Genetic forms of primary progressive aphasia within the GENetic Frontotemporal dementia Initiative (GENFI) cohort: comparison with sporadic primary progressive aphasia
Author:
Samra Kiran1, MacDougall Amy M2, Bouzigues Arabella1, Bocchetta Martina1ORCID, Cash David M1ORCID, Greaves Caroline V1, Convery Rhian S1, Hardy Chris1, van Swieten John C3, Seelaar Harro3ORCID, Jiskoot Lize C3ORCID, Moreno Fermin45, Sanchez-Valle Raquel6ORCID, Laforce Robert7, Graff Caroline89ORCID, Masellis Mario10, Tartaglia Maria Carmela11, Rowe James B12, Borroni Barbara13ORCID, Finger Elizabeth14, Synofzik Matthis1516ORCID, Galimberti Daniela1718, Vandenberghe Rik192021ORCID, de Mendonça Alexandre22, Butler Chris R2324, Gerhard Alexander2526ORCID, Ducharme Simon2728ORCID, Le Ber Isabelle293031, Santana Isabel3233, Pasquier Florence343536ORCID, Levin Johannes373839, Otto Markus40, Sorbi Sandro4142, Warren Jason D1, Rohrer Jonathan D1, Russell Lucy L1, Afonso Sónia, Almeida Maria Rosario, Anderl-Straub Sarah, Andersson Christin, Antonell Anna, Archetti Silvana, Arighi Andrea, Balasa Mircea, Barandiaran Myriam, Bargalló Nuria, Bartha Robart, Bender Benjamin, Benussi Alberto, Bertoux Maxime, Bertrand Anne, Bessi Valentina, Black Sandra, Borrego-Ecija Sergi, Bras Jose, Brice Alexis, Bruffaerts Rose, Camuzat Agnès, Cañada Marta, Cantoni Valentina, Caroppo Paola, Castelo-Branco Miguel, Colliot Olivier, Cope Thomas, Deramecourt Vincent, Arriba María de, Fede Giuseppe Di, Díez Alina, Duro Diana, Fenoglio Chiara, Ferrari Camilla, Ferreira Catarina B, Fox Nick, Freedman Morris, Fumagalli Giorgio, Funkiewiez Aurélie, Cerveau Institut du, Gabilondo Alazne, Gasparotti Roberto, Gauthier Serge, Gazzina Stefano, Giaccone Giorgio, Gorostidi Ana, Guerreiro Rita, Heller Carolin, Hoegen Tobias, Indakoetxea Begoña, Jelic Vesna, Karnath Hans-Otto, Keren Ron, Kuchcinski Gregory, Langheinrich Tobias, Lebouvier Thibaud, João Leitão Maria, Lladó Albert, Lombardi Gemma, Loosli Sandra, Maruta Carolina, Mead Simon, Meeter Lieke, Miltenberger Gabriel, Minkelen Rick van, Mitchell Sara, Moore Katrina, Nacmias Benedetta, Nelson Annabel, Öijerstedt Linn, Olives Jaume, Ourselin Sebastien, Padovani Alessandro, Panman Jessica, Papma Janne M, Pijnenburg Yolande, Polito Cristina, Premi Enrico, Prioni Sara, Prix Catharina, Rademakers Rosa, Redaelli Veronica, Rinaldi Daisy, Cerveau Institut du, Rittman Tim, Rogaeva Ekaterina, Rollin Adeline, Rosa-Neto Pedro, Rossi Giacomina, Rossor Martin, Santiago Beatriz, Saracino Dario, Sayah Sabrina, Scarpini Elio, Schönecker Sonja, Semler Elisa, Shafei Rachelle, Shoesmith Christen, Swift Imogen, Tábuas-Pereira Miguel, Tainta Mikel, Taipa Ricardo, Tang-Wai David, Thomas David L, Thompson Paul, Thonberg Hakan, Timberlake Carolyn, Tiraboschi Pietro, Todd Emily, Damme Philip Van, Vandenbulcke Mathieu, Veldsman Michele, Verdelho Ana, Villanua Jorge, Wilke Carlo, Woollacott Ione, Wlasich Elisabeth, Zetterberg Henrik, Zulaica Miren,
Affiliation:
1. Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology , London , UK 2. Department of Medical Statistics, London School of Hygiene and Tropical Medicine , London , UK 3. Department of Neurology, Erasmus Medical Centre , Rotterdam , Netherlands 4. Cognitive Disorders Unit, Department of Neurology, Donostia Universitary Hospital , San Sebastian , Spain 5. Neuroscience Area, Biodonostia Health Research Institute , San Sebastian, Gipuzkoa , Spain 6. Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d’Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona , Barcelona , Spain 7. Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval , Québec City , Canada 8. Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet , Solna , Sweden 9. Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital , Solna , Sweden 10. Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto , Toronto , Canada 11. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto , Toronto, ON , Canada 12. Department of Clinical Neurosciences, University of Cambridge , Cambridge , UK 13. Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia , Brescia , Italy 14. Department of Clinical Neurological Sciences, University of Western Ontario , London, ON , Canada 15. Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen , Tübingen , Germany 16. Centre for Neurodegenerative Diseases (DZNE) , Tübingen , Germany 17. Fondazione Ca’ Granda, IRCCS Ospedale Policlinico , Milan , Italy 18. University of Milan, Centro Dino Ferrari , Milan , Italy 19. Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven , Leuven , Belgium 20. Neurology Service, University Hospitals Leuven , Leuven , Belgium 21. Leuven Brain Institute, KU Leuven , Leuven , Belgium 22. Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon , Lisbon , Portugal 23. Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford , Oxford , UK 24. Department of Brain Sciences, Imperial College London , London , UK 25. Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester , Manchester , UK 26. Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg-Essen , Germany 27. Department of Psychiatry, McGill University Health Centre, McGill University , Montreal, Québec , Canada 28. McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , Montreal, Québec , Canada 29. Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière , Paris , France 30. Centre de référence des démences rares ou précoces, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière , Paris , France 31. Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière , Paris , France 32. University Hospital of Coimbra (HUC), Neurology Service, Faculty of Medicine, University of Coimbra , Coimbra , Portugal 33. Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra , Coimbra , Portugal 34. Univ Lille, Inserm 1172 , Lille , France 35. Inserm 1172 , Lille , France 36. CHU, CNR-MAJ, Labex Distalz , LiCEND Lille , France 37. Department of Neurology, Ludwig-Maximilians Universität München , Munich , Germany 38. German Centre for Neurodegenerative Diseases (DZNE) , Munich , Germany 39. Munich Cluster of Systems Neurology (SyNergy) , Munich , Germany 40. Department of Neurology, University of Ulm , Ulm , Germany 41. Department of Neurofarba, University of Florence , Florence , Italy 42. IRCCS Fondazione Don Carlo Gnocchi , Florence , Italy
Abstract
AbstractPrimary progressive aphasia is most commonly a sporadic disorder, but in some cases, it can be genetic. This study aimed to understand the clinical, cognitive and imaging phenotype of the genetic forms of primary progressive aphasia in comparison to the canonical nonfluent, semantic and logopenic subtypes seen in sporadic disease. Participants with genetic primary progressive aphasia were recruited from the international multicentre GENetic Frontotemporal dementia Initiative study and compared with healthy controls as well as a cohort of people with sporadic primary progressive aphasia. Symptoms were assessed using the GENetic Frontotemporal dementia Initiative language, behavioural, neuropsychiatric and motor scales. Participants also underwent a cognitive assessment and 3 T volumetric T1-weighted MRI. One C9orf72 (2%), 1 MAPT (6%) and 17 GRN (44%) symptomatic mutation carriers had a diagnosis of primary progressive aphasia. In the GRN cohort, 47% had a diagnosis of nonfluent variant primary progressive aphasia, and 53% had a primary progressive aphasia syndrome that did not fit diagnostic criteria for any of the three subtypes, called primary progressive aphasia-not otherwise specified here. The phenotype of the genetic nonfluent variant primary progressive aphasia group largely overlapped with that of sporadic nonfluent variant primary progressive aphasia, although the presence of an associated atypical parkinsonian syndrome was characteristic of sporadic and not genetic disease. The primary progressive aphasia -not otherwise specified group however was distinct from the sporadic subtypes with impaired grammar/syntax in the presence of relatively intact articulation, alongside other linguistic deficits. The pattern of atrophy seen on MRI in the genetic nonfluent variant primary progressive aphasia group overlapped with that of the sporadic nonfluent variant primary progressive aphasia cohort, although with more posterior cortical involvement, whilst the primary progressive aphasia-not otherwise specified group was strikingly asymmetrical with involvement particularly of the insula and dorsolateral prefrontal cortex but also atrophy of the orbitofrontal cortex and the medial temporal lobes. Whilst there are overlapping symptoms between genetic and sporadic primary progressive aphasia syndromes, there are also distinct features. Future iterations of the primary progressive aphasia consensus criteria should encompass such information with further research needed to understand the earliest features of these disorders, particularly during the prodromal period of genetic disease.
Funder
Dementia Research Centre Alzheimer's Research UK Alzheimer's Society Brain Research UK The Wolfson Foundation National Institute for Health Research University College London/Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility UK Dementia Research Institute UK Dementia Research Institute Ltd UK Medical Research Council Alzheimer's Society and Alzheimer's Research UK EU Joint Programme—Neurodegenerative Disease Research Miriam Marks Brain Research UK Senior Fellowship Medical Research Council Clinician Scientist Fellowship National Institute for Health Research Rare Disease Translational Research Collaboration Medical Research Council UK GENFI Bluefield Project European Reference Network for Rare Neurological Diseases Frontotemporal Dementia Research Studentships Memory of David Blechner The National Brain Appeal Alzheimer’s Society Dementia Research Institute Ltd Alzheimer’s Research UK Royal National Institute Deaf People Dunhill Medical Trust Pauline Ashley Fellowship Wellcome Institutional Strategic Support Fund Dioraphte Foundation Association for Frontotemporal Dementias Research Grant 2009 Netherlands Organization for Scientific Research ZonMw Memorabel Alzheimer Nederland and the Bluefield Tau Consortium and the Center for Networked Biomedical Research Alzheimer’s Research UK Clinical Research Training Fellowship Fundació Marató de TV3, Spain Swedish FTD Inititative-Schörling Foundation Alzheimer Foundation Brain Foundation and Stockholm County Council ALF Canadian Institute of Health Research Weston Brain Institute and Ontario Brain Institute Welcome Trust Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council National Institute for Health Research Cambridge Biomedical Research Centre Italian Ministry of Health Mady Browaeys Fund for Research into Frontotemporal Dementia Germany’s Federal Ministry of Education and Research Deutsche Forschungsgemeinschaft German Research Foundation under Germany’s Excellence Strategy Munich Cluster for Systems Neurology
Publisher
Oxford University Press (OUP)
Subject
Neurology,Cellular and Molecular Neuroscience,Biological Psychiatry,Psychiatry and Mental health
Cited by
4 articles.
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