-429, Amyloid imaging, White matter, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Nuclear magnetic resonance, Genetics, medicine, Centiloid, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, business.industry, Significant difference, Neurosciences, Florbetapir, lcsh:RC952-954.6, Psychiatry and Mental health, medicine.anatomical_structure, chemistry, Neurology (clinical), business, Pittsburgh compound B, 030217 neurology & neurosurgery
Abstract: Introduction Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B–based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally. Results Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.
Published: 2019

4. Nucleus Basalis of Meynert Stimulation for Lewy Body Dementia: A Phase I Randomized Clinical Trial

Author: Julie Bourilhon, Olivier Godefroy, Luc Defebvre, Didier Hannequin, Romain Lefaucheur, Stéphane Derrey, Stéphane Thobois, Pierre Vera, Jean-Luc Houeto, Kathy Dujardin, André Gillibert, David Wallon, Teodor Danaila, Olivier Martinaud, Pierre Krystkowiak, Marie-Laure Welter, Mathieu Chastan, David Maltête, Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), and Normandie Université (NU)
Subjects: Male, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Deep Brain Stimulation, MESH: Mental Recall, Stimulation, Neuropsychological Tests, Nucleus basalis, law.invention, Lingual gyrus, 0302 clinical medicine, Postoperative Complications, Randomized controlled trial, MESH: Fluorodeoxyglucose F18, law, MESH: Postoperative Complications, MESH: Double-Blind Method, 030212 general & internal medicine, MESH: Treatment Outcome, MESH: Aged, MESH: Middle Aged, Cross-Over Studies, Brain, MESH: Neuropsychological Tests, Middle Aged, MESH: Positron-Emission Tomography, surgical procedures, operative, Implantable Neurostimulators, Treatment Outcome, Anesthesia, Basal Nucleus of Meynert, MESH: Basal Nucleus of Meynert, therapeutics, MESH: Radiopharmaceuticals, Lewy Body Disease, Deep brain stimulation, MESH: Sleep, MESH: Prosthesis Implantation, behavioral disciplines and activities, MESH: Cross-Over Studies, Article, Prosthesis Implantation, MESH: Brain, 03 medical and health sciences, Double-Blind Method, Fluorodeoxyglucose F18, medicine, Dementia, Humans, MESH: Lewy Body Disease, Aged, MESH: Humans, Lewy body, business.industry, medicine.disease, MESH: Male, MESH: Implantable Neurostimulators, nervous system diseases, nervous system, Positron-Emission Tomography, Mental Recall, Neurology (clinical), MESH: Deep Brain Stimulation, Radiopharmaceuticals, business, Sleep, 030217 neurology & neurosurgery, Stroop effect
Abstract: ObjectivesNucleus basalis of Meynert deep brain stimulation (NBM-DBS) has been proposed for patients with dementia. Here, we aim to assess the safety and effects of NBM-DBS in patients with Lewy body dementia (LBD), in a randomized, double-blind, crossover clinical trial.MethodsSix patients with mild to moderate LBD (mean [SD] age, 62.2 [7.8] years) were included, operated on for bilateral NBM-DBS, and assigned to receive either active or sham NBM-DBS followed by the opposite condition for 3 months. The primary outcome was the difference in the total free recalls of the Free and Cued Selective Reminding Test (FCSRT) between active and sham NBM-DBS. Secondary outcomes were assessments of the safety and effects of NBM-DBS on cognition, motor disability, sleep, and PET imaging.ResultsThere was no significant difference in the FCSRT score with active vs sham NBM-DBS. The surgical procedures were well tolerated in all patients, but we observed significant decreases in Stroop and Benton scores after electrode implantation. We observed no significant difference in other scales between active and sham NBM-DBS. With active NBM-DBS relative to baseline, phonemic fluency and motor disability significantly decreased. Lastly, the superior lingual gyrus metabolic activity significantly increased with active NBM-DBS.ConclusionsNBM-DBS does not appear to be totally safe for patients with LBD with no evidence of cognitive benefit.ClinicalTrials.gov IdentifierNCT01340001.Classification of EvidenceThis study provides Class II evidence that, for patients with LBD operated on for bilateral NBM-DBS, active NBM-DBS stimulation compared to sham stimulation did not significantly change selective recall scores.
Published: 2021

5. 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

6. 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

7. Overview of dominantly inherited AD and top‐line DIAN‐TU results of solanezumab and gantenerumab

Author: Didier Hannequin, Jared R. Brosch, B. Joy Snider, Anna Santacruz, Anne M. Fagan, Suman Jayadev, William S. Brooks, Colin L. Masters, Erik D. Roberson, Mario Masellis, Susan Mills, Christopher H. Dyck, Florence Pasquier, Paulo Fontoura, Bruno Dubois, Monika Baudler, Lawrence S. Honig, Doug R. Galasko, James J. Lah, Peter J. Snyder, David Wallon, Geoffrey A. Kerchner, Eric McDade, Guoqiao Wang, Andrew J. Aschenbrenner, Jason Hassenstab, Roy Yaari, Ghulam M. Surti, Raquel Sánchez-Valle, Jérémie Pariente, Stephen Salloway, Carlos Cruchaga, Randall J. Bateman, Ivonne Z. Jimenez-Velazquez, Robert A. Koeppe, John C. Morris, Serge Gauthier, Clifford R. Jack, Sarah B. Berman, Alison Goate, Catherine J. Mummery, Martin R. Farlow, Karen C. Holdridge, Rachelle S. Doody, Tammie L.S. Benzinger, Scott W. Andersen, Chengjie Xiong, Ging-Yuek Robin Hsiung, Roger Clarnette, Paul Delmar, Maïté Formaglio, Mark A. Mintun, Kelley Coalier, John R. Sims, Brian A. Gordon, and David B. Clifford
Subjects: Physics, Epidemiology, Health Policy, Geometry, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Solanezumab, Geriatrics and Gerontology, Line (text file), Gantenerumab, medicine.drug
Published: 2020

8. Phenotypes associated with MAPT duplications

Author: Stéphane Epelbaum, Muriel Quillard-Muraine, David Wallon, Dominique Campion, François Sellal, Antoine Bonnevalle, Gaël Nicolas, Michel Bottlaender, Susana Boluda, Marie Sarazin, Camille Heitz, Isabelle Le Ber, Didier Hannequin, Thérèse Rivasseau Jonveaux, Anne-Claire Richard, Anne Rovelet-Lecrux, Stéphane Rousseau, Charles Duyckaerts, Julien Lagarde, Olivier Quenez, Camille Charbonnier, Eloi Magnin, and Mathieu Chastan
Subjects: Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology, Biology, Phenotype
Published: 2020

9. Solanezumab in‐depth outcomes

Author: Roger Clarnette, Ivonne Z. Jimenez-Velazquez, Ghulam M. Surti, Suman Jayadev, Anne M. Fagan, Clifford R. Jack, Peter J. Snyder, Christopher H. van Dyck, Erik D. Roberson, Guoqiao Wang, Mario Masellis, David B. Clifford, Chengjie Xiong, Randall J. Bateman, Jérémie Pariente, Tammie L.S. Benzinger, Ging-Yuek Robin Hsiung, Serge Gauthier, Rachelle S. Doody, Paul Delmar, Didier Hannequin, Doug R. Galasko, Sarah B. Berman, Florence Pasquier, Robert A. Koeppe, James J. Lah, Carlos Cruchaga, Paulo Fontoura, Alison Goate, Eric McDade, Raquel Sánchez-Valle, David Wallon, Dian‐Tu Study Team, Catherine J. Mummery, Colin L. Masters, Jared R. Brosch, Maïté Formaglio, B. Joy Snider, Susan Mills, Monika Baudler, Lawrence S. Honig, Bruno Dubois, John C. Morris, Kelley Coalier, Brian A. Gordon, Stephen Salloway, Andrew J. Aschenbrenner, Jason Hassenstab, Anna Santacruz, William S. Brooks, Geoffrey A. Kerchner, and Martin R. Farlow
Subjects: Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Solanezumab, Geriatrics and Gerontology, business, Gantenerumab, medicine.drug
Published: 2020

10. Neurobiol Aging

Author: Pascaline Cassagnaud, David Wallon, Vincent Deramecourt, Florence Pasquier, Didier Hannequin, NeuroCEB Brain Bank, Thibaud Lebouvier, Sophie Auriacombe, Bruno Dubois, Mathieu Ceccaldi, Claude-Alain Maurage, Isabelle Le Ber, Marie Sarazin, Florence Lebert, Maxime Bertoux, Bordeaux population health (BPH), and 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)
Subjects: Male, 0301 basic medicine, Aging, Pathology, medicine.medical_specialty, Amnesia, Autopsy, Disease, Neuropsychological Tests, SEPIA, 03 medical and health sciences, Cognition, 0302 clinical medicine, Alzheimer Disease, Memory, Predictive Value of Tests, medicine, Humans, Dementia, Cognitive decline, Pathological, Aged, Cued speech, Verbal Behavior, business.industry, General Neuroscience, Middle Aged, medicine.disease, 030104 developmental biology, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Cues, Geriatrics and Gerontology, Verbal memory, medicine.symptom, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Amnesia is a key component of Alzheimer's disease (AD) and the most important feature of its clinical diagnosis but its specificity has recently been challenged. This study investigated the ability of amnesia to predict AD in a clinicopathological dementia series. Ninety-one patients to which free and cued verbal memory assessment was administered during early cognitive decline, were followed until autopsy. Patients' histological diagnoses were classified as pure AD, mixed AD, and non-AD pathologies. Data-driven automated classification procedures explored the correspondence between memory performance and pathological diagnoses. Classifications revealed 3 clusters of performance reflecting different levels of amnesia. Little correspondence between these clusters and the presence of AD pathology was retrieved. A third of patients with pure/mixed AD pathology were non-amnesic at presentation and ≈45% of patients without AD pathology were amnesic. Data-driven prediction of AD pathology based on memory also had a poor accuracy. Free and cued memory assessments are fair tools to diagnose an amnesic syndrome but lack accuracy to predict AD pathology.
Published: 2020

11. Relevance of Follow-Up in Patients with Core Clinical Criteria for Alzheimer Disease and Normal CSF Biomarkers

Author: Olivier Vercruysse, Claire Paquet, Audrey Gabelle, Xavier Delbeuck, Frederic Blanc, David Wallon, Julien Dumurgier, Eloi Magnin, Olivier Martinaud, Barbara Jung, Olivier Bousiges, Sylvain Lehmann, Constance Delaby, Muriel Quillard-Murain, Katell Peoc`h, Jean-Louis Laplanche, Elodie Bouaziz-Amar, Didier Hannequin, Bernard Sablonniere, Luc Buee, Jacques Hugon, Susanna Schraen, Florence Pasquier, Stephanie Bombois, null for the e-PLM group, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Strasbourg (UNISTRA), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Plateforme de Protéomique Clinique, CHU Saint-Eloi, Université Paris Diderot - Paris 7 (UPD7), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille, Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], tau Proteins, 030218 nuclear medicine & medical imaging, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Internal medicine, medicine, Humans, Dementia, Cognitive Dysfunction, Diagnostic Errors, Phosphorylation, Vascular dementia, ComputingMilieux_MISCELLANEOUS, Depression (differential diagnoses), Aged, Retrospective Studies, Hippocampal sclerosis, Amyloid beta-Peptides, business.industry, Brain, medicine.disease, Peptide Fragments, 3. Good health, Neurology, Mood disorders, Biomarker (medicine), Female, Neurology (clinical), Alzheimer's disease, business, Biomarkers, 030217 neurology & neurosurgery, Follow-Up Studies, Frontotemporal dementia
Abstract: Background: Few patients with a normal cerebrospinal fluid (CSF) biomarker profile fulfill the clinical criteria for Alzheimer disease (AD). Objective: The aim of this study was to test the hypothesis of misdiagnoses for these patients. Method: Patients from the e-PLM centers fulfilling the core clinical criteria for probable AD dementia or mild cognitive impairment due to AD (AD-MCI), with normal CSF Aβ1-42, T-tau and P-tau biomarkers and clinical follow-up, were included. Clinical and imaging data were reviewed by an independent board, from baseline (visit with clinical evaluation and CSF analysis) to the end of the follow-up, for a final diagnosis. Results: In the e-PLM cohort of 1098 AD patients with CSF analysis, 37 (3.3%) patients (20 with AD dementia core clinical criteria and 17 with AD-MCI core clinical criteria) had normal CSF biomarker profile and a clinical follow-up. All patients presented with episodic memory impairment and 27 (73%) had medial temporal lobe atrophy on MRI-scan. After a median follow-up of 36 months (range 7-74), the final diagnosis was AD MCI or dementia for 9 (24%) patients, and unlikely due to AD for 28 (76%) patients. A misdiagnosis was corrected in 18 (49%) patients (mood disorders, non-AD degenerative dementia, vascular cognitive impairment, alcohol cognitive disorders, temporal epilepsy and hippocampal sclerosis), and 10 (27%) patients had cognitive disorders of undetermined etiology. Conclusion: AD diagnosis (MCI or dementia) with normal CSF biomarkers is a rare condition. A clinical follow- up is particularly recommended to consider an alternative diagnosis.
Published: 2018

12. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies

Author: Pierre Sarda, Yves Sznajer, Florence Riant, Claire-Sophie Davoine, Christelle Tesson, Cyril Goizet, François Tison, Anthony Behin, Mélanie Fradin, Marie-Lorraine Monin, Giovanni Stevanin, Claire Ewenczyk, Rémi Valter, Pierre Labauge, Marie Coutelier, Urielle Ullmann, Didier Hannequin, Giulia Coarelli, Giovanni Castelnovo, Lionel Van Maldergem, Albert David, Mathieu Anheim, Alexis Brice, Perrine Charles, Alexandra Durr, Juliette Konop, Fanny Mochel, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and UCL - (SLuc) Centre de génétique médicale UCL
Subjects: Adult, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Ataxia, Adolescent, Cerebellar Ataxia, Genotype, Genetic counseling, Biology, CACNA1A, SPG7, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Humans, Spinocerebellar ataxia type 6, Age of Onset, Child, Aged, Genes, Dominant, Aged, 80 and over, Genetics, Cerebellar ataxia, Metalloendopeptidases, Middle Aged, channelopathies, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, Spinocerebellar ataxia, ATPases Associated with Diverse Cellular Activities, Female, Calcium Channels, Neurology (clinical), Age of onset, medicine.symptom, 030217 neurology & neurosurgery
Abstract: Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype-phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more 'conventional' ataxias. After exclusion of CAG/polyglutamine expansions in spinocerebellar ataxia genes in 412 index cases with dominantly inherited cerebellar ataxias, we aimed to establish the relative frequencies of mutations in other genes, with an approach combining panel sequencing and TaqMan® polymerase chain reaction assay. We found relevant genetic variants in 59 patients (14.3%). The most frequently mutated were channel genes [CACNA1A (n = 16), KCND3 (n = 4), KCNC3 (n = 2) and KCNA1 (n = 2)]. Deletions in ITPR1 (n = 11) were followed by biallelic variants in SPG7 (n = 9). Variants in AFG3L2 (n = 7) came next in frequency, and variants were rarely found in STBN2 (n = 2), ELOVL5, FGF14, STUB1 and TTBK2 (n = 1 each). Interestingly, possible risk factor variants were detected in SPG7 and POLG. Clinical comparisons showed that ataxias due to channelopathies had a significantly earlier age at onset with an average of 24.6 years, versus 40.9 years for polyglutamine expansion spinocerebellar ataxias and 37.8 years for SPG7-related forms (P = 0.001). In contrast, disease duration was significantly longer in the former (20.5 years versus 9.3 and 13.7, P=0.001), though for similar functional stages, indicating slower progression of the disease. Of interest, intellectual deficiency was more frequent in channel spinocerebellar ataxias, while cognitive impairment in adulthood was similar among the three groups. Similar differences were found among a single gene group, comparing 23 patients with CACNA1A expansions (spinocerebellar ataxia 6) to 22 patients with CACNA1A point mutations, which had lower average age at onset (25.2 versus 47.3 years) with longer disease duration (18.7 versus 10.9), but lower severity indexes (0.39 versus 0.44), indicating slower progression of the disease. In conclusion, we identified relevant genetic variations in up to 15% of cases after exclusion of polyglutamine expansion spinocerebellar ataxias, and confirmed CACNA1A and SPG7 as major ataxia genes. We could delineate firm genotype-phenotype correlations that are important for genetic counselling and of possible prognostic value.
Published: 2017

13. 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

14. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author: van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till F M, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ifgc, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavanramasamy, Kwok, John B. J., Carol, Dobson-Stone, Brooks, William S., Schofield, Peterr., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Laurenbartley, Elizabeth, Thompson, Eric, Haan, Isabel, Hernández, Agustín, Ruiz, Mercè, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigiforloni, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, Jordi, Clarimón, Alberto, Lleó, Rafael, Blesa, Maria Landqvist Waldö, Karinnilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, DavidM. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietrini, P., Huey, Edward D., Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robertperneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, George-Hyslop, Peterst., 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, William, Deschamps, Tim, Vanlangenhove, Marc, Cruts, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle Le Ber, Didier, Hannequin, Véronique, Golfier, Martine, Vercelletto, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuelmayhaus, 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, Annarichardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Fran-cesca, 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., Davidknopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, Vanswieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philipscheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolosorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Florencepasquier, Adeline, Rollin, Vincent, Deramecourt, Florence, Lebert, Dimitrioskapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni, Ironside, James W, van Berckel, Bart N M, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel J T, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande A L, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Sociology, The Social Context of Aging (SoCA), Universidad de Cantabria, DESGESCO Dementia Genetics, EADB Alzheimer Dis European, IFGC Int FTD-Genomics, IPDGC Int Parkinson Dis Genomics, RiMod-FTD Risk Modifying, Netherlands Brain Bank NBB, GIFT Genetic Invest, van der Lee, Sven J [0000-0003-1606-8643], Andlauer, Till FM [0000-0002-2917-5889], Tesi, Niccolo [0000-0002-1413-5091], Scheltens, Philip [0000-0002-1046-6408], Holstege, Henne [0000-0002-7688-3087], Apollo - University of Cambridge Repository, Amsterdam Neuroscience - Neurodegeneration, Neurology, Epidemiology and Data Science, Radiology and nuclear medicine, Other Research, Divisions, APH - Societal Participation & Health, APH - Aging & Later Life, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Personalized Medicine, and APH - Methodology
Subjects: 0301 basic medicine, Parkinson's disease, Dementia with Lewy bodies, genetics [Alzheimer Disease], Disease, metabolism [Microglia], Bioinformatics, Neurodegenerative disease, 0302 clinical medicine, genetics [Lewy Body Disease], pathology [Brain], genetics [Parkinson Disease], Missense mutation, genetics [Frontotemporal Dementia], ALZHEIMER’S DISEASE, Brain, Parkinson Disease, purl.org/becyt/ford/3.1 [https], Alzheimer's disease, Phospholipase C Gamma 2, Biobank, 3. Good health, genetics [Amyotrophic Lateral Sclerosis], genetics [Phospholipase C gamma], purl.org/becyt/ford/3 [https], immunology [Brain], Microglia, Alzheimer’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Longevity, Multiple sclerosis, PLCG2, Parkinson’s disease, Progressive supranuclear palsy, Lewy Body Disease, Risk, education, Neuroimaging, Pathology and Forensic Medicine, PARKINSON’S DISEASE, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, genetics [Dementia], medicine, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Original Paper, Phospholipase C gamma, business.industry, genetics [Multiple Sclerosis], medicine.disease, 030104 developmental biology, metabolism [Brain], Mutation, Dementia, Human medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, genetics [Longevity], Genome-Wide Association Study
Abstract: ATENCIÓ: la correcció està també al DDD, cal relacionar??? https://ddd.uab.cat/record/226203 Altres ajuts: The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ramirez was partly supported by the ADAPTED consortium: Alzheimer's disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"), by Fundación bancaria "La Caixa" and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA - NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer's Association (IIRG-03-6168), The Alzheimer's Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http://pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the "German Competence Network Multiple Sclerosis" (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.
Published: 2019

15. Familial intracranial aneurysm, the relationship of the aortic diameter

Author: Jean-Nicolas Dacher, J. Belien, R. Johannides, François Proust, P. Verdure, Lucie Guyant-Maréchal, V. Gilard, Didier Hannequin, and Helene Cebula
Subjects: Male, medicine.medical_specialty, Subarachnoid hemorrhage, Population, Aneurysm, medicine.artery, Familial predisposition, medicine, Humans, Prospective Studies, Prospective cohort study, education, Aorta, Dominance (genetics), education.field_of_study, business.industry, Intracranial Aneurysm, Organ Size, Middle Aged, medicine.disease, Penetrance, Cross-Sectional Studies, cardiovascular system, Female, Surgery, Neurology (clinical), Radiology, business
Abstract: Objectives Familial predisposition appears as an identified risk factor for cerebrovascular disease. The primary objective of our study was to assess intracranial aneurysm (IA) recurrence rate in a population of familial IA. Secondary objectives were first to analyse the inheritance categorisation/pattern of these families and second to assess the correlation between the aortic diameter on MRI and the aneurysmal characteristics. Patients and methods Over a period of 20 years (1990–2010), 26 patients from 23 families, identified from a regional register, accepted to participate in this prospective trial in order to determine, the inheritance pattern, the screening of de novo aneurysms by CT angioscan, and the aortic mensuration by MRI. The transmission pattern was categorised into autosomal dominant inheritance, autosomal recessive and autosomal dominance with incomplete penetrance. The aortic diameter was measured: anatomic coverage in the caudo-cranial direction from the iliac arteries to the ventriculo-aortic junction. Results All 26 patients [from 55.4 ± 11.2 years, sex ratio female/male: 1.36] were reviewed after a mean follow-up of 7.9 ± 6.6 years after the diagnosis of a cerebral aneurysm. The characteristics of this population were the diagnostic circumstances such as a subarachnoid hemorrhage (SAH) in 14 (53.8%), the multiple locations in 10 (38.5%) and a giant aneurysm in 4 (15.4%). Four de novo aneurysms were diagnosed in 3 patients (11.5%) after a mean follow-up of 22.3 ± 4 years, which corresponds to an annual incidence of 1.9 (95% CI 1.4–2.6%). The transmission pattern was autosomal dominant in 16 (61.5%), recessive in 3 (11.5%) and not defined in 7 (26.9%). As regards the aortic diameter, a significant decrease in the aortic diameter was observed in patients with an aneurysmal diameter superior to 10 mm. Conclusion The rate of de novo aneurysm justifies prolonged monitoring by imaging of these patients with familial intracranial aneurysm. The narrowing of the terminal part of the aorta could be a hemodynamic factor involved into the IA development.
Published: 2015

16. New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay

Author: Rodrigue Rossignol, Isabelle Coupry, Michel Koenig, Magalie Barth, Cyril Goizet, Nadège Bellance, Dominique Bonneau, Agnès Guichet, Diana Rodriguez, Christelle M. Durand, Nada Houcinat, Julie Bouron, Sébastien Moutton, Julie Lavie, Sandra Chantot-Bastaraud, Julie Pilliod, Alexandra Durr, Karine Nguyen, Alexis Brice, Didier Hannequin, Giovanni Benard, Mathieu Anheim, Perrine Charles, Christel Thauvin-Robinet, Alexandra Afenjar, Elise Maurat, Guillaume Fromager, Patrick Berquin, Didier Lacombe, Caroline Rooryck, Dan Milea, Sylvie Forlani, Philippe Convers, Elisabeth Maillart, Christophe Verny, Stéphanie Valence, Julien Van-Gils, Fanny Mochel, Christophe Hubert, Giovanni Stevanin, Lucie Guyant-Maréchal, Lydie Burglen, and Gaetan Lesca
Subjects: Genetics, Mutation, Ataxia, Mitochondrion, Biology, medicine.disease_cause, medicine.disease, 3. Good health, Neurology, medicine, Spinocerebellar ataxia, Biomarker (medicine), Missense mutation, Neurology (clinical), medicine.symptom, Gene, Exome sequencing
Abstract: Objective Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the description of numerous protein domains and the recent focus on its potential role in the regulation of mitochondrial physiology. This study aimed to identify new mutations in a large population of ataxic patients and to functionally analyze their cellular effects in the mitochondrial compartment. Methods A total of 321 index patients with spastic ataxia selected from the SPATAX network were analyzed by direct sequencing of the SACS gene, and 156 patients from the ATAXIC project presenting with congenital ataxia were investigated either by targeted or whole exome sequencing. For functional analyses, primary cultures of fibroblasts were obtained from 11 patients carrying either mono- or biallelic variants, including 1 case harboring a large deletion encompassing the entire SACS gene. Results We identified biallelic SACS variants in 33 patients from SPATAX, and in 5 nonprogressive ataxia patients from ATAXIC. Moreover, a drastic and recurrent alteration of the mitochondrial network was observed in 10 of the 11 patients tested. Interpretation Our results permit extension of the clinical and mutational spectrum of ARSACS patients. Moreover, we suggest that the observed mitochondrial network anomalies could be used as a trait biomarker for the diagnosis of ARSACS when SACS molecular results are difficult to interpret (ie, missense variants and heterozygous truncating variant). Based on our findings, we propose new diagnostic definitions for ARSACS using clinical, genetic, and cellular criteria. Ann Neurol 2015;78:871–886
Published: 2015

17. Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: An MRI Study of 16 French Cases

Author: Simon Samaan, Emmanuel Ellie, Didier Hannequin, Frédérique Etcharry-Bouyx, Giovanni Castelnovo, Clarisse Carra-Dalliere, Yann Nadjar, I. Le Ber, Kevin Mouzat, Xavier Ayrignac, Imen Dorboz, F. Mochel, Odile Boespflug-Tanguy, Christophe Verny, Pierre Labauge, Serge Lumbroso, Pekes Codjia, Cecilia Marelli, Serge Belliard, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), 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), Le CHCB, Centre Hospitalier de la Côte Basque, Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [Rennes], Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]
Subjects: Adult, Male, Pathology, medicine.medical_specialty, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Neuroimaging, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Fluid-attenuated inversion recovery, 030218 nuclear medicine & medical imaging, White matter, Leukoencephalopathy, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Leukoencephalopathies, medicine, Humans, Radiology, Nuclear Medicine and imaging, Axonal spheroids, business.industry, Adult Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Hyperintensity, 3. Good health, medicine.anatomical_structure, Corticospinal tract, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neurology (clinical), France, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: International audience; Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to CSF1R gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.
Published: 2018

18. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease

Author: Dominique Campion, Colin Smith, Manon S. Oud, Safa Al Sarraj, Stefan H. Lelieveld, Gaël Nicolas, Anne-Claire Richard, Florent Marguet, Christian Gilissen, Thierry Frebourg, Alexander Hoischen, Joris A. Veltman, Rocio Acuna-Hidalgo, Didier Hannequin, Stéphane Rousseau, Patrick F. Chinnery, Olivier Quenez, Olaf Ansorge, Christopher Morris, Annie Laquerrière, Michael J. Keogh, Johannes Attems, David Wallon, Marloes Steehouwer, Chinnery, Patrick [0000-0002-7065-6617], Apollo - University of Cambridge Repository, PORCHET, Nathalie, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Radboud University Medical Center [Nijmegen], Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), Department of Human Genetics [Nijmegen], Département de Pathologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Building Research Establishment (BRE/Edinburgh), University of Edinburgh, John Radcliffe Hospital [Oxford University Hospital], King‘s College London, Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Service de neurologie [Rouen], Mitochondrial Research Group, University of Northumbria at Newcastle [United Kingdom], and Department of Pathology, Rouen University Hospital
Subjects: 0301 basic medicine, Post‐zygotic, Adult, Male, Epidemiology, Somatic cell, [SDV]Life Sciences [q-bio], SORL1, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biology, medicine.disease_cause, Deep sequencing, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Developmental Neuroscience, Alzheimer Disease, PSEN2, medicine, PSEN1, Humans, Genetic Predisposition to Disease, Prion‐like, Allele, Prion-like, Aged, Genes, Dominant, Genetics, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Mosaicism, Post-zygotic, Health Policy, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Amplicon, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, 030104 developmental biology, Alzheimer, Female, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery
Abstract: Introduction A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP , PSEN1 , or PSEN2 . We hypothesized that negatively screened patients may harbor somatic variants in these genes. Methods We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, Results We identified and confirmed nine somatic variants (allele fractions: 0.2%–10.8%): two APP , five SORL1 , one NCSTN , and one MARK4 variant by independent amplicon-based deep sequencing. Discussion Two of the SORL1 variant might have contributed to the disease, the two APP variants were interpreted as likely benign and the other variants remained of unknown significance. Somatic variants in the autosomal dominant AD genes may not be a common cause of sporadic AD, including early onset cases.
Published: 2018

19. Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers

Author: Nathalie Sastre, Cécile Adam, Didier Hannequin, Sophie Chauvelier, Marie–Ange Cariot, Hermine Lenoir, Laure Caillard, Djamila Krabchi, Léna Joffredo, Jean-Marc Tréluyer, Olivier Hanon, Françoise Lala, Frédéric Bloch, Bruno Vellas, Stéphanie Bombois, Laurence Hugonot–Diener, Philippe-Henri Robert, Céline Guillemaud, Xavier Delbeuck, Julien Dumurgier, Jean-François Mangin, Nathalie Charasz, Jean-Luc Novella, Vincent Camus, Pierre Anthony, Sylvain Lehmann, Anne-Sophie Rigaud, Audrey Gabelle, Clémence Boully, Lisette Volpe–Gillot, Jacques Touchon, Jacques Boddaert, Vincent Deramecourt, Giovanni Castelnovo, Yasmina Boudali, Marie Chupin, S. Schraen-Maschke, Olivier Guerin, Joël Belmin, Isabelle Saulnier, Valérie Chauviré, Nathalie Schwald, Salim Gherabli, Philippe Robert, Sarah Benisty, Candice Picard, Marie Laurent, Foucaud du Boisgueheneuc, Florien Labourée, Gabiel Abitbol, Sophie Haffen, Patrick Gelé, Hélène Briault, Jean Luc Novella, François Sellal, Claire Gervais, Marie–Agnès Picat, Anne Chawakilian, Marie–Thérèse Rabus, Pierre Jean Ousset, Galdric Orvoen, Thierry Dantoine, Pierre Vandel, Jaques Hugon, Rezki Daheb, Jean-Sébastien Vidal, David Wallon, Diane Dupuy, Karl Mondon, Lisette Volpe-Gillot, Adeline Rollin Sillaire, Christine Delmaire, Frédéric Blanc, Emmanuelle Duron, Anna Kearney–Schwartz, Evelyne Galbrun, Florence Latour, Christine Perret–Guillaume, Florence Moulin, C. Bayle, Sylvie Pariel, Jean-Philippe David, Mohamed Abdellaoui, Stéphanie Libercier, Valérie Gissot, Bernadette Allinquant, Jean-Yves Gaubert, Elena Paillaud, Jean–Marc Michel, Caroline Hommet, Gilles Berrut, Luc Buée, Eliana Alonso, Agnès Devendeville, Anne–Cécile Troussiere, Marie–Anne Mackowiak, Yann Spivac, Jacques Hugon, Pascaline Cassagnaud, Olivier Martinaud, Marion Paulin, Claire Paquet, Matthieu Plichart, Guillaume Sacco, Olivier Godefroy, Sophie Pichierri, Athanase Benetos, M.-L. Seux, Marc Paccalin, Edouard Chaussade, Centre de Mémoire de Ressources et de Recherche [Paris Broca], AP-HP - Hôpital Broca [Paris], Maladie d'Alzheimer : marqueurs génétiques et vasculaires, neuropsychologies (EA 4468), Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche [Hôpitaux Civils de Colmar, Strasbourg], Hôpitaux Civils de Colmar, CATI Multicenter Neuroimaging Platform (CATI), Université Paris-Saclay, Centres Mémoire de Ressources et de Recherche Montpellier (CMRR), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Centre Mémoire de Ressources et de Recherche Paris Nord Ile-de-France (CMRR), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Mémoire de Ressources et de Recherche [CHU de Toulouse, Hôpital Purpan], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre Hospitalier Emile Roux [AP-HP], Centres Mémoire de Ressources et de Recherche [CHRU Nancy] (CMRR de Lorraine), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Mémoire de Ressources et de Recherche [CHU de Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Mémoire de Ressources et Recherche - CMRR [Haute-Normandie], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Léopold-Bellan, Centre Mémoire de Ressources et de Recherche [CHRU de Poitiers La Miletrie], CHRU de Poitiers La Miletrie [Poitiers], Centre Mémoire de Ressources et de Recherche [Nice] (CMRR Nice), Université Côte d'Azur (UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre Mémoire de Ressources et de Recherche [CHU Amiens], CHU Amiens-Picardie, Centre de Mémoire de Ressources et de Recherches [Limoges] (CMRR Limoges), CHU Limoges-CH Esquirol [Limoges] (CH Esquirol), Centre Mémoire de Ressources et de Recherche [CHRU de Tours Hôpital Bretonneau], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau [Tours], Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Gériatrique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Mémoire de Ressources et de Recherche [CHRU de Besançon] (CMRR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques [CHRU de Besançon], Laboratoire de Neurosciences Intégratives et Cliniques - UFC (EA 481) (NEURO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre de Mémoire de Ressource et Recherche [Champagne-Ardenne-Reims] (CMRR Reims - Champagne-Ardenne), Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Fédération nationale des Centres de Mémoire de Ressources et de Recherche (FCMRR), Vieillissement, Fragilité (VIEFRA - EA 3797), Université de Reims Champagne-Ardenne (URCA), French Ministry of Health (Programme Hospitalier de Recherche Clinique [PHRC 2009/01-04 and PHRC-13-0404]), Fondation Plan Alzheimer, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Hôpital Bretonneau [Tours], Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de gériatrie à orientation cardiologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Centre Mémoire [CHU de Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Laboratoire de Neurosciences Intégratives et Cliniques - UFC (UR 481) (NEURO), DE CARVALHO, Philippe, Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Psychiatrie et Neurosciences (U894), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, 0301 basic medicine, Apolipoprotein E, Epidemiology, [SDV]Life Sciences [q-bio], 0302 clinical medicine, Cerebrospinal fluid, Prospective Studies, Prospective cohort study, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Health Policy, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Middle Aged, Alzheimer's disease, Mental Status and Dementia Tests, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, Biomarker (medicine), Female, Cohort study, medicine.medical_specialty, Amyloid, 03 medical and health sciences, Cellular and Molecular Neuroscience, Amyloid β peptides, Developmental Neuroscience, Alzheimer Disease, Internal medicine, mental disorders, medicine, Humans, Dementia, Cognitive Dysfunction, Plasma biomarkers, CSF biomarkers, Aged, Amyloid beta-Peptides, business.industry, Mild cognitive impairment, Plasma levels, medicine.disease, 030104 developmental biology, Endocrinology, Csf biomarkers, Neurology (clinical), Geriatrics and Gerontology, business, Biomarkers, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; INTRODUCTION:Diagnostic relevance of plasma amyloid β (Aβ) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aβ42 and Aβ40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers.METHODS:One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoïd pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included.RESULTS:Plasma Aβ1-42 and Aβ1-40 were lower in AD (36.9 [11.7] and 263 [80] pg/mL) than in amnestic MCI (38.2 [11.9] and 269 [68] pg/mL) than in nonamnestic MCI (39.7 [10.5] and 272 [52] pg/mL), respectively (P = .01 for overall difference between groups for Aβ1-42 and P = .04 for Aβ1-40). Globally, plasma Aβ1-42 correlated with age, Mini-Mental State Examination, and APOE ε4 allele. Plasma Aβ1-42 correlated with all CSF biomarkers in MCI but only with CSF Aβ42 in AD.DISCUSSION:Plasma Aβ was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose.Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Published: 2018

20. Novel VCP mutations expand the mutational spectrum of frontotemporal dementia

Author: Didier Hannequin, Agnès Camuzat, Yassaman Ghassab, Isabelle David, Sylvie Forlani, Morwena Latouche, Dario Saracino, Eric Le Guern, Lena Guillot-Noel, Cinzia Coppola, Mira Didic, Daisy Rinaldi, Vincent Anquetil, Lucie Guyant-Maréchal, Alexis Brice, Ftd-Als, Fabienne Clot, Giuseppe Di Iorio, Isabelle Le Ber, 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), Second Division of Neurology, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania 'Luigi Vanvitelli', Naples, Italy, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Otten, Lisa, Saracino, Dario, Clot, Fabienne, Camuzat, Agnè, Anquetil, Vincent, Hannequin, Didier, Guyant-Maréchal, Lucie, Didic, Mira, Guillot-Noël, Léna, Rinaldi, Daisy, Latouche, Morwena, Forlani, Sylvie, Ghassab, Yassaman, Coppola, Cinzia, Di Iorio, Giuseppe, David, Isabelle, Le Guern, Eric, Brice, Alexi, Le Ber, Isabelle, CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, Aging, Valosin-containing protein, Mutation, Missense, Frontotemporal lobar degeneration, medicine.disease_cause, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Valosin Containing Protein, medicine, Dementia, Humans, Amyotrophic lateral sclerosis, Gene, Amyotrophic lateral sclerosi, ComputingMilieux_MISCELLANEOUS, Aged, Genetics, Mutation, biology, [SCCO.NEUR]Cognitive science/Neuroscience, General Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, TAR DNA binding protein 43, Middle Aged, medicine.disease, Pedigree, 030104 developmental biology, Paget's disease of bone, Frontotemporal Dementia, biology.protein, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, Developmental Biology, Frontotemporal dementia
Abstract: Valosin-containing protein (VCP) mutations are rare causes of autosomal dominant frontotemporal dementias associated with Paget's disease of bone, inclusion body myopathy, and amyotrophic lateral sclerosis. We analyzed the VCP gene in a cohort of 199 patients with frontotemporal dementia and identified 7 heterozygous mutations in unrelated families, including 3 novel mutations segregating with dementia. This expands the VCP mutation spectrum and suggests that although VCP mutations are rare (3.5% in this study), the gene should be analyzed even in absence of the full syndromic complex. Reporting genetic variants with convincing arguments for pathogenicity is important considering the large amount of data generated by next-generation sequencing and the growing difficulties to interpret rare genetic variants identified in isolated cases.
Published: 2018

21. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study

Author: David J. Irwin, Nilufer Ertekin-Taner, Sara Rollinson, Mads Kjolby, John Hardy, Julia Kofler, Robert A. Rissman, Bernardino Ghetti, Stuart Pickering-Brown, Jonathan Glass, Carlos Cruchaga, Jonathan D. Rohrer, Keith A. Josephs, Maura Gallo, Parastoo Momeni, Emilia J. Sitek, Matthis Synofzik, Sandro Sorbi, Carlo Wilke, Oscar L. Lopez, Nigel J. Cairns, Miren Zulaica, Peter Heutink, Leonard Petrucelli, Bret M. Evers, Luisa Benussi, Jeroen van Rooij, Olivier Piguet, Sandra E. Black, Bradley F. Boeve, Cyril Pottier, Eric M. Reiman, Melissa E. Murray, Ralph B. Perkerson, Daniela Galimberti, Thomas G. Beach, Giorgio G. Fumagalli, Giacomina Rossi, David M. A. Mann, John B.J. Kwok, Harro Seelaar, Edward B. Lee, Jean-Paul Vonsattel, Didier Hannequin, Rosa Rademakers, John R. Hodges, Nicole A. Finch, John Q. Trojanowski, David S. Knopman, Yingxue Ren, Albert Lladó, Anders Nykjaer, Claire Troakes, Linn Öijerstedt, EunRan Suh, Isabelle Le Ber, Juliane Winkelmann, Ian R. Mackenzie, Glenda M. Halliday, William W. Seeley, Salvatore Spina, Simon Mead, Elio Scarpini, Fabrizio Tagliavini, Bruce L. Miller, Mariely DeJesus-Hernandez, Dennis W. Dickson, Elizabeth Christopher, Mario Masellis, Florence Pasquier, Roberta Ghidoni, Janine Diehl-Schmid, Silvia Bagnoli, Barbara Borroni, Adam L. Boxer, Adrian L. Oblak, Elizabeth Finger, Carol F. Lippa, Giuliano Binetti, Eileen H. Bigio, Vivianna M. Van Deerlin, Anna Karydas, William S. Brooks, Julie S. Snowden, Anna Richardson, Lea T. Grinberg, Manuela Neumann, Jordan Grafman, Zbigniew K. Wszolek, Edward D. Huey, Caroline Graff, John C. van Swieten, Sandra Weintraub, Raffaele Maletta, Ekaterina Rogaeva, Fermin Moreno, Raffaele Ferrari, Charles L. White, Adolfo López de Munain, Neill R. Graff-Radford, Camilla Ferrari, Jill R. Murell, Marwan N. Sabbagh, Raquel Sánchez-Valle, Marka van Blitterswijk, Alessandro Padovani, Peter Johannsen, Daniel J. Serie, Francesca Frangipane, Safa Al-Sarraj, Anna Antonell, Kevin F. Bieniek, Tsz H. Wong, Ging-Yuek Robin Hsiung, Jarosław Sławek, Matthew B. Baker, Gregory D. Jenkins, Ronald C. Petersen, Murray Grossman, Benedetta Nacmias, Tammee M. Parsons, Lawrence S. Honig, Maria Anfossi, Richard J. Caselli, Changiz Geula, Marla Gearing, M.-Marsel Mesulam, Xiaolai Zhou, Joanna M. Biernacka, Joseph E. Parisi, Irene Piaceri, Jorgen E. Nielsen, Amalia C. Bruni, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Erasmus MC other, and Neurology
Subjects: 0301 basic medicine, Oncology, Male, RNA, Messenger/metabolism, Genome-wide association study, Disease, Gene mutation, genetics [Progranulins], 0302 clinical medicine, Progranulins, Cerebellum, GFRA2 protein, human, Medicine, Age of Onset, genetics [Genetic Predisposition to Disease], Genetic Predisposition to Disease/genetics, Frontotemporal lobar degeneration, metabolism [Cerebellum], Middle Aged, 3. Good health, Frontotemporal Dementia, Female, genetics [Frontotemporal Lobar Degeneration], Frontotemporal dementia, medicine.medical_specialty, Glial Cell Line-Derived Neurotrophic Factor Receptors, Mutation/genetics, Genetic counseling, genetics [Mutation], Progranulins/genetics, metabolism [RNA, Messenger], Article, 03 medical and health sciences, Internal medicine, Humans, Genetic Predisposition to Disease, ddc:610, RNA, Messenger, Cerebellum/metabolism, Aged, business.industry, metabolism [Progranulins], Case-control study, genetics [Glial Cell Line-Derived Neurotrophic Factor Receptors], Odds ratio, medicine.disease, metabolism [Frontotemporal Lobar Degeneration], metabolism [Glial Cell Line-Derived Neurotrophic Factor Receptors], 030104 developmental biology, Case-Control Studies, Mutation, GRN protein, human, Frontotemporal Lobar Degeneration/genetics, Neurology (clinical), Human medicine, Frontotemporal Lobar Degeneration, business, Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.
Published: 2018

22. O4-02-01: PHASE 2A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF THE HISTONE DEACETYLASE INHIBITOR (HDACI), FRM-0334, IN ASYMPTOMATIC CARRIERS OF, OR PATIENTS WITH FRONTOTEMPORAL LOBAR DEGENERATION (FTLD) DUE TO, PROGRANULIN GENE MUTATIONS

Author: Marco Onofrj, Holger Patzke, Murray Grossman, Rik Vandenberghe, Henry Riordan, Isabelle Le Ber, Sophie Auriacombe, Jacob Hesterman, Hans J Moebius, Gerhard Koenig, Giovanni B. Frisoni, Adam L. Boxer, Bradley F. Boeve, Gary Wisniewski, Ken Marek, Ira J. Goodman, Florence Pasquier, Didier Hannequin, Baruch Harris, Barbara Borroni, Scott M. McGinnis, Dana Hilt, John C. van Swieten, and Catherine J. Mummery
Subjects: medicine.medical_specialty, Epidemiology, medicine.drug_class, business.industry, Health Policy, Histone deacetylase inhibitor, Placebo-controlled study, Frontotemporal lobar degeneration, Gene mutation, medicine.disease, Gastroenterology, Double blind, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Geriatrics and Gerontology, business, Asymptomatic carrier
Published: 2019

23. Exploring the diagnosis delay and ALS functional impairment at diagnosis as relevant criteria for clinical trial enrolment*

Author: Philippe Corcia, Pierre-Marie Preux, Didier Hannequin, Jean-Christophe Antoine, Véronique Danel-Brunaud, Fausto Viader, Bello Hamidou, Giroud Maurice, Marie-Christine Arnes-Bes, Katell Beauvais, Marie Nicol, Benoît Marin, Christine Tranchant, Philippe Couratier, William Camu, Pierre Clavelou, Géraldine Lautrette, 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), Service de Neurologie [CHU Limoges], CHU Limoges, Centre référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Bretonneau, Centre Sclérose Latérale amyotrophique [CHU Toulouse], Département Neurologie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Centre de compétence de la Sclérose Latérale Amyotrophique [CHU Clermont-Ferrand] (SLA), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Neurophysiologie Clinique (CHU Dijon), Centre Sclérose Latérale Amyotrophique et maladies du motoneurone [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Service de Neurologie [CHU de Saint-Étienne], Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), 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), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Sclérose Latérale Amyotrophique et maladies, Unité de neurophysiologie clinique [CHU Toulouse], CHU Toulouse [Toulouse], Centre Sclérose Latérale Amyotrophique et maladies du motoneurone [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de neurologie [CHU de Saint-Étienne], Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, diagnosis delay, Delayed Diagnosis, Functional impairment, phenotype, Diagnostic Techniques, Neurological, ALSFRS-R slope, 03 medical and health sciences, 0302 clinical medicine, Lumbar, Internal medicine, Prevalence, medicine, Humans, Amyotrophic lateral sclerosis, Aged, Clinical Trials as Topic, business.industry, Genetic heterogeneity, Patient Selection, Diagnosis delay, clinical trial, Middle Aged, medicine.disease, 3. Good health, Surgery, Clinical trial, Cross-Sectional Studies, 030104 developmental biology, Neurology, Disease Progression, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, Neurology (clinical), Symptom Assessment, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Objectives were: i) to describe the phenotypic heterogeneity of incident amyotrophic lateral sclerosis (ALS) patients diagnosed in 2012 in French ALS centres; ii) to look at the associations between ALSFRS-R score and ALSFRS-R slope (ΔFS) at time of diagnosis with diagnosis delay, ALS phenotypes and Airlie House diagnosis criteria (AHDC); iii) to describe the rate of progression on ΔFS, according to diagnosis delay.METHODS:Incident ALS cases diagnosed in French ALS centres were included. The rate of progression was evaluated as follows: ΔFS = (48 - ALSFRS-R at time of diagnosis)/duration from onset to diagnosis (months). Fast and slow progressors were defined by ΔFS >1 and
Published: 2017

24. Convergent genetic and expression data implicate immunity in Alzheimer's disease

Author: John R. Gilbert, Simon Lovestone, Diana Zelenika, Walter A. Kukull, Peter Passmore, Chiao-Feng Lin, Nathalie Fievet, Brian W. Kunkle, Dominique Campion, Philip L. De Jager, Adam C. Naj, Kara L. Hamilton-Nelson, Lina Keller, Jean-Charles Lambert, Denise Harold, Paul K. Crane, John Powell, Kathryn L. Lunetta, Paolo Caffarra, Lei Yu, Anthony Bayer, Tricia A. Thornton-Wells, Christiane Reitz, Eric B. Larson, Florentino Sanchez Garcia, Lindsay A. Farrer, Charlene Thomas, Ekaterina Rogaeva, Victoria Alavarez, Alfredo Ramirez, Pascale Barberger-Gateau, Dan Rujescu, Paul Hollingworth, Margaret A. Pericak-Vance, Daniela Galimberti, J. Kornhuber, Alexey Vedernikov, Philippe Amouyel, Peter Holmans, Gianfranco Spalletta, Carole Dufouil, Wolfgang Maier, Patrick G. Kehoe, Florence Pasquier, Lesley Jones, Harald Hampel, Stephen Todd, Valur Emilsson, Pau Pastor, Manuel Mayhaus, Claudine Berr, Seth Love, Michelangelo Mancuso, Mikko Hiltunen, Simon Mead, Hilkka Soininen, Vincent Deramecourt, Bernadette McGuinness, Magda Tsolaki, Jean-François Dartigues, Jordi Clarimón, Marie-Thérèse Bihoreau, Laura Fratiglioni, Duane Beekly, Sabrina Pichler, Caroline Graff, Albert V. Smith, Nick C. Fox, Amy Gerrish, Karen Ritchie, Carlos Cruchaga, John Hardy, Benedetta Nacmias, Maria Candida Deniz Naranjo, Christine Van Broeckhoven, Laura B. Cantwell, Minerva M. Carrasquillo, Richard Mayeux, Karolien Bettens, Vincent Chouraki, Clive Holmes, Thomas H. Mosley, David C. Rubinsztein, Gyungah Jun, Anita L. DeStefano, Lenore J. Launer, Alexander Richards, Jerome I. Rotter, Lars Lannfelt, Annette L. Fitzpatrick, Fanggeng Zou, Joseph D. Buxbaum, Cristina Razquin, Mercè Boada, Najaf Amin, Palmi V. Jonsson, Martin Dichgans, Thomas J. Montine, Yoichiro Kamatani, Debby W. Tsuang, Alexis Brice, Hakon Hakonarson, John Collinge, Albert Hofman, Eden R. Martin, Oscar L. Lopez, Olivier Hanon, Melanie L. Dunstan, Kevin Morgan, Nicola Jones, Cornelia M. van Duijn, Valentina Escott-Price, Vilmundur Gudnason, Susanne Moebus, Peter St George-Hyslop, Michael Conlon O'Donovan, Michael Gill, Tim Becker, Markus M. Nöthen, Sandro Sorbi, Céline Bellenguez, Mike A. Nalls, Martin Ingelsson, Otto Valladares, Kristel Sleegers, Sudha Seshadri, Gerard D. Schellenberg, María J. Bullido, Patrizia Mecocci, Eric Boerwinkle, Michael John Owen, Helena Schmidt, Kristelle Brown, Julie Williams, Renée F.A.G. de Bruijn, Jonathan L. Haines, Mark Lathrop, Maria Del Zompo, Denis A. Evans, Rebecca Sims, Badri N. Vardarajan, John S. K. Kauwe, Luc Letteneur, Agustín Ruiz, David Craig, Steven G. Younkin, Bruce M. Psaty, Ignacio Mateo, Tatiana Foroud, David Wallon, P. Bosco, Alberti Lleò, Amanda J. Myers, Alberto Pilotto, Petra Proitsi, Reinhold Schmidt, Matthew J. Huentelman, David A. Bennett, Onofre Combarros, Kelley Faber, Gudny Eiriksdottir, M. Arfan Ikram, Lluís Tárraga, Francesco Panza, Carla A. Ibrahim-Verbaas, Joshua C. Bis, Li-San Wang, Matthias Riemenschneider, Gary W. Beecham, Alison Goate, Seung Hoan Choi, John Gallacher, Robert Clarke, Didier Hannequin, Deborah Blacker, Frank Jessen, Christophe Tzourio, Tamara B. Harris, Benjamin Grenier-Boley, Paola Bossù, Janet A. Johnston, M. Ilyas Kamboh, Giancarlo Russo, Timothy Stone, Carol Brayne, Eliecer Coto, French National Foundation on Alzheimer’s Disease and Related Disorders, Institut Pasteur, National Institutes of Health (US), Centre National de Genotypage (France), Fédération pour la Recherche sur le Cerveau (France), Erasmus University Rotterdam, Medical Research Council (UK), International Genomics of Alzheimer's Disease Consortium (IGAP), Neurology, and Epidemiology
Subjects: Pathway analysis, Epidemiology, ALIGATOR, Alzheimer's disease, Cholesterol metabolism, Dementia, Endocytosis, Immune response, Neurodegeneration, Ubiquitination, Weighted gene co-expression network analysis, Medizin, Genome-wide association study, genetics [Alzheimer Disease], Gene expression, Genetics, education.field_of_study, Health Policy, Brain, Single Nucleotide, 3. Good health, Psychiatry and Mental Health, Algorithms, Alzheimer Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Developmental Neuroscience, Neurology (clinical), Geriatrics and Gerontology, Cellular and Molecular Neuroscience, Alzheimer’s disease, metabolism [Alzheimer Disease], Population, Genomics, Biology, Aligator, Article, Biological pathway, SDG 3 - Good Health and Well-being, medicine, ddc:610, Polymorphism, education, medicine.disease, Protein ubiquitination, metabolism [Brain], Human medicine
Abstract: © 2015, Elsevier Inc. All rights reserved. Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics., Medical Research Council, Alzheimer’s Research UK, and theWelsh Assembly Government. ADGC and CHARGE were supported by the National Institutes of Health, National Institute on Aging (NIH-NIA). CHARGE was also supported by Erasmus Medical Center and Erasmus University. IGAP was funded by the French National Foundation on Alzheimer’s Disease and Related Disorders, the Centre National de Genotypage and the Institut Pasteur de Lille, Inserm, FRC (Fondation pour la Recherche sur le Cerveau), and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).
Published: 2015

25. Factors influencing the age at onset in familial frontotemporal lobar dementia: Important weight of genetics

Author: Kathy Larcher, Florence Pasquier, Emmanuelle Génin, Marion Houot, Alexis Brice, Jérémie Pariente, Didier Hannequin, Paola Caroppo, Agnès Camuzat, Clémence Fournier, Audrey Sabbagh, Isabelle Le Ber, Fabienne Clot, Daisy Rinaldi, and Mathieu Barbier
Subjects: 0301 basic medicine, Genetics, Genetic counseling, Heritability, Biology, medicine.disease, Explained variation, Article, Correlation, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, C9orf72, medicine, Dementia, Variance components, Neurology (clinical), Amyotrophic lateral sclerosis, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: Objective:To quantify the effect of genetic factors and generations influencing the age at onset (AAO) in families with frontotemporal lobar dementia (FTD) due to C9ORF72 hexanucleotide repeat expansions and GRN mutations.Methods:We studied 504 affected individuals from 133 families with C9ORF72 repeat expansions and 90 FTD families with mutations in GRN, 2 major genes responsible for FTD and/or amyotrophic lateral sclerosis. Intrafamilial correlations of AAO were analyzed, and variance component methods were used for heritability estimates. Generational effects on hazard rates for AAO were assessed using mixed-effects Cox proportional hazard models.Results:A generational effect influencing AAO was detected in both C9ORF72 and GRN families. Nevertheless, the estimated proportion of AAO variance explained by genetic factors was high in FTD caused by C9ORF72 repeat expansions (44%; p = 1.10e−4), 62% when the AAO of dementia was specifically taken into account (p = 8.10e−5), and to a lesser degree in GRN families (26%; p = 0.17). Intrafamilial correlation analyses revealed a significant level of correlations in C9ORF72 families according to the degree of kinship. A pattern of intrafamilial correlations also suggested potential X-linked modifiers acting on AAO. Nonsignificant correlation values were observed in GRN families.Conclusions:Our results provide original evidence that genetic modifiers strongly influence the AAO in C9ORF72 carriers, while their effects seem to be weaker in GRN families. This constitutes a rational to search for genetic biomarkers, which could help to improve genetic counseling, patient care, and monitoring of therapeutic trials.
Published: 2017

26. [P1–240]: CLINICAL IMPACT OF CEREBROSPINAL FLUID BIOMARKERS IN MILD COGNITIVE IMPAIRMENT DIAGNOSIS

Author: Jacques Hugon, Florence Pasquier, Julien Dumurgier, François Mouton-Liger, Eloi Magnin, Anne-Cécile Troussière, Emmanuel Cognat, Emmanuelle Duron, Claire Paquet, Audrey Gabelle, Philippe Robert, Didier Hannequin, and David Wallon
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Gastroenterology, 030227 psychiatry, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cerebrospinal fluid, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Geriatrics and Gerontology, business, Cognitive impairment, 030217 neurology & neurosurgery
Published: 2017

27. Brain Calcifications in Adult-Onset Genetic Leukoencephalopathies: A Review

Author: Clarisse Carra-Dalliere, Didier Hannequin, Gaël Nicolas, Xavier Ayrignac, Pierre Labauge, 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), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: 0301 basic medicine, Collagen Type IV, Pathology, medicine.medical_specialty, Tomography Scanners, X-Ray Computed, Cerebral calcification, [SDV]Life Sciences [q-bio], Brain calcifications, Leukoencephalopathy, 03 medical and health sciences, 0302 clinical medicine, Calcinosis, Leukoencephalopathies, Basal ganglia, medicine, Humans, Tomography Scanners, Brain Diseases, medicine.diagnostic_test, business.industry, Leukodystrophy, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Hyperintensity, 3. Good health, X-Ray Computed, 030104 developmental biology, Mutation, Neurology (clinical), Radiology, business, 030217 neurology & neurosurgery
Abstract: International audience; Importance: Adult-onset genetic leukoencephalopathies and leukodystrophies are increasingly recognized as a heterogeneous group of disorders with new diagnostic approaches and potential treatments. In the new era of genomics, the challenging interpretation of individual genetic variations requires an accurate phenotypic description and classification. Clinical and magnetic resonance imaging (MRI)-based approaches have been proposed to improve the diagnostic process of adult-onset leukoencephalopathies. Cerebral calcifications, when associated with white matter hyperintensities, are of major importance in the decision-making process to focus the diagnosis among the diversity of rare causes. Observations: This literature review demonstrated that the morphologic features and topography of the calcifications observed in a careful combined analysis of computed tomographic and MRI scans may help indicate the diagnosis of adult-onset genetic leukoencephalopathies. Vascular genetic leukoencephalopathies are an important cause of leukoencephalopathy with calcifications. Among them, COL4A1-related disorders are frequently associated with spotlike calcifications in the basal ganglia. Adult-onset leukoencephalopathy with axonal spheroids, a probably underestimated disorder, is associated with a specific pattern of calcifications: small, symmetric, sparing the basal ganglia, and a stepping stone appearance in the frontal pericallosal region. Moreover, disorders primarily associated with basal ganglia calcifications, such as primary familial brain calcifications, can be associated with marked leukoencephalopathy. Conclusions and Relevance: The number of identified causes of adult-onset genetic leukoencephalopathies has recently increased. A diagnostic algorithm should take into account the pattern of calcifications to better target the genetic analyses.
Published: 2017

28. Contribution to Alzheimer's disease risk of rare variants in TREM_2, SORL_1, and ABCA_7 in 1779 cases and 1273 controls

Author: Céline Bellenguez, Camille Charbonnier, Benjamin Grenier-Boley, Olivier Quenez, Kilan Le Guennec, Gaël Nicolas, Ganesh Chauhan, David Wallon, Stéphane Rousseau, Anne Claire Richard, Anne Boland, Guillaume Bourque, Hans Markus Munter, Robert Olaso, Vincent Meyer, Adeline Rollin-Sillaire, Florence Pasquier, Luc Letenneur, Richard Redon, Jean-François Dartigues, Christophe Tzourio, Thierry Frebourg, Mark Lathrop, Jean-François Deleuze, Didier Hannequin, Emmanuelle Genin, Philippe Amouyel, Stéphanie Debette, Jean-Charles Lambert, Dominique Campion, Olivier Martinaud, Aline Zarea, Stéphanie Bombois, Marie-Anne Mackowiak, Vincent Deramecourt, Agnès Michon, Isabelle Le Ber, Bruno Dubois, Olivier Godefroy, Frédérique Etcharry-Bouyx, Valérie Chauviré, Ludivine Chamard, Eric Berger, Eloi Magnin, Jean-Francois Dartigues, Sophie Auriacombe, François Tison, Vincent de la Sayette, Dominique Castan, Elsa Dionet, Francois Sellal, Olivier Rouaud, Christel Thauvin, Olivier Moreaud, Mathilde Sauvée, Maïté Formaglio, Hélène Mollion, Isabelle Roullet-Solignac, Alain Vighetto, Bernard Croisile, Mira Didic, Olivier Félician, Lejla Koric, Mathieu Ceccaldi, Audrey Gabelle, Cecilia Marelli, Pierre Labauge, Thérèse Jonveaux, Martine Vercelletto, Claire Boutoleau-Bretonnière, Giovanni Castelnovo, Claire Paquet, Julien Dumurgier, Jacques Hugon, Foucauld De Boisgueheneuc, Serge Belliard, Serge Bakchine, Marie Sarazin, Marie-Odile Barrellon, Bernard Laurent, Frédéric Blanc, Jérémie Pariente, Snejana Jurici, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Excellence Laboratory LabEx DISTALZ, 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), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, Metacohorts Consortium, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), McGill University and Genome Quebec Innovation Centre, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de neurologie [Lille], Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Institut National de la Santé et de la Recherche Médicale (Inserm)-Université de Bordeaux, Université de Bordeaux (UB), INSERM, Team Psycoépidémiologie du Vieillissement et des Maladies Chroniques - Population Health Center, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Epidémiologie, santé publique et développement, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR99-ISPED, Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Université de Lille, Troubles cognitifs vasculaires et dégénératifs, Université de Lille, Sciences et Technologies, Réseau International des Instituts Pasteur (RIIP), Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CNR MAJ collaborators, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), European Project: 305299,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,AGEDBRAINSYSBIO(2013), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Male, Adult, Aging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, SORL1, Apolipoprotein E4, Genome-wide association study, Biology, ABCA7, 03 medical and health sciences, Young Adult, Immunologic, Alzheimer Disease, Genetic variation, Receptors, medicine, 80 and over, TREM2, Humans, Genetic Predisposition to Disease, Receptors, Immunologic, Genetic Association Studies, LDL-Receptor Related Proteins, Aged, Aged, 80 and over, Genetics, Membrane Glycoproteins, Whole Genome Sequencing, General Neuroscience, Genetic Variation, Membrane Transport Proteins, Heritability, Middle Aged, Alzheimer's disease, medicine.disease, Minor allele frequency, 030104 developmental biology, biology.protein, ATP-Binding Cassette Transporters, Female, Neurology (clinical), Geriatrics and Gerontology, Developmental Biology, Genome-Wide Association Study
Abstract: International audience; We performed whole-exome and whole-genome sequencing in 927 late-onset Alzheimer disease (LOAD) cases, 852 early-onset AD (EOAD) cases, and 1273 controls from France. We assessed the evidence for gene-based association of rare variants with AD in 6 genes for which an association with such variants was previously claimed. When aggregating protein-truncating and missense-predicted damaging variants, we found exome-wide significant association between EOAD risk~and rare variants in SORL1, TREM2, and ABCA7. No exome-wide significant signal was obtained in the LOAD sample, and significance of the order of 10$^{-6}$ was observed in the whole AD group for TREM2. Our study confirms previous gene-level results for TREM2, SORL1, and ABCA7 and provides a~clearer insight into the classes of rare variants involved. Despite different effect sizes and~varying~cumulative minor allele frequencies, the rare protein-truncating and missense-predicted~damaging variants in TREM2, SORL1, and ABCA7 contribute similarly to the heritability of EOAD and explain between 1.1% and 1.5% of EOAD heritability each, compared with 9.12% for APOE $\varepsilon$4.
Published: 2017

29. Étude rétrospective multicentrique de 15 cas adultes de xanthomatose cérébrotendineuse : aspects cliniques et paracliniques typiques et atypiques

Author: Clarisse Carra, M. Clanet, G. Androdias, J. de Seze, Didier Hannequin, G. Besson, F. Blanc, D. Gayraud, Nicolas Collongues, Giovanni Castelnovo, C. Zaenker, Thierry Levade, Xavier Ayrignac, A. Gerdelat-Mas, Sandra Vukusic, Hélène Zéphir, Christine Tranchant, Olivier Outteryck, David Brassat, Patrick Vermersch, C. Lionnet, Pierre Labauge, Cyrille B. Confavreux, and David Wallon
Subjects: Neurology, Neurology (clinical)
Abstract: Resume Introduction La xanthomatose cerebrotendineuse, leucodystrophie metabolique de transmission autosomique recessive, est secondaire a un deficit en 27-sterol-hydroxylase, enzyme intervenant dans le catabolisme du cholesterol. Les symptomes classiquement revelateurs sont des xanthomes cutanes et tendineux (cliniques ou infracliniques), une cataracte precoce, une atteinte neurologique complexe et une diarrhee. L’imagerie cerebrale met en evidence une atteinte symetrique de la substance blanche et des noyaux denteles. Le diagnostic, suspecte sur une augmentation du cholestanol serique, est confirme par la presence d’une mutation dans le gene CYP27A1. Le traitement repose sur l’acide chenodesoxycholique. Methode Nous rapportons une serie multicentrique retrospective de 15 cas de xanthomatose cerebrotendineuse diagnostiques a l’âge adulte. Les donnees cliniques, moleculaires et IRM ont ete analysees pour chaque patient inclus. Resultats L’âge moyen de diagnostic etait de 39 ans (extremes : 27–65). Soixante-treize pour cent des patients debuterent leur maladie dans l’enfance et 27 % a l’âge adulte. Toutes les formes a debut pediatrique ont eu un diagnostic a l’âge adulte (âge moyen du diagnostic : 40 ans [extremes : 28–65]). Les symptomes cliniques associaient de maniere variable un syndrome cerebelleux, pyramidal, des troubles cognitifs, une epilepsie, une neuropathie (recherchee chez 10 de nos malades, presente chez 8 et de profil variable), des troubles psychiatriques, une cataracte et des xanthomes. Un patient avait une presentation atypique a savoir, une monoparesie associee a des xanthomes. L’IRM cerebrale, anormale chez tous nos malades, pouvait montrer une atteinte des noyaux denteles (47 %), une leucopathie periventriculaire (73 %) predominant dans les regions posterieures (60 %), une atteinte de la substance blanche de mecanisme vasculaire (7 %), une atteinte des faisceaux cortico-spinaux (53 %), des pallidums, du corps calleux ou une atrophie cortico-sous-corticale (33 %). Quatre-vingt-treize pour cent des patients avaient un taux de cholestanol serique eleve. La mutation la plus frequente etait 1183C>T, retrouvee chez 5 de nos 15 malades. Un traitement par acide chenodesoxycholique a permis une amelioration initiale chez 8 malades, suivie d’une stabilisation chez cinq d’entre eux, et d’une aggravation chez les trois autres. Quatre patients sont decedes des complications de la maladie. Conclusion Cette serie est la plus importante serie francaise rapportee a ce jour. Une xanthomatose cerebrotendineuse doit etre recherchee devant l’association de xanthomes (cliniques ou radiologiques) a un trouble neurologique. La maladie debute frequemment dans l’enfance mais de maniere aspecifique rendant compte du retard diagnostique. L’atteinte des noyaux denteles est tres evocatrice mais peu sensible. La leucopathie sus-tentorielle a souvent un gradient antero-posterieur. Une distribution vasculaire et une atteinte du corps calleux ne doivent pas faire exclure le diagnostic. Le dosage du cholestanol est tres fiable, son elevation permet de retenir le diagnostic, neanmoins celui-ci doit etre confirme par la biologie moleculaire.
Published: 2014

30. P4-358: DIAGNOSTIC VALUE OF THE AMNESTIC SYNDROME FOR ALZHEIMER'S DISEASE: A CLINICOPATHOLOGICAL STUDY

Author: Isabelle Le Ber, Sophie Auriacombe, Marie Sarazin, Didier Hannequin, Mathieu Ceccaldi, Vincent Deramecourt, Bruno Dubois, Charles Duyckaerts, Florence Pasquier, Maxime Bertoux, Pascaline Cassagnaud, and Thibaud Lebouvier
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, Amnestic syndrome, Gastroenterology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, Value (mathematics)
Published: 2019

31. Cognitive impairment after cerebral venous thrombosis: a two-center study

Author: Martine F. Roussel, Aude Triquenot-Bagan, Sandrine Canaple, Olivier Godefroy, Evelyne Guegan-Massardier, Didier Hannequin, David Wallon, Olivier Martinaud, Jean-Marc Bugnicourt, Chantal Lamy, and Claire Leclercq
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Neurology, Neuropsychological Tests, Aphasia, Humans, Medicine, Neuropsychological assessment, Retrospective Studies, Neuroradiology, Venous Thrombosis, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Retrospective cohort study, Cognition, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Venous thrombosis, Physical therapy, Female, Neurology (clinical), Intracranial Thrombosis, medicine.symptom, Cognition Disorders, Mental Status Schedule, business, Follow-Up Studies
Abstract: The objective of this observational study of consecutive patients hospitalized for cerebral venous thrombosis (CVT) was to determine the prevalence of post-CVT cognitive impairment and identify factors associated with this condition. Out of a total of 73 patients hospitalized for CVT, 52 were included in the study and 44 were assessed with a comprehensive neuropsychological battery. At the last outpatient visit (mean ± SD time since CVT: 22 ± 13 months), a standardized, neuropsychological assessment was administered. Cognitive impairment was defined as significant impairment (with a cut-off at the 5th percentile) in at least two of the cognitive domains tested in the neuropsychological battery or severe aphasia or cognitive disorders with MMSE score ≤ 17 out of 30. Cognitive impairment was observed in 16 patients (31 %; 95 % CI 18-43 %): 4 with major disability precluding comprehensive assessment (3 with severe aphasia, 1 with MMSE ≤ 17) and 12 with significant impairments in at least two cognitive domains. Determinants of long-term cognitive impairment were straight sinus involvement (OR 22.4; 95 % CI 1.79-278.95; p = 0.016) and the presence of parenchymal lesions on follow-up magnetic resonance imaging (OR 7.8; 95 % CI 1.40-43.04; p = 0.019). The sole predictor of failure to return to full-time employment was cognitive impairment (OR 21.0; 95 % CI 3.35-131.44; p = 0.001). Cognitive impairment persists in up to one-third of cases of CVT. It is more frequent in patients with deep CVT and persistent parenchymal lesions and is associated with failure to return to full-time employment.
Published: 2012

32. Early verbal fluency decline after STN implantation: Is it a cognitive microlesion effect?

Author: Didier Hannequin, David Maltête, Nathalie Chastan, Emmanuel Gerardin, Stéphane Derrey, Olivier Martinaud, David Wallon, and Romain Lefaucheur
Subjects: Adult, Male, medicine.medical_specialty, Deep brain stimulation, Deep Brain Stimulation, medicine.medical_treatment, Disease duration, Motor Activity, Neuropsychological Tests, Audiology, Developmental psychology, Subthalamic Nucleus, medicine, Humans, Verbal fluency test, Aged, Analysis of Variance, Verbal Behavior, Subthalamic nucleus deep brain stimulation, Linguistics, Parkinson Disease, Cognition, Middle Aged, Subthalamic nucleus, Neurology, Cluster size, Female, Neurology (clinical), Analysis of variance, Cognition Disorders, Psychology, Follow-Up Studies
Abstract: Backgrounds Worsening of verbal fluency is reported after subthalamic nucleus deep brain stimulation in Parkinson's disease. It is postulated that these changes could reflect microlesion consecutive to the surgical procedure itself. Methods We evaluated verbal fluency, in 26 patients (mean age, 57.9 ± 8.5 years; mean disease duration, 11.4 ± 3.5 years) both before surgery (baseline) and, after surgery respectively the third day (T3), the tenth day (T10) just after STN implantation before turning on the stimulation and at six months (T180). Results Number of total words and switches was significantly reduced at T3 and T10, while average cluster size was unchanged. Repeated post-operative neuropsychological testing demonstrated reliable improvement from T3 to T180 on verbal fluency. Conclusion This study provides evidence of transient verbal fluency decline consecutive to a microlesion effect. Further studies needed to determine a putative relationship between early and long-term verbal fluency impairment.
Published: 2012

33. Seizures in dominantly inherited Alzheimer disease

Author: Aline, Zarea, Camille, Charbonnier, Anne, Rovelet-Lecrux, Gaël, Nicolas, Stéphane, Rousseau, Alaina, Borden, Jeremie, Pariente, Isabelle, Le Ber, Florence, Pasquier, Maite, Formaglio, Olivier, Martinaud, Adeline, Rollin-Sillaire, Marie, Sarazin, Bernard, Croisile, Claire, Boutoleau-Bretonnière, Mathieu, Ceccaldi, Audrey, Gabelle, Ludivine, Chamard, Frédéric, Blanc, François, Sellal, Claire, Paquet, Dominique, Campion, Didier, Hannequin, David, Wallon, Karl, Mondon, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche -CMRR [Lille-Bailleul], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Mémoire de Ressources et de Recherche, CHU Marseille, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Strasbourg, Service de neurologie, Hôpital pasteur [Colmar], Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lariboisière-François Widal, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Supported by the Hospital Program for Clinical Research (PHRC) ofthe French Ministry of Health (GMAJ, PHRC 2008/067) and sponsoredby the National Reference Center for Young Alzheimer Patients(CNR-MAJ)., CHU Lille, CNRS, Inserm, Université de Lille, Troubles cognitifs dégénératifs et vasculaires - U1171, Troubles cognitifs dégénératifs et vasculaires - U 1171 [TCDV], Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Imagerie cérébrale et handicaps neurologiques, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 ), Troubles cognitifs dégénératifs et vasculaires ( DN2M ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -INSERM, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Hôpital Roger Salengro, Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôpital Nord Laënnec, Institut de Neurosciences des Systèmes ( INS ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Nantes ( UN ) -Hôpital Nord Laënnec-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), PHRC GMAJ Collaborators, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], 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 Wallon, David
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, [ SDV.MHEP.PSM ] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, DNA Mutational Analysis, Bioinformatics, Gastroenterology, Statistics, Nonparametric, Cohort Studies, 03 medical and health sciences, Amyloid beta-Protein Precursor, Young Adult, 0302 clinical medicine, Alzheimer Disease, Internal medicine, PSEN2, Gene duplication, Presenilin-2, PSEN1, medicine, Presenilin-1, Humans, Age of Onset, Aged, Epilepsy, business.industry, Proportional hazards model, Hazard ratio, Middle Aged, medicine.disease, Confidence interval, 030104 developmental biology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Cohort, Mutation, Female, Neurology (clinical), France, Alzheimer's disease, business, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations. METHODS: A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded. RESULTS: We included 132 patients from 77 families: 94 PSEN1 mutation carriers (MCs), 16 APP duplication carriers, 15 APP MCs, and 7 PSEN2 MCs. Seizure frequency was 47.7% after a mean follow-up of 8.4 years (range 5-25). After 5-year follow-up and using a Cox model analysis, the percentages of patients with seizures were respectively 19.1% (10.8%-26.7%) for PSEN1, 28.6% (0%-55.3%) for PSEN2, 31.2% (4.3%-50.6%) for APP duplications, and no patient for APP mutation. APP duplication carriers showed a significantly increased seizure risk compared to both APP MCs (hazard ratio [HR] = 5.55 [95% confidence interval 1.87-16.44]) and PSEN1 MCs (HR = 4.46 [2.11-9.44]). Among all PSEN1 mutations, those within the domains of protein hydrophilic I, transmembrane II (TM-II), TM-III, TM-IV, and TM-VII were associated with a significant increase in seizure frequency compared to other domains (HR = 4.53 [1.93-10.65], p = 0.0005). CONCLUSIONS: Seizures are a common feature of ADEOAD. In this population, risk was significantly higher in the APP duplication group than in all other groups. Within PSEN1, 5 specific domains were associated with a higher seizure risk indicating specific correlations between causative mutation and seizures. 87
Published: 2016

34. P1‐394: Prevalence and Characteristics of Patients with Alzheimer’s Disease Eligible for a Disease Modifying Drug (Panacea)

Author: Bruno Dubois, Florence Pasquier, Martine Vercelletto, Athanase Benetos, David Wallon, Olivier Rouaud, Philippe Robert, Pierre Krolak Salmon, Didier Hannequin, Stéphane Epelbaum, Anne-Sophie Rigaud, François Sellal, Caroline Hommet, Claire Boutoleau-Bretonnière, and Aurélie Mouton
Subjects: Drug, medicine.medical_specialty, biology, Epidemiology, business.industry, Health Policy, media_common.quotation_subject, Disease, biology.organism_classification, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Physical therapy, Neurology (clinical), Geriatrics and Gerontology, Intensive care medicine, business, Panacea (butterfly), media_common
Published: 2016

35. Utility of CSF biomarkers in psychiatric disorders: a national multicentre prospective study

Author: Carole Miguet-Alfonsi, Frank Bellivier, Elodie Bouaziz-Amar, Didier Hannequin, David Wallon, Susanna Schraen, Muriel Quillard, Jacques Hugon, Emilie Beaufils, Alain Jager, Florence Pasquier, Philippe Robert, Anne-Cécile Troussière, Frédéric Blanc, Eloi Magnin, Julien Dumurgier, Claire Paquet, François Mouton-Liger, BMC, BMC, Laboratoire d'Histologie et de Biologie du Vieillissement, Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Mémoire [AP-HP Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Mémoire de Ressources et de Recherche [CHRU de Besançon] (CMRR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques [CHRU de Besançon], Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Mémoire de Ressources et Recherche - CMRR [Haute-Normandie], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre Mémoire de Ressources et de Recherche -CMRR [Lille-Bailleul], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro, Centre de Neurologie [Thionville], Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Département de Gériatrie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS)-Hôpital de jour St François [Strasbourg], Centre Mémoire Ressources Recherche (CMRR), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service de Biochimie [Besançon], Laboratoire de biochimie générale [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), UF de Neurobiologie [Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cognition Behaviour Technology (CobTek), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice)-Université Côte d'Azur (UCA), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de jour St François [Strasbourg]-Les Hôpitaux Universitaires de Strasbourg (HUS), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Normandie Université (NU)-Centre hospitalier universitaire de Rouen, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Pôle : Biologie-Pathologie-Génétique - CHRU Lille, Université Nice Sophia Antipolis (... - 2019) (UNS), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut Claude Pompidou [Nice] (ICP - Nice), Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ), Centre Mémoire de Ressources et de Recherche - CMRR [Besançon] ( CMRR ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Hôpital Roger Salengro, Centre hospitalier régional Metz-Thionville ( CHR Metz-Thionville ), Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie ( ICube ), Institut National des Sciences Appliquées - Strasbourg ( INSA Strasbourg ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg ( ENGEES ) -Réseau nanophotonique et optique, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Matériaux et nanosciences d'Alsace, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Mémoire Ressources Recherche ( CMRR ), Hôpital Bretonneau-CHRU Tours, Centre Hospitalier Régional Universitaire Hôpital Jean Minjoz [Besançon], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Centre hospitalier universitaire de Rouen, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Pôle : Biologie-Pathologie-Génétique - CHRU Lille, Cognition Behaviour Technology ( CobTek ), Université Nice Sophia Antipolis ( UNS ), and Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -CHU Nice-Institut Claude Pompidou [Nice] ( ICP - Nice )
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Neurology, Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC], Cognitive Neuroscience, [SDV]Life Sciences [q-bio], Clinical Neurology, Disease, Clinical practice, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Psychiatric history, Surveys and Questionnaires, Medicine, Dementia, Humans, Prospective Studies, Cognitive decline, Psychiatry, Prospective cohort study, Aged, Retrospective Studies, [ SDV ] Life Sciences [q-bio], business.industry, Mental Disorders, Research, Cognitive disorder, Neurodegenerative Diseases, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Cerebrospinal fluid, Psychiatric disease, Dual diagnosis, Female, Neurology (clinical), business, Alzheimer’s disease, 030217 neurology & neurosurgery, Biomarkers
Abstract: Background Affective and psychotic disorders are mental or behavioural patterns resulting in an inability to cope with life’s ordinary demands and routines. These conditions can be a prodromal event of Alzheimer’s disease (AD). The prevalence of underlying AD lesions in psychiatric diseases is unknown, and it would be helpful to determine them in patients. AD cerebrospinal fluid (CSF) biomarkers (amyloid β, tau and phosphorylated tau) have high diagnostic accuracy, both for AD with dementia and to predict incipient AD (mild cognitive impairment due to AD), and they are sometimes used to discriminate psychiatric diseases from AD. Our objective in the present study was to evaluate the clinical utility of CSF biomarkers in a group of patients with psychiatric disease as the main diagnosis. Methods In a multicentre prospective study, clinicians filled out an anonymous questionnaire about all of their patients who had undergone CSF biomarker evaluation. Before and after CSF biomarker results were obtained, clinicians provided a diagnosis with their level of confidence and information about the treatment. We included patients with a psychiatric disorder as the initial diagnosis. In a second part of the study conducted retrospectively in a followed subgroup, clinicians detailed the psychiatric history and we classified patients into three categories: (1) psychiatric symptoms associated with AD, (2) dual diagnosis and (3) cognitive decline not linked to a neurodegenerative disorder. Results Of 957 patients, 69 had an initial diagnosis of a psychiatric disorder. Among these 69 patients, 14 (20.2 %) had a CSF AD profile, 5 (7.2 %) presented with an intermediate CSF profile and 50 (72.4 %) had a non-AD CSF profile. Ultimately, 13 (18.8 %) patients were diagnosed with AD. We show that in the AD group psychiatric symptoms occurred later and the delay between the first psychiatric symptoms and the cognitive decline was shorter. Conclusions This study revealed that about 20 % of patients with a primary psychiatric disorder diagnosis before undergoing a CSF exploration for cognitive disorder displayed a CSF biomarker AD profile. In memory clinics, it seems important to consider AD as a possible diagnosis before finalizing a diagnosis of a psychiatric disorder.
Published: 2016

36. Detailed neuropsychological evaluation in a patient with Floating Harbor syndrome

Author: Alice Goldenberg, Didier Hannequin, D. Pouliquen, C. Lecointre, O. Martinaud, Valérie Cormier-Daire, and J. Lechevallier
Subjects: Adult, Heart Septal Defects, Ventricular, medicine.medical_specialty, Intelligence, Disease, Neuropsychological Tests, Audiology, Short stature, Craniofacial Abnormalities, Executive Function, Borderline intellectual functioning, Memory, Intellectual disability, medicine, Humans, Abnormalities, Multiple, Attention, Psychiatry, Growth Disorders, Language Disorders, Mood Disorders, Neuropsychology, Bone age, medicine.disease, Clinical Psychology, Neurology, Floating–Harbor syndrome, Space Perception, Speech delay, Female, Neurology (clinical), medicine.symptom, Cognition Disorders, Psychology, Personality
Abstract: The Floating Harbor syndrome is a rare genetic disease characterized by a triad of clinical signs: specific dysmorphic facial features, short stature with delayed bone age, and language and speech disorders. These signs are, in most cases, associated with borderline normal intelligence to moderate delay concerning intellectual functioning. We report an extensive neuropsychological evaluation for an adult female patient and show, in particular, a severe visuospatial impairment. We discuss this deficit in the light of the previous reported cases and suggest that visuospatial abilities should be explored more systematically.
Published: 2012

37. Accident vasculaire cérébral ischémique et cornée verticillée révélant une maladie de Fabry chez une femme

Author: A. Bagan-Triquenot, E. Tollard, E. Guegan-Massardier, S. Bekri, Didier Hannequin, D. Fetter, and Lucie Guyant-Maréchal
Subjects: Gynecology, medicine.medical_specialty, Neurology, Stroke etiology, business.industry, medicine, Cornea verticillata, Neurology (clinical), medicine.symptom, business
Abstract: Resume Introduction La maladie de Fabry est une maladie du metabolisme lysosomale liee a l’X, due a un deficit enzymatique en alpha-galactosidase A, responsable d’une accumulation de glycosphingolipides. Son atteinte multisystemique est plus frequente chez l’homme. Nous rapportons le cas d’une femme dont le diagnostic fut revele par l’atteinte neurologique centrale. Observation Une patiente, âgee de 53 ans, avec des facteurs de risque cardiovasculaires presenta brutalement une hemiparesie droite. Son bilan retrouva une leucopathie vasculaire associee a des megadolicho-vaisseaux, une myocardiopathie concentrique et une cornee verticillee. Le sequencage du gene de l’alpha-galactosidase A (GLA) revela une nouvelle mutation c.150_151del responsable d’une perte de fonction. Elle n’avait pas d’antecedents familiaux. Discussion L’imagerie revelant une leucopathie impose un bilan systematique comprenant l’examen ophtalmologique qui peut etre determinant dans l’orientation etiologique en faveur d’une maladie genetique. Les signes principaux de la maladie de Fabry chez la femme sont lies aux atteintes neurologique et cardiaque. Le traitement est base sur une substitution enzymatique par enzyme recombinante avec des benefices cardiologiques alors que le benefice neurologique reste incertain. Des facteurs de risque cardiovasculaires ne doivent pas faire ecarter une enquete etiologique systematique capable de mettre en evidence une cause rare d’AVC chez un patient jeune.
Published: 2012

38. ABCA7 rare variants and Alzheimer disease risk

Author: Kilan, Le Guennec, Gaël, Nicolas, Olivier, Quenez, Camille, Charbonnier, David, Wallon, Céline, Bellenguez, Benjamin, Grenier-Boley, Stéphane, Rousseau, Anne-Claire, Richard, Anne, Rovelet-Lecrux, Delphine, Bacq, Jean-Guillaume, Garnier, Robert, Olaso, Anne, Boland, Vincent, Meyer, Jean-François, Deleuze, Philippe, Amouyel, Hans Markus, Munter, Guillaume, Bourque, Mark, Lathrop, Thierry, Frebourg, Richard, Redon, Luc, Letenneur, Jean-François, Dartigues, Florence, Pasquier, Adeline, Rollin-Sillaire, Emmanuelle, Génin, Jean-Charles, Lambert, Didier, Hannequin, Dominique, Campion, Karl, Mondon, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Article, 03 medical and health sciences, 0302 clinical medicine, Belgium, Gene Frequency, Alzheimer Disease, Internal medicine, Missense mutation, Medicine, Humans, Exome, Genetic Predisposition to Disease, Allele frequency, Genetic Association Studies, Aged, business.industry, Case-control study, Odds ratio, Confidence interval, Minor allele frequency, 030104 developmental biology, Meta-analysis, Case-Control Studies, Mutation, ATP-Binding Cassette Transporters, Neurology (clinical), France, business, 030217 neurology & neurosurgery
Abstract: Objective:To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting.Methods:We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls.Results:After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.68–7.35, p = 0.0002). Performing a meta-analysis with previously published data, we found that in a combined sample of 1,256 patients and 1,347 controls from France and Belgium, the OR was 2.81 (95% CI 1.89–4.20, p = 3.60 × 10−7).Conclusions:These results confirm that ABCA7 LOF variants are enriched in patients with AD and extend this finding to predicted damaging missense variants.
Published: 2015

39. De l’identification des bases moléculaires des calcifications cérébrales primaires aux mécanismes physiopathologiques : de nouvelles étapes

Author: Donatella Giovannini, Didier Hannequin, Marc Sitbon, Jean-Luc Battini, Gaël Nicolas, Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biology, 03 medical and health sciences, 0302 clinical medicine, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology
Abstract: International audience
Published: 2015

40. No replication of genetic association between candidate polymorphisms and Alzheimer's disease

Author: Sandrine Mace, Dominique Campion, Alexis Brice, Laurent Pradier, Didier Hannequin, Jean-François Deleuze, Colette Dib, Emmanuelle Cousin, Corinne Rocher, Emmanuelle Génin, and Gaëlle Muzard
Subjects: Aging, Candidate gene, Genotype, SORL1, Penetrance, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, PRNP, Alzheimer Disease, Databases, Genetic, medicine, PSEN1, Humans, Genetic Predisposition to Disease, Aged, Genetic association, Genetics, General Neuroscience, Haplotype, Genetic Variation, Middle Aged, medicine.disease, France, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Genome-Wide Association Study, Developmental Biology
Abstract: Alzheimer's disease is a genetically complex disorder, for which new putative susceptibility genes are constantly proposed in the literature. We selected 16 candidate genes involved in biological pathways closely related to the pathology, and for which a genetic association with Alzheimer's disease was previously detected: ACE, BACE1, BDNF, ECE1, HSPG2, IDE, IL1a, IL6, IL10, MAPT, PLAU, PrnP, PSEN1, SORL1, TFCP2 and TGFb1. The variants originally associated with the disease were genotyped in a French Caucasian sample including 428 cases and 475 controls and tested for association in order to replicate the initial results. Despite a careful replication study design, we failed to validate the initial findings for any of these variants, with the possible exception of MAPT, SORL1 and TFCP2 for which some nominal but inconsistent evidence of association was observed.
Published: 2011

41. Troubles de la mémoire d’installation progressive chez un homme de 62ans

Author: L. Koric, François Sellal, Didier Hannequin, T. Maisonobe, Vincent Deramecourt, and Dominique Campion
Subjects: Neurology (clinical), Psychology
Published: 2011

42. Nosologie des dégénérescences lobaires frontotemporales

Author: I. Le Ber, Dominique Campion, D. Wallon, Didier Hannequin, Olivier Martinaud, Vincent Deramecourt, and David Maltête
Subjects: medicine.medical_specialty, Physical medicine and rehabilitation, Progressive nonfluent aphasia, business.industry, medicine, Semantic dementia, Neurology (clinical), Frontotemporal lobar degeneration, Amyotrophic lateral sclerosis, medicine.disease, business, Progressive supranuclear palsy, Frontotemporal dementia
Published: 2011

43. Quantitative assessment of the evolution of cerebellar signs in spinocerebellar ataxias

Author: Didier Hannequin, Ellis Chan, Leorah Freeman, Perrine Charles, Nadia Vandenberghe, David Devos, Cyril Goizet, Maya Tchikviladzé, Pascale Ribai, Cecilia Marelli, Alexandra Durr, Mathieu Anheim, Isabelle Le Ber, Alexis Brice, Alice Le Bayon, Pierre Labauge, Sophie Tezenas du Montcel, Karine Nguyen, Lucie Guyant-Maréchal, and Carlo Maria Vincitorio
Subjects: medicine.medical_specialty, Ataxia, Cerebellar ataxia, macromolecular substances, medicine.disease, Clinical trial, nervous system, Neurology, Rating scale, Internal medicine, Severity of illness, medicine, Spinocerebellar ataxia, Physical therapy, Neurology (clinical), Analysis of variance, medicine.symptom, Young adult, Psychology
Abstract: Background: Responsive ataxia rating scales are essential for determining outcome measures in clinical trials. Methods: We evaluated the responsiveness over time of the composite cerebellar functional severity score, a quantitative score measuring cerebellar ataxia in 133 patients with autosomal dominant cerebellar ataxias (ADCA), which were prospectively evaluated at inclusion and after one-year of follow-up. A more responsive tool was developed, the Cerebellar Functional Severity score writing, incorporating the writing test at dominant hand to the Cerebellar Functional Severity score. Results: Within the one-year follow-up period, the Cerebellar Functional Severity score and its writing version increased significantly and the Scale for the Assessment and Rating of Ataxia decreased significantly reflecting increased severity of the cerebellar symptoms. The Cerebellar Functional Severity score writing responsiveness was best in genotypes SCA1, 2, and 3 compared with the other genotypes (effect size = 0.196, standardized response mean (SRM) = 0.624 versus effect size = −0.051, SRM = −0.150). The Cerebellar Functional Severity score writing used as an outcome measure would require only 163 SCA1, 2, or 3 patients per group in a two-arm interventional trial for a 50% reduction in progression and 80% of power. Discussion: Our study demonstrates that the Cerebellar Functional Severity score and Cerebellar Functional Severity score writing are responsive quantitative scores for evaluating sensitivity to change in ADCA patients and can be used as outcome measures in clinical trials, especially when targeting genotypes SCA1, 2 and 3. © 2011 Movement Disorder Society
Published: 2011

44. An Autopsy Case of Amyotrophic Lateral Sclerosis with Waldenström Macroglobulinemia and Anti-MAG Gammopathy

Author: Fabrice Jardin, Jean-Michel Vallat, Didier Hannequin, Annie Laquerrière, Olivier Martinaud, Anne-Laure Bedat-Millet, Lucile Musset, and Snejana Jurici
Subjects: Waldenström macroglobulinemia, Pathology, medicine.medical_specialty, biology, business.industry, Anti mag, Waldenstrom macroglobulinemia, Autopsy case, Anti-MAG, Amyotrophic lateral sclerosis, medicine.disease, Published: December, 2011, lcsh:RC346-429, Monoclonal gammopathy, nervous system, Immunoglobulin M, Gammopathy, medicine, biology.protein, Neurology (clinical), Antibody, medicine.symptom, business, lcsh:Neurology. Diseases of the nervous system
Abstract: We report the case of a 71-year-old woman with typical signs of bulbar amyotrophic lateral sclerosis (ALS) associated with immunoglobulin M (IgM) monoclonal gammopathy and anti-MAG (myelin-associated glycoprotein) antibodies. This unusual association between ALS and anti-MAG antibodies has previously been reported in a single case. Our present case, at neuropathological examination, demonstrated no causative link between anti-MAG antibodies and ALS.
Published: 2011

45. Clinical imaging and neuropathological correlations in an unusual case of cerebrotendinous xanthomatosis

Author: L.A.J. Kluijtmans, D. Wallon, H.G. Yntema, Olivier Martinaud, Lucie Guyant-Maréchal, Didier Hannequin, R.A. Wevers, Pascale Saugier-Veber, and Annie Laquerrière
Subjects: Pathology, medicine.medical_specialty, Genetics and epigenetic pathways of disease [NCMLS 6], Lipid storage disorder, Neuropathology, Neuroinformatics [DCN 3], Compound heterozygosity, Cerebrotendinous Xanthomatosis, Pathology and Forensic Medicine, Genomic disorders and inherited multi-system disorders [IGMD 3], CYP27A1, medicine, Humans, Cognitive decline, Tomography, Emission-Computed, Single-Photon, medicine.diagnostic_test, business.industry, Cholestanol, Magnetic resonance imaging, Xanthomatosis, Cerebrotendinous, General Medicine, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Neurology, Cholestanetriol 26-Monooxygenase, Female, Neurology (clinical), business, Functional Neurogenomics [DCN 2]
Abstract: Item does not contain fulltext Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder due to a deficiency of the mitochondrial enzyme sterol 27-hydroxylase (CYP 27) with reduced or no chenodeoxycholic synthesis. This deficiency leads to an accumulation of cholestanol in different sites such as the eye lens, central nervous system or tendons. We report a 64-year-old female patient with a progressive gait disorder associated with cognitive decline since the age of 59. The patient had no mental retardation, cataract or chronic diarrhea. Her family reported increasing behavioral modifications 10 years previously. Clinical examination revealed a spastic paraplegia and bilateral xanthomas on the Achilles tendons. Cerebral magnetic resonance imaging (MRI) revealed diffuse hyperintense T2 abnormalities in the pyramidal tracts from the internal capsules to the cerebral peduncles also Technetium-99m-ECD brain SPECT showed a severe cerebellar hypoperfusion. Serum cholestanol analysis was 7 micromol/l (N). After 2 years, she was bedridden and died of aspiration pneumonia. The neuropathological study confirmed the CTX diagnosis and the sequencing analysis revealed that she was compound heterozygous for two mutations in the CYP27A1 gene: 1435 C > T (exon 7) on one allele and a new mutation, 1017 G > C (exon 5) on the other. The interest of the present case is to report neuropathology findings strongly correlated with the MRI and SPECT abnormalities.
Published: 2010

46. Démences : nouveaux concepts, nouveaux enjeux

Author: Florence Pasquier, Pour le comité d’organisation, Didier Hannequin, Olivier Godefroy, Hélène Amieva, and Bruno Dubois
Subjects: Gerontology, Neurology, medicine, Dementia, Neurology (clinical), Psychology, medicine.disease
Published: 2013

47. Une lectrice aphasique

Author: C. Thery-Langlois, Didier Hannequin, Olivier Martinaud, Emmanuel Gerardin, C. Amosse, Sandrine Bioux, and Romain Lefaucheur
Subjects: 05 social sciences, Dyslexia, Neurological disorder, medicine.disease, 050105 experimental psychology, Central nervous system disease, 03 medical and health sciences, 0302 clinical medicine, Neurology, Communication disorder, Aphasia, medicine, 0501 psychology and cognitive sciences, Language disorder, Neurology (clinical), medicine.symptom, Psychology, Humanities, 030217 neurology & neurosurgery
Abstract: Resume L’alexie asemantique est une lecture normale sans acces au sens, par dysfonctionnement de la voie lexicosemantique. Nous rapportons un cas d’origine vasculaire, chez une patiente stenodactylographe, suggerant que la contribution de l’hemisphere droit assurerait cette preservation de la lecture.
Published: 2009

48. Anatomy of executive deficit following ruptured anterior communicating artery aneurysm

Author: Olivier Godefroy, S. Bioux, D. Le Gars, E. Gérardin, Olivier Martinaud, François Proust, B. Perin, Didier Hannequin, Breton, Céline, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Laboratoire de Neurosciences Fonctionnelles et Pathologies (LNFP), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Service d'imagerie médicale [CHU Rouen], Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de neurochirurgie [CHU Rouen], Service de neurochirurgie, CHU Amiens-Picardie, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen]-CHU Rouen
Subjects: Male, Aneurysm, Ruptured, Neuropsychological Tests, MESH: Magnetic Resonance Imaging, 0302 clinical medicine, Centrum semiovale, Medicine, MESH: Aged, MESH: Middle Aged, 05 social sciences, Brain, MESH: Neuropsychological Tests, Middle Aged, Executive functions, Magnetic Resonance Imaging, medicine.anatomical_structure, Neurology, Cardiology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, Adult, medicine.medical_specialty, MESH: Intracranial Aneurysm, 050105 experimental psychology, Lateralization of brain function, Lesion, MESH: Brain, 03 medical and health sciences, Internal medicine, Humans, Middle frontal gyrus, 0501 psychology and cognitive sciences, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive deficit, Aged, MESH: Humans, business.industry, Ventral striatum, MESH: Adult, Intracranial Aneurysm, MESH: Male, MESH: Cognition Disorders, Superior frontal gyrus, Neurology (clinical), Cognition Disorders, business, MESH: Aneurysm, Ruptured, MESH: Female, Neuroscience, 030217 neurology & neurosurgery
Abstract: Background and purpose: To evaluate behavioral and cognitive deficits following anterior communicating artery aneurysm rupture and determine critical lesion locations. Methods: We investigated 74 patients with standardized cognitive tests and behavioral inventory. Two examiners rated MRI signal abnormalities in 51 predetermined regions of interest. Classification tree analysis was used to select regions associated with each cognitive deficit. Results: Eleven patients presented behavioral executive deficits and 10 had cognitive executive deficit. Their presence depended on left hemisphere lesions only: (i) ventral striatum lesion was associated with behavioral executive deficit (P = 0.04), reduction of activities (P = 0.01), and hyperactivity (P = 0.02); (ii) superior frontal gyrus lesion, with cognitive executive deficit (P = 0.01), action initiation deficit (P = 0.02), and rule deduction deficit (P = 0.02); (iii) anterior half of centrum semiovale lesion, with Stroop inhibition deficit (P = 0.02); (iv) medial superior and middle frontal gyri lesions, with task coordination deficit (P = 0.01); and (v) middle frontal gyrus lesion, with words generation deficit (P = 0.02). Conclusion: This study supports that (i) cognitive executive deficits depend mostly on lateral prefrontal lesions, (ii) with locations varying according to executive process, and (iii) behavioral executive deficits are mainly due to left ventral striatum lesion in post-aneurysmal damage.
Published: 2009

49. Génétique de la maladie d’Alzheimer : formes autosomiques dominantes

Author: Didier Hannequin, Lucie Guyant-Maréchal, and Dominique Campion
Subjects: Gynecology, medicine.medical_specialty, Neurology, medicine, Neurology (clinical), Cerebral amyloid angiopathy, Biology, medicine.disease
Abstract: Resume Il s’agit d’une mise au point des connaissances concernant les formes autosomiques dominantes de maladie d’Alzheimer (MA). Ces formes sont dues a des mutations de PSEN1 (69 %), de l’APP (13 %), duplication de l’APP (7,5 %), et rarement de PSEN2 (2 %). Le phenotype de ces formes autosomiques dominantes est essentiellement caracterise par un âge de debut precoce, en regle avant 60 ans. La premiere partie est consacree a la presentation de phenotypes particuliers qui elargissent le spectre de la MA : hematomes intracerebraux causes par une angiopathie amyloide severe, paraplegie spastique, demence a corps de Lewy, et rares ataxies cerebelleuses. La seconde partie est consacree aux consequences de ces alterations genetiques sur le metabolisme du peptide Aβ, qui ont fortement contribue a valider l’hypothese de la cascade amyloidergique comme primum movens de la MA.
Published: 2009

50. Microsubthalamotomy effect at day 3: Screening for determinants

Author: David Maltête, Emmanuel Gerardin, Didier Hannequin, Bertrand Debono, Bruno Mihout, Stéphane Derrey, Nathalie Chastan, and Romain Lefaucheur
Subjects: medicine.medical_specialty, Levodopa, Parkinson's disease, Deep brain stimulation, medicine.medical_treatment, Central nervous system disease, 03 medical and health sciences, 0302 clinical medicine, Degenerative disease, Internal medicine, medicine, Premovement neuronal activity, 030304 developmental biology, 0303 health sciences, business.industry, medicine.disease, nervous system diseases, Surgery, Subthalamic nucleus, Neurology, Dyskinesia, Cardiology, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: A microsubthalamotomy (mSTN) effect has been frequently reported after implantation that improves Parkinson's motor disability. It is usually believed that mSTN effect reflects the post-traumatic tissue reaction within the STN. However, it has never, to our knowledge, been reported whether pre and intraoperative factors could predict this mSTN effect. Preoperative clinical characteristics, that is, age, disease duration, Mattis Dementia Rating Scale score, levodopa responsiveness, severity of motor fluctuations and dyskinesia, and intraoperative parameters, that is, the number of tracks, distance of typical STN neuronal activity recorded along all microelectrodes, and along the definitive electrodes, were assessed in 40 consecutive PD patients submitted for STN stimulation. Multiple stepwise regression analysis showed that only the number of tracks used for microelectrodes recordings was predictor of the contralateral mSTN effect (F (4,73) = 1.83, P = 0.02). This result suggests that the contralateral mSTN depends on the tissue changes along the entirety of surgical trajectories affecting both STN and its adjacent structures. © 2008 Movement Disorder Society
Published: 2008

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