Author: "Martine, Vercelletto" / Topic: frontotemporal dementia - Searchworks@Jio Institute Digital Library Search Results

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1. 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
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2. DAPHNE: A New Tool for the Assessment of the Behavioral Variant of Frontotemporal Dementia

Author: Claire Boutoleau-Bretonnière, Christelle Evrard, Jean Benoît Hardouin, Laëtitia Rocher, Tiphaine Charriau, Frédérique Etcharry-Bouyx, Sophie Auriacombe, Aurélie Richard-Mornas, Florence Lebert, Florence Pasquier, Anne Sauvaget, Samuel Bulteau, Martine Vercelletto, Pascal Derkinderen, Cédric Bretonnière, and Catherine Thomas-Antérion
Subjects: Frontotemporal dementia, Behavioral disorders, Alzheimer’s disease, Bipolar disorder, Progressive supranuclear palsy, Scale, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract: Background: The diagnosis of behavioral variant of frontotemporal dementia (bvFTD) relies primarily on clinical features and remains challenging. The specificity of the recently revised criteria can be disappointing, justifying development of new clinical tools. Objective: We produced a behavioral inventory named DAPHNE. This scale (adapted from Rascovsky's criteria) explores six domains: disinhibition, apathy, perseverations, hyperorality, personal neglect and loss of empathy. It is composed of ten items (five answer categories). The aim was (1) to assess the validity and reliability of DAPHNE and (2) to evaluate its contribution in differentiating patients. Methods: Two scores were computed: DAPHNE-6 (screening) from the six domains and DAPHNE-40 (diagnosis) from the ten items. Reliability and reproducibility were assessed. External validity was studied with the Frontal Behavioral Inventory (FBI) and the Frontotemporal Behavioral Scale (FBS). Finally, the diagnostic performance of DAPHNE was compared to revised criteria, FBI and FBS. Results: DAPHNE was administered to the caregivers of 89 patients, 36 with bvFTD, 22 with Alzheimer's disease, 15 with progressive supranuclear palsy and 16 with bipolar disorder. Reliability and reproducibility were excellent, as was external validity. DAPHNE-6 allowed bvFTD diagnosis (score ≥4) with a sensitivity of 92%, while DAPHNE-40 (score ≥15) had a specificity of 92%. Conclusion: We demonstrate excellent psychometric features for DAPHNE. This quick tool could help for both diagnosing and screening bvFTD.
Published: 2015
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3. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author: Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS
Subjects: Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract: The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.
Published: 2021
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4. 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
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5. Primary Progressive Aphasia Associated With

Author: Dario, Saracino, Sophie, Ferrieux, Marie, Noguès-Lassiaille, Marion, Houot, Aurélie, Funkiewiez, Leila, Sellami, Vincent, Deramecourt, Florence, Pasquier, Philippe, Couratier, Jérémie, Pariente, Amandine, Géraudie, Stéphane, Epelbaum, David, Wallon, Didier, Hannequin, Olivier, Martinaud, Fabienne, Clot, Agnès, Camuzat, Simona, Bottani, Daisy, Rinaldi, Sophie, Auriacombe, Marie, Sarazin, Mira, Didic, Claire, Boutoleau-Bretonnière, Christel, Thauvin-Robinet, Julien, Lagarde, Carole, Roué-Jagot, François, Sellal, Audrey, Gabelle, Frédérique, Etcharry-Bouyx, Alexandre, Morin, Cinzia, Coppola, Richard, Levy, Bruno, Dubois, Alexis, Brice, Olivier, Colliot, Maria Luisa, Gorno-Tempini, Marc, Teichmann, Raffaella, Migliaccio, Isabelle, Le Ber, and Martine, Vercelletto
Subjects: Male, Tomography, Emission-Computed, Single-Photon, Language Tests, Middle Aged, Neuropsychological Tests, Magnetic Resonance Imaging, Cohort Studies, Aphasia, Primary Progressive, Cross-Sectional Studies, Progranulins, Gene Frequency, Frontotemporal Dementia, Mutation, Humans, Speech, Female, Prospective Studies, Atrophy, Biomarkers, Aged
Abstract: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated withPatients with PPA carryingAmong the 235 patients with PPA, 45 (19%) carriedThis study shows that the most frequent PPA variant associated with
Published: 2020

6. 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
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7. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

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

9. Ugly aesthetic perception associated with emotional changes in experience of art by behavioural variant of frontotemporal dementia patients

Author: Olivier Koenig, Pascal Derkinderen, Laetitia Rocher, Catherine Thomas-Antérion, Claire Boutoleau-Bretonnière, Cédric Bretonnière, Audric Mazzietti, Martine Vercelletto, and Christelle Evrard
Subjects: Male, Unconscious mind, Esthetics, Cognitive Neuroscience, Emotions, Experimental and Cognitive Psychology, Neuropsychological Tests, 050105 experimental psychology, Arousal, Creativity, 03 medical and health sciences, Behavioral Neuroscience, Judgment, 0302 clinical medicine, medicine, Reaction Time, Humans, 0501 psychology and cognitive sciences, Valence (psychology), Emotional bias, Aged, Painting, 05 social sciences, Cognition, Middle Aged, medicine.disease, Frontotemporal Dementia, Female, Psychology, Cognition Disorders, Mental Status Schedule, Adjective, 030217 neurology & neurosurgery, Art, Frontotemporal dementia, Cognitive psychology
Abstract: The aesthetic experience through art is a window into the study of emotions. Patients with behavioural variant of frontotemporal dementia (bvFTD) have early alteration of emotional processing. A new appreciation of art has been reported in some of these patients. We designed a computerized task using 32 abstract paintings that allowed us to investigate the integrity of patients' emotions when viewing the artwork. We evaluated both conscious and explicit appraisal of emotions [aesthetic judgment (beautiful/ugly), emotional relevance (affected or not by the painting), emotional valence (pleasant/unpleasant), emotional reaction (adjective choice) and arousal] and unconscious processing. Fifteen bvFTD patients and 15 healthy controls were included. BvFTD patients reported that they were "little touched" by the paintings. Aesthetic judgment was very different between the two groups: the paintings were considered ugly (negative aesthetic bias) and unpleasant (negative emotional bias) more often by the patients than by controls. Valence and aesthetic judgments correlated in both groups. In addition, there was a positive bias in the implicit task and for explicit emotional responses. Patients frequently chose the word "sad" and rarely expressed themselves with such adjectives as "happy". Our results suggest that bvFTD patients can give an aesthetic judgment, but present abstraction difficulties, as spectators, resulting from impairments in the cognitive processes involved. They also have difficulties in terms of emotional processes with the loss of the ability to feel the emotion per se (i.e., to feel an emotion faced with art) linked to behaviour assessment. This cognitive approach allows us to better understand which spectators are bvFTD patients and to show interactions between emotions and behavioural disorders.
Published: 2016

10. Prospective Evaluation of Behavioral Scales in the Behavioral Variant of Frontotemporal Dementia

Author: Martine Vercelletto, Claire Boutoleau-Bretonnière, Christelle Volteau, Thibaud Lebouvier, Catherine Thomas-Antérion, Philippe Jaulin, Lucette Lacomblez, and Philippe Damier
Subjects: Male, medicine.medical_specialty, Psychometrics, Cognitive Neuroscience, Population, Neuropsychological Tests, Severity of Illness Index, Prospective evaluation, Correlation, mental disorders, medicine, Humans, Longitudinal Studies, Prospective Studies, Psychiatry, education, Aged, education.field_of_study, Cognition, Caregiver burden, Middle Aged, Neuropsychiatric inventory, medicine.disease, Clinical trial, Psychiatry and Mental health, Cross-Sectional Studies, Frontotemporal Dementia, Disease Progression, Female, Geriatrics and Gerontology, Psychology, Frontotemporal dementia
Abstract: Background: The Neuropsychiatric Inventory (NPI) and the Frontal Behavioral Inventory (FBI) are widely used in patients with the behavioral variant of frontotemporal dementia (bvFTD). Yet, few data are available on the long-term relevance of these scales. Material and Methods: Based on a bvFTD population that participated in the Memantine Clinical Trial (NCT00200538), we studied the evolution and correlation between scores obtained on behavioral scales (NPI and FBI), cognitive scales [Mini-Mental State Examination (MMSE) and Mattis Dementia Rating Scale (MDRS)] and a burden scale [Zarit Burden Inventory (ZBI)]. The assessments were performed at 1 year in 41 patients and at 2 years in 23 patients who agreed to participate in this open-label study. Results: The 2-year scores obtained on the FBI were significantly higher than the scores at inclusion while those obtained on the NPI did not change. There were significant correlations between the FBI, and the MDRS and MMSE, especially regarding the negative items. The ZBI correlated with behavioral scales at all stages for positive items. Conclusions: This study based on a large population shows that the FBI is a better tool than the NPI for the long-term assessment of bvFTD patients. Moreover, the FBI allows a distinction to be made between behavioral disturbances that involve cognitive functions from those which have an important impact on caregiver burden.
Published: 2012
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11. Démence sémantique : réflexions d’un groupe de travail pour des critères de diagnostic en français et la constitution d’une cohorte de patients

Author: Catherine Thomas-Antérion, J. Boutantin, Martine Vercelletto, Frédéric Bernard, N. Le Carret, Valérie Hahn-Barma, Florence Pasquier, Olivier Rouaud, E. Coutant, Danielle David, P. Renou, Julie S. Snowden, Vincent Deramecourt, Y. Gaestel, E. Guichart, M.-E. Virat-Brassaud, Jérémie Pariente, A. Memin, Claire Boutoleau-Bretonnière, E. Lamy, Olivier Moreaud, C. Lebrun-Givois, B. Lebail, Sandrine Basaglia-Pappas, Sophie Auriacombe, Marie Sarazin, Annik Charnallet, Serge Belliard, S. Garnier, B. Lemesle, and L. Bon
Subjects: medicine.medical_specialty, Neuropsychology, Semantic dementia, Frontotemporal lobar degeneration, Audiology, medicine.disease, Developmental psychology, Neurology, Communication disorder, Aphasia, medicine, Semantic memory, Language disorder, Neurology (clinical), medicine.symptom, Psychology, Frontotemporal dementia
Abstract: Semantic dementia (SD) is a syndrome of progressive loss of semantic knowledge for objects and people. International criteria propose that SD be included in the frontotemporal lobar degeneration syndromes, with progressive non-fluent aphasia and frontotemporal dementia (FTD). However, several related syndromes have been defined that clinically and conceptually share both similarities and differences with SD: fluent progressive aphasia, progressive prosopagnosia, temporal variant of FTD. In order to establish a French consensus for the diagnosis and modalities of evaluation and follow-up of SD, a working group, composed of neurologists, neuropsychologists and speech-therapists, was established by the Groupe de reflexion sur les evaluations cognitives (GRECO). New criteria were elaborated, based on clinical, neuropsychological, and imaging data. They define typical and atypical forms of SD. A diagnosis of typical SD relies on an isolated and progressive loss of semantic knowledge, attested by a deficit of word comprehension and a deficit of objects and/or people identification, with imaging showing temporal atrophy and/or hypometabolism. SD is atypical if the deficit of semantic knowledge is present only within a single modality (verbal versus visual), or if non-semantic deficits (mild and not present at onset) and/or neurological signs, are associated with the semantic loss.
Published: 2008
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12. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study

Author: Valérie Hahn-Barma, Bruno Dubois, Jean-Charles Lambert, Dominique Campion, Serge Bakchine, Agnès Camuzat, Christine Van Broeckhoven, Serge Belliard, Michèle Puel, Patrice Verpillat, Eric Guedj, Alexis Brice, Fabienne Clot, Marie-Odile Habert, Isabelle Le Ber, Jacqueline Mikol, Pascal Lejeune, Ftd-Mnd, Julie van der Zee, Mustapha Ghanim, Didier Hannequin, Vincent Deramecourt, Christian Meyrignac, Martine Vercelletto, Anne Rovelet-Lecrux, Florence Pasquier, Lucette Lacomblez, Vincent de La Sayette, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of Genetics, University Hospital, Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service Central de Biophysique et de Médecine Nucléaire, Hôpital de la Timone [CHU - APHM] (TIMONE), Centre des Maladies Cognitives et Comportementales [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Université de Reims Champagne-Ardenne (URCA), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d′Anatomie et de Cytologie Pathologiques [Lariboisiere], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroendocrinologie et physiopathologie neuronale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre Hospitalier Intercommunal, Centre Hospitalier Départemental, Laboratoire de Neuropsychologie, 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), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de neurologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Clinique neurologique, Hôpital Laennec, Service de neurologie, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire [CHU Pitié-Salpétrière], Neuro-anatomie fonctionnelle du comportement et de ses troubles, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre du Langage et de Neuropsychologie, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-06-MRAR-005-01, ANR, Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE), Université de Rennes (UR), French research Network on FTD/FTD-MND, and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: Male, Pathology, Neuropsychological Tests, MESH: Epidemiologic Methods, MESH: Aphasia, Primary Progressive, Apraxia, MESH: Magnetic Resonance Imaging, Primary progressive aphasia, Progranulins, MESH: Aged, 80 and over, 0302 clinical medicine, MESH: Motor Neuron Disease, Corticobasal degeneration, Age of Onset, MESH: Brain Mapping, MESH: Heterozygote, Aged, 80 and over, MESH: Aged, Brain Mapping, 0303 health sciences, MESH: Middle Aged, Parkinsonism, Brain, MESH: Neuropsychological Tests, Middle Aged, Magnetic Resonance Imaging, MESH: Dementia, 3. Good health, Phenotype, Disease Progression, Intercellular Signaling Peptides and Proteins, Female, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Psychology, Haploinsufficiency, Frontotemporal dementia, Adult, Heterozygote, medicine.medical_specialty, MESH: Mutation, MESH: Age of Onset, MESH: Phenotype, MESH: Brain, 03 medical and health sciences, medicine, Humans, Dementia, Motor Neuron Disease, MESH: Intercellular Signaling Peptides and Proteins, Aged, 030304 developmental biology, MESH: Humans, Lewy body, MESH: Adult, medicine.disease, MESH: Male, MESH: Cognition Disorders, Aphasia, Primary Progressive, Mutation, Neurology (clinical), Cognition Disorders, Epidemiologic Methods, MESH: Female, 030217 neurology & neurosurgery
Abstract: Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.
Published: 2008
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13. Lateral Temporal Lobe: An Early Imaging Marker of the Presymptomatic GRN Disease?

Author: Paola, Caroppo, Marie-Odile, Habert, Stanley, Durrleman, Aurélie, Funkiewiez, Vincent, Perlbarg, Valérie, Hahn, Hugo, Bertin, Malo, Gaubert, Alexandre, Routier, Didier, Hannequin, Vincent, Deramecourt, Florence, Pasquier, Sophie, Rivaud-Pechoux, Martine, Vercelletto, Geoffrey, Edouart, Romain, Valabregue, Pascal, Lejeune, Mira, Didic, Jean-Christophe, Corvol, Habib, Benali, Stephane, Lehericy, Bruno, Dubois, Olivier, Colliot, Alexis, Brice, Isabelle, Le Ber, Arthur, Tenenhaus, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Imagerie Biomédicale (LIB), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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), Neurosciences précliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Transferts, écoulements, fluides, énergétique (TREFLE), Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), Institut de Mécanique et d'Ingénierie de Bordeaux (I2M), Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'océanographie de Villefranche (LOV), Observatoire océanologique de Villefranche-sur-mer (OOVM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), 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), 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), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), CHU Pitié-Salpêtrière [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), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université 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), Université Sciences et Technologies - Bordeaux 1 (UB)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-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), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Lille, CNRS, Inserm, Université de Lille, Lille Neurosciences & Cognition (LilNCog) - U 1172, Troubles cognitifs dégénératifs et vasculaires - U1171, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172, Troubles cognitifs dégénératifs et vasculaires - U 1171 [TCDV], 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], École Nationale Supérieure d'Arts et Métiers (ENSAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Institut National de la Recherche Agronomique (INRA), Colliot, Olivier, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Polytechnique de Bordeaux-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire océanologique de Villefranche-sur-mer (OOVM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], and CHU Pitié-Salpêtrière [APHP]
Subjects: Adult, Male, longitudinal, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, frontotemporal dementia, Cortical thickness, Progranulins, Fluorodeoxyglucose F18, preclinical study, progranulin, Humans, Longitudinal Studies, frontotemporal lobar degeneration, GRN, PET, dementia, presymptomatic, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Organ Size, Magnetic Resonance Imaging, Temporal Lobe, Frontal Lobe, Positron-Emission Tomography, Asymptomatic Diseases, Mutation, Disease Progression, Intercellular Signaling Peptides and Proteins, Female, Radiopharmaceuticals, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Research Article
Abstract: International audience; The preclinical stage of frontotemporal lobar degeneration (FTLD) is not well characterized. We conducted a brain metabolism (FDG-PET) and structural (cortical thickness) study to detect early changes in asymptomatic GRN mutation carriers (aGRN+) that were evaluated longitudinally over a 20-month period. At baseline, a left lateral temporal lobe hypometabolism was present in aGRN+ without any structural changes. Importantly, this is the first longitudinal study and, across time, the metabolism more rapidly decreased in aGRN+ in lateral temporal and frontal regions. The main structural change observed in the longitudinal study was a reduction of cortical thickness in the left lateral temporal lobe in carriers. A limit of this study is the relatively small sample (n = 16); nevertheless, it provides important results. First, it evidences that the pathological processes develop a long time before clinical onset, and that early neuroimaging changes might be detected approximately 20 years before the clinical onset of disease. Second, it suggests that metabolic changes are detectable before structural modifications and cognitive deficits. Third, both the baseline and longitudinal studies provide converging results implicating lateral temporal lobe as early involved in GRN disease. Finally, our study demonstrates that structural and metabolic changes could represent possible biomarkers to monitor the progression of disease in the presymptomatic stage toward clinical onset.
Published: 2015
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14. TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts

Author: Isabelle Le Ber, Anne De Septenville, Stéphanie Millecamps, Agnès Camuzat, Paola Caroppo, Philippe Couratier, Frédéric Blanc, Lucette Lacomblez, François Sellal, Marie-Céline Fleury, Vincent Meininger, Cécile Cazeneuve, Fabienne Clot, Olivier Flabeau, Eric LeGuern, Alexis Brice, Sophie Auriacombe, Mira Didic, Bruno Dubois, Véronique Golfier, Didier Hannequin, Richard Levy, Bernard-François Michel, Florence Pasquier, Catherine Thomas-Anterion, Michèle Puel, François Salachas, and Martine Vercelletto
Subjects: Aging, Mutation rate, Protein Serine-Threonine Kinases, medicine.disease_cause, Cohort Studies, Mutation Rate, C9orf72, mental disorders, medicine, Missense mutation, Humans, Amyotrophic lateral sclerosis, Loss function, Genetic Association Studies, Optineurin, Genetics, Mutation, business.industry, General Neuroscience, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, medicine.disease, nervous system diseases, Frontotemporal Dementia, Neurology (clinical), France, Geriatrics and Gerontology, business, Developmental Biology, Frontotemporal dementia
Abstract: TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.
Published: 2015

15. Neurotransmitter Dysfunction and Neurotransmitter Replacement Therapy as Part of Frontotemporal Dementia Treatment

Author: Lucette Lacomblez, Michel Bourin, Martine Vercelletto, Patrice Verpillat, and Pascal Derkinderen
Subjects: biology, business.industry, Tau protein, Cognition, medicine.disease, Serotonergic, Clinical trial, Psychiatry and Mental health, chemistry.chemical_compound, chemistry, mental disorders, biology.protein, Medicine, Cholinergic, Dementia, business, Neurotransmitter, Neuroscience, Frontotemporal dementia
Abstract: Very few studies on the neurotransmitter systems involved in frontotemporal dementia (FTD) have been published. No cholinergic deficiency is associated with FTD. Correlating non-specific, serotoninergic dysfunction and behavioral disorders permitted developing clinical trials on selective serotonin reuptake inhibitors (SSRIs). All five trials included a limited number of patients. Two preliminary trials involving the treatment of cognitive and attentional dysfunctions by noradrenergic agents were also developed on the hypothesis that noradrenergic system dysfunction was associated with FTD. Replacement neurotransmitter therapy to treat behavioral and cognitive symptoms in FTD has, however, proved disappointing so far. The pathophysiology of FTD is still poorly understood. Abnormalities linked to the tau protein level and excitotoxicity have been hypothesised. The most promising biological therapy would currently be to inhibit tau protein aggregation. Developing clinical trials on neuroprotective drugs will therefore require prior development of rating scales specific to this essentially behavioral type of dementia.
Published: 2005
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16. DAPHNE: A New Tool for the Assessment of the Behavioral Variant of Frontotemporal Dementia

Author: Christelle Evrard, Samuel Bulteau, Claire Boutoleau-Bretonnière, Catherine Thomas-Antérion, Frédérique Etcharry-Bouyx, Martine Vercelletto, Laëtitia Rocher, Tiphaine Charriau, Aurélie Richard-Mornas, Florence Lebert, Florence Pasquier, Sophie Auriacombe, Jean-Benoit Hardouin, Anne Sauvaget, Cédric Bretonnière, Pascal Derkinderen, MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Service de Neurologie [Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Département de neurologie [Lille], and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: medicine.medical_specialty, Bipolar disorder, Cognitive Neuroscience, Perseveration, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Validity, lcsh:Geriatrics, lcsh:RC346-429, Alzheimer’s disease, Progressive supranuclear palsy, Neglect, External validity, medicine, Apathy, Original Research Article, Psychiatry, lcsh:Neurology. Diseases of the nervous system, ComputingMilieux_MISCELLANEOUS, media_common, Alzheimer's disease, medicine.disease, Scale, Behavioral disorders, lcsh:RC952-954.6, Psychiatry and Mental health, medicine.symptom, Psychology, Frontotemporal dementia, Clinical psychology
Abstract: Background: The diagnosis of behavioral variant of frontotemporal dementia (bvFTD) relies primarily on clinical features and remains challenging. The specificity of the recently revised criteria can be disappointing, justifying development of new clinical tools. Objective: We produced a behavioral inventory named DAPHNE. This scale (adapted from Rascovsky's criteria) explores six domains: disinhibition, apathy, perseverations, hyperorality, personal neglect and loss of empathy. It is composed of ten items (five answer categories). The aim was (1) to assess the validity and reliability of DAPHNE and (2) to evaluate its contribution in differentiating patients. Methods: Two scores were computed: DAPHNE-6 (screening) from the six domains and DAPHNE-40 (diagnosis) from the ten items. Reliability and reproducibility were assessed. External validity was studied with the Frontal Behavioral Inventory (FBI) and the Frontotemporal Behavioral Scale (FBS). Finally, the diagnostic performance of DAPHNE was compared to revised criteria, FBI and FBS. Results: DAPHNE was administered to the caregivers of 89 patients, 36 with bvFTD, 22 with Alzheimer's disease, 15 with progressive supranuclear palsy and 16 with bipolar disorder. Reliability and reproducibility were excellent, as was external validity. DAPHNE-6 allowed bvFTD diagnosis (score ≥4) with a sensitivity of 92%, while DAPHNE-40 (score ≥15) had a specificity of 92%. Conclusion: We demonstrate excellent psychometric features for DAPHNE. This quick tool could help for both diagnosing and screening bvFTD.
Published: 2015
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17. [Frontal variant of frontotemporal dementia]

Author: Thibaud Lebouvier, Claire Boutoleau-Bretonnière, and Martine Vercelletto
Subjects: Pediatrics, medicine.medical_specialty, Disease, Neuropsychological Tests, Memantine, Prevalence, Medicine, Humans, Biological Psychiatry, Aged, business.industry, Incidence, medicine.disease, Neuropsychology and Physiological Psychology, Curative treatment, Frontotemporal Dementia, Disease Progression, Dementia, Neurology (clinical), Cholinesterase Inhibitors, France, Geriatrics and Gerontology, business, Rare disease, Frontotemporal dementia, medicine.drug
Abstract: The behavioral variant of frontotemporal dementia (bvFTD), characterized by early behavioral disorders, is a rare disease (about 5.000 cases in France). Diagnostic criteria have been revised in 2011 and propose three levels of diagnostic probability. However, it still could be difficult to discriminate FTD from other cerebral affections or psychiatric diseases. Genetic and molecular research has greatly expanded during the past fifteen years. About ten mutations have been discovered, bringing to describe particular phenotypes. To date, there is no curative treatment. Memantine had aroused some hope but is now abandoned. Inhibitors of serotonine recapture often permit to temporarily reduce behavioral troubles. But the caregiver's burden is high. The evolution of the bvFTD is faster than that of AD, particularly when associated with motor neuron disease (15% of cases). The therapeutic hope relies today on potential disease modifying drugs which could ensue from genetic discoveries.
Published: 2014

18. Frontal type dementia preceding amyotrophic lateral sclerosis: a neuropsychological and SPECT study of five clinical cases

Author: M. Huvet, C. Magne, J. R. Feve, M. Ronin, and Martine Vercelletto
Subjects: Male, Pediatrics, medicine.medical_specialty, Echolalia, Neuropsychological Tests, Single-photon emission computed tomography, medicine, Humans, Dementia, Amyotrophic lateral sclerosis, Psychiatry, Aged, Tomography, Emission-Computed, Single-Photon, medicine.diagnostic_test, business.industry, Amyotrophic Lateral Sclerosis, Neuropsychology, Brain, Language impairment, Middle Aged, medicine.disease, Paraphasia, Neurology, Neurology (clinical), medicine.symptom, business, Frontotemporal dementia
Abstract: Between 1993 and 1995, we observed five sporadic cases of frontotemporal dementia (FTD) which in all cases preceded the appearance of typical amyotrophic lateral sclerosis (ALS). The FTD rapidly became severe (within 12-18 months) and the delay between the presumed onset of mental change and ALS was short (12-26 months). The frontal dysfunction was characteristic (disinhibited, jocular, impatient, gluttonous, stereotypical gestures). The language impairment (less talkative, persistent errors, fantastic and semantic paraphasia, neologistic errors, echolalia) was constant. Single photon emission computed tomography (SPECT) with 99 Tcm HMPAO (hexamethyl propylamine oxime) was done at the same time as neuropsychological testing in four cases and showed serious diffuse bifrontal defect, sometimes with less serious internal temporal hypofixation. All patients died with bulbar ALS complications. The total course can last from 14-48 months. Most of the reported cases suggested a relationship between dementia-ALS and frontal dysfunction. The mechanism underlying dementia-ALS remains to be solved. Our five cases resemble those reported by Mitsuyama (1993), who suggested that dementia-ALS has the same clinicopathological entity.
Published: 1999
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19. Frontotemporal dementia and its subtypes: A genome-wide association study

Author: Yolande A.L. Pijnenburg, Wei Gu, Harro Seelaar, Robert Perneczky, Alfredo Postiglione, Ronald C. Petersen, Timothy D. Griffiths, Pau Pastor, Marc Cruts, Elise G.P. Dopper, Sabrina Pichler, Chiara Fenoglio, Patrizia Rizzu, Adeline Rollin, Maria Serpente, Peter Heutink, Sandro Sorbi, Lauren Bartley, Maria Landqvist Waldö, Luigi Ferrucci, William S. Brooks, Luisa Benussi, William W. Seeley, Maria Anfossi, Atik Baborie, Innocenzo Rainero, Rosa Capozzo, Alessandro Padovani, Stefano F. Cappa, Glenda M. Halliday, Jørgen E. Nielsen, Sara Ortega-Cubero, Vivianna M. Van Deerlin, Ekaterina Rogaeva, Mike A. Nalls, Giacomina Rossi, Alberto Lleó, Edward D. Huey, Jordi Clarimón, Simon Mead, Janine Diehl-Schmid, John Q. Trojanowski, Adaikalavan Ramasamy, Matthias Riemenschneider, John Hardy, Annibale Alessandro Puca, Cristina Razquin, Mercè Boada, Martine Vercelletto, Isabelle Le Ber, Graziella Milan, Johannes Attems, Francesca Frangipane, Jason D. Warren, Lena E. Hjermind, John R. Hodges, Gianluigi Forloni, Dennis W. Dickson, Daniela Galimberti, Elisa Rubino, Karin Nilsson, Raffaele Maletta, Christine Van Broeckhoven, Valeria Novelli, Anna Richardson, Anna Karydas, David S. Knopman, Nick C. Fox, Stuart Pickering-Brown, Carlos Cruchaga, Isabel Hernández, Livia Bernardi, Philip Scheltens, Martin N. Rossor, Julie S. Snowden, Massimo Franceschi, Rosa Rademakers, Bruce L. Miller, Alan J. Thomas, Florence Lebert, Matthew C. Baker, Jonathan D. Rohrer, Keith A. Josephs, Tim Van Langenhove, Fabrizio Tagliavini, Carol Dobson-Stone, Elizabeth Thompson, Silvia Bagnoli, Barbara Borroni, Sara Rollinson, Irene Piaceri, David M. A. Mann, Bernd Ibach, Ian G. McKeith, Agustín Ruiz, Huw R. Morris, Giancarlo Logroscino, Maura Gallo, Elena Alonso, Alexis Brice, Adrian Danek, Paolo Sorrentino, Nicoletta Smirne, Raffaele Ferrari, Panagiotis Alexopoulos, Johannes C. M. Schlachetzki, Alexander Gerhard, Manuel Mayhaus, Alexander Kurz, Amalia C. Bruni, Michael Tierney, Didier Hannequin, William Deschamps, Florence Pasquier, Joseph E. Parisi, Rafael Blesa, Elio Scarpini, Ian R. A. Mackenzie, Peter R. Schofield, Giuliano Binetti, Evelyn Jaros, Julie van der Zee, John Collinge, Maria Elena Conidi, Howard J. Rosen, Caroline Graff, Christer Nilsson, Huei-Hsin Chiang, Nigel J. Cairns, Jordan Grafman, Eric M. Wassermann, Parastoo Momeni, Maria Grazia Spillantini, Ging-Yuek Robin Hsiung, Andrew B. Singleton, Chiara Cupidi, James Uphill, Dimitrios Kapogiannis, Bradley F. Boeve, Christopher Morris, Vincent Deramecourt, Giorgio Giaccone, James B. Rowe, Murray Grossman, Benedetta Nacmias, Roberta Ghidoni, Véronique Golfier, Dena G. Hernandez, Lorenzo Pinessi, Neill R. Graff-Radford, John C. van Swieten, Pietro Pietrini, Gilles Gasparoni, Peter St George-Hyslop, Mark Kristiansen, Eric Haan, Olivier Piguet, John B.J. Kwok, Human genetics, Neurology, NCA - neurodegeneration, Surgery, Clinical Genetics, Erasmus MC other, Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jb, Dobson Stone, C, Brooks, W, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hern?ndez, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarim?n, J, Lle?, A, Blesa, R, Wald?, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ir, Hsiung, Gy, Mann, Dm, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega Cubero, S, Alonso, E, Perneczky, R, Diehl Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jc, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossman, M, Trojanowski, Jq, van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Eg, Seelaar, H, Pijnenburg, Ya, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, Alfredo, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebert, F, Kapogiannis, D, Ferrucci, L, Pickering Brown, S, Singleton, Ab, Hardy, J, and Momeni, P.
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Genotype, Semantic dementia, Genome-wide association study, Locus (genetics), classification [Frontotemporal Dementia], methods [Genome-Wide Association Study], diagnosis [Frontotemporal Dementia], C9orf72, mental disorders, medicine, Dementia, Humans, ddc:610, genetics [Frontotemporal Dementia], Aged, Genetics, Aged, 80 and over, Genetic heterogeneity, Middle Aged, medicine.disease, Frontotemporal Dementia, Female, Human medicine, Neurology (clinical), Alzheimer's disease, Psychology, Frontotemporal dementia, Genome-Wide Association Study
Abstract: Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes— MAPT , GRN , and C9orf72 —have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p −8 ) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p −8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 −8 ; odds ratio=1·204 [95% CI 1·11–1·30]), rs9268856 (p=5·51 × 10 −9 ; 0·809 [0·76–0·86]) and rs1980493 (p value=1·57 × 10 −8 , 0·775 [0·69–0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38 / CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 −7 ; 0·814 [0·71–0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis . Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.
Published: 2014
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20. C9ORF72 repeat expansions in the frontotemporal dementias spectrum of diseases: a flow-chart for genetic testing

Author: Patrice Verpillat, Isabelle Le Ber, François Sellal, Michèle Puel, Marie Fleury, Lena Guillot-Noel, Catherine Thomas-Antérion, Sophie Rivaud-Péchoux, Isabelle Wargon, Didier Hannequin, Frédéric Blanc, Vincent Deramecourt, Florence Pasquier, Merle Ruberg, Lucette Lacomblez, Philippe Couratier, Martine Vercelletto, Jérémie Pariente, Cyril Goizet, Alexis Brice, Véronique Golfier, Christel Thauvin-Robinet, Karl Mondon, Olivier Martinaud, Elisabeth Tournier-Lasserve, Eric Berger, William Camu, François Salachas, Bruno Dubois, Mira Didic, Agnès Camuzat, Charles Duyckaerts, Stéphanie Millecamps, Danielle Seilhean, Gabriel Viennet, Bernard-François Michel, Mathilde Sauvée, Vincent Meininger, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Imagerie cérébrale et handicaps neurologiques (ICHN), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Troubles cognitifs vasculaires et dégénératifs - EA 2691 (TCDV), Université de Lille, Droit et Santé, Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Neurologie [CHU Limoges], CHU Limoges, Service de neurologie, Hôpital pasteur [Colmar], Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Mémoire de Ressource et Recherche (CMRR), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), 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), The Mediterranean Institute of Neurobiology, Physiologie et physiopathologie de la motricité chez l'homme, Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Estrogènes, Expression génique et pathologies du Système Nerveux Central - UFC (E2SNC / ESTROGENES), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie [Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Saint-Etienne-Hôpital Bellevue, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Pathology, MESH: DNA Repeat Expansion, MESH: Genetic Markers, Primary progressive aphasia, Cohort Studies, 0302 clinical medicine, MESH: Aged, 80 and over, C9orf72, Software Design, Corticobasal degeneration, MESH: Proteins, MESH: Cohort Studies, Aged, 80 and over, MESH: Aged, 0303 health sciences, DNA Repeat Expansion, MESH: Middle Aged, medicine.diagnostic_test, MESH: Genetic Testing, General Neuroscience, Parkinsonism, Age Factors, General Medicine, Middle Aged, Penetrance, Pedigree, Psychiatry and Mental health, Clinical Psychology, Frontotemporal Dementia, Female, Psychology, Frontotemporal dementia, Adult, Genetic Markers, medicine.medical_specialty, MESH: Pedigree, MESH: Frontotemporal Dementia, Progressive supranuclear palsy, 03 medical and health sciences, Sex Factors, MESH: Sex Factors, Internal medicine, mental disorders, medicine, Humans, Genetic Testing, 030304 developmental biology, Genetic testing, Aged, MESH: Age Factors, MESH: Humans, C9orf72 Protein, Proteins, MESH: Adult, medicine.disease, MESH: Male, nervous system diseases, MESH: Software Design, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Geriatrics and Gerontology, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.
Published: 2013
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21. Memantine in behavioral variant frontotemporal dementia: negative results

Author: Martine, Vercelletto, Claire, Boutoleau-Bretonnière, Christelle, Volteau, Michèle, Puel, Sophie, Auriacombe, Marie, Sarazin, Bernard-François, Michel, Philippe, Couratier, Catherine, Thomas-Antérion, Patrice, Verpillat, Audrey, Gabelle, Véronique, Golfier, Evelyne, Cerato, Lucette, Lacomblez, Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Imagerie cérébrale et handicaps neurologiques (ICHN), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Bordeaux [Bordeaux], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie [CHU Limoges], CHU Limoges, Neuroépidémiologie Tropicale et Comparée (NETEC), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Unité de neuropsychologie, CM2R, CHU Saint-Etienne, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de recherche en biothérapie (IRB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, MESH: Frontotemporal Dementia, Neuropsychological Tests, Placebo group, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, Memantine, Internal medicine, MESH: Memantine, medicine, Clinical endpoint, Dementia, Humans, MESH: Double-Blind Method, 030212 general & internal medicine, Psychiatry, Aged, MESH: Aged, MESH: Humans, MESH: Middle Aged, General Neuroscience, MESH: Neuropsychological Tests, General Medicine, Middle Aged, medicine.disease, MESH: Male, 3. Good health, Clinical trial, Psychiatry and Mental health, Clinical Psychology, Tolerability, Frontotemporal Dementia, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Geriatrics and Gerontology, Psychology, MESH: Female, 030217 neurology & neurosurgery, medicine.drug, Frontotemporal dementia
Abstract: International audience; We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC-Plus (Clinician's Interview-Based Impression of Change Plus Caregiver Input). The secondary endpoints included: Neuropsychiatric Inventory (NPI), Frontal Behavioral Inventory (FBI), Mattis Dementia Rating Scale (MDRS), MMSE, Disability Assessment for Dementia (DAD), and the Zarit Burden Inventory (ZBI). Forty-nine patients were analyzed. At baseline, mean age was 65.6 years and mean MMSE was 25.0 (range: 19-30). On the CIBIC-Plus, 52 weeks after baseline, there were no significant differences between the memantine group (n = 23) and the placebo group (n = 26); p = 0.4458; however, 10 patients had worsened in the memantine group versus 17 in the placebo group. For the secondary endpoints there were no differences in the evolution of score between the memantine group and the placebo group (MMSE, p = 0.63); (MDRS, p = 0.95); (NPI, p = 0.25); (ZBI, p = 0.43); (DAD, p = 0.10) except for the FBI score, which was lower in the memantine group (p = 0.0417). Memantine was well-tolerated. This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.
Published: 2010
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22. [Caregiver burden in dementia: relationships with the activities of daily living, behavioral, and psychological symptoms]

Author: Claire, Boutoleau-Bretonnière and Martine, Vercelletto
Subjects: Personality Inventory, Dementia, Vascular, Mental Disorders, Population Dynamics, Dependency, Psychological, Institutionalization, Neuropsychological Tests, Disability Evaluation, Self-Help Groups, Cross-Sectional Studies, Caregivers, Cost of Illness, Alzheimer Disease, Frontotemporal Dementia, Activities of Daily Living, Adaptation, Psychological, Humans, France, Aged
Abstract: The prevalence of Alzheimer disease and other dementia is increasing. Caregivers' burden is a major determinant of patient's institutionalization. Therefore, it seems relevant to take it into account to postpone nursing home placement. Zarit Burden Inventory (ZBI) is the most widely used tool to assess the caregiver burden. Recent studies have shown that it is not correlated to the patients' daily functional abilities, but to the patient's level of behavioral disturbances. It also depends on how they are experienced by the caregiver and, in particular, on the caregiver's personality. This encourages the development of caregiver group interventions aimed to improve their coping strategies.
Published: 2010

23. Frontal Assessment Battery is a marker of dorsolateral and medial frontal functions: A SPECT study in frontotemporal dementia

Author: Michèle Puel, Marie-Odile Habert, Gilles Allali, Lucette Lacomblez, Isabelle Le Ber, Didier Hannequin, M. Volteau, Christine Magne, Anne-Marie Bernard, Alexis Brice, Martine Vercelletto, Pierre Vera, Anne Hitzel, Celine Goetz, Bruno Dubois, Mira Didic, Catherine Thomas-Antérion, Jean-Albert Lotterie, Eric Guedj, Marielle Decousus, Ftd-Mnd, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuro-anatomie fonctionnelle du comportement et de ses troubles, Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Service de médecine nucléaire [Rouen], CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Service de Médecine Nucléaire [Nantes], Hôpital Laennec, Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Service de médecine nucléaire [Rennes], CRLCC Eugène Marquis (CRLCC), 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), Epilepsies, Lesions Cerebrales et Systemes Neuraux de la Cognition, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Nucléaire - Pierre-Paul Riquet [CHU Toulouse], Pôle imagerie médicale [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de référence sur les démences rares et maladie de Pick, 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), Fédération des Maladies du Système Nerveux, Service de pharmacologie médicale [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie, Hôpital Bellevue, Service de Médecine Nucléaire [Toulouse], CHU Toulouse [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Service de médecine nucléaire [CHU Pitié-Salpétrière], Breton, Céline, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service de Médecine nucléaire [CHU Pitié-Salpétrière]
Subjects: Male, medicine.medical_specialty, MESH: Frontal Lobe, Neuropsychological Tests, computer.software_genre, Brain mapping, behavioral disciplines and activities, MESH: Tomography, Emission-Computed, Single-Photon, Central nervous system disease, 03 medical and health sciences, 0302 clinical medicine, Degenerative disease, MESH: Aged, 80 and over, Voxel, Internal medicine, mental disorders, medicine, Humans, Dementia, 030212 general & internal medicine, MESH: Brain Mapping, Aged, Aged, 80 and over, Tomography, Emission-Computed, Single-Photon, MESH: Aged, Brain Mapping, MESH: Humans, MESH: Middle Aged, MESH: Neuropsychological Tests, Middle Aged, medicine.disease, MESH: Dementia, MESH: Male, Frontal Lobe, Neurology, Frontal lobe, Cardiology, Female, Neurology (clinical), Psychology, Perfusion, Neuroscience, computer, MESH: Female, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: International audience; The objective of this study is to identify the cerebral regions that are assessed by the Frontal Assessment Battery (FAB). Using SPM voxel-based analysis, we looked for correlations between FAB performance and brain SPECT perfusion in 47 patients with the frontal variant of frontotemporal dementia (fv-FTD) recruited by the French FTD research network, a multicentre initiative of French University hospitals with expertise in the field of dementia. A significant correlation was found between FAB performance and perfusion in the medial and dorsolateral frontal cortex bilaterally, independently of age, gender and MMSE. No correlations were observed with orbital frontal or parietal perfusion, in spite of the presence of hypoperfusion in these areas, or with perfusion of any other cortical or subcortical region. These findings confirm that the FAB is an adequate tool for assessing functions related to the dorsolateral and medial frontal cortex, and is thus useful for the evaluation of diseases associated with frontal dysfunction.
Published: 2008

24. Zarit burden inventory and activities of daily living in the behavioral variant of frontotemporal dementia

Author: Estelle Lamy, Martine Vercelletto, Claire Boutoleau-Bretonnière, Christelle Volteau, and Pierre Renou
Subjects: Adult, Male, medicine.medical_specialty, Activities of daily living, Psychomotor agitation, Cognitive Neuroscience, Disease, Neuropsychological Tests, Severity of Illness Index, Cost of Illness, Surveys and Questionnaires, Activities of Daily Living, medicine, Dementia, Humans, Interpersonal Relations, Prospective Studies, Psychiatry, Psychomotor Agitation, Aged, Aged, 80 and over, Cognitive disorder, Institutionalization, Caregiver burden, Middle Aged, medicine.disease, Psychiatry and Mental health, Cross-Sectional Studies, Caregivers, Female, Geriatrics and Gerontology, Alzheimer's disease, medicine.symptom, Psychology, Cognition Disorders, human activities, Frontotemporal dementia
Abstract: Background: Activities of daily living (ADL) and caregiver burden are known to have a major impact on the decision to institutionalize patients with Alzheimer’s disease (AD), yet little research has been done on these aspects in patients with frontotemporal dementia (FTD). Aim: To compare ADL and caregiver burden in FTD and in early-onset AD. Methods: We compared 26 FTD and 28 AD patients with respect to the Neuropsychiatric Inventory (NPI), Mini Mental State Examination, Mattis Dementia Rating Scale (MDRS), Disability Assessment for Dementia (DAD) and Zarit Burden Inventory (ZBI). Results: Demographic variables for FTD and AD were similar. FTD patients obtained a significantly higher NPI behavioral score than AD patients (median, 39.5 vs. 11; p < 0.0001). However, the two groups did not differ in their total DAD score. No correlations were observed between DAD and cognitive status (MDRS) or between DAD and behavioral impairment (NPI). The ZBI was higher in FTD than in AD patients (median, 40 vs. 18.5; p = 0.0004) and was correlated with the NPI in both groups. Conclusion: Functional disability was similar in FTD and AD patients. Nevertheless, the caregiver burden was higher in FTD than in AD, a result that has important implications for caregiver help.
Published: 2007

25. Progranulin null mutations in both sporadic and familial frontotemporal dementia

Author: Michèle Puel, Marleen Van den Broeck, Annie Laquerrière, Marc Cruts, Agnès Camuzat, Martine Vercelletto, Bernard-François Michel, Bruno Dubois, Mira Didic, Patrice Verpillat, Catherine Thomas-Antérion, Véronique Golfier, Alexis Brice, Didier Hannequin, Ilse Gijselinck, Tim De Pooter, Lucette Lacomblez, François Sellal, Dominique Campion, François Salachas, Isabelle Le Ber, Charles Duyckaerts, Christine Van Broeckhoven, Julie van der Zee, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Neurodegenerative Brain Diseases Group, University of Antwerp (UA)-Flanders Interuniversity Institute of Biotechnology, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of Genetics, University Hospital, Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Department of Neuropathology, Neuro-anatomie fonctionnelle du comportement et de ses troubles, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de Neurologie, CHU Saint-Etienne, Service de neurologie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte Marguerite, Service de neurologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), 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), Epilepsies, Lesions Cerebrales et Systemes Neuraux de la Cognition, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-06-MRAR-005-01, ANR Maladies Rares DFT-MND, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Université de Rennes (UR), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], and French Research Network on FTD/FTD-MND
Subjects: Male, medicine.disease_cause, Apraxia, 0302 clinical medicine, Progranulins, MESH: Aged, 80 and over, MESH: Genetic Screening, MESH: Codon, Nonsense, Family history, Genetics (clinical), Genetics, Aged, 80 and over, MESH: Aged, 0303 health sciences, Mutation, MESH: Middle Aged, medicine.diagnostic_test, Parkinsonism, Middle Aged, Penetrance, MESH: Dementia, 3. Good health, Pedigree, MESH: tau Proteins, Phenotype, Codon, Nonsense, Intercellular Signaling Peptides and Proteins, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Frontotemporal dementia, MESH: Pedigree, tau Proteins, Biology, MESH: Phenotype, 03 medical and health sciences, mental disorders, medicine, Dementia, Humans, Genetic Testing, MESH: Intercellular Signaling Peptides and Proteins, 030304 developmental biology, Genetic testing, Aged, MESH: Humans, nutritional and metabolic diseases, medicine.disease, MESH: Male, nervous system diseases, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD.
Published: 2007
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26. Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

Author: Isabelle Le Ber, Tim De Pooter, Bart Dermaut, Marleen Van den Broeck, Sebastian Maurer-Stroh, Frederic Rousseau, Sebastiaan Engelborghs, Christine Van Broeckhoven, Patrick Santens, Julie van der Zee, Rik Vandenberghe, Dominique Campion, Joost Schymkowitz, Peter Paul De Deyn, AgnÃ¨s Camuzat, Kristel Sleegers, Alexis Brice, Karin Peeters, Ilse Gijselinck, Jean-Jacques Martin, Marc Cruts, Didier Hannequin, Maria Mattheijssens, Nathalie Brouwers, Lucette Lacomblez, Martine Vercelletto, Clinical sciences, and Neurology
Subjects: Adult, Male, Protein Conformation, media_common.quotation_subject, Nonsense, DNA Mutational Analysis, Molecular Sequence Data, Mutation, Missense, Case-control studies, Biology, Frameshift mutation, Progranulins, protein folding, mental disorders, Genetics, medicine, Missense mutation, Humans, Amino Acid Sequence, Intercellular Signaling Peptides and Proteins/biosynthesis, Gene, Genetics (clinical), Conserved Sequence, media_common, Aged, Medicine(all), Dementia/genetics, Middle Aged, medicine.disease, Stop codon, Protein Structure, Tertiary, Chromosome 17 (human), Intercellular Signaling Peptides and Proteins, Dementia, Female, Haploinsufficiency, aged, 80 and over, Frontotemporal dementia, Microsatellite Repeats
Abstract: Null mutations in the progranulin gene (GRN, PGRN) were recently identified as the causal mechanism underlying frontotemporal dementia (FTD) with ubiquitin-positive brain pathology linked to chromosome 17 (FTDU-17). In a Belgian and French FTD series comprising 332 patients, we reported 13 PGRN null mutations which were mainly nonsense and frameshift mutations resulting in premature stop codons. Here we report in the same patient series three missense mutations of which two (c.743C>T, p.Pro248Leu and c.1294C>T, p.Arg432Cys) were predicted in silico to severely affect protein folding and/or processing leading to PGRN protein haploinsufficiency. In addition, we observed three sequence variations in the 5' regulatory region that might potentially affect PGRN transcription activity. Our findings extend the mutation spectrum in PGRN leading to loss of functional PGRN as the basis for FTD. © 2007 Wiley-Liss, Inc.
Published: 2007
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27. Demographic, neurological and behavioural characteristics and brain perfusion SPECT in frontal variant of frontotemporal dementia

Author: Martine Vercelletto, Jacques Pasquier, Agnès Camuzat, Michèle Puel, François Salachas, Patrice Verpillat, Audrey Gabelle, Jean-Albert Lotterie, Lucette Lacomblez, Jean Bochet, Isabelle Le Ber, Marie-Odile Habert, Didier Hannequin, Bruno Dubois, Mira Didic, François Sellal, Marielle Decousus, Pierre Vera, Catherine Thomas-Antérion, Véronique Golfier, M. Volteau, Eric Guedj, Alexis Brice, Anne-Marie Bernard, Christine Magne, Bernard-François Michel, Izzie Jacques Namer, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Central de Biophysique et Médecine Nucléaire, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Neuro-anatomie fonctionnelle du comportement et de ses troubles, Service de Neurologie [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire [Rouen], CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), 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), Epilepsies, Lesions Cerebrales et Systemes Neuraux de la Cognition, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Nucléaire - Pierre-Paul Riquet [CHU Toulouse], Pôle imagerie médicale [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Neurologie, Centre hospitalier Saint-Brieuc, Service de médecine nucléaire [Rennes], CRLCC Eugène Marquis (CRLCC), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Service de Médecine Nucléaire [Nantes], Hôpital Laennec, Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Laboratoire de signalisation moléculaire et neurodégénerescence, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire [Strasbourg], CHU Strasbourg, Service de Neurogériatrie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service de Médecine Nucléaire [Saint-Quentin], Polyclinique Saint-Claude, French research network on FTD/FTD-MND, Centre de neuropsychologie et du langage, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Fédération des Maladies du Système Nerveux, Service de neurologie, Hôpital Bellevue, Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte Marguerite, Breton, Céline, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de pharmacologie médicale [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Service de Médecine Nucléaire [Toulouse]
Subjects: Male, Pathology, MESH: Social Behavior Disorders, Cross-sectional study, Perfusion scanning, Neuropsychological Tests, 0302 clinical medicine, Age of Onset, MESH: Brain Mapping, MESH: Aged, Brain Mapping, 0303 health sciences, MESH: Middle Aged, Brain, MESH: Neuropsychological Tests, Frontotemporal lobar degeneration, MESH: Cerebrovascular Circulation, Middle Aged, Prognosis, MESH: Dementia, 3. Good health, Cerebrovascular Circulation, MESH: Survival Analysis, Disease Progression, Cardiology, Female, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Psychology, Perfusion, Frontotemporal dementia, Adult, medicine.medical_specialty, MESH: Age of Onset, MESH: Prognosis, MESH: Tomography, Emission-Computed, Single-Photon, 03 medical and health sciences, MESH: Brain, MESH: Cross-Sectional Studies, Internal medicine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Survival analysis, Aged, 030304 developmental biology, Tomography, Emission-Computed, Single-Photon, MESH: Humans, Social Behavior Disorders, MESH: Adult, medicine.disease, Survival Analysis, MESH: Male, Cross-Sectional Studies, Disinhibition, MESH: Brain Stem, Dementia, Neurology (clinical), Age of onset, MESH: Female, 030217 neurology & neurosurgery, Brain Stem
Abstract: International audience; We conducted a French multicentric cross-sectional study to describe in detail the demographic, neurological and behavioural characteristics of the frontal variant of frontotemporal dementia (fvFTD) and to characterize the pattern of brain perfusion SPECT in comparison to a healthy control group. A total of 68 fvFTD patients had technetium-99m-ECD brain perfusion SPECT at inclusion, 61 of which also underwent an in-depth evaluation including 70 items assessing behaviour, language and affect/emotion at onset and at inclusion. The mean age-at-onset was 60.4 +/- 7.8 years (35-75). Twenty-six per cent of the patients were older than 65 at onset. A positive familial history consistent with an autosomal dominant inheritance was found in 18% of the patients. At onset, the behavioural profile was predominantly inert in 25% of the patients, disinhibited in 18% and mixed in others. The behavioural features progressed to predominantly mixed or inert forms. Although, inertia was associated with predominant medial frontal and cingulate hypoperfusion, and patients with disinhibition exhibited predominant ventromedial prefrontal and temporal hypoperfusion, there were no major clinical differences between disinhibited and inert patients. Forty-five per cent of the deceased patients survived 8 years (long survival). This shows that the final outcome of fvFTD is highly variable. No clinical factors predictive of short or long survival were identified. Unexpected, however, was the finding that brainstem hypoperfusion distinguished patients with a short survival from patients with long survival. In conclusion, this study shows that fvFTD is clinically a rather homogeneous entity. It also provides evidence that different behavioural presentations at onset are related to different anatomical localizations of degenerative damage. Finally, it demonstrates the prognostic value of brainstem hypoperfusion in a subgroup of patients with a short survival.
Published: 2006
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27 results on '"Martine, Vercelletto"'

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

2. DAPHNE: A New Tool for the Assessment of the Behavioral Variant of Frontotemporal Dementia

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

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

5. Primary Progressive Aphasia Associated With

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

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

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

9. Ugly aesthetic perception associated with emotional changes in experience of art by behavioural variant of frontotemporal dementia patients

10. Prospective Evaluation of Behavioral Scales in the Behavioral Variant of Frontotemporal Dementia

11. Démence sémantique : réflexions d’un groupe de travail pour des critères de diagnostic en français et la constitution d’une cohorte de patients

12. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study

13. Lateral Temporal Lobe: An Early Imaging Marker of the Presymptomatic GRN Disease?

14. TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts

15. Neurotransmitter Dysfunction and Neurotransmitter Replacement Therapy as Part of Frontotemporal Dementia Treatment

16. DAPHNE: A New Tool for the Assessment of the Behavioral Variant of Frontotemporal Dementia

17. [Frontal variant of frontotemporal dementia]

18. Frontal type dementia preceding amyotrophic lateral sclerosis: a neuropsychological and SPECT study of five clinical cases

19. Frontotemporal dementia and its subtypes: A genome-wide association study

20. C9ORF72 repeat expansions in the frontotemporal dementias spectrum of diseases: a flow-chart for genetic testing

21. Memantine in behavioral variant frontotemporal dementia: negative results

22. [Caregiver burden in dementia: relationships with the activities of daily living, behavioral, and psychological symptoms]

23. Frontal Assessment Battery is a marker of dorsolateral and medial frontal functions: A SPECT study in frontotemporal dementia

24. Zarit burden inventory and activities of daily living in the behavioral variant of frontotemporal dementia

25. Progranulin null mutations in both sporadic and familial frontotemporal dementia

26. Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

27. Demographic, neurological and behavioural characteristics and brain perfusion SPECT in frontal variant of frontotemporal dementia

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27 results on '"Martine, Vercelletto"'

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