Anterior Insula Drives Progressive Structural Brain Network Atrophy in the Behavioural Variant of Frontotemporal Dementia

The behavioural variant of frontotemporal dementia (bvFTD) is a younger-onset dementia syndrome characterised by early atrophy of frontoinsular cortices, manifesting in profound socioemotional disturbances. Converging evidence from correlational, data-driven, and computational approaches indicates large-scale network degeneration in bvFTD. While the insula is consistently implicated, it remains unclear whether insular atrophy causally impacts progressive large-scale structural network alterations in bvFTD. Eighty-two patients with clinically probable bvFTD were classified as very mild/mild (n = 35), moderate (n = 30), and severe (n = 17) using the CDR plus NACC FTLD. Grey matter volume comparison between the entire bvFTD group and a healthy control group matched for age and education identified the left anterior insula as the initial maximal site of atrophy in bvFTD. To determine potential causal effects of insular atrophy on network-based dysfunction in bvFTD, a voxel-wise causal structural covariance network (CaSCN) was constructed based on pseudo-time-series morphometric data using the left anterior insula as the seed region. Sex, age, years of education, total intracranial volume (TIV), and scanning site were included as covariates, along with the difference between the sum of boxes score for the CDR plus NACC FTLD across the two pseudo-time points. Finally, an event-based model (EBM) was applied to confirm the sequence of regional atrophy precipitated by left anterior insula atrophy, which emerged in the CaSCN analysis. BvFTD patients in the very mild/mild disease subgroup showed predominant atrophy of frontotemporal (e.g., insula, middle frontal gyrus), limbic (e.g., hippocampus, amygdala), and subcortical (e.g., putamen, nucleus accumbens) structures. Widespread grey matter atrophy was evident in the moderate bvFTD subgroup, extending to the middle cingulate, paracingulate gyri, and the thalamus, which progressed to posterior brain regions, including the fusiform gyrus and the cerebellum in the severe subgroup. Importantly, the CaSCN and event-based model analysis reinforced the disease-staging results by revealing progression of atrophy from the initial seed region of the left anterior insula to the orbitofrontal cortex, putamen/nucleus accumbens, anterior cingulate cortex, dorsolateral prefrontal cortex, inferior temporal gyrus, and supramarginal gyrus, before progressing posteriorly to the lingual gyrus. Using causal structural covariance network analysis and event-based modelling, our findings indicate a causal role for the left anterior insula in driving the spread of pathology in bvFTD through well-delineated functional brain networks known to support higher-order cognitive and socioemotional processing. By capturing the direction of atrophy progression, our findings hold utility for potentially monitoring and tracking the efficacy of novel therapeutics on brain function in bvFTD.