Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia.
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Authors
Bazinet, Vincent
Manera, Ana L
Borroni, Barbara
Moreno, Fermin
Laforce, Robert
Galimberti, Daniela
Rowe, James B
Tartaglia, Maria Carmela
Finger, Elizabeth
Vandenberghe, Rik
de Mendonça, Alexandre
Tagliavini, Fabrizio
Santana, Isabel
Butler, Chris
Gerhard, Alex
Danek, Adrian
Levin, Johannes
Otto, Markus
Sorbi, Sandro
van Swieten, John C
Rohrer, Jonathan D
Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI)
GENetic Frontotemporal dementia Initiative (GENFI)
Publication Date
2023-01-05Journal Title
Brain
ISSN
0006-8950
Publisher
Oxford University Press (OUP)
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Shafiei, G., Bazinet, V., Dadar, M., Manera, A. L., Collins, D. L., Dagher, A., Borroni, B., et al. (2023). Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia.. Brain https://doi.org/10.1093/brain/awac069
Abstract
Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioural variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). First, we identified distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbours, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicentre of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. We found that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome.
Keywords
connectome, disease epicentre, frontotemporal dementia, gene expression, network spreading
Sponsorship
Wellcome Trust (103838/Z/14/Z)
Medical Research Council (MR/J009482/1)
Embargo Lift Date
2023-02-21
Identifiers
External DOI: https://doi.org/10.1093/brain/awac069
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335746
Rights
Attribution-NonCommercial 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc/4.0/
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