Journal Article

DZNE-2022-00740

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia

Shafiei, G. ; Bazinet, V. ; Dadar, M. ; Manera, A. L. ; Collins, D. L. ; Dagher, A. ; Borroni, B. ; Sanchez-Valle, R. ; Moreno, F. ; Laforce, R. ; Graff, C. ; Synofzik, M.DZNE* ; Galimberti, D. ; Rowe, J. B. ; Masellis, M. ; Tartaglia, M. C. ; Finger, E. ; Vandenberghe, R. ; de Mendonça, A. ; Tagliavini, F. ; Santana, I. ; Butler, C. ; Gerhard, A. ; Danek, A.Extern* ; Levin, J.DZNE* ; Otto, M. ; Sorbi, S. ; Jiskoot, L. C. ; Seelaar, H. ; van Swieten, J. C. ; Rohrer, J. D. ; Misic, B. ; Ducharme, S. ; Initiative, F. L. D. N. (Collaboration Author) ; Initiative, G. F. d. (Collaboration Author)

2022
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi: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.

Keyword(s): Humans (MeSH) ; Frontotemporal Dementia: diagnostic imaging (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Transcriptome (MeSH) ; Brain: pathology (MeSH) ; Pick Disease of the Brain: pathology (MeSH) ; Atrophy: pathology (MeSH) ; Connectome (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Neuropsychological Tests (MeSH) ; connectome ; disease epicentre ; frontotemporal dementia ; gene expression ; network spreading

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser 1)
2. Clinical Dementia Research München (Clinical Dementia Research München)

Research Program(s):

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

Appears in the scientific report 2022

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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 >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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