Cellular signatures of functional resilience in presymptomatic frontotemporal dementia
Authors: Tsvetanov Kamen A , Malpetti Maura , Jones P Simon , Rittman Timothy , Whiteside David J , Murley Alexander G , Bethlehem Richard A.I. , Paquola Casey , Premi Enrico , Bouzigues Arabella , Russell Lucy , Foster Phoebe H , Ferry-Bolder Eve , van Swieten John C , Jiskoot Lize C , Seelaar Harro , Sanchez-Valle Raquel , Laforce Robert , Graff Caroline , Galimberti Daniela , Vandenberghe Rik , de Mendonça Alexandre , Tiraboschi Pietro , Santana Isabel , Gerhard Alexandre , Levin Johannes , Sorbi Sandro , Otto Markus , Bertoux Maxime , Lebouvier Thibaud , Ducharme Simon , Butler Chris R , Le Ber Isavelle , Finger Elizabeth , Tartaglia Carmela , Masellis Mario , Synofzik Matthis , Moreno Fermin , Borroni Barbara , Rohrer Johnathan D , Rowe James ,   GENFI Consortium
Published: February 2025

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 mutation carriers 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 FTD-mutation carriers using functional magnetic resonance imaging in relation to cognition and contrast with 271 family members without mutations. 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 arises from 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.