1. Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia
- Author
-
Shafiei, Golia, Bazinet, Vincent, Dadar, Mahsa, Manera, Ana L, Collins, D Louis, Dagher, Alain, Borroni, Barbara, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B, Masellis, Mario, 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, Jiskoot, Lize C, Seelaar, Harro, van Swieten, John C, Rohrer, Jonathan D, Misic, Bratislav, Ducharme, Simon, Initiative, Frontotemporal Lobar Degeneration Neuroimaging, Rosen, Howard, Dickerson, Bradford C, Domoto-Reilly, Kimoko, Knopman, David, Boeve, Bradley F, Boxer, Adam L, Kornak, John, Miller, Bruce L, Seeley, William W, Gorno-Tempini, Maria-Luisa, McGinnis, Scott, Mandelli, Maria Luisa, Initiative, GENetic Frontotemporal dementia, Esteve, Aitana Sogorb, Nelson, Annabel, Bouzigues, Arabella, Heller, Carolin, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Russell, Lucy L, Bocchetta, Martina, Shafei, Rachelle, Convery, Rhian S, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, van der Ende, Emma, Poos, Jackie, Papma, Janne M, Giannini, Lucia, and van Minkelen, Rick
- Subjects
Biomedical and Clinical Sciences ,Health Sciences ,Psychology ,Acquired Cognitive Impairment ,Dementia ,Aging ,Neurodegenerative ,Frontotemporal Dementia (FTD) ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Alzheimer's Disease ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Humans ,Frontotemporal Dementia ,Transcriptome ,Brain ,Pick Disease of the Brain ,Atrophy ,Connectome ,Magnetic Resonance Imaging ,Neuropsychological Tests ,Frontotemporal Lobar Degeneration Neuroimaging Initiative ,GENetic Frontotemporal dementia Initiative ,connectome ,disease epicentre ,frontotemporal dementia ,gene expression ,network spreading ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences - 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.
- Published
- 2023