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1. 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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2. 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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3. 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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4. 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

5. Defining the spectrum of frontotemporal dementias associated with TARDBP mutations

Author

Isabelle Le Ber, Agnès Camuzat, Véronique Golfier, John C. van Swieten, Serena Lattante, Serge Belliard, Alexis Brice, Bernard Laurent, Sophie Auriacombe, Stéphanie Millecamps, Bruno Dubois, Lena Guillot-Noel, Catherine Thomas-Antérion, Philippe Couratier, Tsz Hang Wong, Paola Caroppo, Fabienne Clot, Marc Teichmann, The Foundation 'Carlo Besta' Institute of Neurology ( IRCCS ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Laboratoire d'Etude des Mécanismes Cognitifs ( EMC ), Université Lumière - Lyon 2 ( UL2 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Lumière - Lyon 2 ( UL2 ), Erasmus Medical Center Rotterdam, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 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), Laboratoire d'Etude des Mécanismes Cognitifs (EMC), Université Lumière - Lyon 2 (UL2), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Neurology

Subjects
0301 basic medicine, Proband, Genetic counseling, Settore MED/03 - GENETICA MEDICA, TARDBP, Article, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Genotype, Medicine, Family history, frontotemporal dementias, Genetics (clinical), Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Penetrance, Phenotype, 3. Good health, 030104 developmental biology, Neurology (clinical), business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

International audience; Objectives: We describe the largest series of patients with TARDBP mutations presenting with frontotemporal dementia (FTD) and review the cases in the literature to precisely characterize FTD diseases associated with this genotype.Methods: The phenotypic characteristics of 29 TARDBP patients, including 10 new French and Dutch cases and 19 reviewed from the literature, were evaluated.Results: The most frequent phenotype was a behavioral variant frontotemporal dementia (bvFTD), but a significant proportion (40%) of our patients had semantic (svFTD) or nonfluent variants (nfvFTD) at onset; and svFTD was significantly more frequent in TARDBP carriers than in other FTD genotypes (p < 0.001). Remarkably, only a minority (40%) of our patients secondarily developed amyotrophic lateral sclerosis (ALS). Two patients carried a homozygous mutation but strikingly different phenotypes (bvFTD and ALS) indicating that homozygosity does not result in a specific phenotype. Earlier age at onset in children than parent's generations, mimicking an apparent “anticipation” (21.8 ± 9.3 years, p = 0.001), and possible reduced penetrance were present in most families.Conclusions: This study enlarges the phenotypic spectrum of TARDBP and will have important clinical implications: (1) FTD can be the only clinical manifestation of TARDBP mutations; (2) Initial language or semantic disorders might be indicative of a specific genotype; (3) Mutations should be searched in all FTD phenotypes after exclusion of major genes, even in the absence of ALS in the proband or in family history; (4) reduced penetrance and clinical variability should be considered to deliver appropriate genetic counseling.

Published
2016
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6. 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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7. 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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8. An unfavorable dietary pattern is associated with symptomatic ischemic stroke and carotid atherosclerosis

Author

François Paillard, Véronique Golfier, Guillaume Mahé, Jean-Michel De Bray, Bruno Laviolle, Thomas Ronzière, Thomas Cochery, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Pharmacologie du Sepsis et Choc Septique, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)-Service de Pharmacologie [Rennes], CHU Pontchaillou [Rennes]-CHU Pontchaillou [Rennes], Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)-Service de Pharmacologie [Rennes]

Subjects
Carotid Artery Diseases, Male, MESH: Food Habits, 030204 cardiovascular system & hematology, Gastroenterology, Brain Ischemia, Brain ischemia, Fatty Acids, Monounsaturated, Hospitals, University, 0302 clinical medicine, MESH: Fatty Acids, Omega-3, Risk Factors, MESH: Risk Factors, Vegetables, MESH: Diet Records, MESH: Fatty Acids, Omega-6, Stroke, chemistry.chemical_classification, Ultrasonography, Doppler, Duplex, MESH: Middle Aged, Cerebral infarction, Fatty Acids, food and beverages, MESH: Brain Ischemia, MESH: Life Style, Middle Aged, MESH: Case-Control Studies, Diet Records, 3. Good health, MESH: Fatty Acids, MESH: Fatty Acids, Monounsaturated, Female, France, Cardiology and Cardiovascular Medicine, MESH: Fruit, Polyunsaturated fatty acid, Adult, medicine.medical_specialty, MESH: Ultrasonography, Doppler, Duplex, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Hospitals, General, MESH: Stroke, Central nervous system disease, Duplex scanning, 03 medical and health sciences, MESH: Diet, Internal medicine, Fatty Acids, Omega-6, Fatty Acids, Omega-3, medicine, Humans, Life Style, MESH: Hospitals, University, MESH: Humans, Vascular disease, business.industry, MESH: Carotid Artery Diseases, Case-control study, MESH: Hospitals, General, MESH: Adult, Feeding Behavior, medicine.disease, MESH: Vegetables, MESH: Male, Surgery, Diet, MESH: France, chemistry, Case-Control Studies, Fruit, business, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; OBJECTIVE: Ischemic strokes represent more than 80% of total strokes in Western countries. The influence of dietary factors on ischemic stroke risk is debated mainly because available data are limited. Our objective was to compare the dietary pattern of symptomatic ischemic stroke patients under 65 years old with control subjects using a validated 14-item food frequency questionnaire (FFQ). We also compared symptomatic ischemic stroke patients with carotid atherosclerosis with those without according to the presence or the absence of carotid plaque defined by duplex scanning. METHODS: This was a case-control multi-center study that took place in one University hospital and two general hospitals in France. One hundred twenty-four symptomatic ischemic stroke patients (confirmation by a neurologist and imaging; 66% smokers) and 50 controls (34% smokers) without any known cardiovascular disease or previous nutritional advice were included. The main outcome measure(s) were intake scores for saturated (SFA), monounsaturated (MUFA), Omega-3 polyunsaturated (Omega-3 PUFA), and Omega-6 polyunsaturated fatty acids (Omega-6PUFA). Fruit and vegetables and an overall cardiovascular dietary score were evaluated with the FFQ. The overall cardiovascular score is calculated as (MUFA + Omega-3 PUFA + fruits and vegetables) - (SFA) scores. RESULTS: Compared with controls, ischemic stroke patients had a higher SFA score (6.6 +/- 3.0 vs 4.9 +/- 2.7; P < .001), lower scores of MUFA (0.8 +/- 0.9 vs 1.5 +/- 1.2; P < .001), Omega-3 PUFA (1.7 +/- 1.6 vs 2.2 +/- 1.5; P = .013), Omega-6PUFA (2.6 +/- 2.5 vs 3.9 +/- 2.7; P = .002), fruit and vegetables (2.9 +/- 1.7 vs 3.8 +/- 1.6; P = .005), and a lower overall dietary score (-1.2 +/- 5.0 vs 2.5 +/- 4.4; P < .001). These results remained statistically significant after adjustment for age, gender, and smoking status. Ischemic stroke patients with carotid atherosclerosis (n = 54) had a worse overall cardiovascular dietary score than those without (n = 68): -2.2 +/- 4.4 vs -0.2 +/- 5.2; P = .024. CONCLUSION: Compared with controls, ischemic stroke patients, especially those with carotid atherosclerosis, have an unfavorable dietary pattern (high SFA, low fruit and vegetables, and Omega-3 PUFA consumptions) that may have been a facilitating condition of the ischemic stroke. Dietary recommendations of a healthy diet should be useful in ischemic stroke prevention, especially in patients with cardiovascular risk factors.

Published
2010
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9. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration

Author

Lina, Benajiba, Isabelle, Le Ber, Agnès, Camuzat, Mathieu, Lacoste, Catherine, Thomas-Anterion, Philippe, Couratier, Solenn, Legallic, François, Salachas, Didier, Hannequin, Marielle, Decousus, Lucette, Lacomblez, Eric, Guedj, Véronique, Golfier, William, Camu, Bruno, Dubois, Dominique, Campion, Vincent, Meininger, Alexis, Brice, Neuroépidémiologie Tropicale et Comparée (NETEC), Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Université de Limoges (UNILIM), Service de Neurologie [CHU Limoges], and CHU Limoges

Subjects
Male, Pathology, DNA Mutational Analysis, medicine.disease_cause, 0302 clinical medicine, Degenerative disease, Motoneuron disease, MESH: Motor Neuron Disease, MESH: DNA Mutational Analysis, MESH: Aged, 0303 health sciences, Mutation, MESH: Middle Aged, Frontotemporal lobar degeneration, Middle Aged, MESH: Dementia, DNA-Binding Proteins, Neurology, Female, Adult, medicine.medical_specialty, MESH: Mutation, Phenylalanine, Semantic dementia, Biology, TARDBP, Central nervous system disease, 03 medical and health sciences, MESH: Phenylalanine, mental disorders, medicine, Dementia, Humans, Motor Neuron Disease, 030304 developmental biology, Aged, Family Health, MESH: Humans, nutritional and metabolic diseases, MESH: Adult, medicine.disease, MESH: Male, nervous system diseases, MESH: Family Health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Neuroscience, MESH: Female, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins
Abstract

International audience; TDP-43 (TAR-DNA binding protein) aggregates in neuronal inclusions in motoneuron disease (MND), as well as in frontotemporal lobar degeneration (FTLD) and FTLD associated with MND (FTLD-MND). Mutations in TARDBP gene, coding for TDP-43, were found in patients with pure MND. We now describe TARDBP mutations in two patients with FTLD-MND, presenting with a behavioral variant of FTLD and semantic dementia, suggesting that TDP-43 may also have a direct pathogenic role in FTLD disorders.

Published
2009
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10. 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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11. 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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