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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 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 Rohrer42,
  31. Elizabeth Finger6
  1. 1 Neuroscience, Brain and Mind Institute, University of Western Ontario, London, Ontario, Canada
  2. 2 Psychiatry, Anatomy & Cell Biology, Brain and Mind Institute, University of Western Ontario, London, Ontario, Canada
  3. 3 Cognitive Neurology, St. Joseph's Health Care, London, Ontario, Canada
  4. 4 Infectious Disease Epidemiologic Research Unit, Mount Sinai Hospital, Toronto, Ontario, Canada
  5. 5 Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
  6. 6 Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
  7. 7 Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK
  8. 8 Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
  9. 9 Faculty of Medicine, Centre of Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
  10. 10 Neurologische Klinik und Poliklinik, Ludwig-Maximilians Universitat, Munich, Germany
  11. 11 Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, United Kingdom
  12. 12 Geriatric Medicine and Nuclear Medicine, University of Duisburg-Essen, Duisburg, Germany
  13. 13 Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
  14. 14 Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
  15. 15 Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
  16. 16 Canadian Sports Concussion Project, Toronto, Ontario, Canada
  17. 17 Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden
  18. 18 Neurodegenerative Diseases Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
  19. 19 Centro Dino Ferrari, University of Milan, Milano, Lombardia, Italy
  20. 20 Neurology and Neuropathology, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy
  21. 21 Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital Gipuzkoa Building, San Sebastian, País Vasco, Spain
  22. 22 Neuroscience Area, Biodonostia Health Research Institute, Donostia-san Sebastian, Guipuzcoa, Spain
  23. 23 Instituto di Recovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratell, Brescia, Italy
  24. 24 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
  25. 25 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
  26. 26 Department of Neurology, University Hospital, LMU Munich, Munich, Germany
  27. 27 Neurology, Erasmus MC, Rotterdam, The Netherlands
  28. 28 Neurology, University of Ulm, Ulm, Germany
  29. 29 Department of Neurodegenerative Diseases and Center of Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany
  30. 30 German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
  31. 31 Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d’Investigacións Biomèdiques August Pi I Sunyer, Barcelona, Spain
  32. 32 Alzheimer’s disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d’Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain
  33. 33 Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Flanders, Belgium
  34. 34 Neurology Service, KU Leuven University Hospitals Leuven, Leuven, Flanders, Belgium
  35. 35 Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques du CHU de Québec, Université Laval, Québec City, Quebec, Canada
  36. 36 Molecular Markers Lab, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
  37. 37 Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy
  38. 38 McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada
  39. 39 Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
  40. 40 Neurology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  41. 41 Medicine, Neurology, University of Toronto, Toronto, Ontario, Canada
  42. 42 Dementia 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.

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Footnotes

  • Twitter @tamtav1, @sducharme66

  • 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.

  • Patient consent for publication Not required.

  • Ethics approval Local ethics committees at each site approved the study and all participants provided written informed consent at enrolment.

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

  • 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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