Distinct clinical subtypes of genetic frontotemporal dementia identified using disease progression modelling

Abstract Understanding the order in which symptoms occur in genetic frontotemporal dementia (FTD) may provide valuable insight into disease progression. Here we use a methodology called Ordinal Subtype and Stage Inference (SuStaIn) in the GENetic FTD Initiative (GENFI) cohort to estimate a probable order in which symptoms occur, and identify different subtypes based on the pattern of symptom progression within the main genetic FTD mutation groups. 968 participants were included in the cross-sectional study: 280 C9orf72, 242 GRN and 101 MAPT mutation carriers, and 345 mutation-negative controls. 379 participants underwent longitudinal analysis: 162 C9orf72, 146 GRN and 71 MAPT mutation carriers. The standardised GENFI clinical assessment provided severity scores for all FTD-relevant symptoms ranging from 0 where symptoms are absent to 3 where symptoms are severe. Ordinal SuStaIn was run in each mutation group to generate symptom progression profiles for mutation carriers from each group. In the C9orf72 cohort, Ordinal SuStaIn identified three subtypes: subtype 1 with early behavioural and cognitive deficits, subtype 2 with impaired speech and swallowing, and subtype 3 with limb impairment. In the GRN cohort, SuStaIn identified two subtypes: subtype 1 with behavioural and cognitive deficits as well as limb motor involvement, and subtype 2 with early language impairment. The MAPT cohort was best described as a single subtype with a combination of cognitive (mainly semantic) and behavioural impairment with parkinsonism. SuStaIn stage significantly correlated with clinical severity scores for all the cohorts. The subtypes were somewhat longitudinally consistent, with a trend towards increased SuStaIn stage in each subtype over time. Identifying within-genotype data-driven subtypes of FTD is a novel approach for untangling the heterogeneity of this disorder, in turn drawing us closer to individualised care.

Authors

Institutions

Publication Details

Journal
Brain Communications
Published
2026-10-14
DOI
https://doi.org/10.1093/braincomms/fcag392
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Distinct clinical subtypes of genetic frontotemporal dementia identified using disease progression modelling

Mattias Nilsson, Morris Freedman, David F. Tang‐Wai, Ron Keren et al.
Brain Communications
Amyotrophic Lateral Sclerosis Research
article

Distinct clinical subtypes of genetic frontotemporal dementia identified using disease progression modelling

Mattias Nilsson, Morris Freedman, David F. Tang‐Wai, Ron Keren, Kiran Samra, John Cornelis Van Swieten, Sandro Sorbi, Rick van Minkelen, Carolina Maruta, Caroline Graff, Ekaterina A. Rogaeva, Giacomina Rossi, Andrea Arighi, Liset de Boer, Valentina Bessi, Maria Carmela Tartaglia, Jaume Olives, Tobias Christoph Langheinrich, Enrico Premi, James Benedict Rowe, Albert Lladó, Timothy Rittman, Giorgio Giaccone, Alexander Gerhard, Lucia Giannini, Alexandra L. Young, Christopher Robert Butler, Roberto Gasparotti, María Serpente, Matthis Synofzik, Emanuele Buratti, Vesna Jelić, Linn Öijerstedt, Johannes Levin, Gemma Lombardi, Alexandre de Mendonça, Eve Ferry‐Bolder, Mircea Balasa, David M. Cash, Paola Caroppo, Isabelle Le Ber, Camilla Ferrari, Thomas Cope, Sara Prioni, William J. Scotton, Raquel Sánchez‐Valle, Veronica Redaelli, Harro Seelaar, Jackie M. Poos, Sergi Borrego‐Écija, Jonathan D. Rohrer, Pietro Tiraboschi, Frederico Simões do Couto, Phoebe H. Foster, Arabella Bouzigues, Isabel Santana, Lize Corrine Jiskoot, Cristina Polito, Martina Bocchetta, Antonella Alberici, Vittoria Borracci, Lucy Louise Russell, Markus Otto, Rik R. Vandenberghe, Maxime Bertoux, Elizabeth C. Finger, Valentina Cantoni, Neil P. Oxtoby, Chiara Fenoglio, Melissa Taheri Rydell, Ana Verdelho, Henrik Viklund, Daniela Galimberti, Thibaud Lebouvier, Mario Masellis, Emanuela Rotondo, David Lee Thomas, Rhian S. Convery, Tiziana Carandini, Giuseppe Di Fede, Barbara Borroni, Yolande A.L. Pijnenburg, Janne M. Papma, Julie F. H. De Houwer, Fermín Moreno, Sara Berman Mitchell, Simon Ducharme, Gabriel Miltenberger, Anna Antonell, Rosa Rademakers, Sophie Goldsmith, Christen L. Shoesmith, Sandra Black, Núria Bargalló, Benedetta Nacmias, GENFI, Robart Bartha, Robert Laforce, Tiago Coelho, Miguel Castelo-Branco
article en

Abstract

Abstract Understanding the order in which symptoms occur in genetic frontotemporal dementia (FTD) may provide valuable insight into disease progression. Here we use a methodology called Ordinal Subtype and Stage Inference (SuStaIn) in the GENetic FTD Initiative (GENFI) cohort to estimate a probable order in which symptoms occur, and identify different subtypes based on the pattern of symptom progression within the main genetic FTD mutation groups. 968 participants were included in the cross-sectional study: 280 C9orf72, 242 GRN and 101 MAPT mutation carriers, and 345 mutation-negative controls. 379 participants underwent longitudinal analysis: 162 C9orf72, 146 GRN and 71 MAPT mutation carriers. The standardised GENFI clinical assessment provided severity scores for all FTD-relevant symptoms ranging from 0 where symptoms are absent to 3 where symptoms are severe. Ordinal SuStaIn was run in each mutation group to generate symptom progression profiles for mutation carriers from each group. In the C9orf72 cohort, Ordinal SuStaIn identified three subtypes: subtype 1 with early behavioural and cognitive deficits, subtype 2 with impaired speech and swallowing, and subtype 3 with limb impairment. In the GRN cohort, SuStaIn identified two subtypes: subtype 1 with behavioural and cognitive deficits as well as limb motor involvement, and subtype 2 with early language impairment. The MAPT cohort was best described as a single subtype with a combination of cognitive (mainly semantic) and behavioural impairment with parkinsonism. SuStaIn stage significantly correlated with clinical severity scores for all the cohorts. The subtypes were somewhat longitudinally consistent, with a trend towards increased SuStaIn stage in each subtype over time. Identifying within-genotype data-driven subtypes of FTD is a novel approach for untangling the heterogeneity of this disorder, in turn drawing us closer to individualised care.

Brain Communications
Western University (CA), Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), Sunnybrook Health Science Centre (CA), Karolinska University Hospital (SE), University of Lisbon (PT), Inserm (FR), University of Milan (IT), Universität Ulm (DE), Université de Lille (FR), Institut Pasteur de Lille (FR), German Center for Neurodegenerative Diseases (DE), McGill University Health Centre (CA), Nuffield Orthopaedic Centre (GB), Erasmus MC (NL), Cambridge University Hospitals NHS Foundation Trust (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Sorbonne Université (FR), University of Oxford (GB), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Centro Cardiologico Monzino (IT), Bridge University (SS), Assistance Publique – Hôpitaux de Paris (FR), Centre de Recherche Jean Pierre Aubert (FR), Biogipuzkoa Health Research Institute (ES), Occupational Cancer Research Centre (CA), Centro San Giovanni di Dio Fatebenefratelli (IT), Hospital Clínic de Barcelona (ES), Don Carlo Gnocchi Foundation (IT), Pitié-Salpêtrière Hospital (FR), UK Dementia Research Institute (GB), Klinikum Arnsberg (DE), Donostiako Unibertsitate Ospitalea (ES), NIHR Queen Square Dementia Biomedical Research Unit (GB), Hertie Institute for Clinical Brain Research (DE), Institut du Cerveau (FR), Ontario Brain Institute (CA), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Université Laval (CA), Stiftung Universitätsmedizin Essen (DE), University of Florence (IT), University College London (GB), Imperial College London (GB), McGill University (CA), University of Duisburg-Essen (DE), Universitat de Barcelona (ES), University of Coimbra (PT), University of Brescia (IT), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), KU Leuven (BE)
Openalex Percentile: Top 14%
Amyotrophic Lateral Sclerosis Research
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.