Journal Article

DZNE-2026-00856

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Cellular signatures underlying functional resilience in presymptomatic frontotemporal dementia.

Tsvetanov, K. A. ; Malpetti, M. ; Jones, P. S. ; Rittman, T. ; Whiteside, D. J. ; Murley, A. G. ; Bethlehem, R. ; Paquola, C. ; Premi, E. ; Bouzigues, A. ; Russell, L. L. ; Foster, P. H. ; Ferry-Bolder, E. ; van Swieten, J. C. ; Jiskoot, L. C. ; Seelaar, H. ; Sanchez-Valle, R. ; Laforce, R. ; Graff, C. ; Galimberti, D. ; Vandenberghe, R. ; de Mendonça, A. ; Tiraboschi, P. ; Santana, I. ; Gerhard, A. ; Levin, J.DZNE* ; Sorbi, S. ; Otto, M. ; Bertoux, M. ; Lebouvier, T. ; Ducharme, S. ; Butler, C. R. ; Le Ber, I. ; Finger, E. ; Tartaglia, M. C. ; Masellis, M. ; Synofzik, M.DZNE* ; Moreno, F. ; Borroni, B. ; Rohrer, J. D. ; Rowe, J. B. ; Genetic FTD Initiative, G. (Collaboration Author) ; Convery, R. (Contributor) ; Bocchetta, M. (Contributor) ; Cash, D. (Contributor) ; Goldsmith, S. (Contributor) ; Samra, K. (Contributor) ; Thomas, D. L. (Contributor) ; Cope, T. (Contributor) ; Malpetti, M. (Contributor) ; Alberici, A. (Contributor) ; Premi, E. (Contributor) ; Gasparotti, R. (Contributor) ; Buratti, E. (Contributor) ; Cantoni, V. (Contributor) ; Arighi, A. (Contributor) ; Fenoglio, C. (Contributor) ; Borracci, V. (Contributor) ; Serpente, M. (Contributor) ; Carandini, T. (Contributor) ; Rotondo, E. (Contributor) ; Rossi, G. (Contributor) ; Giaccone, G. (Contributor) ; Di Fede, G. (Contributor) ; Caroppo, P. (Contributor) ; Prioni, S. (Contributor) ; Redaelli, V. (Contributor) ; Tang-Wai, D. (Contributor) ; Rogaeva, E. (Contributor) ; Krüger, J. (Contributor) ; Castelo-Branco, M. (Contributor) ; Freedman, M. (Contributor) ; Keren, R. (Contributor) ; Black, S. (Contributor) ; Mitchell, S. (Contributor) ; Shoesmith, C. (Contributor) ; Bartha, R. (Contributor) ; Rademakers, R. (Contributor) ; Poos, J. (Contributor) ; Papma, J. M. (Contributor) ; Giannini, L. (Contributor) ; de Boer, L. (Contributor) ; de Houwer, J. (Contributor) ; van Minkelen, R. (Contributor) ; Pijnenburg, Y. (Contributor) ; Nacmias, B. (Contributor) ; Ferrari, C. (Contributor) ; Polito, C. (Contributor) ; Lombardi, G. (Contributor) ; Bessi, V. (Contributor) ; Fainardi, E. (Contributor) ; Chiti, S. (Contributor) ; Nilsson, M. (Contributor) ; Viklund, H. (Contributor) ; Rydell, M. T. (Contributor) ; Jelic, V. (Contributor) ; Öijerstedt, L. (Contributor) ; Langheinrich, T. (Contributor) ; Lladó, A. (Contributor) ; Antonell, A. (Contributor) ; Olives, J. (Contributor) ; Balasa, M. (Contributor) ; Bargalló, N. (Contributor) ; Borrego-Ecija, S. (Contributor) ; Verdelho, A. (Contributor) ; Maruta, C. (Contributor) ; Costa-Coelho, T. (Contributor) ; Miltenberger, G. (Contributor) ; Couto, F. S. d. (Contributor) ; Gabilondo, A. (Contributor) ; Croitoru, I. (Contributor) ; Tainta, M. (Contributor) ; Barandiaran, M. (Contributor) ; Alves, P. (Contributor) ; Bender, B. (Contributor) ; Mengel, D. (Contributor)Extern* ; Graf, L. (Contributor)Extern* ; Vogels, A. (Contributor) ; Vandenbulcke, M. (Contributor) ; Van Damme, P. (Contributor) ; Bruffaerts, R. (Contributor) ; Poesen, K. (Contributor) ; Rosa-Neto, P. (Contributor) ; Montembault, M. (Contributor) ; Migliaccio, R. L. (Contributor) ; Burgos, N. (Contributor) ; Rinaldi, D. (Contributor) ; Prix, C. (Contributor)Extern* ; Wlasich, E. (Contributor) ; Wagemann, O. (Contributor)Extern* ; Schönecker, S. (Contributor) ; Bernhardt, A. M. (Contributor)Extern* ; Stockbauer, A. (Contributor)Extern* ; Lombardi, J. (Contributor) ; Anderl-Straub, S. (Contributor) ; Rollin, A. (Contributor) ; Kuchcinski, G. (Contributor) ; Deramecourt, V. (Contributor) ; Durães, J. (Contributor) ; Lima, M. (Contributor) ; Leitão, M. J. (Contributor) ; Almeida, M. R. (Contributor) ; Tábuas-Pereira, M. (Contributor) ; Afonso, S. (Contributor) ; Lemos, J. (Contributor)

2026
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awaf443

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 characterization 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 MRI 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.

Keyword(s): Humans (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: physiopathology (MeSH) ; Frontotemporal Dementia: diagnostic imaging (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Frontotemporal Dementia: psychology (MeSH) ; Magnetic Resonance Imaging: methods (MeSH) ; Brain: physiopathology (MeSH) ; Brain: pathology (MeSH) ; Brain: diagnostic imaging (MeSH) ; Female (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Connectome: methods (MeSH) ; Adult (MeSH) ; Aged (MeSH) ; Prodromal Symptoms (MeSH) ; Cognition: physiology (MeSH) ; Atrophy (MeSH) ; familial ; frontotemporal dementia (FTD) ; functional magnetic resonance imaging (fMRI) ; network connectivity ; presymptomatic ; resilience

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))
2. Clinical Neurodegeneration (AG Levin)
3. Parkinson Genetics (AG Gasser)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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