TY - JOUR
T1 - Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia
AU - Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI)
AU - GENetic Frontotemporal dementia Initiative (GENFI)
AU - Shafiei, Golia
AU - Bazinet, Vincent
AU - Dadar, Mahsa
AU - Manera, Ana L.
AU - Collins, D. Louis
AU - Dagher, Alain
AU - Borroni, Barbara
AU - Sanchez-Valle, Raquel
AU - Moreno, Fermin
AU - Laforce, Robert
AU - Graff, Caroline
AU - Synofzik, Matthis
AU - Galimberti, Daniela
AU - Rowe, James B.
AU - Masellis, Mario
AU - Tartaglia, Maria Carmela
AU - Finger, Elizabeth
AU - Vandenberghe, Rik
AU - de Mendonça, Alexandre
AU - Tagliavini, Fabrizio
AU - Santana, Isabel
AU - Butler, Chris
AU - Gerhard, Alex
AU - Danek, Adrian
AU - Levin, Johannes
AU - Otto, Markus
AU - Sorbi, Sandro
AU - Jiskoot, Lize C.
AU - Seelaar, Harro
AU - van Swieten, John C.
AU - Rohrer, Jonathan D.
AU - Misic, Bratislav
AU - Ducharme, Simon
AU - Rosen, Howard
AU - Dickerson, Bradford C.
AU - Domoto-Reilly, Kimoko
AU - Knopman, David
AU - Boeve, Bradley F.
AU - Boxer, Adam L.
AU - Kornak, John
AU - Miller, Bruce L.
AU - Seeley, William W.
AU - Gorno-Tempini, Maria Luisa
AU - McGinnis, Scott
AU - Mandelli, Maria Luisa
AU - Esteve, Aitana Sogorb
AU - Nelson, Annabel
AU - Bouzigues, Arabella
AU - Heller, Carolin
AU - Greaves, Caroline V.
N1 - Publisher Copyright:
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - connectome
KW - disease epicentre
KW - frontotemporal dementia
KW - gene expression
KW - network spreading
UR - http://www.scopus.com/inward/record.url?scp=85162902736&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85162902736&partnerID=8YFLogxK
U2 - 10.1093/brain/awac069
DO - 10.1093/brain/awac069
M3 - Article
C2 - 35188955
AN - SCOPUS:85162902736
SN - 0006-8950
VL - 146
SP - 321
EP - 336
JO - Brain
JF - Brain
IS - 1
ER -