Author: "Florence Pasquier" / Topic: medicine.disease - Searchworks@Jio Institute Digital Library Search Results

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343 results on '"Florence Pasquier"'

1. Association of Amyotrophic Lateral Sclerosis and Alzheimer’s Disease: New Entity or Coincidence? A Case Series

Author: Claire Paquet, Pierre Lozeron, Elodie Bouaziz-Amar, Florence Pasquier, Vincent Deramecourt, Eloi Magnin, Agathe Vrillon, and David Wallon
Subjects: Pathology, medicine.medical_specialty, Amyloid, business.industry, General Neuroscience, General Medicine, Disease, Neuropathology, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Cerebrospinal fluid, medicine, Geriatrics and Gerontology, Amyotrophic lateral sclerosis, business, Episodic memory, Pathological, Frontotemporal dementia
Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia have a strong clinical, genetic, and pathological connection but association of ALS with Alzheimer’s disease (AD) is seldom reported. We report a series of 5 cases of AD associated with ALS. Our patients presented with cognitive deterioration with episodic memory impairment meeting criteria for AD. ALS occurred subsequently in all cases and its phenotype was not homogenous. Amyloid process was confirmed in four cases with cerebrospinal fluid biomarkers. One case underwent postmortem exam, demonstrating hallmarks lesions of both diseases. This series highlights that ALS-AD phenotype could be a specific underexplored entity.
Published: 2021

2. Primary progressive aphasias associated with C9orf72 expansions: Another side of the story

Author: idier Hannequin, Eino Solje, Sabrina Sayah, Emmanuel Gerardin, Marie Sarazin, Florence Pasquier, Marion Houot, Assi-Hervé Oya, Martine Vercelletto, Julien Lagarde, Marie Noguès-Lassiaille, Marie Chupin, Vincent Deramecourt, Sophie Auriacombe, Agnès Camuzat, Marc Teichmann, Jérémie Pariente, Sophie Ferrieux, Lucette Lacomblez, Mathieu Chastan, Jacques Monteil, Yaohua Chen, Marie-Paule Boncoeur, Lorenzo Cipriano, Anne Bissery, Simona Bottani, David Wallon, Christine Delmaire, Carole Roué-Jagot, Benjamin Le Toullec, Bernard-François Michel, Grégory Petyt, Olivier Martinaud, Philippe Couratier, Dario Saracino, Adeline Rollin-Sillaire, Daisy Rinaldi, Mira Didic, Serge Belliard, Amandine Géraudie, Géraldine Lautrette, Frédérique Etcharry-Bouyx, Xavier Delbeuck, Richard Levy, Frédéric Blanc, Mathieu Ceccaldi, Christel Thauvin-Robinet, Marie-Odile Habert, Eve Benchetrit, Maïté Formaglio, Alexis Brice, Isabelle Le Ber, Charles Duyckaerts, Véronique Golfier, Raffaella Migliaccio, Marie-Anne Mackowiak, Catherine Thomas-Antérion, Anne Bertrand, Olivier Colliot, François Sellal, Claire Boutoleau-Bretonnière, Anne M. Remes, Hugo Bertin, Aurélie Funkiewiez, and Stéphanie Bombois
Subjects: medicine.medical_specialty, C9orf72 Protein, Apraxias, Cognitive Neuroscience, Inferior frontal gyrus, Experimental and Cognitive Psychology, Frontotemporal lobar degeneration, respiratory system, Audiology, medicine.disease, Magnetic Resonance Imaging, Apraxia, Primary progressive aphasia, Aphasia, Primary Progressive, Neuropsychology and Physiological Psychology, Atrophy, C9orf72, medicine, Humans, Speech, Orbitofrontal cortex, Psychology, Language, Frontotemporal dementia
Abstract: C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72–related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.
Published: 2021

3. Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study

Author: Sandro Sorbi, Vince D. Calhoun, James B. Rowe, Isabelle Le Ber, Matthis Synofzik, Roberto Gasparotti, Martina Bocchetta, Enrico Premi, Dave Cash, Alexandre de Mendonça, Armin Iraji, Johannes Levin, Stefano Gazzina, A. Danek, Lize C. Jiskoot, Marcello Giunta, Alexander Gerhard, Markus Otto, Raquel Sánchez-Valle, Emily Todd, Genetic Frontotemporal dementia Initiative, Isabel Santana, Silvana Archetti, Rhian S Convery, Robert Laforce, Srinivas Rachakonda, Florence Pasquier, Fermin Moreno, John C. van Swieten, Georgia Peakman, Elizabeth Finger, Jonathan D. Rohrer, Christopher C Butler, Daniela Galimberti, Alberto Benussi, Carmela Tartaglia, Rik Vandenberghe, Caroline Graff, Mario Masellis, Fabrizio Tagliavini, Barbara Borroni, Simon Ducharme, Genetic Frontotemporal dementia Initiative (GENFI), Neurology, and Clinical Genetics
Subjects: Adult, Male, resting-state functional MRI, Heterozygote, Aging, Time Factors, Dissemination in time, Spatial Behavior, spatial chronnectome, Granulin, Biology, Research initiative, frontotemporal dementia, Executive Function, dynamic functional network connectivity, Frontotemporal Dementia, GRN mutation, medicine, Humans, Default mode network, Granulins, General Neuroscience, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Asymptomatic Diseases, Mutation, Mutation (genetic algorithm), Female, Neurology (clinical), Geriatrics and Gerontology, Neuroscience, Insula, Language network, Developmental Biology, Frontotemporal dementia
Abstract: The presymptomatic brain changes of granulin (GRN) disease, preceding by years frontotemporal dementia, has not been fully characterized. New approaches focus on the spatial chronnectome can capture both spatial network configurations and their dynamic changes over time. To investigate the spatial dynamics in 141 presymptomatic GRN mutation carriers and 282 noncarriers from the Genetic Frontotemporal dementia research Initiative cohort. We considered time-varying patterns of the default mode network, the language network, and the salience network, each summarized into 4 distinct recurring spatial configurations. Dwell time (DT) (the time each individual spends in each spatial state of each network), fractional occupacy (FO) (the total percentage of time spent by each individual in a state of a specific network) and total transition number (the total number of transitions performed by each individual in a specifict state) were considered. Correlations between DT, FO, and transition number and estimated years from expected symptom onset (EYO) and clinical performances were assessed. Presymptomatic GRN mutation carriers spent significantly more time in those spatial states characterised by greater activation of the insula and the parietal cortices, as compared to noncarriers (p < 0.05, FDR-corrected). A significant correlation between DT and FO of these spatial states and EYO was found, the longer the time spent in the spatial states, the closer the EYO. DT and FO significantly correlated with performances at tests tapping processing speed, with worse scores associated with increased spatial states’ DT. Our results demonstrated that presymptomatic GRN disease presents a complex dynamic reorganization of brain connectivity. Change in both the spatial and temporal aspects of brain network connectivity could provide a unique glimpse into brain function and potentially allowing a more sophisticated evaluation of the earliest disease changes and the understanding of possible mechanisms in GRN disease.
Published: 2021

4. A multimodal, longitudinal study of cognitive heterogeneity in early‐onset Alzheimer's disease

Author: Florence Pasquier, Grégory Kuchcinski, Stéphanie Bombois, Xavier Delbeuck, Cécile Bordier, Renaud Lopes, Adeline Rollin-Sillaire, Emilie Skrobala, and Marianne Pollet
Subjects: Apolipoprotein E, Pediatrics, medicine.medical_specialty, Longitudinal study, medicine.diagnostic_test, business.industry, Neuroimaging, Cognition, Neuropsychological test, Disease, Neuropsychological Tests, medicine.disease, Neurology, Alzheimer Disease, Cohort, medicine, Humans, Early-onset Alzheimer's disease, Longitudinal Studies, Neurology (clinical), business
Abstract: BACKGROUND AND PURPOSE Alzheimer's disease (AD) is a heterogeneous pathology. Young patients with AD are particularly likely to have an atypical presentation. The objectives of the present cluster analysis were to determine whether patients with early-onset AD (EOAD) had several distinct cognitive profiles and to compare the resulting clusters with regard to clinical, neuroimaging, and laboratory characteristics. METHODS We collected cognitive, behavioural, functional, neuroimaging, and laboratory data on 72 patients meeting the criteria for probable mild EOAD. The patients were first classified into clinical phenotype groups by a multidisciplinary board of clinicians. The patients' cognitive and functional decline was monitored for 24 months. A k-means clustering analysis was then used to determine clusters on the basis of the patients' neuropsychological test results. RESULTS Two distinct clusters were identified: the patients in the first cluster (C1, n = 38) had a predominant memory impairment, whereas patients in the second (C2, n = 34) did not. Dyslipidaemia and the presence of ɛ4 apolipoprotein E allele were more frequent in C1, whereas the cognitive and functional decline was faster in the patients in C2. Moreover, posterior brain abnormalities were more severe in patients in C2 than in patients in C1. CONCLUSIONS By applying a k-means clustering analysis, we identified two clusters of patients in an EOAD cohort. The clusters differed with regard to certain clinical, imaging, and laboratory characteristics. This clustering procedure might be of value for managing patients with EOAD in general and for identifying those at risk of more rapid decline in particular.
Published: 2021

5. Is Fall Risk Systematically Evaluated in Memory Clinics? A National Survey of Practice in France

Author: Florence Pasquier, Victoire Leroy, Pierre Krolak-Salmon, Bertrand Fougère, Françcois Puisieux, Naiara Demnitz, Yaohua Chen, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Elderly Health Service, Hôpital des Charpennes [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Éducation Éthique Santé EA 7505 (EES), and Université de Tours (UT)
Subjects: Male, Risk, medicine.medical_specialty, Specialty, Standardized test, Computer-assisted web interviewing, Timed Up and Go test, Risk Assessment, [SHS]Humanities and Social Sciences, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Outpatient clinic, Dementia, 030212 general & internal medicine, Practice Patterns, Physicians', Geriatric Assessment, Postural Balance, Aged, Aged, 80 and over, Memory Disorders, business.industry, General Neuroscience, Memory clinic, General Medicine, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Health Care Surveys, Family medicine, Accidental Falls, Female, France, Geriatrics and Gerontology, business, Neurocognitive, 030217 neurology & neurosurgery
Abstract: International audience; Background: Falls are a major health problem in older persons but are still under-diagnosed and challenging to prevent. Current guidelines do not target high-risk populations, especially people living with dementia. In France, people with neurocognitive disorders are mainly referred to memory clinics (MCs). Objective: We aimed to survey the routine practice of physicians working in MCs regarding fall risk assessment. Methods: We conducted a cross-sectional survey in France from January to May 2019 among physicians working in MCs, through an anonymous online questionnaire: twenty-seven questions about the physician’s background and their practice of fall risk assessment, especially use of clinical and paraclinical tools. We compared the results according to the age and the specialty of the physician. Results: We obtained 171 responses with a majority of women (60%) and geriatricians (78%). All age classes and all French regions were represented. Most of respondents (98.8%) stated that they address gait and/or falls in outpatient clinic and 95.9%in day hospitals. When asked about how they assess fall risk, fall history (83%) and gait examination (68.4%) were the most widely used, while orthostatic hypotension (24%) and clinical standardized tests (25.7%) were less common. Among standardized tests, One-leg Balance, Timed Up and Go Test, and gait speed measurements were the most used. Geriatricians had more complete fall risk assessment than neurologists (e.g., 56%versus 13%for use of standardized tests, p
Published: 2021

6. Effects of azacitidine in 93 patients with IDH1/2 mutated acute myeloid leukemia/myelodysplastic syndromes: a French retrospective multicenter study

Author: Claude Preudhomme, Cyril Quivoron, Sophie Broutin, Emmanuelle Clappier, Aline Renneville, S. de Botton, Christophe Willekens, Angelo Paci, Ramy Rahmé, Julien Rossignol, Pierre Fenaux, Laurence Simon, Raphael Itzykson, Alice Marceau, Eyal C. Attar, Véronique Saada, Mark G. Frattini, Jean-Baptiste Micol, Madalina Uzunov, Florence Pasquier, Laurent Pascal, Thorsten Braun, Emmanuel Raffoux, Matthieu Duchmann, Julia Delahousse, V. Vidal, Virginie Penard-Lacronique, and Lionel Adès
Subjects: Cancer Research, Myeloid, IDH1, business.industry, Myelodysplastic syndromes, Azacitidine, Myeloid leukemia, Hematology, medicine.disease, IDH2, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Isocitrate dehydrogenase, Oncology, Multicenter study, 030220 oncology & carcinogenesis, medicine, Cancer research, business, 030215 immunology, medicine.drug
Abstract: Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) re...
Published: 2020

7. Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders

Author: Florence Pasquier, Mathieu Vandenbulcke, John R. Hodges, Mario Masellis, Alan J. Lerner, Chiadi U. Onyike, Yolande A.L. Pijnenburg, Wendy Kelso, Dennis Velakoulis, Fiona Kumfor, Carole Azuar, Robert Laforce, Peter Pressman, John C. van Swieten, Ratnavalli Ellajosyula, Jan Van den Stock, Calvin Trieu, Dhamidhu Eratne, Leonardo Cruz de Souza, Daniela Galimberti, Everard G. B. Vijverberg, Bradley F. Boeve, Maria Landqvist Waldö, Howard J. Rosen, Olivier Piguet, Rik Vandenberghe, Alexander Santillo, Annemiek Dols, Flora Gossink, Harro Seelaar, Ramon Landin-Romero, Mario F. Mendez, Elio Scarpini, Caroline Dallaire-Théroux, David C. Perry, Janine Diehl-Schmid, Simon Ducharme, Edward D. Huey, Michael Hornberger, Paulo Caramelli, Emma Devenney, Manabu Ikeda, Sandra Baez, Isabelle Le Ber, Richard Levy, APH - Mental Health, Amsterdam Neuroscience - Neurodegeneration, Neurology, and Psychiatry
Subjects: Male, Delayed Diagnosis, Neuropsychological Tests, Neurodegenerative, frontotemporal dementia, Medical and Health Sciences, Diagnosis, differential diagnosis, Neuropsychological assessment, guidelines, Review Articles, Neurologic Examination, screening and diagnosis, medicine.diagnostic_test, Psychiatric assessment, Mental Disorders, Corrigenda, Magnetic Resonance Imaging, psychiatry, Frontotemporal Dementia (FTD), Detection, Mental Health, Schizophrenia, Frontotemporal Dementia, Neurological, Major depressive disorder, Female, Frontotemporal dementia, 4.2 Evaluation of markers and technologies, medicine.medical_specialty, Neuroimaging, Diagnosis, Differential, Fluorodeoxyglucose F18, Clinical Research, Behavioral and Social Science, medicine, Acquired Cognitive Impairment, Dementia, Humans, Medical history, Bipolar disorder, Psychiatry, Neurology & Neurosurgery, business.industry, Prevention, Psychology and Cognitive Sciences, Neurosciences, biomarkers, medicine.disease, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, Positron-Emission Tomography, Differential, Neurology (clinical), business
Abstract: The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.
Published: 2020

8. A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers

Author: Yolande A.L. Pijnenburg, Alessandro Padovani, Lieke H.H. Meeter, Rita Guerreiro, Mathieu Vandenbulcke, Rose Bruffaerts, Sonja Schönecker, Sofia Bergström, Florence Pasquier, Mikel Tainta, Beatriz Santiago, Roberto Gasparotti, Maria Rosário Almeida, Núria Bargalló, Abbe Ullgren, Martina Bocchetta, James B. Rowe, Pietro Tiraboschi, Robart Bartha, Rachelle Shafei, Benjamin Bender, Anna Månberg, Enrico Premi, Sergi Borrego-Écija, Sandro Sorbi, Christopher C Butler, Rick van Minkelen, Alberto Benussi, Marta Cañada, Carlo Wilke, Christin Andersson, Caroline Graff, Isabel Santana, Elisa Semler, Valentina Bessi, Miren Zulaica, Benedetta Nacmias, Tobias Langheinrich, Christen Shoesmith, Philip Van Damme, Camilla Ferrari, Martin Rosser, Pedro Rosa-Neto, Alexandre de Mendonça, Jennifer M. Nicholas, Catharina Prix, Sebastien Ourselin, Michele Veldsman, Jessica L. Panman, Håkan Thonberg, Jennie Olofsson, Paul M. Thompson, Ana Gorostidi, Andrea Arighi, Raquel Sánchez-Valle, Anna Antonell, Vesna Jelic, Ana Verdelho, Sara Mitchell, Janne M. Papma, Alina Díez, Giuliano Binetti, Rhian S Convery, Silvana Archetti, Ekaterina Rogaeva, Michela Pievani, C. Ferreira, Hans-Otto Karnath, Veronica Redaelli, Giuseppe Di Fede, Giovanni B. Frisoni, Carolina Maruta, Giacomina Rossi, Jaume Olives, Simon Ducharme, Roberta Ghidoni, Alexander Gerhard, Ron Keren, Johannes Levin, Sandra V. Loosli, Jose Bras, Isabelle Le Ber, Emily Todd, Robert Laforce, Sónia Afonso, Matthis Synofzik, Alazne Gabilondo, Elizabeth Finger, Thomas E. Cope, Paola Caroppo, Jorge Villanua, Diana Duro, Georgia Peakman, Giorgio G. Fumagalli, Serge Gauthier, Mario Masellis, Markus Otto, Caroline V. Greaves, Carolyn Timberlake, Harro Seelaar, Ione O.C. Woollacott, Sara Prioni, Jason D. Warren, Cristina Polito, Miguel Tábuas-Pereira, David F. Tang-Wai, Carmela Tartaglia, Linn Öijerstedt, Luisa Benussi, Barbara Borroni, Ricardo Taipa, Albert Lladó, Mircea Balasa, Rosa Rademakers, Lize C. Jiskoot, Miguel Castelo-Branco, Julia Remnestål, Fabrizio Tagliavini, Giorgio Giaccone, Maria João Leitão, Henrik Zetterberg, Valentina Cantoni, Daniela Galimberti, Sarah Anderl-Straub, Simon Mead, Myriam Barandiaran, Adrian Danek, Timothy Rittman, Chiara Fenoglio, Katrina M. Moore, David M. Cash, Rik Vandenberghe, Peter Nilsson, Elisabeth Wlasich, John C. van Swieten, Morris Freedman, Sandra E. Black, Carolin Heller, Stefano Gazzina, Gabriel Miltenberger, Fermin Moreno, Nick C. Fox, David L. Thomas, Jonathan D. Rohrer, Begoña Indakoetxea, Tobias Hoegen, Gemma Lombardi, Elio Scarpini, Bergström, Sofia [0000-0003-2910-4754], Apollo - University of Cambridge Repository, Neurology, Amsterdam Neuroscience - Neurodegeneration, Genetic Frontotemporal Dementia Initiative (GENFI), Jiskoot, Lize (Beitragende*r), Rowe, James B. (Beitragende*r), de Mendonça, Alexandre (Beitragende*r), Tagliavini, Fabrizio (Beitragende*r), Santana, Isabel (Beitragende*r), Le Ber, Isabelle (Beitragende*r), Levin, Johannes (Beitragende*r), Danek, Adrian (Beitragende*r), Otto, Markus (Beitragende*r), Frisoni, Giovanni (Beitragende*r), Ghidoni, Roberta (Beitragende*r), Sorbi, Sandro (Beitragende*r), Pasquier, Florence (Beitragende*r), Jelic, Vesna (Beitragende*r), Andersson, Christin (Beitragende*r), Afonso, Sónia (Beitragende*r), Almeida, Maria Rosario (Beitragende*r), Anderl-Straub, Sarah (Beitragende*r), Antonell, Anna (Beitragende*r), Archetti, Silvana (Beitragende*r), Arighi, Andrea (Beitragende*r), Balasa, Mircea (Beitragende*r), Barandiaran, Myriam (Beitragende*r), Bargalló, Nuria (Beitragende*r), Bartha, Robart (Beitragende*r), Bender, Benjamin (Beitragende*r), Benussi, Alberto (Beitragende*r), Benussi, Luisa (Beitragende*r), Bessi, Valentina (Beitragende*r), Binetti, Giuliano (Beitragende*r), Black, Sandra (Beitragende*r), Bocchetta, Martina (Beitragende*r), Borrego-Ecija, Sergi (Beitragende*r), Bras, Jose (Beitragende*r), Bruffaerts, Rose (Beitragende*r), Cañada, Marta (Beitragende*r), Cantoni, Valentina (Beitragende*r), Caroppo, Paola (Beitragende*r), Cash, David (Beitragende*r), Castelo-Branco, Miguel (Beitragende*r), Convery, Rhian (Beitragende*r), Cope, Thomas (Beitragende*r), Di Fede, Giuseppe (Beitragende*r), Díez, Alina (Beitragende*r), Duro, Diana (Beitragende*r), Fenoglio, Chiara (Beitragende*r), Ferrari, Camilla (Beitragende*r), Ferreira, Catarina B. (Beitragende*r), Fox, Nick (Beitragende*r), Freedman, Morris (Beitragende*r), Fumagalli, Giorgio (Beitragende*r), Gabilondo, Alazne (Beitragende*r), Gasparotti, Roberto (Beitragende*r), Gauthier, Serge (Beitragende*r), Gazzina, Stefano (Beitragende*r), Giaccone, Giorgio (Beitragende*r), Gorostidi, Ana (Beitragende*r), Greaves, Caroline (Beitragende*r), Guerreiro, Rita (Beitragende*r), Heller, Carolin (Beitragende*r), Hoegen, Tobias (Beitragende*r), Indakoetxea, Begoña (Beitragende*r), Karnath, Hans-Otto (Beitragende*r), Keren, Ron (Beitragende*r), Langheinrich, Tobias (Beitragende*r), Leitão, Maria João (Beitragende*r), Lladó, Albert (Beitragende*r), Lombardi, Gemma (Beitragende*r), Loosli, Sandra (Beitragende*r), Maruta, Carolina (Beitragende*r), Mead, Simon (Beitragende*r), Meeter, Lieke (Beitragende*r), Miltenberger, Gabriel (Beitragende*r), van Minkelen, Rick (Beitragende*r), Mitchell, Sara (Beitragende*r), Moore, Katrina (Beitragende*r), Nacmias, Benedetta (Beitragende*r), Nicholas, Jennifer (Beitragende*r), Olives, Jaume (Beitragende*r), Ourselin, Sebastien (Beitragende*r), Padovani, Alessandro (Beitragende*r), Panman, Jessica (Beitragende*r), Papma, Janne M. (Beitragende*r), Peakman, Georgia (Beitragende*r), Pievani, Michela (Beitragende*r), Pijnenburg, Yolande (Beitragende*r), Polito, Cristina (Beitragende*r), Premi, Enrico (Beitragende*r), Prioni, Sara (Beitragende*r), Prix, Catharina (Beitragende*r), Rademakers, Rosa (Beitragende*r), Redaelli, Veronica (Beitragende*r), Rittman, Tim (Beitragende*r), Rogaeva, Ekaterina (Beitragende*r), Rosa-Neto, Pedro (Beitragende*r), Rossi, Giacomina (Beitragende*r), Rosser, Martin (Beitragende*r), Santiago, Beatriz (Beitragende*r), Scarpini, Elio (Beitragende*r), Schönecker, Sonja (Beitragende*r), Semler, Elisa (Beitragende*r), Shafei, Rachelle (Beitragende*r), Shoesmith, Christen (Beitragende*r), Tábuas-Pereira, Miguel (Beitragende*r), Tainta, Mikel (Beitragende*r), Taipa, Ricardo (Beitragende*r), Tang-Wai, David (Beitragende*r), Thomas, David L. (Beitragende*r), Thompson, Paul (Beitragende*r), Thonberg, Håkan (Beitragende*r), Timberlake, Carolyn (Beitragende*r), Tiraboschi, Pietro (Beitragende*r), Todd, Emily (Beitragende*r), Van Damme, Philip (Beitragende*r), Vandenbulcke, Mathieu (Beitragende*r), Veldsman, Michele (Beitragende*r), Verdelho, Ana (Beitragende*r), Villanua, Jorge (Beitragende*r), Warren, Jason (Beitragende*r), Wilke, Carlo (Beitragende*r), Woollacott, Ione (Beitragende*r), Wlasich, Elisabeth (Beitragende*r), Zetterberg, Henrik (Beitragende*r), and Zulaica, Miren (Beitragende*r)
Subjects: medicine.medical_specialty, Neurology, NEFM, Medizin, genetics [Mutation], LASSO, Biology, Aquaporin 4 (AQP4), Neurosecretory protein VGF (VGF), DISEASE, genetics [Progranulins], Cellular and Molecular Neuroscience, Progranulins, CEREBROSPINAL-FLUID, C9orf72, ddc:570, medicine, CRITERIA, Humans, Neuronal pentraxin 2 (NPTX2), RC346-429, genetics [Frontotemporal Dementia], Molecular Biology, Pathological, Genetics, Science & Technology, Neurosciences, RC952-954.6, Brain, Neurofilament medium polypeptide (NEFM), medicine.disease, Molecular medicine, Cerebrospinal fluid, Aquaporin 4, Geriatrics, Suspension bead array, Frontotemporal Dementia, Mutation, Mutation (genetic algorithm), Neurosciences & Neurology, Neurology. Diseases of the nervous system, Neurology (clinical), Life Sciences & Biomedicine, Random forest, Biomarkers, Research Article, Frontotemporal dementia
Abstract: Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.
Published: 2021

9. 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

10. Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial

Author: Peter A. Ljubenkov, Mary Koestler, Florence Pasquier, Dana Hilt, Beth Ann Haynes, Renaud La Joie, Lauren Edwards, Bradley F. Boeve, Jacob Hesterman, Ira J. Goodman, Leonardo Iaccarino, Rik Vandenberghe, Catherine J. Mummery, Marco Onofrj, Sophie Auriacombe, Henry Riordan, Gerhard Koenig, Julio C. Rojas, Hans J Moebius, Adam L. Boxer, Giovanni B. Frisoni, Scott M. McGinnis, Gary Wisniewski, Ken Marek, Didier Hannequin, Murray Grossman, John C. van Swieten, Holger Patzke, Isabelle Le Ber, Baruch Harris, Barbara Borroni, University of California [San Francisco] (UCSF), University of California, Mayo Clinic [Rochester], ASST Spedali Civili of Brescia, University of Brescia, Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Pennsylvania [Philadelphia], 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), Excellence Laboratory LabEx DISTALZ, University College of London [London] (UCL), University Hospitals Leuven [Leuven], Leuven Brain Institute [Leuven, Belgium] (LBI), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), 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), CHU Rouen, Normandie Université (NU), Massachusetts General Hospital, Charlestown, MA, USA, Massachusetts Alzheimer's Disease Research Center, CHU Bordeaux [Bordeaux], University 'G. d'Annunzio' of Chieti-Pescara [Chieti and Pescara, Italy], GlaxoSmithKline [King of Prussia] (GSK), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, Lille Neurosciences & Cognition - U 1172 (LilNCog), 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), 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), and Neurology
Subjects: Oncology, Male, Haploinsufficiency, law.invention, 0302 clinical medicine, Progranulins, Randomized controlled trial, law, Organic Chemicals, media_common, Original Investigation, 0303 health sciences, PLASMA, General Medicine, Middle Aged, CEREBROSPINAL-FLUID BIOMARKERS, DEGENERATION, 3. Good health, Online Only, Tolerability, Neurology, Frontotemporal Dementia, Female, Life Sciences & Biomedicine, Frontotemporal dementia, Adult, medicine.medical_specialty, Clinical Dementia Rating, Biological Availability, Placebo, SEQUENCE, 03 medical and health sciences, Medicine, General & Internal, Internal medicine, General & Internal Medicine, mental disorders, medicine, media_common.cataloged_instance, Humans, European union, 030304 developmental biology, Aged, Science & Technology, business.industry, MUTATIONS, Research, FRONTOTEMPORAL DEMENTIA, medicine.disease, Clinical trial, Histone Deacetylase Inhibitors, SEVERITY, Pharmacodynamics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, 030217 neurology & neurosurgery
Abstract: Key Points Question What is the safety, tolerability, pharmacodynamic, and pharmacokinetic profile of the histone deacetylase inhibitor FRM-0334 in participants with progranulin gene (GRN) haploinsufficiency? Findings In this randomized placebo-controlled clinical trial including 27 participants with GRN haploinsufficiency, FRM-0334 was safe and well tolerated; however, it failed to increase plasma progranulin and cerebrospinal fluid progranulin and failed to demonstrate dose-dependent oral bioavailability. Meaning The studied formulation of FRM-0334 should not be investigated in future clinical trials enrolling participants with GRN haploinsufficiency; this study did not fully address the potential of histone deacetylase inhibition to alter GRN expression., This randomized clinical trial investigates the pharmacokinetic and pharmacodynamic profile, tolerability, and safety of the histone deacetylase inhibitor FRM-0334 in people with progranulin gene haploinsufficiency., Importance Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. Objective To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)–positron emission tomography (PET), in individuals with GRN haploinsufficiency. Design, Setting, and Participants In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. Interventions Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. Main Outcomes and Measures Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). Results A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, –10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, –0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer’s Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = −3.6 × 10−2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, −4.9 × 10−2 to −2.2 × 10−2; P
Published: 2021

11. Three-year changes of cortical 18F-FDG in amnestic vs. non-amnestic sporadic early-onset Alzheimer’s disease

Author: Xavier Leclerc, Xavier Delbeuck, Adeline Rollin Sillaire, Renaud Lopes, Alice Jaillard, Franck Semah, Grégory Kuchcinski, Matthieu Vanhoutte, Rachid Fahmi, and Florence Pasquier
Subjects: Fluorodeoxyglucose, medicine.diagnostic_test, business.industry, Central nervous system, Neuropsychology, Physiology, Physical examination, General Medicine, Disease, medicine.disease, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Biomarker (medicine), Radiology, Nuclear Medicine and imaging, Early-onset Alzheimer's disease, business, medicine.drug
Abstract: To examine and compare longitudinal changes of cortical glucose metabolism in amnestic and non-amnestic sporadic forms of early-onset Alzheimer’s disease and assess potential associations with neuropsychological performance over a 3-year period time. Eighty-two participants meeting criteria for early-onset (
Published: 2019

12. Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms

Author: Pierre Hirsch, Barbara Schmaltz-Panneau, Jean-Henri Bourhis, Caroline Deswarte, Christophe Marzac, Christine Bellanné-Chantelot, Jean-Baptiste Micol, Christine Delaunay-Darivon, Flore Sicre de Fontbrune, Hélène Guermouche, Albert Najman, William Vainchenker, Céline Lemaitre, Jean-Côme Meniane, Eolia Brissot, Florence Pasquier, Philippe Pellet, Gwendoline Leroy, François Delhommeau, Patrick R. Benusiglio, Samy Chraibi, Isabelle Plo, Olivier Caron, Pascal Fuseau, Simona Lapusan, Pascale Cony-Makhoul, Odile Bera, Chrystelle Colas, Jean Pegliasco, Graciela Rabadan Moraes, and Françoise Isnard
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, Myeloid, Adolescent, DNA Copy Number Variations, Vesicular Transport Proteins, Autophagy-Related Proteins, Biology, Germline, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Duplication, Gene duplication, medicine, Biomarkers, Tumor, Humans, Gene, Dominance (genetics), Aged, Retrospective Studies, Chromosomes, Human, Pair 14, Myeloproliferative Disorders, Essential thrombocythemia, Myeloid leukemia, Hematology, Middle Aged, medicine.disease, Prognosis, Repressor Proteins, Survival Rate, Haematopoiesis, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, Germ Cells, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Myelodysplastic Syndromes, Mutation, Cancer research, Female, Disease Susceptibility, Clonal Hematopoiesis, Follow-Up Studies
Abstract: The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.
Published: 2021

13. Investigating the association between cancer and the risk of dementia: Results from the Memento cohort

Author: Mathieu Ceccaldi, Audrey Gabelle, Bruno Dubois, Carole Dufouil, David Wallon, Olivier Hanon, Armelle Gentric, Pierre Krolak-Salmon, Yannick Béjot, Geneviève Chêne, Olivier Godefroy, Jonviea D Chamberlain, Anaïs Rouanet, Florence Pasquier, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Mémoire de Ressources et de Recherches (CMRR), Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Bordeaux [Bordeaux], Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), and Gestionnaire, HAL Sorbonne Université 5
Subjects: Male, medicine.medical_specialty, media_common.quotation_subject, Neuropsychological Tests, illness-death model, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, illness‐death model, 0302 clinical medicine, Developmental Neuroscience, Internal medicine, Neoplasms, Epidemiology, medicine, Dementia, Humans, cancer, Cognitive Dysfunction, selection bias, 030212 general & internal medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Mortality, Research Articles, media_common, Aged, Selection bias, business.industry, Health Policy, Hazard ratio, Cancer, Cognition, Alzheimer's disease, medicine.disease, Confidence interval, 3. Good health, Psychiatry and Mental health, Cohort, Female, epidemiology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), France, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Research Article, dementia
Abstract: International audience; IntroductionStudies on the association of cancer and risk of dementia are inconclusive due to result heterogeneity and concerns of survivor bias and unmeasured confounding.MethodsThis study uses data from the Memento cohort, a French multicenter cohort following persons with either mild or isolated cognitive complaints for a median of 5 years. Illness‐death models (IDMs) were used to estimate transition‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cancer in relation to dementia from time since study entry.ResultsThe analytical sample (N = 2258) excluded 65 individuals without follow‐up information. At the end of follow‐up, 286 individuals were diagnosed with dementia, 166 with incident cancer, and 95 died. Incident cancer was associated with a reduced risk of dementia (HR = 0.58, 95% CI = 0.35‐0.97), with a corresponding E‐value of 2.84 (lower CI = 1.21).DiscussionThis study supports a protective relationship between incident cancer and dementia, encouraging further investigations to understand potential underlying mechanisms.
Published: 2021

14. 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

15. 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

16. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

Author: Lianne M. Reus, Bogdan Pasaniuc, Danielle Posthuma, Toni Boltz, Yolande A.L. Pijnenburg, Roel A. Ophoff, Raffaele Ferrari, Dena G. Hernandez, Michael A. Nalls, Jonathan D. Rohrer, Adaikalavan Ramasamy, John B.J. Kwok, Carol Dobson-Stone, William S. Brooks, Peter R. Schofield, Glenda M. Halliday, John R. Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Isabel Hernández, Agustín Ruiz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, Nigel J. Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R.A. Mackenzie, Ging-Yuek R. Hsiung, David M.A. Mann, Jordan Grafman, Christopher M. Morris, Johannes Attems, Timothy D. Griffiths, Ian G. McKeith, Alan J. Thomas, Pietro Pietrini, Edward D. Huey, Eric M. Wassermann, Atik Baborie, Evelyn Jaros, Michael C. Tierney, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St. George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B. Rowe, Johannes C.M. Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M. Van Deerlin, Murray Grossman, John Q. Trojanowski, Julie van der Zee, Christine Van Broeckhoven, Stefano F. Cappa, Isabelle Le Ber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E. Nielsen, Lena E. Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N. Rossor, Nick C. Fox, Jason D. Warren, Maria Grazia Spillantini, Huw R. Morris, Patrizia Rizzu, Peter Heutink, Julie S. Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia C. Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W. Dickson, Neill R. Graff-Radford, Ronald C. Petersen, David Knopman, Keith A. Josephs, Bradley F. Boeve, Joseph E. Parisi, William W. Seeley, Bruce L. Miller, Anna M. Karydas, Howard Rosen, John C. van Swieten, Elise G.P. Dopper, Harro Seelaar, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale A. Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Florence Lebert, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering-Brown, Andrew B. Singleton, John Hardy, Parastoo Momeni, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Child and Adolescent Psychiatry / Psychology, Erasmus MC other, Neurology, Psychiatry, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), and Amsterdam Neuroscience - Neurodegeneration
Subjects: 0301 basic medicine, Candidate gene, 17q21.31 inversion region, Dorsolateral prefrontal cortex, Expression quantitative trait loci (eQTL), Frontotemporal dementia, SEC22B, Transcriptome-wide association study, Semantic dementia, Gene Expression, Locus (genetics), Biology, 03 medical and health sciences, 0302 clinical medicine, Progressive nonfluent aphasia, mental disorders, medicine, Humans, Gene, Biological Psychiatry, Genetics, nutritional and metabolic diseases, medicine.disease, Genetic architecture, nervous system diseases, 030104 developmental biology, medicine.anatomical_structure, Frontotemporal Dementia, 030217 neurology & neurosurgery
Abstract: Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.
Published: 2021

17. Clinical relevance of brain atrophy subtypes categorization in memory clinics

Author: Olivier Godefroy, François Tison, Yannick Béjot, Frédéric Blanc, David Wallon, Vincent Bouteloup, Clara Fischer, Marie-Odile Habert, Bruno Dubois, Mathilde Sauvée, Geneviève Chêne, Cédric Annweiler, Olivier Hanon, Vincent Planche, Carole Dufouil, J. Delrieu, Marie Chupin, Audrey Gabelle, Isabelle Jalenques, Pierre Krolak-Salmon, Matthieu Ceccaldi, Claire Paquet, Isabelle Bourdel-Marchasson, Florence Pasquier, Jean-François Mangin, Centre de résonance magnétique des systèmes biologiques (CRMSB), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Epidemiology, [SDV]Life Sciences [q-bio], Ambulatory Care Facilities, Hippocampus, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Atrophy, Developmental Neuroscience, Alzheimer Disease, mental disorders, Humans, Medicine, Dementia, Cognitive decline, ComputingMilieux_MISCELLANEOUS, Aged, Memory Disorders, Lewy body, business.industry, Health Policy, Brain, Cognition, medicine.disease, Magnetic Resonance Imaging, Psychiatry and Mental health, 030104 developmental biology, Categorization, Cohort, Female, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, business, 030217 neurology & neurosurgery
Abstract: Introduction The clinical relevance of brain atrophy subtypes categorization in non-demented persons without a priori knowledge regarding their amyloid status or clinical presentation is unknown. Methods A total of 2083 outpatients with either subjective cognitive complaint or mild cognitive impairment at study entry were followed during 4 years (MEMENTO cohort). Atrophy subtypes were defined using baseline magnetic resonance imaging (MRI) and previously described algorithms. Results Typical/diffuse atrophy was associated with faster cognitive decline and the highest risk of developing dementia and Alzheimer's disease (AD) over time, both in the whole analytic sample and in amyloid-positive participants. Hippocampal-sparing and limbic-predominant atrophy were also associated with incident dementia, with faster cognitive decline in the limbic predominant atrophy group. Lewy body dementia was more frequent in the hippocampal-sparing and minimal/no atrophy groups. Discussion Atrophy subtypes categorization predicted different subsequent patterns of cognitive decline and rates of conversion to distinct etiologies of dementia in persons attending memory clinics.
Published: 2020

18. The impact of culture on neuropsychological performance: A global social cognition study across 12 countries

Author: Anne Botzung, Sandra Baez, Ricardo F. Allegri, Begoña Indakoetxea, Catalina Trujillo, Lucia Crivelli, Fermin Moreno, Andrea Slachevsky, Sol Fittipaldi, Leonardo Cruz de Souza, Frédéric Blanc, François Quesque, Johan S. Grisales, Gada Musa, Alberto Benussi, Olga Iakovlena, Michael Hornberger, Maxime Bertoux, María Florencia Clarens, Antoine Coutrot, Antônio Lúcio Teixeira, Galina Prianishnikova, Junhua Liang, Thomas Duning, Ismael Calandri, David Huepe, Juan F. Cardona, Lina Zhao, Myriam Barandiaran, Luciana Cassimiro, Elena Lyashenko, Nahuel Magrath, Patricia Lillo, Paulo Caramelli, Thibaud Lebouvier, Anna Morozova, Nathalie Philippi, Carol Hudon, Florence Pasquier, Nadezda Veryugina, Adolfo M. García, Maura Cosseddu, Agustín Ibáñez, Fen Wang, Emma Flanagan, Hannah Mulet‐Perreault, Millena Vieira Brandão Moura, Carolina Delgado, Lucas Sedeño, Jennifer Kemp, Alejandra Neely-Prado, Sharon Cox, Mônica Sanches Yassuda, Andreas Johnen, and Barbara Borroni
Subjects: Epidemiology, Health Policy, media_common.quotation_subject, Neuropsychology, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Social cognition, Multiculturalism, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, Psychology, media_common, Clinical psychology
Published: 2020

19. Association of Alzheimer's disease and amyotrophic lateral sclerosis: A series of cases and review of the literature

Author: Pierre Lozeron, Florence Pasquier, David Wallon, Vincent Deramecourt, Agathe Vrillon, Elodie Bouaziz Amar, and Claire Paquet
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, medicine.disease, Dermatology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Amyotrophic lateral sclerosis, business, Association (psychology)
Published: 2020

20. Alzheimer's disease phenotypes misdiagnosed with frontotemporal lobar degeneration: A retrospective neuropathologic study

Author: Claude Alain Maurage, Melanie Leroy, Florence Pasquier, Simon Lecerf, Vincent Deramecourt, Florence Lebert, and Thibaud Lebouvier
Subjects: Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Neuropathology, Frontotemporal lobar degeneration, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Clinical phenotype, business
Published: 2020

21. Dementia with Lewy bodies: Characteristics of the prodromal stage in a nationwide longitudinal cohort

Author: Anne Botzung, Izzie Jacques Namer, Carole Dufouil, Frédéric Blanc, Jean-François Dartigues, Catherine Martin-Hunyadi, Jean-François Mangin, Marie Chupin, Clara Fischer, Marie-Odile Habert, Paulo Loureiro de Sousa, Claire Paquet, Vincent Bouteloup, Mathieu Ceccaldi, Nathalie Philippi, Pierre Krolak Salmon, Florence Pasquier, Renaud David, David Wallon, Geneviève Chêne, Catherine Demuynck, Olivier Bousiges, Stéphane Kremer, Catherine Belin, Timothée Albasser, Olivier Moreaud, Mathilde Sauvée, Benjamin Cretin, and Audrey Gabelle
Subjects: medicine.medical_specialty, Epidemiology, Dementia with Lewy bodies, Behavioral neurology, business.industry, Health Policy, Prodromal Stage, Neuropsychiatry, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Longitudinal cohort, Psychiatry, business
Published: 2020

22. lncRNAs as a novel source of diagnostic applications for early Alzheimer’s disease and other dementia types

Author: Moira Marizzoni, Hüseyin Firat, Sabrina Danilin, Frédéric Blanc, Eloi Magnin, Jean-François Démonet, Hakan Gurvit, Bruno Dubois, Giovanni B. Frisoni, Eric Schordan, Florence Pasquier, Stéphanie Boutillier, François Sellal, Sami Ait Abbi Nazi, Jean Christophe Bier, Saliha Moussaoui, Audrey Gabelle, Catherine Mutter, Renaud David, and Adrian Ivanoiu
Subjects: Epidemiology, business.industry, Health Policy, Disease, medicine.disease, Bioinformatics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuroimaging, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2020

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

Author: Noémie Robil, Agnès Camuzat, Vincent Anquetil, Isabelle Le Ber, Ivan Moszer, Florence Pasquier, Philippe Couratier, Emmanuelle Becker, Ludmila Jornea, David Wallon, Olivier Colliot, Dario Saracino, Sylvie Forlani, Thomas Gareau, Daisy Rinaldi, Virgilio Kmetzsch, Pierre de la Grange, Dynamics, Logics and Inference for biological Systems and Sequences (Dyliss), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Service de Neurologie [CHU Limoges], CHU Limoges, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Rouen, Université de Lille, Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), GenoSplice [Paris], FRONTLAB: Fonctions et dysfonctions de systèmes frontaux [ICM Paris] (FRONTlab), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-14-CE15-0016,PREV-DEMALS,Prédire pour prévenir les démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA)(2014), ANR-11-INBS-0013,IFB (ex Renabi-IFB),Institut français de bioinformatique(2011), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École pratique des hautes études (EPHE), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FRONTlab - Systèmes frontaux : fonctions et dysfonctions (FRONTlab), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Kmetzsch, Virgilio, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Appel à projets générique - Prédire pour prévenir les démences frontotemporales (DFT) et la sclérose latérale amyotrophique (SLA) - - PREV-DEMALS2014 - ANR-14-CE15-0016 - Appel à projets générique - VALID, Infrastructures - Institut français de bioinformatique - - IFB (ex Renabi-IFB)2011 - ANR-11-INBS-0013 - INBS - VALID, Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Oncology, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Chromosome 9, Disease, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], C9orf72, Internal medicine, microRNA, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amyotrophic lateral sclerosis, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Mutation, business.industry, medicine.disease, [STAT.ML] Statistics [stat]/Machine Learning [stat.ML], Psychiatry and Mental health, Surgery, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: ObjectiveTo identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72 patients and presymptomatic carriers.MethodsThe PREV-DEMALS study is a prospective study including 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.ResultsFour miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72 mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.ConclusionsWe identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.Trial registration numberNCT02590276.
Published: 2020

24. Scedosporiosis/lomentosporiosis observational study (SOS): Clinical significance of Scedosporium species identification

Author: Boris Melloni, Benoit Roze, Lilia Hasseine, Jacques-Olivier Bay, Laurence Delhaes, Dominique Toubas, Gaelle Guillerm, Xavier Iriart, Thomas Similowski, Valérie Letscher-Bru, Liana Carausu, Adela Angoulvant, Eric Caumes, Marie-Elisabeth Bougnoux, Yves Leprince, Taieb Chouaki, Cécile Molucon-Chabrot, Eric Dannaoui, Hervé Dutronc, Youssef El-Samad, Florent Morio, Morgane Mourguet, Alexandre Alanio, Berengere Gruson, Pierre Cahen, Stéphane Ranque, Anne Boullié, Julie Bonhomme, Violaine Noel, Françoise Dromer, Elisabeth Chachaty, Felipe Suarez, Beate Heym, François Bissuel, Cécile Jensen, Jean-Pierre Gangneux, Emmanuelle Mouchon, Philippe Zann, Patricia Mariani, Bernard Bouteille, Véronique Leflon-Guibout, Dea Garcia-Hermoso, Anne Scemla, Stéphane Blanche, Agnes Lefort, Dorothée Raoux-Barbot, Didier Bronnimann, Olivier Lortholary, Matthieu Revest, Fanny Lanternier, Philippe Poirier, Luc Quaesaet, Marie Machouart, Françoise Botterel-Chartier, Viviane Queyrel-Moranne, Thomas Perpoint, Anne De Tinteniac, Pascale Penn, Ana Presedo, Marie Balsat, Anne Huynh, Lelia Escaut, Noémie Gadaud, Antoine Huguenin, Martine Gari-Toussaint, Sophie Brun, Jean-Marie Forel, Blandine Rammaert, Nicole Desbois, Alain Delmer, Valérie Moal, Arnaud Fekkar, Damien Hoinard, Elizabeth Rivaud, Delphine Lancement, Laurence Pougnet, Valérie Zeller, Jacques Grill, Florence Pasquier, Fabrice Larosa, Jean-François Papon, Nina Arakelyan-Laboure, Thomas Daix, Catherine Cordonnier, Nicolas Limal, Patrick Lutz, Laurence Maulin, Céline Nourrisson, Stéphane Bretagne, Françoise Uettwiller, Florence Ader, Céline Dieval, Nicolas Traversier, Sophie Bayle, Sorya Belaz, Frédéric Villega, Flore Sicre De Fontbrune, Didier Poisson, Olivier Moquet, Guillaume Martin-Blondel, Kamel Laribi, Delphine Horeau-Langlard, Gilles Nevez, Stéphanie Branger, Audrey Hessel, Philippe Herman, Jérémie Orain, Emilie Catherinot, Frédéric Mechai, Cristina Audoly, Frédéric Gabriel, Jean-François Velly, Caroline Fritz, Muriel Alvarez, Romain Guillemain, Pascal Turlure, Grégoire Leclerc, Frederic Pene, Lionel Mannone, Frédéric Grenouillet, Yoann Prevot, Louis-Jean Couderc, Isabelle Degasne, Giovanna Ingenuo, Joséphine Dorin, Florence Persat, Pierre-Marie Roger, Nathalie Brieu, David Boutoille, Pierre Frange, Nicolas Paleiron, Christophe Joubert, Laurent Hustache-Mathieu, Raoul Herbrecht, Frédéric Janvier, Lenaïg Le Clech, Cécile Gautier, Joelle Guitard, Nicolas Durrleman, Romain Guery, Stéphane De Botton, Sophie Cassaing, Marine Paul, Rachel Brault, Claire Briere-Bellier, Catherine Kauffmann-Lacroix, Nicolas Engrand, Audrey Berric, Hôpital Henri Mondor, Diane Bouvry, André Paugam, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Victor Segalen - Bordeaux 2, Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier du Pays d'Aix, CHU Amiens-Picardie, The National Reference Center for Invasive Mycoses and Antifungals is supported in part by Santé Publique France and Institut Pasteur., Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris], and Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP]
Subjects: Adult, Male, medicine.medical_specialty, Antifungal Agents, Adolescent, LOMENTOSPORA PROLIFICANS, Lomentospora prolificans, Microbial Sensitivity Tests, Neutropenia, Scedosporium sp, Scedosporium, Young Adult, 03 medical and health sciences, Scedosporium species, Internal medicine, Humans, Medicine, Clinical significance, Child, Mycological Typing Techniques, scedosporiosis, Phylogeny, Fungemia, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Aged, Retrospective Studies, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, 030306 microbiology, business.industry, Infant, Newborn, Infant, Scedosporium apiospermum, General Medicine, Middle Aged, medicine.disease, cardiovascular localization, 3. Good health, Infectious Diseases, Child, Preschool, outcome, Female, Observational study, France, business, Invasive Fungal Infections
Abstract: International audience; Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes. We retrospectively studied cases of invasive scedosporiosis in France from 2005 through 2017 based on isolates characterized by polyphasic approach. We recorded 90 cases, mainly related to Scedosporium apiospermum (n = 48), S. boydii/S. ellipsoideum (n = 20), and Lomentospora prolificans (n = 14). One-third of infections were disseminated, with unexpectedly high rates of cerebral (41%) and cardiovascular (31%) involvement. In light of recent Scedosporium taxonomic revisions, we aimed to study the clinical significance of Scedosporium species identification and report for the first time contrasting clinical presentations between infections caused S. apiospermum, which were associated with malignancies and cutaneous involvement in disseminated infections, and infections caused by S. boydii, which were associated with solid organ transplantation, cerebral infections, fungemia, and early death. The clinical presentation of L. prolificans also differed from that of other species, involving more neutropenic patients, breakthrough infections, fungemia, and disseminated infections. Neutropenia, dissemination, and lack of antifungal prescription were all associated with 3-month mortality. Our data support the distinction between S. apiospermum and S. boydii and between L. prolificans and Scedosporium sp. Our results also underline the importance of the workup to assess dissemination, including cardiovascular system and brain. Lay Summary Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes.
Published: 2020

25. Visit-to-Visit Blood Pressure Variability Is Associated With Cognitive Decline and Incident Dementia: The S.AGES Cohort

Author: Nicolas Danchin, Bruno Falissard, Philippe Cestac, Jean-Sébastien Vidal, Matthieu Piccoli, Florence Pasquier, Gilles Berrut, Françoise Forette, Philippe Bertin, Emmanuelle Corruble, Brigitte Sallerin, Rissane Ourabah, Linda Benattar-Zibi, Michel Pinget, Laure Rouch, Geneviève Derumeaux, and Olivier Hanon
Subjects: Male, Mean arterial pressure, medicine.medical_specialty, Blood Pressure, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Cognition, Internal medicine, Internal Medicine, Medicine, Dementia, Humans, Cognitive Dysfunction, Cognitive decline, Aged, Aged, 80 and over, business.industry, Proportional hazards model, Incidence, Hazard ratio, Blood Pressure Determination, medicine.disease, Mental Status and Dementia Tests, Pulse pressure, Blood pressure, Cohort, Cardiology, Disease Progression, Female, business, 030217 neurology & neurosurgery
Abstract: To investigate the impact of visit-to-visit systolic blood pressure variability (BPV), diastolic BPV, mean arterial pressure variability, and pulse pressure variability on cognitive decline and incident dementia in noninstitutionalized patients aged ≥65 years. A total of 3319 subjects from the S.AGES (Sujets AGÉS—Aged Subjects) cohort underwent clinical examinations every 6 months during 3 years. Variability was evaluated using standard deviation (SD), coefficient of variation, average real variability, successive variation, variation independent of mean, and residual SD. Cognition was assessed using the Mini-Mental State Examination and dementia with the Diagnostic Statistical Manual of Mental Disorders. Linear mixed models and Cox proportional hazards models were used. Higher systolic BPV was associated with poorer cognition independently of baseline SBP: adjusted 1-SD increase of coefficient of variation: β (SE)=−0.12 (0.06), P =0.04. Similar results were observed for diastolic BPV and mean arterial pressure variability: β (SE)=−0.20 (0.06), P P =0.02). Among the 3319 subjects, 93 (2.8%) developed dementia. Higher systolic BPV was associated with greater dementia risk (adjusted 1-SD increase of coefficient of variation: hazard ratios=1.23 [95% CI, 1.01–1.50], P =0.04). Similar results were found for diastolic BPV and mean arterial pressure variability ( P
Published: 2020

26. Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Author: Manuel Mayhaus, Sandro Sorbi, Peter R. Schofield, A. Rollin, A. Karydas, Alessandro Padovani, Gilles Gasparoni, Peter St George-Hyslop, Carol Dobson-Stone, Stefano F. Cappa, D. S. Knopman, John Hardy, John R. Hodges, Graziella Milan, Florence Pasquier, Christopher Morris, Edward D. Huey, Marc Cruts, Y.A.L. Pijnenburg, R. C. Petersen, Elisa Rubino, P. Scheltens, Vincent Deramecourt, Neil Graff-Radford, Elio Scarpini, Ting Wang, Panagiotis Alexopoulos, Peter Heutink, Lena E. Hjermind, AB Singleton, Jordan Grafman, Elizabeth Thompson, Adrian Danek, Pietro Pietrini, Raffaele Ferrari, Innocenzo Rainero, C. Van Broeckhoven, Rosa Capozzo, Adaikalavan Ramasamy, J. van der Zee, Eric M. Wassermann, Karin Nilsson, Ging-Yuek Robin Hsiung, J. C. van Swieten, Ping Zeng, Rosa Rademakers, Siro Bagnoli, Amalia C. Bruni, Anna Richardson, Dimitrios Kapogiannis, Ian R. A. Mackenzie, Martin N. Rossor, Bruce L. Miller, Roberta Ghidoni, Raffaele Maletta, Massimo Franceschi, Rafael Blesa, Vivianna M. Van Deerlin, Christer Nilsson, Glenda M. Halliday, Jordi Clarimón, John Q. Trojanowski, Michael Tierney, Valeria Novelli, Agustín Ruiz, Didier Hannequin, Giorgio Giaccone, Elise G.P. Dopper, Nicoletta Smirne, F Tagliavini, I. Leber, Julie S. Snowden, Sara Rollinson, Alexis Brice, Ian G. McKeith, John E. Nielsen, Paolo Sorrentino, Véronique Golfier, Maura Gallo, Lauren Bartley, B. F. Boeve, Giancarlo Logroscino, Elena Alonso, Lorenzo Pinessi, Matt Baker, Nigel J. Cairns, Matthias Riemenschneider, William S. Brooks, Alexander Gerhard, Mark Kristiansen, Eric Haan, Israel Hernandez, Ekaterina Rogaeva, Jason D. Warren, Thibaud Lebouvier, Nick C. Fox, Stuart Pickering-Brown, Giacomina Rossi, Carlos Cruchaga, G. Binetti, Maria Landqvist Waldö, William W. Seeley, Jonathan D. Rohrer, Keith A. Josephs, Diego Albani, Wei Gu, Huei-Hsin Chiang, Luigi Ferrucci, H. Zhao, Howie Rosen, Pau Pastor, Alfredo Postiglione, Evelyn Jaros, Livia Bernardi, Dena G. Hernandez, Alberto Lleó, James B. Rowe, Parastoo Momeni, Maria Serpente, Huw R. Morris, Timothy D. Griffiths, Maria Grazia Spillantini, Alan J. Thomas, Maria Elena Conidi, M. Anfossi, Sabrina Pichler, Martine Vercelletto, Murray Grossman, Johannes C. M. Schlachetzki, Gianluigi Forloni, Dennis W. Dickson, Chiara Fenoglio, Olivier Piguet, John B.J. Kwok, Benedetta Nacmias, Harro Seelaar, Robert Perneczky, A. Baborie, Patrizia Rizzu, Y. Gao, Simon Mead, Janine Diehl-Schmid, Sara Ortega-Cubero, Mike A. Nalls, Daniela Galimberti, Annibale Alessandro Puca, Cristina Razquin, Mercè Boada, Johannes Attems, Luisa Benussi, Chiara Cupidi, Irene Piaceri, Xinghao Yu, Joseph E. Parisi, Alexander Kurz, John Collinge, James Uphill, Barbara Borroni, Francesca Frangipane, Caroline Graff, Bernd Ibach, D. M. A. Mann, Amsterdam Neuroscience - Neurodegeneration, Human genetics, Neurology, Apollo - University of Cambridge Repository, and Int FTD-Genomics Consortium IFGC
Subjects: 0301 basic medicine, Oncology, lcsh:Medicine, Genome-wide association study, Neurodegenerative, 631/208, 0302 clinical medicine, Leukocytes, Odds Ratio, 2.1 Biological and endogenous factors, Aetiology, Amyotrophic lateral sclerosis, lcsh:Science, Telomerase, Telomere Shortening, education.field_of_study, Multidisciplinary, 692/617, article, Mendelian Randomization Analysis, Amyotrophic Lateral Sclerosis, Asian Continental Ancestry Group, Cholesterol, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Lipoproteins, LDL, Polymorphism, Single Nucleotide, Proportional Hazards Models, Telomere, Frontotemporal Dementia, Single Nucleotide, Neurology, Engineering sciences. Technology, 692/499, medicine.medical_specialty, Lipoproteins, 692/308, Population, White People, LDL, Mendelian randomization (MR) , leukocyte telomere length (LTL) , amyotrophic lateral sclerosis (ALS), 03 medical and health sciences, Medical research, Rare Diseases, Asian People, Internal medicine, Mendelian randomization, Genetics, medicine, Polymorphism, education, Genetic association, business.industry, Proportional hazards model, International FTD-Genomics Consortium, lcsh:R, Neurosciences, Odds ratio, medicine.disease, Computational biology and bioinformatics, Brain Disorders, 030104 developmental biology, Risk factors, lcsh:Q, 631/114, ALS, business, ddc:600, 030217 neurology & neurosurgery
Abstract: Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.
Published: 2020

27. Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD

Author: Adam H. Dyer, Claire Murphy, Brian Lawlor, Sean P. Kennelly, Ricardo Segurado, Sean Kennelly, Marcel G.M. Olde Rikkert, Robert Howard, Florence Pasquier, Anne Börjesson-Hanson, Magda Tsolaki, Ugo Lucca, D. William Molloy, Robert Coen, Matthias W. Riepe, János Kálmán, Rose Anne Kenny, Fiona Cregg, Sarah O'Dwyer, Cathal Walsh, Jessica Adams, Rita Banzi, Laetitia Breuilh, Leslie Daly, Suzanne Hendrix, Paul Aisen, Siobhan Gaynor, Ali Sheikhi, Diana G. Taekema, Frans R. Verhey, Raffaello Nemni, Flavio Nobili, Massimo Franceschi, Giovanni Frisoni, Orazio Zanetti, Anastasia Konsta, Orologas Anastasios, Styliani Nenopoulou, Fani Tsolaki-Tagaraki, Magdolna Pakaski, Olivier Dereeper, Vincent de la Sayette, Olivier Sénéchal, Isabelle Lavenu, Agnès Devendeville, Gauthier Calais, Fiona Crawford, Michael Mullan, Pauline Aalten, Maria A. Berglund, Jurgen A. Claassen, Rianne A. De Heus, Daan L.K. De Jong, Olivier Godefroy, Siobhan Hutchinson, Aikaterini Ioannou, Michael Jonsson, Annette Kent, Jürgen Kern, Petros Nemtsas, Minoa-Kalliopi Panidou, Laila Abdullah, Daniel Paris, Angelina M. Santoso, Gerrita J. van Spijker, Martha Spiliotou, Georgia Thomoglou, Anders Wallin, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Service de Neurologie, CHU Amiens-Picardie, University of Gothenburg (GU), Department of Psychiatry, Institute of Psychiatry, Institute of psychiatry, CHU Lille, 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), Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Aristotle University of Thessaloniki, Istituto di Ricerce Farmacologiche Mario Negri, IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], University of San Diego (USD), Irish Clinical Research Infrastructures Network (ICRIN), Unità operativa di neurologia riabilitativa, Centro IRCCS Santa Maria Nascente', Fondazione Don Carlo Gnocchi, Università degli studi di Genova = University of Genoa (UniGe), Multimedica-Santa Maria, Castellanza, Université de Genève = University of Geneva (UNIGE), Istituto Centro San Giovanni di Dio Fatebenefratelli, Partenaires INRAE, IRCCS San Giovanni di Dio Fatebenefratelli, Laboratoire d'Automatique, de Mécanique et d'Informatique industrielles et Humaines - UMR 8201 (LAMIH), Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-INSA Institut National des Sciences Appliquées Hauts-de-France (INSA Hauts-De-France), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Maastricht University [Maastricht], Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience
Subjects: cognition, medicine.medical_specialty, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], [SDV]Life Sciences [q-bio], Rate ratio, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Alzheimer Disease, Internal medicine, benzodiazepines, benzodiazepines and related drugs, cognition, Dementia, Medicine, Dementia, Humans, 030212 general & internal medicine, Cognitive decline, Adverse effect, OLDER-ADULTS, benzodiazepines, General Nursing, Aged, benzodiazepines and related drugs, RISK, DECLINE, business.industry, Health Policy, General Medicine, Odds ratio, medicine.disease, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Europe, Pharmaceutical Preparations, Delirium, Geriatrics and Gerontology, Deprescribing, medicine.symptom, business, DELIRIUM, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 218263.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD. DESIGN: This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates. SETTING AND PARTICIPANTS: 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries. RESULTS: Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (beta = 1.62, -1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates. CONCLUSIONS AND IMPLICATIONS: This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD.
Published: 2020

28. Different impact of calreticulin mutations on human hematopoiesis in myeloproliferative neoplasms

Author: Stefan N. Constantinescu, Xénia Cabagnols, Florence Lorre, Philippe Rameau, Caroline Marty, Florence Pasquier, Valérie Ugo, Jerome Rey, Matthieu Mosca, Isabelle Plo, Amandine Tisserand, William Vainchenker, Mira El-Khoury, Fabrizia Favale, Lydia Roy, Christophe Marzac, Hana Raslova, Najet Debili, Gaëlle Vertenoeil, Olivier Bluteau, Eric Solary, Nicole Casadevall, Graciela Rabadan Moraes, Jean-Christophe Ianotto, UCL - SSS/DDUV/SIGN - Cell signalling, and UCL - (SLuc) Service d'hématologie
Subjects: Male, 0301 basic medicine, Cancer Research, 03 medical and health sciences, 0302 clinical medicine, Megakaryocyte, Genetics, medicine, Humans, Progenitor cell, Myelofibrosis, Molecular Biology, Dominance (genetics), Myeloproliferative Disorders, biology, Essential thrombocythemia, medicine.disease, Phenotype, Hematopoiesis, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, biology.protein, Cancer research, Female, Calreticulin
Abstract: Mutations of calreticulin (CALRm) define a subtype of myeloproliferative neoplasms (MPN). We studied the biological and genetic features of CALR-mutated essential thrombocythemia and myelofibrosis patients. In most cases, CALRm were found in granulocytes, monocytes, B and NK cells, but also in T cells. However, the type 1 CALRm spreads more easily than the type 2 CALRm in lymphoid cells. The CALRm were also associated with an early clonal dominance at the level of hematopoietic stem and progenitor cells (HSPC) with no significant increase during granulo/monocytic differentiation in most cases. Moreover, we found that half of type 2 CALRm patients harbors some homozygous progenitors. Those patients were associated with a higher clonal dominance during granulo/monocytic differentiation than patients with only heterozygous type 2 CALRm progenitors. When associated mutations were present, CALRm were the first genetic event suggesting that they are both the initiating and phenotypic event. In blood, type 1 CALRm led to a greater increased number of all types of progenitors compared with the type 2 CALRm. However, both types of CALRm induced an increase in megakaryocytic progenitors associated with a ruxolitinib-sensitive independent growth and with a mild constitutive signaling in megakaryocytes. At the transcriptional level, type 1 CALRm seems to deregulate more pathways than the type 2 CALRm in megakaryocytes. Altogether, our results show that CALRm modify both the HSPC and megakaryocyte biology with a stronger effect for type 1 than for type 2 CALRm.
Published: 2020

29. 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

30. Antihypertensive agents in Alzheimer's disease: beyond vascular protection

Author: Patrick Duriez, Yaohua Chen, Régis Bordet, Florence Pasquier, and Thibaud Lebouvier
Subjects: medicine.medical_specialty, Disease, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Alzheimer Disease, Internal medicine, medicine, Secondary Prevention, Dementia, Humans, Pharmacology (medical), Cognitive decline, Stroke, Neprilysin, Antihypertensive Agents, Vascular disease, business.industry, General Neuroscience, medicine.disease, 030227 psychiatry, Observational study, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Introduction: Midlife hypertension has been consistently linked with increased risk of cognitive decline and Alzheimer's disease (AD). Observational studies and randomized trials show that the use of antihypertensive therapy is associated with a lesser incidence or prevalence of cognitive impairment and dementia. However, whether antihypertensive agents specifically target the pathological process of AD remains elusive.Areas covered: This review of literature provides an update on the clinical and preclinical arguments supporting anti-AD properties of antihypertensive drugs. The authors focused on validated all classes of antihypertensive treatments such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), β-blockers, diuretics, neprilysin inhibitors, and other agents. Three main mechanisms can be advocated: action on the concurrent vascular pathology, action on the vascular component of Alzheimer's pathophysiology, and action on nonvascular targets.Expert opinion: In 2019, while there is no doubt that hypertension should be treated in primary prevention of vascular disease and in secondary prevention of stroke and mixed dementia, the place of antihypertensive agents in the secondary prevention of 'pure' AD remains an outstanding question.
Published: 2019

31. The relationship between CSF biomarkers and cerebral metabolism in early-onset Alzheimer’s disease

Author: Florence Pasquier, Stéphanie Bombois, Xavier Delbeuck, Susanna Schraen, Emilie Skrobala, Adeline Rollin-Sillaire, Franck Semah, Alice Jaillard, Aurélien Maureille, and Matthieu Vanhoutte
Subjects: Male, Oncology, Apolipoprotein E, medicine.medical_specialty, tau Proteins, Disease, Cerebral metabolism, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Internal medicine, Genotype, medicine, Cluster Analysis, Humans, Radiology, Nuclear Medicine and imaging, Early-onset Alzheimer's disease, Normal range, Amyloid beta-Peptides, medicine.diagnostic_test, Lumbar puncture, business.industry, Brain, General Medicine, Middle Aged, Phosphoproteins, medicine.disease, Magnetic Resonance Imaging, Peptide Fragments, Positron-Emission Tomography, 030220 oncology & carcinogenesis, Csf biomarkers, Female, business, Biomarkers
Abstract: One can reasonably suppose that cerebrospinal spinal fluid (CSF) biomarkers can identify distinct subgroups of Alzheimer’s disease (AD) patients. In order to better understand differences in CSF biomarker patterns, we used FDG PET to assess cerebral metabolism in CSF-based subgroups of AD patients. Eighty-five patients fulfilling the criteria for probable early-onset AD (EOAD) underwent lumbar puncture, brain 18F-FDG PET and MRI. A cluster analysis was performed, with the CSF biomarkers for AD as variables. Vertex-wise, partial-volume-corrected metabolic maps were computed for the patients and compared between the clusters of patients. Linear correlations between each CSF biomarker and the metabolic maps were assessed. Three clusters emerged. The “Aβ42” cluster contained 32 patients with low levels of Aβ42, while tau and p-tau remained within the normal range. The “Aβ42 + tau” cluster contained 41 patients with low levels of Aβ42 and high levels of tau and p-tau. Lastly, the “tau” cluster contained 12 patients with very high levels of tau and p-tau and low-normal levels of Aβ42. There were no inter-cluster differences in age, sex ratio, educational level, APOE genotype, disease duration or disease severity. The “Aβ42 + tau” and “tau” clusters displayed more marked frontal hypometabolism than the “Aβ42” cluster did, and frontal metabolism was significantly negatively correlated with the CSF tau level. The “Aβ42” and “Aβ42 + tau” clusters displayed more marked hypometabolism in the left occipitotemporal region than the “tau” cluster did, and metabolism in this region was significantly and positively correlated with the CSF Aβ42 level. The CSF biomarkers can be used to identify metabolically distinct subgroups of patients with EOAD. Future research should seek to establish whether these biochemical differences have clinical consequences.
Published: 2018

32. Sex Differences in the Occurrence of Major Clinical Events in Elderly People with Type 2 Diabetes Mellitus Followed up in the General Practice

Author: Linda Benattar-Zibi, Philippe Bertin, Jean Doucet, Sophie Bucher, Michel Pinget, Olivier Hanon, Françoise Forette, Virginie Ringa, Emmanuelle Corruble, Florence Pasquier, Rissane Ourabah, Bruno Falissard, Nicolas Danchin, Laurent Becquemont, Geneviève Derumeaux, Abdallah Al-Salameh, Gilles Berrut, Bernard Bauduceau, CHU Amiens-Picardie, Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, Pôle hospitalo-universitaire de gérontologie clinique [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Service de cardiologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Henri Mondor, Maladie d'Alzheimer : marqueurs génétiques et vasculaires, neuropsychologies (URP_4468), Groupe hospitalier Broca-Université Paris Cité (UPCité), Université Paris-Saclay, Université de Lille, Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Diabète et thérapies cellulaires (DIATHEC), Université de Strasbourg (UNISTRA), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Acute coronary syndrome, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, General Practice, 030209 endocrinology & metabolism, Comorbidity, Type 2 diabetes, Disease, Revascularization, Lower risk, elderly, primary care, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Endocrinology, cardiovascular disease, Internal medicine, Internal Medicine, Humans, Medicine, Functional ability, Stroke, Aged, Aged, 80 and over, Sex Characteristics, Primary Health Care, business.industry, Type 2 Diabetes Mellitus, General Medicine, medicine.disease, mortality, Hospitalization, Cerebrovascular Disorders, 030104 developmental biology, Diabetes Mellitus, Type 2, Cardiovascular Diseases, sex- and gender-related differences, Female, France, business, Follow-Up Studies
Abstract: Aims The main aim of the present work was to assess if sex influences the occurrence of major clinical events in elderly people with type 2 diabetes followed up in the primary care. Methods 983 subjects aged ≥65years with type 2 diabetes were included by 213 general practitioners and followed up prospectively for three years. Major clinical events were recorded every six month. The first endpoint was a composite of all-cause death and major vascular events (acute coronary syndrome, non-fatal stroke or transient ischemic attack, or revascularization for peripheral artery disease). The second endpoint was all-cause hospitalization. The occurrence of each endpoint was analyzed in order to estimate the role of sex and determine other predictors of major clinical events. Results At baseline, women were older than men but they had a lower prevalence of coexisting diseases (cardiovascular disease and cancer) and equivalent diabetes control (Glycated hemoglobin A1C: 6.9%±0.9 vs. 7.0%±1.1). Over the follow-up period, women were at lower risk to develop the composite endpoint (HR 0.60, 95% CI 0.40-0.91, p=0.016) and the hospitalization endpoint (OR 0.71, 95% CI 0.52-0.96, p=0.029). Coexisting diseases, functional ability and concomitant medications emerged as significant predictors of both endpoints. Conclusions Elderly women with well-controlled type 2 diabetes were less likely to experience major clinical events than their male counterparts. More studies are needed to determine the reasons for the higher hospitalization rate in men.
Published: 2018

33. 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

34. 18F-FDG PET hypometabolism patterns reflect clinical heterogeneity in sporadic forms of early-onset Alzheimer's disease

Author: Xavier Delbeuck, Renaud Lopes, Florence Pasquier, Franck Semah, Adeline Rollin Sillaire, Grégory Petyt, Aurélien Maureille, Matthieu Vanhoutte, Rachid Fahmi, Alice Jaillard, and Grégory Kuchcinski
Subjects: 0301 basic medicine, Aging, Paralimbic cortex, computer.software_genre, 03 medical and health sciences, 0302 clinical medicine, Voxel, Clinical heterogeneity, medicine, Early-onset Alzheimer's disease, Prefrontal cortex, medicine.diagnostic_test, General Neuroscience, Neuropsychology, Cognition, Neuropsychological test, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Neurology (clinical), Geriatrics and Gerontology, Psychology, Neuroscience, computer, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Until now, hypometabolic patterns and their correlations with neuropsychological performance have not been assessed as a function of the various presentations of sporadic early-onset Alzheimer's disease (EOAD). Here, we processed and analyzed the patients' metabolic maps at the vertex and voxel levels by using a nonparametric, permutation method that also regressed out the effects of cortical thickness and gray matter volume, respectively. The hypometabolism patterns in several areas of the brain were significantly correlated with the clinical manifestations. These areas included the paralimbic regions for typical presentations of sporadic EOAD. For atypical presentations, the hypometabolic regions included Broca's and Wernicke's areas and the pulvinar in language forms, bilateral primary and higher processing visual regions (with right predominance) in visuospatial forms, and the bilateral prefrontal cortex in executive forms. Similar hypometabolism patterns were also observed in a correlation analysis of the 18F-FDG PET data versus domain-specific, neuropsychological test scores. These heterogeneities might reflect different underlying pathophysiological processes in particular clinical presentations of sporadic EOAD and should be taken into account in future longitudinal and therapeutic studies.
Published: 2017

35. Topographic distribution of brain iron deposition and small cerebrovascular lesions in amyotrophic lateral sclerosis and in frontotemporal lobar degeneration: a post-mortem 7.0-tesla magnetic resonance imaging study with neuropathological correlates

Author: Didier Leys, Nicolas Durieux, Caroline Moreau, David Devos, Vincent Deramecourt, Jacques De Reuck, Régis Bordet, Claude-Alain Maurage, Florent Auger, Florence Pasquier, and Charlotte Cordonnier
Subjects: Male, Pathology, medicine.medical_specialty, Iron, Thalamus, Caudate nucleus, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Humans, Amyotrophic lateral sclerosis, Aged, Cerebral Hemorrhage, Neuroradiology, Aged, 80 and over, medicine.diagnostic_test, business.industry, Amyotrophic Lateral Sclerosis, Brain, nutritional and metabolic diseases, Magnetic resonance imaging, General Medicine, Frontotemporal lobar degeneration, Middle Aged, medicine.disease, Magnetic Resonance Imaging, nervous system diseases, Cerebrovascular Disorders, Subthalamic nucleus, Globus pallidus, Frontotemporal Dementia, Female, Neurology (clinical), Frontotemporal Lobar Degeneration, business, 030217 neurology & neurosurgery
Abstract: Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal lobar degeneration (FTLD) in 15% of the cases. A neuropathological continuity between ALS and FTLD-TDP is suspected. The present post-mortem 7.0-tesla magnetic resonance imaging (MRI) study compares the topographic distribution of iron (Fe) deposition and the incidence of small cerebrovascular lesions in ALS and in FTLD brains. Seventy-eight post-mortem brains underwent 7.0-tesla MRI. The patients consisted of 12 with ALS, 38 with FTLD, and 28 controls. Three ALS brains had minor FTLD features. Three coronal sections of a cerebral hemisphere were submitted to T2 and T2* MRI sequences. The amount of Fe deposition in the deep brain structures and the number of small cerebrovascular lesions was determined in ALS and the subtypes of FTLD compared to control brains, with neuropathological correlates. A significant increase of Fe deposition was observed in the claustrum, caudate nucleus, globus pallidus, thalamus, and subthalamic nucleus of the FTLD-FUS and FTLD-TDP groups, while in the ALS one, the Fe increase was only observed in the caudate and the subthalamic nuclei. White matter changes were only significantly more severe in the FTLD compared to those in ALS and in controls brains. Cortical micro-bleeds were increased in the frontal and temporal lobes of FTLD as well as of ALS brains compared to controls. Cortical micro-infarcts were, on the other hand, more frequent in the control compared to the ALS and FTLD groups. The present study supports the assumption of a neuropathological continuity between ALS and FTLD and illustrates the favourable vascular risk profile in these diseases.
Published: 2017

36. Low Prevalence and Clinical Effect of Vascular Risk Factors in Early-Onset Alzheimer’s Disease

Author: Jean Dallongeville, Yaohua Chen, David Wallon, Emilie Skrobala, Adeline Rollin Sillaire, Bruno Dubois, Florence Pasquier, and Didier Hannequin
Subjects: Male, medicine.medical_specialty, Population, late onset Alzheimer disease, Context (language use), Comorbidity, 03 medical and health sciences, Apolipoproteins E, 0302 clinical medicine, Alzheimer Disease, Risk Factors, Internal medicine, Epidemiology, Prevalence, Animals, Humans, Medicine, Dementia, Longitudinal Studies, Prospective Studies, 030212 general & internal medicine, Age of Onset, education, Prospective cohort study, education.field_of_study, business.industry, General Neuroscience, Case-control study, General Medicine, Middle Aged, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Logistic Models, vascular risk factors, Cardiovascular Diseases, early onset Alzheimer disease, Multivariate Analysis, Female, France, Geriatrics and Gerontology, business, Body mass index, APOE, 030217 neurology & neurosurgery, Research Article, Cohort study
Abstract: BACKGROUND: Determinants of early-onset Alzheimer's disease (EOAD) are not well known. In late-onset AD, vascular risk factors (VRFs) are associated with earlier clinical manifestation. OBJECTIVE: The objective of this study was to assess the putative association between VRFs and EOAD. METHODS: We studied participants with dementia meeting criteria for EOAD (recruited into the French CoMAJ prospective cohort study from 1 June 2009 to 28 February 2014) and age-, gender-matched controls (ratio 1:3, drawn randomly from the French MONA-LISA population-based survey between 2005 and 2007). Demographic data, VRFs, comorbidities, treatments, and APOE genotypes were compared in multivariable logistic regression analyses. RESULTS: We studied 102 participants with dementia (mean±standard deviation age: 59.5±3.8; women: 59.8%) and 306 controls. Compared with controls, EOAD participants had spent less time in formal education (9.9±2.9 versus 11.7±3.8 y; p
Published: 2017

37. Do spouse caregivers of young and older persons with dementia have different needs? A comparative study

Author: Francine Ducharme, Pascal Antoine, Marie-Jeanne Kergoat, Emilie Wawrziczny, and Florence Pasquier
Subjects: Gerontology, medicine.medical_specialty, Disease onset, Common framework, medicine.disease, Spouse Caregivers, 3. Good health, Test (assessment), 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Spouse, medicine, Dementia, Late onset dementia, 030212 general & internal medicine, Geriatrics and Gerontology, Psychiatry, Psychology, 030217 neurology & neurosurgery, Early onset dementia
Abstract: AIM: The aim of this study was to explore the needs of spouse caregivers of persons with dementia (PWD) and then to compare them based on the PWD's age at disease onset. This data could be used to adapt support programmes to address differences between the two groups. METHOD: Thirty-eight spouse caregivers of persons with late-onset dementia and 40 spouse caregivers of persons with early-onset dementia (PEOD) agreed to participate in the study. The mean ± SD age of the PEOD was 57.6 ± 4.0 years, whereas it was 80.9 ± 5.3 years for the persons with late-onset dementia. Interviews were conducted in the spouse caregivers' homes with only the spouse caregiver. The semi-structured interviews were based on the French version of the Carers Outcome Agreement Tool. The interviews were analyzed in two steps. The first step was qualitative to identify needs. The data were thematically analyzed using QSR NVivo 10. The second step was quantitative to compare the needs depending on the PWD's age at onset. The comparison between the two groups was performed using the χ(2) test. RESULTS: The results demonstrated that the majority of needs are the same for the two groups of spouse caregivers. All caregivers need to unwind, to stimulate and pay attention to the PWD, to break the isolation, and to be more prepared and confident. However, some differences emerge, with the spouse caregivers of PEOD expressing a greater number of needs. The caregivers of PEOD seem to have a greater need to interact and maintain contacts with other people (P = 0.001), have more general care-related needs (P = 0.005), require more appropriate care structures (P = 0.037), and need greater assistance with administrative procedures (P = 0.004). CONCLUSION: To improve spouse caregivers' well-being and sense of efficiency, it would be interesting to develop a support programme with a common framework and specific modules depending on the PWD's age at disease onset.
Published: 2017

38. Cerebrovascular Lesions in Mixed Neurodegenerative Dementia: A Neuropathological and Magnetic Resonance Study

Author: Didier Leys, Claude-Alain Maurage, Vincent Deramecourt, Régis Bordet, Florent Auger, Florence Pasquier, Nicolas Durieux, Jacques De Reuck, and Charlotte Cordonnier
Subjects: Lewy Body Disease, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Mri studies, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, mental disorders, Magnetic resonance study, Humans, Medicine, Aged, Cerebrovascular pathology, Aged, 80 and over, business.industry, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, nervous system diseases, Cerebrovascular Disorders, 030104 developmental biology, Neurology, Mixed dementia, Dementia, Female, Neurology (clinical), Lewy body pathology, Cerebral amyloid angiopathy, Neurodegenerative dementia, business, Lewy body disease, 030217 neurology & neurosurgery
Abstract: Background: In elderly brains of demented patients, Alzheimer and Lewy body pathology (LBP) are frequently associated. Cortical microinfarcts (CoMIs) are more observed in Lewy body disease, even in the absence of cerebral amyloid angiopathy (CAA). The present neuropathological and 7.0-tesla MRI studies investigate whether CoMIs are also more frequent in mixed neurodegenerative dementia syndromes. Summary: Both examinations revealed that CoMIs are increased to different degrees in mixed dementia syndromes according to the severity of the LBP. They were mainly associated with a trend of older age and arterial hypertension in the patients with the most severe LBP. Messages: The increased number of CoMIs in mixed dementia syndromes with LBP is mainly due to the associated cerebrovascular pathology, even in the absence of CAA.
Published: 2017

39. Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer’s Disease Before 51 Years

Author: Aline Zarea, Eloi Magnin, Stéphane Epelbaum, Claire Paquet, Valérie Chauviré, Florence Pasquier, Anne Boland, Marie Sarazin, David Wallon, Bruno Salomon, Dominique Campion, Olivier Godefroy, Olivier Martinaud, Mathilde Sauvée, Sophie Auriacombe, Cecilia Marelli, Frédérique Etcharry-Bouyx, Gaël Nicolas, Jean-François Deleuze, Anne-Claire Richard, Vincent de la Sayette, Audrey Gabelle, Thérèse Rivasseau Jonveaux, Stéphane Rousseau, Jérémie Pariente, Mathieu Ceccaldi, Maïté Formaglio, Anne Rovelet-Lecrux, Didier Hannequin, Adeline Rollin-Sillaire, Bernard Croisile, Isabelle Le Ber, Morgane Lacour, Olivier Quenez, Olivier Rouaud, Muriel Quillard-Muraine, Claire Boutoleau-Bretonnière, 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), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de neurologie [Rouen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Neurosciences Fonctionnelles et Pathologies (LNFP), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Lyon], CHU Lyon, Hospices Civils de Lyon (HCL), 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 Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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)-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)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, MESH: Mutation, 03 medical and health sciences, Amyloid beta-Protein Precursor, 0302 clinical medicine, MESH: Whole Exome Sequencing, Alzheimer Disease, Risk Factors, MESH: Risk Factors, MESH: Amyloid beta-Protein Precursor, PSEN2, Genotype, Genetic variation, Presenilin-2, Exome Sequencing, medicine, PSEN1, Presenilin-1, Humans, Early-onset Alzheimer's disease, Genetic Predisposition to Disease, Risk factor, Allele, Exome sequencing, Genetics, MESH: Humans, MESH: Middle Aged, business.industry, General Neuroscience, MESH: Genetic Predisposition to Disease, General Medicine, Middle Aged, medicine.disease, MESH: Presenilin-1, MESH: Male, 3. Good health, MESH: Presenilin-2, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female, Geriatrics and Gerontology, business, MESH: Female, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract: International audience; Background:Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer’s disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants.Objective:To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. Methods:We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. Results:Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p
Published: 2019

40. Diagnosis of severe cognitive disorder: the family history as a key issue

Author: Bertrand de Toffol, Celine Derollez, Stéphanie Bombois, Stéphane Haïk, and Florence Pasquier
Subjects: medicine.medical_specialty, Neurology, Bipolar Disorder, business.industry, Cognitive disorder, Dermatology, General Medicine, medicine.disease, Psychiatry and Mental health, Cognition, medicine, Key (cryptography), Humans, Family, Neurology (clinical), Neurosurgery, Family history, Psychiatry, business, Cognition Disorders, Neuroradiology
Published: 2019

41. O1‐06‐04: ASSOCIATION BETWEEN HYPERTENSION AND ALZHEIMER'S DISEASE AND RELATED CAUSES OF DEMENTIA: A PATHWAYS ANALYSIS IN THE MEMENTO COHORT

Author: Jérémie Lespinasse, Isabelle Rouch-Leroyer, Florence Pasquier, Olivier Moreaud, Audrey Gabelle, Jean-François Mangin, Athanasios Benetos, Pierre Vandel, Renaud David, Carole Dufouil, François Tison, Cédric Annweiler, Frédéric Blanc, Claire Paquet, Bruno Dubois, Cécile Proust-Lima, Olivier Hanon, Marie-Odile Habert, Geneviève Chêne, Pierre Jean Ousset, Marie Chupin, François Sellal, Olivier Godefroy, Isabelle Jalenques, Mathieu Ceccaldi, and Hugo Bertin
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, Cohort, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, business, Association (psychology)
Published: 2019

42. An acceptance, role transition, and couple dynamics-based program for caregivers:A qualitative study of the experience of spouses of persons with young-onset dementia

Author: Clotilde Larochette, Emilie Wawrziczny, Florence Pasquier, David Papo, Pascal Antoine, Université de Lille, CNRS, CHU Lille, Sciences Cognitives et Sciences Affectives (SCALab) - UMR 9193, Laboratoire Sciences Cognitives et Sciences Affectives - UMR 9193 [SCALab], Troubles cognitifs dégénératifs et vasculaires - U1171, Troubles cognitifs dégénératifs et vasculaires - U 1171 [TCDV], Sciences Cognitives et Sciences Affectives (SCALab) - UMR 9193 (SCALab), Université de Lille-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), Laboratoire Sciences Cognitives et Sciences Affectives - UMR 9193 (SCALab), 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), Université de Lille, LillOA, and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Sociology and Political Science, NO, Developmental psychology, 03 medical and health sciences, Qualitative feedback, [SCCO]Cognitive science, 0302 clinical medicine, couple, Surveys and Questionnaires, caregiver, young-onset dementia, acceptance, couple, role transition, medicine, Humans, Dementia, Spouses, Qualitative Research, caregiver, 030214 geriatrics, 4. Education, Transition (fiction), General Social Sciences, role transition, [SCCO] Cognitive science, General Medicine, medicine.disease, Caregivers, Dynamics (music), acceptance, young-onset dementia, Young onset dementia, Psychology, 030217 neurology & neurosurgery, Qualitative research
Abstract: Objective In this study, we assessed a support program based on acceptance, role transition, and couple dynamics for spouses of people with young-onset dementia. The qualitative feedback from the caregivers’ experience is analyzed. The goal was to explore how this home-based support program is perceived and to appraise the impact of the different approaches that were offered. Design A thematic analysis was conducted on the answers to the end-of-session questionnaires and the follow-up semistructured interviews. Results Five themes emerged from the analyses. They highlighted caregivers’ ability to overcome their emotional struggle as well as the control of their loved one’s behaviors. The results also showed the possibility for caregivers to access new ways to support their loved ones and to maintain the quality of their relationship. Conclusion These findings represent preliminary evidence of this program’s efficacy for caregivers.
Published: 2019

43. 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

44. CPX-351 Induces Deep Response and Suppress the Impact of Poor Prognosis Mutations (TP53, ASXL1, RUNX1 and EVI1) Defined By ELN-2017 in t-AML and MRC AML: A Report from a Multicentric French Cohort

Author: Xavier Thomas, Alexis Genthon, Thomas Cluzeau, Mathieu Sauvezie, Edmond Chiche, Gabrielle Roth Guepin, Caroline Bonmati, Christian Recher, Ramy Rahmé, Patrice Chevallier, Florence Pasquier, Patrick Auberger, Lionel Ades, Michael Loschi, Mohamad Mohty, Arnaud Pigneux, Olivier Legrand, Emmanuel Raffoux, Pierre Peterlin, Caroline Lejeune, Alexis Caulier, Magalie Joris, Sarah Bertoli, Jean Baptiste Micol, Université Côte d'Azur - Faculté de Médecine (UCA Faculté Médecine), Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Hôpital Hôtel-Dieu [Nantes] (Centre Hospitalier Universitaire de Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'hématologie clinique et de thérapie cellulaire [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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre méditerranéen de médecine moléculaire (C3M), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), DESSAIVRE, Louise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), CHU Lille, 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 [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Service d'Hématologie, CHU Nice, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Physique de Nice (INPHYNI), Centre National de la Recherche Scientifique (CNRS)-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), Laboratoire d'Hématologie et d'Immunologie [CHU Saint-Antoine], Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Picardie Jules Verne (UPJV), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Lausanne (UNIL), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), XLIM (XLIM), and Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Oncology, medicine.medical_specialty, Daunorubicin, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Hematopoietic stem cell transplantation, medicine.disease_cause, Biochemistry, chemistry.chemical_compound, Internal medicine, hemic and lymphatic diseases, medicine, Mutation, Therapy related, business.industry, Cell Biology, Hematology, medicine.disease, [SDV] Life Sciences [q-bio], RUNX1, chemistry, Cohort, Cytarabine, business, Febrile neutropenia, medicine.drug
Abstract: Introduction CPX-351 is a liposomal formulation of cytarabine and daunorubicin packaged at a 5:1 molar ratio. This drug has recently been approved by FDA and EMEA for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). The primary objective of this study was to analyze the efficacy of CPX-351 in a real-life setting, evaluating the impact of mutations on response and minimal residual disease (MRD) in responding patients. Methods We retrospectively collected data from patients treated by CPX-351 in eleven centers in France. Clinical, biological and treatment information were available for all patients. NGS (19 genes or more) was performed in 67 patients (84%) at diagnosis. Overall response rate (ORR) was defined by complete remission (CR) and CR with incomplete haematological recovery (CRi). Among the patients in CR or CRi, 25 (56%) had MRD evaluation assessed by NGS or flow cytometry. Overall survival (OS) was calculated from the date of AML diagnosis to the date of death or last follow-up. All statistical analyses were performed using SPSS v.22 software (IBM SPSS Statistics). Results Between April 2018 and July 2019, 80 patients treated with CPX-351 were included in this study. Sex ratio M/F was 43/37 and median age was 66 years old (range 20-83). AML subtypes were MRC-AML (61%) including AML with prior myelodysplastic syndrome (MDS-AML) (33%), prior chronic myelomonocytic leukemia (CMML-AML) (7%), or t-AML (29%). Sixteen patients (20%) had received prior treatment by hypomethylating agents (HMA), at the time of MDS diagnosis, before AML evolution. According to ELN 2017 classification, genetic risk was favorable, intermediate and adverse in 1 (1%), 31 (38%) and 47 (58%), respectively. 36% and 28% patients had complex and monosomal karyotypes, respectively. Assessed by NGS the most frequent mutated gene were : RUNX1 (n=17, 25%), TP53 (n=15, 22%), ASXL1 (n=14, 21%), TET2 (n=13, 19%), DNMT3A (n=11, 16%), srsf2 (n=9, 13%), FLT3-ITD (n=8, 12%), CBL (n=7, 10%), WT1 (n=7, 10%), and EZH2 (n=7, 10%). According to a genetic ontogeny-based classifier (Lindsley et al., Blood 2015), 23 patients (34%), 29 (43%), 15 (22%) had de novo/pan-AML, secondary type mutations AML, and TP53 mutated AML, respectively. Only 4 patients discontinuing treatment due to prolonged haematological toxicity. Early death rate was 5% and 8.75% through day 30 and day 60, respectively. Median time to neutrophil recovery (>0,5 G/L) and platelet recovery (>20G/L) after induction was 29 days (range 19-78) and 28 days (range 12-77), respectively. Seventy-five patients (95%) had at least one grade 3 or more AEs, including 69 (86%) febrile neutropenia. We observed gastrointestinal toxicity 32 patients (40%) (nausea/vomiting (30%/11%), mucositis (15%)) including 4% with grade 3 or more and alopecia in only 12%. ORR was 45/80 (56%) after induction 1 including 53% CR and 3% CRi. ORR increased to 58% after induction 2. Among the 45 CR/CRi patients, 25 were evaluable for MRD at the time of the 1st consolidation. 72% had MRD below 10-3 (64% below 10-4). Prior treatment by HMA and presence of monosomal karyotype were identified as factors predicting a lower rate of CR/CRi (P=0.001 and P=0.002, respectively). Lindsley's classifier predicted significantly a better chemosensitivity in de novo/pan-AML mutations (P= 0.037). Poor molecular prognosis subgroups defined by 2017 ELN risk stratification (n = 53) as TP53, ASXL1, RUNX1 and EVI1 mutations were not associated with a lower response rate with CPX-351 (Table 1). Twenty-one (26%) patients underwent an allogeneic haematopoietic stem cell transplant (HSCT) with an improved median OS compared to non-transplanted patients (non reached vs 8 months, P= 0.004). With a median follow up of 8.5 months, median OS was not reached. Survival analysis in subgroups will be available for the ASH meeting. Conclusion These data confirmed the efficacy and safety of CPX-351 in poor risk AML (t-AML and MRC-AML). The high rate of CR with low MRD compares favorably with previous report using 7+3 in elderly unfavorable AML (Sylvie D. Freeman et al., JCO 2013) and may explain the favorable outcome observed in patients after HSCT. Moreover, CPX-351 erases the poor prognosis associated with unfavorable mutations defined in 2017 ELN risk stratification. Lindsley's classifier was the best prognostic scoring system in patients treated by CPX-351. Disclosures Bertoli: Daiichi Sankyo: Consultancy; Astellas: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Peterlin:Jazz Pharma: Consultancy; AbbVie Inc: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy. Chevallier:Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria. Thomas:INCYTE: Honoraria; DAICHI: Honoraria; PFIZER: Honoraria; ABBVIE: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. Pigneux:Daichi: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Roche: Honoraria; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Recher:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ades:Amgen: Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Cluzeau:Abbvie: Consultancy; Jazz Pharma: Consultancy; Menarini: Consultancy.
Published: 2019

45. Aging and cerebrovascular lesions in pure and in mixed neurodegenerative and vascular dementia brains: a neuropathological study

Author: Florence Pasquier, Régis Bordet, Didier Leys, Claude-Alain Maurage, Vincent Deramecourt, Jacques De Reuck, and Charlotte Cordonnier
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, Aging, Neuropathology, Disease, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Medicine, Dementia, Humans, cardiovascular diseases, Vascular dementia, Pathological, Aged, Aged, 80 and over, business.industry, Brain, Neurodegenerative Diseases, Frontotemporal lobar degeneration, medicine.disease, Cerebrovascular Disorders, 030104 developmental biology, Cerebral hemisphere, Female, Neurology (clinical), Cerebral amyloid angiopathy, business, 030217 neurology & neurosurgery
Abstract: Introduction The prevalence of dementia is increasing in our aging population. Because of the complexity of disease pathology, dementia classifications remain controversial. The present post-mortem study investigates whether there are age differences between dementia brains with a single pure neurodegenerative or cerebrovascular disease and those with mixed pathological features. Also, the impact of these vascular lesions is compared. Material and methods A total of 132 dementia brains with a pure neurodegenerative or cerebrovascular disease and 84 with mixed features were examined. Main age and gender distribution were compared between the overall group of pure and of mixed dementia. Also, the most common subgroups were compared separately. In addition to the detection of macroscopic visible lesions, a whole coronal section of a cerebral hemisphere, at the level of the mamillary body, was taken for semi-quantitative microscopic evaluation of white matter changes (WMCs), cortical micro-bleeds (CoMBs), and cortical micro-infarcts (CoMIs). Results Overall, patients with mixed dementia were at death significantly older than those with pure dementia. According to the main diagnosis, the pure forms of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) were more common in the younger age groups while in the older ones the mixed form of Lewy body disease (LBD) predominated. Neuropathological examination revealed an increased severity of cerebral amyloid angiopathy (CAA), territorial infarcts, lobar haematomas, and CoMIs in the mixed AD group. In FTLD only CoMIs were increased in the mixed group, while in LBD no differences in severity of all cerebrovascular lesions were observed. Lacunar infarcts were more frequent in pure vascular dementia, while CAA predominated in the mixed one. Conclusions Mixed dementia during the aging process is mainly due to the severity of AD and LBD pathologies combined with CAA-related cerebrovascular lesions.
Published: 2018

46. Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP

Author: Jiang, Shan, Wen, Natalie, Zeran, Li, Dube, Umber, Del Aguila, Jorge, Budde, John, Martinez, Rita, Hsu, Simon, Fernandez, Maria V, Cairns, Nigel J, Harari, Oscar, Cruchaga, Carlos, Karch, Celeste MRaffaele Ferrari, Dena, G Hernandez, Michael, A Nalls, Jonathan, D Rohrer, Adaikalavan, Ramasamy, John B, J Kwok, Carol, Dobson-Stone, William, S Brooks, Peter, R Schofield, Glenda, M Halliday, John, R Hodges, Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Eric, Haan, Isabel, Hernández, Agustín, Ruiz, Mercè, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Nigel, J Cairns, Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, Jordi, Clarimón, Alberto, Lleó, Rafael, Blesa, Maria Landqvist Waldö, Karin, Nilsson, Christer, Nilsson, Ian R, A Mackenzie, Ging-Yuek, R Hsiung, David M, A Mann, Jordan, Grafman, Christopher, M Morris, Johannes, Attems, Timothy, D Griffiths, Ian, G McKeith, Alan, J Thomas, Pietrini, P, Edward, D Huey, Eric, M Wassermann, Atik, Baborie, Evelyn, Jaros, Michael, C Tierney, Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Lorenzo, Pinessi, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, James, B Rowe, Johannes C, M Schlachetzki, James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Vivianna, M Van Deerlin, Murray, Grossman, John, Q Trojanowski, Julie van der Zee, William, Deschamps, Tim Van Langenhove, Marc, Cruts, Christine Van Broeckhoven, Stefano, F Cappa, Isabelle Le Ber, Didier, Hannequin, Véronique, Golfier, Martine, Vercelletto, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Jørgen, E Nielsen, Lena, E Hjermind, Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Martin, N Rossor, Nick, C Fox, Jason, D Warren, Maria Grazia Spillantini, Huw, R Morris, Patrizia, Rizzu, Peter, Heutink, Julie, S Snowden, Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Amalia, C Bruni, Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dennis, W Dickson, Neill, R Graff-Radford, Ronald, C Petersen, David, Knopman, Keith, A Josephs, Bradley, F Boeve, Joseph, E Parisi, William, W Seeley, Bruce, L Miller, Anna, M Karydas, Howard, Rosen, John, C van Swieten, Elise G, P Dopper, Harro, Seelaar, Yolande A, L Pijnenburg, Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Annibale, A Puca, Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Florence, Pasquier, Adeline, Rollin, Vincent, Deramecourt, Florence, Lebert, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Andrew, B Singleton, John, Hardy, and Parastoo, Momeni
Subjects: 0301 basic medicine, Male, Tau protein, Induced Pluripotent Stem Cells, tau Proteins, medicine.disease_cause, Article, lcsh:RC321-571, Progressive supranuclear palsy, 03 medical and health sciences, Cellular and Molecular Neuroscience, Receptors, GABA, medicine, Animals, Humans, Induced pluripotent stem cell, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Aged, Aged, 80 and over, Neurons, Mutation, biology, Brain, Frontotemporal lobar degeneration, Human brain, medicine.disease, 3. Good health, Cell biology, Mice, Inbred C57BL, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Female, Tauopathy, Supranuclear Palsy, Progressive, CRISPR-Cas Systems, Frontotemporal Lobar Degeneration, Transcriptome, Frontotemporal dementia, Signal Transduction
Abstract: Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P −3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.
Published: 2018

47. Reduced Regional Cortical Thickness Rate of Change in Donepezil-Treated Subjects With Suspected Prodromal Alzheimer’s Disease

Author: Marie Chupin, Enrica Cavedo, Marie Sarazin, Guy Louis Tisserand, Florence Pasquier, Nadine Girard, Olivier Rouaud, Harald Hampel, Samantha Galluzzi, Alain Vighetto, Didier Dormont, Bruno Dubois, Simone Lista, Christine Delmaire, Olivier Colliot, Alain Bonafe, Stéphane Lehéricy, Bernard Croisile, Frédéric Ricolfi, Mathieu Ceccaldi, Françoise Duveau, Jacques Touchon, Pierre-Jean Ousset, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], 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)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), 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), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Casselardit - Junod, Centre Mémoire de Ressources et de Recherche [Nice] (CMRR Nice), 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)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), IRCCS Fatebenefratelli - Brescia, Services de neuroradiologie [Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), IEF, Université Paris-Sud - Paris 11 (UP11), Eisai, CHU Saint-Antoine [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (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 Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Inria de Paris, Service de Neuroradiologie [CHU Pitié-Salpêtrière], Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), 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 neuroradiologie diagnostique et fonctionnelle [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)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Inria de Paris, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Nice Sophia Antipolis (... - 2019) (UNS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Lille, CNRS, Inserm, Université de Lille, Troubles cognitifs dégénératifs et vasculaires - U1171, and Troubles cognitifs dégénératifs et vasculaires - U 1171 [TCDV]
Subjects: Male, 0301 basic medicine, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, law.invention, 0302 clinical medicine, Piperidines, Randomized controlled trial, law, Outcome Assessment, Health Care, Donepezil, Longitudinal Studies, Nootropic Agents, Aged, 80 and over, Cerebral Cortex, medicine.diagnostic_test, Magnetic Resonance Imaging, Psychiatry and Mental health, medicine.anatomical_structure, Cerebral cortex, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Indans, Disease Progression, Cardiology, Female, Alzheimer's disease, Psychology, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, medicine.drug, medicine.medical_specialty, Prodromal Symptoms, Placebo, 03 medical and health sciences, Double-Blind Method, Alzheimer Disease, Internal medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, Humans, Dementia, Cognitive Dysfunction, Aged, Surrogate endpoint, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Magnetic resonance imaging, medicine.disease, 030104 developmental biology, Amnesia, Neuroscience, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: Cortical thinning, previously identified during prodromal stages of Alzheimer's disease (AD), is a "candidate" biomarker implemented in AD clinical therapy trials. We investigated the effect of donepezil treatment on cortical thickness in mild cognitively impaired subjects with the amnestic syndrome of the hippocampal type, a prodromal at-risk group for progression to AD dementia. METHODS: Data were from a longitudinal analysis of a community-based multicenter suspected prodromal AD cohort diagnosed by the Free and Cued Selective Reminding Test (81 donepezil vs 92 placebo) enrolled in a double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day). The study started in November 2006 and concluded in August 2010. All subjects underwent 2 brain structural magnetic resonance imaging (MRI) scans, at baseline and at the end of the trial. Structural MRI images had been processed using the automated pipeline for longitudinal segmentation and surface reconstruction implemented in FreeSurfer. The primary outcome measure of this post hoc study was the annualized percentage change (APC) of cortical thickness. RESULTS: The donepezil group exhibited reduced APC cortical thinning compared to placebo in the rostral anterior cingulate (right: P = .048; left: P = .032), the orbitofrontal (right: P = .012; left: P < .048), and the right inferior frontal (P = .022) cortices and in the right insula (P = .010). These results were not statistically significant after Bonferroni correction likely due to insufficient power for cortical thickness measurements in the study group powered for the predefined hippocampus outcome. CONCLUSIONS: Our findings support the hypothesis that cortical thickness is a reliable candidate surrogate outcome in early predementia AD trials. In addition, donepezil treatment may have an impact on cortical structure/morphology in areas innervated by the medial and lateral cholinergic pathways. BACKGROUND: ClinicalTrials.gov identifier: NCT00403520. 77
Published: 2016

48. TheMAPTgene is differentially methylated in the progressive supranuclear palsy brain

Author: Dominique Caparros-Lefebvre, Florence Pasquier, Vincent Huin, Bernard Sablonnière, Valérie Buée-Scherrer, Luc Buée, Claude-Alain Maurage, Julien Labreuche, Vincent Deramecourt, Hélène Behal, Charles Duyckaerts, Claire-Marie Dhaenens, and Eniko Veronika Kovari
Subjects: 0301 basic medicine, Regulation of gene expression, biology, Tau protein, Methylation, medicine.disease, Molecular biology, eye diseases, Progressive supranuclear palsy, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, CpG site, DNA methylation, medicine, biology.protein, Corticobasal degeneration, Neurology (clinical), Epigenetics, 030217 neurology & neurosurgery
Abstract: Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease causing parkinsonian symptoms. Altered DNA methylation of the microtubule-associated protein tau gene correlates with the expression changes in Alzheimer's disease and Parkinson's disease brains. However, few studies examine the sequences beyond the constitutive promoter.Objectives: Because activating different microtubule associated protein tau gene control regions via methylation might regulate the differential tau expression constituting the specific signatures of individual tauopathies, we compared methylation of a candidate promoter, intron 0.Methods: We assessed DNA methylation in the brains of patients with different tauopathies (35 Alzheimer's disease, 10 corticobasal degeneration, and 18 PSP) and 19 controls by intron 0 pyrosequencing. We also evaluated methylation in an independent cohort of 11 PSP cases and 12 controls. Frontal (affected by tau pathology) and occipital (unaffected) cortices were analyzed.Results: In the initial samples, one CpG island site in intron 0 (CpG1) showed significant hypomethylation in PSP-affected frontal cortices when compared with controls (p = 0.022). Such hypomethylation was observed in replicate samples, but not in occipital cortices or other tauopathies. PSP and control samples (combining the initial and replicate samples) remained significantly different after adjustment for potential confounding factors (age, H1/H1 diplotype; p = 0.0005). PSP-affected tissues exhibited microtubule-associated protein tau RNA hyperexpression when compared with controls (p = 0.004), although no correlation with CpG1 methylation was observed.Conclusions: This exploratory study suggests that regions other than the constitutive promoter may be involved in microtubule-associated protein tau gene regulation in tauopathies and that intron 0 hypomethylation may be a specific epigenetic signature of PSP. These preliminary findings require confirmation.
Published: 2016

49. Couples' experiences with early-onset dementia: An interpretative phenomenological analysis of dyadic dynamics

Author: Pascal Antoine, Emilie Wawrziczny, Francine M. Ducharme, Marie-Jeanne Kergoat, Florence Pasquier, Laboratoire Sciences Cognitives et Sciences Affectives - UMR 9193 (SCALab), Université de Lille-Centre National de la Recherche Scientifique (CNRS), 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), Sciences Cognitives et Sciences Affectives (SCALab) - UMR 9193 (SCALab), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: Male, Sociology and Political Science, [SDV]Life Sciences [q-bio], qualitative study, Developmental psychology, Mesh:Caregivers/psychology, [SCCO]Cognitive science, 0302 clinical medicine, Adaptation, Psychological, 030212 general & internal medicine, Early onset dementia, media_common, Family Characteristics, Interpretative phenomenological analysis, Mesh:Adaptation, General Social Sciences, interpretative phenomenological analysis, General Medicine, Middle Aged, Caregivers, Feeling, Dynamics (music), Spouse, Female, Mesh:Family Characteristics, Psychology, Social psychology, Mesh:Female, media_common.quotation_subject, Mesh:Male, Mesh:Dementia/psychology, early-onset dementia, 03 medical and health sciences, dyadic dynamic, couple, Mesh:Middle Aged, Mesh:Mental Status Schedule, medicine, Humans, Dementia, Interpersonal Relations, Mesh:Interpersonal Relations, 030214 geriatrics, medicine.disease, Mesh:Psychological, Mesh:Humans, Mental Status Schedule, Dyad, Qualitative research
Abstract: Objective The growing interest in early-onset dementia has attracted attention to the situation and experiences of the caregiver, most often the spouse. Several qualitative studies on caregiving spouses have underlined the importance of the feeling of loss, the change of role reported by the caregiving spouses, and the strategies used to protect the person with dementia, all of which raise the question of the relational dynamics at play in these dyads. The present study on 16 couples examines the experiences of each partner, as well as the kinds of interactions taking place within the dyad and how they have evolved since the disease began. Design An interpretative phenomenological analysis was conducted on dyadic semi-structured interviews. Results Seven axes emerged from the analyses, showing that control over symptoms gradually leads to deterioration of marital interactions and to the components of marital dissolution.
Published: 2016

50. Topographic distribution of white matter changes and lacunar infarcts in neurodegenerative and vascular dementia syndromes: A post-mortem 7.0-tesla magnetic resonance imaging study

Author: Didier Leys, Vincent Deramecourt, Charlotte Cordonnier, Claude-Alain Maurage, Nicolas Durieux, Jacques De Reuck, Régis Bordet, Florent Auger, and Florence Pasquier
Subjects: Pathology, medicine.medical_specialty, medicine.diagnostic_test, Lewy body, business.industry, Magnetic resonance imaging, Frontotemporal lobar degeneration, medicine.disease, nervous system diseases, Progressive supranuclear palsy, 03 medical and health sciences, 0302 clinical medicine, Original Research Articles, Coronal plane, medicine, Dementia, cardiovascular diseases, 030212 general & internal medicine, Neurology (clinical), Cerebral amyloid angiopathy, Cardiology and Cardiovascular Medicine, Vascular dementia, business, 030217 neurology & neurosurgery
Abstract: Background White matter changes and lacunar infarcts are regarded as linked to the same underlying small-vessel pathology. On magnetic resonance imaging, white matter changes are frequently observed, while the number of lacunar infarcts is probably underestimated. The present study post-mortem 7.0-tesla magnetic resonance imaging study compares the severity and the distribution of white matter changes and lacunar infarcts in different neurodegenerative and vascular dementia syndromes in order to determine their impact on the disease evolution. Patients and methods Eighty-four post-mortem brains consisting of 15 patients with pure Alzheimer’s disease and 12 with associated cerebral amyloid angiopathy, 14 patients with frontotemporal lobar degeneration, 7 with Lewy body dementia, 10 with progressive supranuclear palsy, 14 with vascular dementia and 12 control brains were examined. Six hemispheric coronal sections of each brain underwent 7.0-tesla magnetic resonance imaging. Location and severity of white matter changes and lacunar infarcts were evaluated semi-quantitatively in each section separately. Results White matter changes predominated in the prefrontal and frontal sections of frontotemporal lobar degeneration and in the post-central section of associated cerebral amyloid angiopathy brains, while overall increased in vascular dementia cases. Lacunar infarcts were more frequent in the vascular dementia brains and mainly increased in the centrum semiovale. Conclusions White matter changes have a different topographic distribution in neurodegenerative diseases and are most severe and extended in vascular dementia. Lacunar infarcts predominate in the deep white matter of vascular dementia compared to the neurodegenerative diseases. Vascular cognitive impairment is mainly linked to white matter changes due to chronic ischaemia as well as to lacunar infarcts due to small-vessel occlusion.
Published: 2016

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