Anatomical progression of genetic frontotemporal lobar degeneration across the lifespan

The recent development of brain charts for the human lifespan offers an ideal modelling framework for pathologies such as genetic frontotemporal lobar degeneration (FTLD) which likely involve both neurodevelopmental and neurodegenerative processes over a lifetime. We have therefore combined this new methodological approach with MRI data from asymptomatic and symptomatic subjects, carrying C9orf72, MAPT or GRN mutations from the Genetic FTD Initiative (GENFI) and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study. We analysed 37 532 MRIs from control subjects covering the entire lifespan and a total of 1341 MRIs from subjects with a pathogenic FTLD mutation, aged from 18 to 86 years old. We detected the first significant regional brain volume differences on average at 27 years old in C9orf72 and MAPT mutation carriers, and at 42 years old in GRN mutation carriers. The delay between the onset of anatomical changes and the average age of symptom onset (i.e. the presymptomatic phase) was 13 years for MAPT, 17 years for GRN and 34 years for C9orf72 mutation carriers. In terms of effect size, cumulative atrophy over the lifespan was twice as severe in affected brain regions in MAPT than in GRN or C9orf72 mutation carriers. However, the neurodegenerative process was spatially more extensive in C9orf72 (35 brain regions affected out of the 61 tested) compared with GRN or MAPT mutation carriers (25 and 18 regions, respectively). Schematically, the chronological staging of atrophy progression showed an initial involvement of the thalamus in C9orf72 expansion carriers, followed by the fronto-temporo-insular regions, the striatum and the amygdala. In GRN mutation carriers, atrophy began in fronto-insular areas, before progressing toward subcortical structures. In MAPT mutation carriers, atrophy affected the anterior temporal pole with the amygdala and hippocampus, before progressing to fronto-insular regions and the striatum. Our results using brain charts for the human lifespan show that C9orf72 is the most diffuse but also the slowest to emerge among genetic FTLD. MAPT FTLD is more aggressive and focal, while GRN FTLD is also rapidly progressive but with a later onset of the presymptomatic phase. Beyond quantification of the anatomical progression of genetic FTLD over the lifespan, these results may help determine the best timing to model and test disease-modifying strategies in FTLD, and monitor their effect in future clinical trials.

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Journal
Brain
Published
2025-05-25
DOI
https://doi.org/10.1093/brain/awaf195
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3
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Folate and B Vitamins Research
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article
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article

Anatomical progression of genetic frontotemporal lobar degeneration across the lifespan

Mattias Nilsson, Elisabeth Wlasich, Morris Freedman, David F. Tang‐Wai et al.
3 citations
Brain
Folate and B Vitamins Research
5.00
article

Anatomical progression of genetic frontotemporal lobar degeneration across the lifespan

Mattias Nilsson, Elisabeth Wlasich, Morris Freedman, David F. Tang‐Wai, Ron Keren, Kiran Samra, Koen Poesen, Maura Malpetti, Alexander Bernhardt, Robert Bartha, Stefano Chiti, Rick van Minkelen, Carolina Maruta, Caroline Graff, Ekaterina A. Rogaeva, Philip Van Damme, Giacomina Rossi, Alazne Gabilondo, Andrea Arighi, Liset de Boer, Vladimir Fonov, Valentina Bessi, Raffaella Migliaccio, Maria Carmela Tartaglia, Jaume Olives, Tobias Christoph Langheinrich, Enrico Premi, James Benedict Rowe, Albert Lladó, Giorgio Giaccone, Alexander Gerhard, Lucia Giannini, Christopher Robert Butler, Roberto Gasparotti, María Serpente, Matthis Synofzik, Vesna Jelić, Linn Öijerstedt, Lisa H. Graf, Johannes Levin, Johanna Krüger, Gemma Lombardi, José V. Manjón, Alexandre de Mendonça, Jolina Lombardi, Eve Ferry‐Bolder, Mircea Balasa, Anna Stockbauer, Pierrick Coupé, David M. Cash, João Durães, David Mengel, Camilla Ferrari, Sara Prioni, Raquel Sánchez‐Valle, Boris Mansencal, Sonja Schönecker, Veronica Redaelli, Rosa Rademakers, Harro Seelaar, Jackie M. Poos, Sergi Borrego‐Écija, Pietro Tiraboschi, Frederico Simões do Couto, Ninon Burgos, Grégory Kuchcinski, Phoebe H. Foster, Benjamin Bender, Tiago Costa-Coelho, Arabella Bouzigues, Lize Corrine Jiskoot, D. Louis Collins, Daisy Rinaldi, Enrico Fainardi, Cristina Polito, Martina Bocchetta, Maxime Montembeault, Annick Vogels, Antonella Alberici, Vittoria Borracci, Lucy Louise Russell, Jonathan D. Rohrer, Markus Otto, Rik R. Vandenberghe, Maxime Bertoux, Jan De Houwer, Elizabeth C. Finger, Patricia Alves, Valentina Cantoni, Mathieu Vandenbulcke, Ioana Croitoru, Adeline Rollin, Chiara Fenoglio, Melissa Taheri Rydell, Ana Verdelho, Henrik Viklund, Catharina Prix, Miguel Tábuas‐Pereira, Marisa Lima, Vincent Planche, Vincent Deramecourt, Thomas Tourdias, Maria João Leitão, Maria Rosário Almeida, Thibaud Lebouvier, Mario Masellis, Emanuela Rotondo, Fermín Moreno, Robert Laforce, David Lee Thomas, Olivia Wagemann, Rhian S. Convery, Tiziana Carandini, Giuseppe Di Fede, João M. Lemos, Barbara Borroni, Pedro Rosa‐Neto, Sarah Anderl‐Straub, Isabelle Le Ber, Miguel Castelo-Branco, Myriam Barandiarán, Yolande A.L. Pijnenburg, Mikel Tainta, Daniela Galimberti, Sara Berman Mitchell, Sandro Sorbi, Rose Bruffaerts, Simon Ducharme, Gabriel Miltenberger, Sònia Afonso, Anna Antonell, Christen Shoesmith, Sophie Goldsmith, John C. van Swieten, Paola Caroppo, Isabel Santana, Janne M. Papma, Sandra Black, Benedetta Nacmias
article en
3 citations

Abstract

The recent development of brain charts for the human lifespan offers an ideal modelling framework for pathologies such as genetic frontotemporal lobar degeneration (FTLD) which likely involve both neurodevelopmental and neurodegenerative processes over a lifetime. We have therefore combined this new methodological approach with MRI data from asymptomatic and symptomatic subjects, carrying C9orf72, MAPT or GRN mutations from the Genetic FTD Initiative (GENFI) and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study. We analysed 37 532 MRIs from control subjects covering the entire lifespan and a total of 1341 MRIs from subjects with a pathogenic FTLD mutation, aged from 18 to 86 years old. We detected the first significant regional brain volume differences on average at 27 years old in C9orf72 and MAPT mutation carriers, and at 42 years old in GRN mutation carriers. The delay between the onset of anatomical changes and the average age of symptom onset (i.e. the presymptomatic phase) was 13 years for MAPT, 17 years for GRN and 34 years for C9orf72 mutation carriers. In terms of effect size, cumulative atrophy over the lifespan was twice as severe in affected brain regions in MAPT than in GRN or C9orf72 mutation carriers. However, the neurodegenerative process was spatially more extensive in C9orf72 (35 brain regions affected out of the 61 tested) compared with GRN or MAPT mutation carriers (25 and 18 regions, respectively). Schematically, the chronological staging of atrophy progression showed an initial involvement of the thalamus in C9orf72 expansion carriers, followed by the fronto-temporo-insular regions, the striatum and the amygdala. In GRN mutation carriers, atrophy began in fronto-insular areas, before progressing toward subcortical structures. In MAPT mutation carriers, atrophy affected the anterior temporal pole with the amygdala and hippocampus, before progressing to fronto-insular regions and the striatum. Our results using brain charts for the human lifespan show that C9orf72 is the most diffuse but also the slowest to emerge among genetic FTLD. MAPT FTLD is more aggressive and focal, while GRN FTLD is also rapidly progressive but with a later onset of the presymptomatic phase. Beyond quantification of the anatomical progression of genetic FTLD over the lifespan, these results may help determine the best timing to model and test disease-modifying strategies in FTLD, and monitor their effect in future clinical trials.

BrainVol. 148(11)
Western University (CA), Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), Sunnybrook Health Science Centre (CA), University of Lisbon (PT), Université de Bordeaux (FR), Inserm (FR), University of Toronto (CA), University of Milan (IT), Universität Ulm (DE), Université de Lille (FR), Douglas Mental Health University Institute (CA), German Center for Neurodegenerative Diseases (DE), Erasmus MC (NL), Cambridge University Hospitals NHS Foundation Trust (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Karolinska Institutet (SE), University of Manchester (GB), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Lille (FR), Brescia University (US), Sorbonne Université (FR), University of Oxford (GB), Institut des Maladies Neurodégénératives (FR), Bridge University (SS), Assistance Publique – Hôpitaux de Paris (FR), Biogipuzkoa Health Research Institute (ES), Occupational Cancer Research Centre (CA), Munich Cluster for Systems Neurology (DE), Centro San Giovanni di Dio Fatebenefratelli (IT), Don Carlo Gnocchi Foundation (IT), Neurocentre Magendie (FR), BioClinicum (Russia) (RU), UK Dementia Research Institute (GB), Donostiako Unibertsitate Ospitalea (ES), Hertie Institute for Clinical Brain Research (DE), Laboratoire Bordelais de Recherche en Informatique (FR), National Hospital for Neurology and Neurosurgery (GB), Institut du Cerveau (FR), University Hospital Ulm (DE), Ontario Brain Institute (CA), Institut Polytechnique de Bordeaux (FR), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Technische Hochschule Ulm (DE), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Université Laval (CA), University College London (GB), McGill University (CA), Universitat Politècnica de València (ES), University of Coimbra (PT), University of Brescia (IT), Ludwig-Maximilians-Universität München (DE), Erasmus University Rotterdam (NL), KU Leuven (BE)
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