Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration
Creators: name: Tavares, Tamara Paulo
name: Mitchell, Derek G V
name: Coleman, Kristy KL
name: Coleman, Brenda L
name: Shoesmith, Christen L
name: Butler, Christopher R
name: Santana, Isabel
name: Danek, Adrian
name: Gerhard, Alexander
name: De Mendonca, Alexandre
name: Borroni, Barbara
name: Tartaglia, Maria Carmela
name: Graff, Caroline
name: Galimberti, Daniela
name: Tagliavini, Fabrizio
name: Moreno, Fermin
name: Frisoni, Giovanni
name: Rowe, James Benedict
name: Levin, Johannes
name: Van Swieten, John Cornelis
name: Otto, Markus
name: Synofzik, Matthis
name: Sanchez-Valle, Raquel
name: Vandenberghe, Rik
name: Laforce, Robert
name: Ghidoni, Roberta
name: Sorbi, Sandro
name: Ducharme, Simon
name: Masellis, Mario
name: Rohrer, Jonathan
name: Finger, Elizabeth
Publisher: name: Apollo - University of Cambridge Repository
Year: 2020
Subjects: Neurodegeneration

description: Funder: UK Medical Research Council
description: Funder: The Bluefield Project
description: Funder: NIHR Cambridge Biomedical Research Centre
description: Funder: Weston Brain Institute
description: Funder: Swedish Brain Foundation
description: Funder: StratNeuro, Swedish Demensfonden
description: 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
description: Funder: The Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant
description: Funder: Karolinska Institutet Doctoral Funding
description: Funder: Stockholm County Council ALF
description: Funder: Swedish Alzheimer Foundation
description: 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.