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Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration

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Tavares, Tamara Paulo  ORCID logo
Mitchell, Derek G V 
Coleman, Kristy KL 
Coleman, Brenda L 
Shoesmith, Christen L 


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.


Funder: UK Medical Research Council

Funder: The Bluefield Project

Funder: NIHR Cambridge Biomedical Research Centre

Funder: Weston Brain Institute

Funder: Swedish Brain Foundation

Funder: StratNeuro, Swedish Demensfonden

Funder: 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

Funder: The Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant

Funder: Karolinska Institutet Doctoral Funding

Funder: Stockholm County Council ALF

Funder: Swedish Alzheimer Foundation



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BMJ Publishing Group
Canadian Institutes of Health Research operating grant (MOP 327387)
JPND Prefrontals Swedish Research Council (529-2014-7504)
MRC Clinician Scientist Fellowship (MR/M008525/1)
Swedish Research Council (2015- 02926, 2018-02754)
MRC UK GENFI grant (MR/ M023664/1)
NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH)
The Italian Ministry of Health (NET-2011-02346784)
Alzheimer’s Society PhD Studentship (AS-PhD-2015- 005)
the Medical Research Council, Wellcome Trust (103848)
Association for frontotemporal Dementias Research Grant 2009, ZonMw Memorabel project (733050103 and 733050813)