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Neurodegeneration
Original research
Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration
  1. Tamara Paulo Tavares1,
  2. Derek G V Mitchell2,
  3. Kristy KL Coleman3,
  4. Brenda L Coleman4,5,
  5. Christen L Shoesmith6,
  6. Christopher R Butler7,
  7. Isabel Santana8,9,
  8. Adrian Danek10,
  9. Alexander Gerhard11,12,
  10. Alexandre de Mendonca13,
  11. Barbara Borroni14,
  12. Maria Carmela Tartaglia15,16,
  13. Caroline Graff17,
  14. Daniela Galimberti18,19,
  15. Fabrizio Tagliavini20,
  16. Fermin Moreno21,22,
  17. Giovanni B Frisoni23,
  18. James Benedict Rowe24,
  19. Johannes Levin25,26,
  20. John Cornelis Van Swieten27,
  21. Markus Otto28,
  22. Matthis Synofzik29,30,
  23. Raquel Sanchez-Valle31,32,
  24. Rik Vandenberghe33,34,
  25. Robert Jr Laforce35,
  26. Roberta Ghidoni36,
  27. Sandro Sorbi37,
  28. Simon Ducharme38,39,
  29. Mario Masellis40,41,
  30. Jonathan D Rohrer42,
  31. Elizabeth Finger6
  32. on behalf of the Genetic FTD Initiative, GENFI
    1. 1Neuroscience, Brain and Mind Institute, University of Western Ontario, London, Ontario, Canada
    2. 2Psychiatry, Anatomy & Cell Biology, Brain and Mind Institute, University of Western Ontario, London, Ontario, Canada
    3. 3Cognitive Neurology, St. Joseph's Health Care, London, Ontario, Canada
    4. 4Infectious Disease Epidemiologic Research Unit, Mount Sinai Hospital, Toronto, Ontario, Canada
    5. 5Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
    6. 6Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
    7. 7Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK
    8. 8Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
    9. 9Faculty of Medicine, Centre of Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
    10. 10Neurologische Klinik und Poliklinik, Ludwig-Maximilians Universitat, Munich, Germany
    11. 11Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK
    12. 12Geriatric Medicine and Nuclear Medicine, University of Duisburg-Essen, Duisburg, Germany
    13. 13Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
    14. 14Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
    15. 15Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
    16. 16Canadian Sports Concussion Project, Toronto, Ontario, Canada
    17. 17Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden
    18. 18Neurodegenerative Diseases Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
    19. 19Centro Dino Ferrari, University of Milan, Milano, Lombardia, Italy
    20. 20Neurology and Neuropathology, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy
    21. 21Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital Gipuzkoa Building, San Sebastian, País Vasco, Spain
    22. 22Neuroscience Area, Biodonostia Health Research Institute, Donostia-san Sebastian, Guipuzcoa, Spain
    23. 23Instituto di Recovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratell, Brescia, Italy
    24. 24Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
    25. 25German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
    26. 26Department of Neurology, University Hospital, LMU Munich, Munich, Germany
    27. 27Neurology, Erasmus MC, Rotterdam, The Netherlands
    28. 28Neurology, University of Ulm, Ulm, Germany
    29. 29Department of Neurodegenerative Diseases and Center of Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany
    30. 30German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
    31. 31Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d’Investigacións Biomèdiques August Pi I Sunyer, Barcelona, Spain
    32. 32Alzheimer’s disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d’Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain
    33. 33Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Flanders, Belgium
    34. 34Neurology Service, KU Leuven University Hospitals Leuven, Leuven, Flanders, Belgium
    35. 35Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques du CHU de Québec, Université Laval, Québec City, Quebec, Canada
    36. 36Molecular Markers Lab, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
    37. 37Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy
    38. 38McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada
    39. 39Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
    40. 40Neurology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
    41. 41Medicine, Neurology, University of Toronto, Toronto, Ontario, Canada
    42. 42Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
    1. Correspondence to Dr Elizabeth Finger, Clinical Neurological Sciences, University of Western Ontario, London, ON N6A 3K7, Canada; elizabeth.finger{at}lhsc.on.ca

    Abstract

    Objectives The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers.

    Methods The current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales.

    Results The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills.

    Conclusion Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.

    Data availability statement

    Data may be obtained from a third party and are not publicly available. The data for this study were obtained from the GENFI data freeze 4. Further details on the GENFI protocol, cohorts and data policies can be found at http://genfi.org.uk/samples.html.

    https://doi.org/10.1136/jnnp-2020-322987

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      Data availability statement

      Data may be obtained from a third party and are not publicly available. The data for this study were obtained from the GENFI data freeze 4. Further details on the GENFI protocol, cohorts and data policies can be found at http://genfi.org.uk/samples.html.

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      Footnotes

      • Twitter @tamtav1, @sducharme66

      • Collaborators Genetic FTD Initiative, GENFI: Alazne Gabilondo, Albert Lladó, Alessandro Padovani, Ana Gorostidi, Ana Verdelho Andrea Arighi, Anna Antonell, Beatriz Santiago, Begoña Indakoetxea, Benedetta Nacmias Benjamin Bender, Camilla Ferrari, Carlo Wilke, Carolin Heller, Carolina Maruta, Caroline Greaves, Carolyn Timberlake, Catarina B. Ferreira, Catharina Prix, Chiara Fenoglio, Christin Andersson, Cristina Polito, David Cash, David L Thomas, David Tang-Wai, Diana Duro, Ekaterina Rogaeva, Elio Scarpini, Elisa Semler, Elisabeth Wlasich, Emily Todd, Enrico Premi, Gabriel Miltenberger, Gemma Lombardi, Georgia Peakman, Giacomina Rossi, Giorgio Fumagalli, Giorgio Giaccone, Giuliano Binetti, Giuseppe Di Fede, Hakan Thonberg, Hans-Otto Karnath, Henrik Zetterberg, Ione Woollacott, Janne Papma, Jason Warren, Jaume Olives, Jennifer Nicholas, Jessica Panman, Jorge Villanua, Jose Bras, Katrina Moore, Lieke Meeter, Linn Öijerstedt, Lize Jiskoot, Luisa Benussi, María de Arriba, Maria João Leitão, Maria Rosario Almeida, Martin Rosser, Martina Bocchetta, Mathieu Vandenbulcke, Maura Cosseddu, Michela Pievani, Michele Veldsman, Miguel Castelo-Branco, Miguel Tábuas-Pereira, Mikel Tainta, Mircea Balasa, Miren Zulaica, Morris Freedman, Myriam Barandiaran, Nick Fox, Nuria Bargalló, Paola Caroppo, Pedro Rosa-Neto, Philip Vandamme, Pietro Tiraboschi, Rachelle Shafei, Rhian Convery, Ricardo Taipa, Rick van Minkelen, Rita Guerreiro, Roberto Gasparotti, Ron Keren, Rosa Rademakers, Rose Bruffaerts, Sandra Black, Sandra Loosli, Sara Mitchell, Sara Prioni, Sarah Anderl-Straub, Sebastien Ourselin, Serge Gauthier, Sergi Borrego-Ecija, Silvana Archetti, Simon Mead, Sónia Afonso, Sonja Schönecker, Stefano Gazzina, Thomas Cope, Tim Rittman, Tobias Hoegen, Toby Flanagan, Valentina Bessi, Veronica Redaelli, Vesna Jelic, Yolande Pijnenburg, Zigor Díaz.

      • Contributors TPT, BLC: drafting/revising the manuscript, analysis or interpretation of data; DGVM, co-investigator: drafting/revising the manuscript analysis or interpretation of data; KKLC, CLS, CRB, IS, AD, JL, SS: data acquisition; AG, CG, FT, EF, Site Investigator: drafting/revising the manuscript, data acquisition, study concept or design, analysis or interpretation of data; AdM, Site Investigator: data acquisition, drafting/revising the manuscript; BB, JBR, MO, MS, Site Investigator: drafting/revising the manuscript, data acquisition, study concept or design; MCT, JCVS, Site Investigator: drafting/revising the manuscript; DG, Site Investigator: drafting/revising the manuscript, accepts responsibility for conduct of research and final approval; FM, RG, Site Investigator: drafting/revising the manuscript, data acquisition; GF, Site Investigator: data acquisition, accepts responsibility for conduct of research and final approval; RS-V, RV, Site Investigator: drafting/revising the manuscript, data acquisition, study concept or design; RL, Site Investigator: data acquisition, analysis or interpretation of data; SD, MM, JR, Site Investigator: drafting/revising the manuscript, data acquisition, study concept or design.

      • Funding This work was funded by the UK Medical Research Council, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and also a Canadian Institutes of Health Research operating grant (MOP 327387) and funding from the Weston Brain Institute to MM and EF. JDR, DC and KMM are supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH), the MRC UK GENFI grant (MR/ M023664/1) and The Bluefield Project. KMM is supported by an Alzheimer’s Society PhD Studentship (AS-PhD-2015-005). JR is supported by the Medical Research Council, Wellcome Trust (103848) and NIHR Cambridge Biomedical Research Centre. FT is supported by the Italian Ministry of Health (Grant NET-2011-02346784). LCJ and JVS are supported by the Association for frontotemporal Dementias Research Grant 2009, ZonMw Memorabel project number 733050103 and 733050813 and the Bluefield project. RG supported by Italian Ministry of Health, Ricerca Corrente. The Swedish contributors CG, LO and CA were supported by grants from JPND Prefrontals Swedish Research Council (VR) 529-2014-7504, Swedish Research Council (VR) 2015-02926, Swedish Research Council (VR) 2018-02754, Swedish FTD Initiative Schörling Foundation, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Karolinska Institutet Doctoral Funding and StratNeuro, Swedish Demensfonden, during the conduct of the study.

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

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