Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration
Open accessAbstract
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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In genetic bvFTD, early-intermediate phases MAPT carriers showed increased predominant behavioral symptoms and C9ORF72 carriers showed increased neuropsychiatric symptoms, after which plateauing takes place.
“In early-intermediate phases, MAPT carriers showed increased predominant behavioral symptoms and C9ORF72 carriers showed increased neuropsychiatric symptoms, where after plateauing takes place (Tavares et al., 2020; Benussi et al., 2021b).”
From The pursuit for markers of disease progression in behavioral variant frontotemporal dementia: a scoping review to optimize outcome measures for clinical trials (2024) · cites this paper as Tavares et al., 2020
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- Authors
- Tavares, T. P., Mitchell, D. G. V., Coleman, K. K., Coleman, B. L., Shoesmith, C. L., Butler, C. R., Santana, I., Danek, A., Gerhard, A., de Mendonca, A., Borroni, B., Tartaglia, M. C., Graff, C., Galimberti, D., Tagliavini, F., Moreno, F., Frisoni, G. B., Rowe, J. B., Levin, J., Van Swieten, J. C., Otto, M., Synofzik, M., Sanchez-Valle, R., Vandenberghe, R., Laforce, R. J., Ghidoni, R., Sorbi, S., Ducharme, S., Masellis, M., Rohrer, J. D., & Finger, E.
- Affiliations
- Western University (CA)
- St Joseph's Health Care (CA)
- Mount Sinai Hospital (CA)
- University of Oxford (GB)
- Unidade Local de Saúde de Coimbra (PT)
- Ludwig-Maximilians-Universität München (DE)
- University of Manchester (GB)
- University of Brescia (IT)
- University of Toronto (CA)
- Karolinska University Hospital (SE)
- University of Milan (IT)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- University of Cambridge (GB)
- German Center for Neurodegenerative Diseases (DE)
- Universität Ulm (DE)
- Universitair Ziekenhuis Leuven (BE)
- Université Laval (CA)
- University of Florence (IT)
- Montreal Neurological Institute and Hospital (CA)
- Sunnybrook Health Science Centre (CA)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Finger, Elizabeth
- ORCID
- Tavares, Tamara Paulo
- Mitchell, Derek G V
- Coleman, Kristy KL
- Coleman, Brenda L
- Shoesmith, Christen L
- Butler, Christopher R
- Santana, Isabel
- Danek, Adrian
- Gerhard, Alexander
- Borroni, Barbara
- Tartaglia, Maria Carmela
- Graff, Caroline
- Galimberti, Daniela
- Tagliavini, Fabrizio
- Frisoni, Giovanni B
- Rowe, James Benedict
- Levin, Johannes
- Van Swieten, John Cornelis
- Otto, Markus
- Synofzik, Matthis
- Vandenberghe, Rik
- Laforce, Robert Jr
- Ghidoni, Roberta
- Sorbi, Sandro
- Ducharme, Simon
- Masellis, Mario
- Rohrer, Jonathan D
- Finger, Elizabeth
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2020-08-07
- Volume
- 91
- Issue
- 9
- Pages
- 975-984
- ISSN
- 0022-3050 (ISSN-L)
- 1468-330X
- PMC
- PMC7611534
- OpenAlex
- W3047873932
- Cited by
- 39
- References
- 25
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 14 · 2020: 4
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-11-16)
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion)
- Lirias (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- DZNE Pub (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- UK Medical Research Council
- Canadian Institutes of Health Research operating grant (MOP 327387)
- The Bluefield Project
- NIHR Cambridge Biomedical Research Centre
- Weston Brain Institute
- Swedish Brain Foundation
- StratNeuro, Swedish Demensfonden
- JPND Prefrontals Swedish Research Council (529-2014-7504)
- MRC Clinician Scientist Fellowship (MR/M008525/1)
- 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
- 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)
- The Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant
- Association for frontotemporal Dementias Research Grant 2009, ZonMw Memorabel project (733050103 and 733050813)
- Karolinska Institutet Doctoral Funding
- Stockholm County Council ALF
- Swedish Alzheimer Foundation
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- frontotemporal lobar degeneration, frontotemporal dementia, C9orf72, progranulin, MAPT, early symptoms, neuropsychiatric symptoms, apathy, disinhibition, family members, biomarkers, symptom heterogeneity
- MeSH terms
- C9orf72 Protein, Progranulins, Adult, Female, Heterozygote, Humans, Male, Middle Aged, Mutation, tau Proteins, Frontotemporal Dementia, Prodromal Symptoms
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