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
McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Radiology and Nuclear Medicine, Laval University, Quebec City, QC, Canada.
Brain. 2023 Jan 5;146(1):321-336. doi: 10.1093/brain/awac069.
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.
脑区之间的连接使得病理扰动能够从单个源区域扩散到多个区域。包括行为变异型额颞叶痴呆（bvFTD）在内的多种疾病中的神经退行性变模式类似于大规模功能系统，但bvFTD相关的萎缩模式与结构网络组织之间的关系仍不清楚。在这里，我们研究散发性和遗传性bvFTD中的神经退行性变模式是否受连接组结构的影响。在遗传性bvFTD（75例患者，247例对照）和散发性bvFTD（70例患者，123例对照）中估计区域萎缩模式。首先，我们在bvFTD中识别出分布性萎缩模式，主要针对与边缘内在网络和岛叶细胞构筑类别相关的区域。区域萎缩与结构和功能连接的相邻区域的萎缩显著相关，表明网络结构塑造了萎缩模式。使用数据驱动和基于模拟的方法，将前岛叶确定为脑萎缩的主要组中心，额叶腹内侧和颞前内侧区域有一些次要区域。我们发现，FTD相关基因，即C9orf72和TARDBP，使疾病具有局部转录组易感性，调节病理通过连接组的传播。总体而言，我们的结果表明，散发性和遗传性bvFTD中的萎缩模式由全局连接组结构和局部转录组易感性共同塑造，为异质性病理实体如何导致相同临床综合征提供了解释。
