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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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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