Cellular signatures underlying functional resilience in presymptomatic frontotemporal dementia

Frontotemporal dementia (FTD) shows autosomal dominant transmission in up to a third of families, enabling the study of presymptomatic and prodromal phases. Despite self-reported well-being and normal daily cognitive functioning, brain structural changes are evident a decade or more before the expected onset of disease. This divergence between cognitive function and brain structure contrasts with the coupling of structural and functional decline after symptom onset. In healthy ageing, it has been shown that functional connectivity is a better predictor of cognitive function than volumetric structural imaging. We previously proposed that in the presymptomatic phase of genetic FTD, the maintenance of brain functional network integrity enables carriers of pathogenic variants to sustain cognitive performance. However, prior work has focused on a small number of, often predefined, networks. This provides a limited and potentially biased characterisation of the substrates and moderators of brain network integration. Here, we test the hypothesis that brain-wide functional integration in FTD determines resilience to progressive pathology before symptom onset. We assess functional connectome integration in 289 presymptomatic carriers of pathogenic variants associated with FTD using functional magnetic resonance imaging in relation to cognition and contrast with 271 family members without pathogenic variants. Because structural atrophy, functional integration and cognitive profiles are multivariate, we used canonical correlation models, supplemented by multiple linear regression models for each imaging modality. We confirmed progressive atrophy and normal cognitive function in presymptomatic carriers compared to non-carriers. Notably, functional integration was preserved in presymptomatic carriers across age, while it declined in familial non-carriers. The strongest effects were observed in cognitive control networks. The changes in functional integration in presymptomatic carriers were behaviourally relevant and independent of the severity of atrophy, suggesting a resilience mechanism in those at risk of dementia. To generate hypotheses about the genetic and neurometabolic basis of resilience, we assessed the spatial overlap between behaviourally-relevant functional integration maps and gene transcription profiles. These spatial correlations suggested resilience signatures to glial cell composition (astrocytes, microglia, oligodendrocytes), revealing cellular mechanisms inaccessible to standard neuroimaging. Our findings suggest that resilience to atrophy is associated with enhanced functional integration, protecting against clinical conversion for many years in individuals at risk of dementia. This result has implications for the design of presymptomatic disease-modifying therapy trials and gives hope for therapeutic strategies aimed at enhancing resilience and ability to maintain function despite the presence of genetically determined neuropathology.

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Journal
Brain
Published
2025-11-21
DOI
https://doi.org/10.1093/brain/awaf443
Primary Topic
Functional Brain Connectivity Studies
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article
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article

Cellular signatures underlying functional resilience in presymptomatic frontotemporal dementia

Mattias Nilsson, Elisabeth Wlasich, Morris Freedman, David F. Tang‐Wai et al.
Brain
Functional Brain Connectivity Studies
article

Cellular signatures underlying functional resilience in presymptomatic frontotemporal dementia

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, Richard A. I. Bethlehem, Valentina Bessi, Raffaella Migliaccio, Maria Carmela Tartaglia, Jaume Olives, Tobias Christoph Langheinrich, Enrico Premi, James Benedict Rowe, Albert Lladó, Timothy Rittman, Giorgio Giaccone, Alexander Gerhard, Lucia Giannini, Casey Paquola, Christopher Robert Butler, Roberto Gasparotti, María Serpente, Matthis Synofzik, Emanuele Buratti, Vesna Jelić, Linn Öijerstedt, Lisa Graf, Johannes Levin, Johanna Krüger, Gemma Lombardi, Alexandre de Mendonça, Jolina Lombardi, Eve Ferry‐Bolder, Mircea Balasa, Sandra E. Black, Anna Stockbauer, David M. Cash, Paola Caroppo, João Durães, David Mengel, Camilla Ferrari, Thomas Cope, Sara Prioni, Raquel Sánchez‐Valle, Sonja Schönecker, Veronica Redaelli, Rosa Rademakers, Núria Bargalló, Harro Seelaar, Jackie M. Poos, Sergi Borrego‐Écija, Pietro Tiraboschi, Frederico Simões do Couto, Ninon Burgos, Grégory Kuchcinski, Phoebe H. Foster, Rose Bruffaerts, Benjamin Bender, Tiago Costa-Coelho, Arabella Bouzigues, Isabel Santana, Lize Corrine Jiskoot, Benedetta Nacmias, Enrico Fainardi, Cristina Polito, Martina Bocchetta, 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, P. Simon Jones, Adeline Rollin, Chiara Fenoglio, Melissa Taheri Rydell, Ana Verdelho, David J. Whiteside, Henrik Viklund, Catharina Prix, Alexander G. Murley, Anna Antonell, Miguel Tábuas‐Pereira, Marisa Lima, Kamen A. Tsvetanov, Vincent Deramecourt, Maria João Leitão, Daisy Rinaldi, Maria Rosário Almeida, Thibaud Lebouvier, Mario Masellis, Emanuela Rotondo, Fermín Moreno, Robert Laforce, David Lee Thomas, Mikel Tainta, 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, Janne M. Papma, Daniela Galimberti, Sara Berman Mitchell, Sandro Sorbi, Simon Ducharme, Gabriel Miltenberger, Sònia Afonso, Sophie Goldsmith, John C. van Swieten, Christen L. Shoesmith, Maxime Montembault
article en

Abstract

Frontotemporal dementia (FTD) shows autosomal dominant transmission in up to a third of families, enabling the study of presymptomatic and prodromal phases. Despite self-reported well-being and normal daily cognitive functioning, brain structural changes are evident a decade or more before the expected onset of disease. This divergence between cognitive function and brain structure contrasts with the coupling of structural and functional decline after symptom onset. In healthy ageing, it has been shown that functional connectivity is a better predictor of cognitive function than volumetric structural imaging. We previously proposed that in the presymptomatic phase of genetic FTD, the maintenance of brain functional network integrity enables carriers of pathogenic variants to sustain cognitive performance. However, prior work has focused on a small number of, often predefined, networks. This provides a limited and potentially biased characterisation of the substrates and moderators of brain network integration. Here, we test the hypothesis that brain-wide functional integration in FTD determines resilience to progressive pathology before symptom onset. We assess functional connectome integration in 289 presymptomatic carriers of pathogenic variants associated with FTD using functional magnetic resonance imaging in relation to cognition and contrast with 271 family members without pathogenic variants. Because structural atrophy, functional integration and cognitive profiles are multivariate, we used canonical correlation models, supplemented by multiple linear regression models for each imaging modality. We confirmed progressive atrophy and normal cognitive function in presymptomatic carriers compared to non-carriers. Notably, functional integration was preserved in presymptomatic carriers across age, while it declined in familial non-carriers. The strongest effects were observed in cognitive control networks. The changes in functional integration in presymptomatic carriers were behaviourally relevant and independent of the severity of atrophy, suggesting a resilience mechanism in those at risk of dementia. To generate hypotheses about the genetic and neurometabolic basis of resilience, we assessed the spatial overlap between behaviourally-relevant functional integration maps and gene transcription profiles. These spatial correlations suggested resilience signatures to glial cell composition (astrocytes, microglia, oligodendrocytes), revealing cellular mechanisms inaccessible to standard neuroimaging. Our findings suggest that resilience to atrophy is associated with enhanced functional integration, protecting against clinical conversion for many years in individuals at risk of dementia. This result has implications for the design of presymptomatic disease-modifying therapy trials and gives hope for therapeutic strategies aimed at enhancing resilience and ability to maintain function despite the presence of genetically determined neuropathology.

Brain
Western University (CA), Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), Allen Institute for Brain Science (US), Sunnybrook Health Science Centre (CA), Karolinska University Hospital (SE), University of Lisbon (PT), Inserm (FR), Forschungszentrum Jülich (DE), Neurosciences Institute (US), University of Milan (IT), MRC Cognition and Brain Sciences Unit (GB), Universität Ulm (DE), Université de Lille (FR), University of Cambridge (GB), Douglas Mental Health University Institute (CA), Institut Pasteur de Lille (FR), German Center for Neurodegenerative Diseases (DE), Cambridge University Hospitals NHS Foundation Trust (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), University of Manchester (GB), Brescia University (US), Sorbonne Université (FR), University of Oxford (GB), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Centro Cardiologico Monzino (IT), Cambridge School (PT), Bridge University (SS), Assistance Publique – Hôpitaux de Paris (FR), Biogipuzkoa Health Research Institute (ES), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Occupational Cancer Research Centre (CA), Munich Cluster for Systems Neurology (DE), Centro San Giovanni di Dio Fatebenefratelli (IT), Don Carlo Gnocchi Foundation (IT), Essen University Hospital (DE), Pitié-Salpêtrière Hospital (FR), BioClinicum (Russia) (RU), UK Dementia Research Institute (GB), Klinikum Arnsberg (DE), Donostiako Unibertsitate Ospitalea (ES), Hertie Institute for Clinical Brain Research (DE), Institut du Cerveau (FR), VIB-KU Leuven Center for Brain & Disease Research (BE), University Hospital Ulm (DE), 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 of Florence (IT), University College London (GB), Imperial College London (GB), University of Duisburg-Essen (DE), University of Coimbra (PT), University of Brescia (IT), Ludwig-Maximilians-Universität München (DE), Erasmus University Rotterdam (NL), KU Leuven (BE)
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