Disease duration is associated with spatiotemporal grey matter atrophy in type 2 diabetes mellitus: a VBM and causal structural covariance network study

Type 2 diabetes mellitus (T2DM) is associated with progressive grey matter atrophy; however, the temporal sequence and directional propagation of structural damage across brain regions remain poorly understood. This study aimed to determine whether disease duration is associated with a spatiotemporal cascade of grey matter volume (GMV) loss and to map its propagation pathways via causal structural covariance network (CaSCN) analysis. A total of 245 T2DM patients and 120 healthy controls were included in the final analysis in this study, all of whom underwent 3D T1-weighted MRI. Voxel-based morphometry (VBM) was performed to identify GMV alterations overall and across disease stages using two complementary grouping strategies (primary 2-stage and validation 3-stage). A seed-based CaSCN analysis was then performed to trace the directionality of atrophy propagation. Partial correlation analysis examined the relationship between disease duration and GMV in key regions. VBM revealed widespread GMV reductions in T2DM patients, predominantly affecting the insula, temporal pole, fusiform gyrus, and prefrontal cortex. Stage-specific analyses showed that GMV loss originated in the left insula at early stages and progressively extended to temporal, frontal, and parietal regions with increasing disease duration. This pattern was consistently validated across both staging strategies. CaSCN analysis demonstrated that GMV decline in the left insula was associated with directional influences on downstream regions, resulting in GMV reductions in the fusiform gyrus, middle temporal gyrus, and dorsolateral prefrontal cortex. Conversely, negative Granger-causal associations were observed between the insula and the hippocampus/amygdala. Because VBM showed no absolute GMV increases, these inverse associations were interpreted as possible relative preservation, slower atrophy, or discordant/nonlinear trajectories rather than true volumetric expansion. Disease duration showed weak but significant negative correlations with GMV in the left and right insula, temporal pole, and fusiform gyrus. Disease duration is associated with a spatiotemporal cascade of GMV atrophy in T2DM, originating in the left insula and propagating to widespread cortical regions.