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 behavioral 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). We first identify 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 neighbors, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicenter of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and anteromedial temporal areas. Finally, we find that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, effectively 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵† Data used in preparation of this article were obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) database (http://4rtni-ftldni.ini.usc.edu/). The investigators at NIFD/FTLDNI contributed to the design and implementation of FTLDNI and/or provided data but did not participate in analysis or writing of this report (unless otherwise listed). The FTLDNI investigators included the following individuals: Howard Rosen - University of California, San Francisco (PI); Bradford C. Dickerson - Harvard Medical School and Massachusetts General Hospital; Kimoko Domoto-Reilly - University of Washington School of Medicine; David Knopman - Mayo Clinic, Rochester; Bradley F. Boeve - Mayo Clinic Rochester; Adam L. Boxer - University of California, San Francisco; John Kornak - University of California, San Francisco; Bruce L. Miller - University of California, San Francisco; William W. Seeley - University of California, San Francisco; Maria-Luisa Gorno-Tempini - University of California, San Francisco; Scott McGinnis - University of California, San Francisco; Maria Luisa Mandelli - University of California, San Francisco
↵‡ List of other GENFI Consortium Members in Appendix
