The role of network connectivity and transcriptomic vulnerability in shaping gray matter atrophy in multiple sclerosis

Clinical progression is strongly linked to gray matter atrophy in multiple sclerosis (MS), detectable early on MRI and progressing nonrandomly across the brain. However, the mechanisms driving its spatiotemporal progression and individual variability remain unclear. Using MRIs from 2187 participants, alongside normative data, we systematically investigated network-based mechanisms underlying MS-related atrophy. Regional atrophy was associated with functional cortical hubness, supporting the nodal stress hypothesis, and was constrained by anatomical and functional connections, consistent with transneuronal degeneration. Lesional disconnection and transcriptomic vulnerability played marginal roles. Patient- and subgroup-level analyses revealed that network-based mechanisms are specifically linked to MS-related neurodegeneration and may operate differently in distinct subtypes or disease phases. Atrophy patterns were anchored to the connectivity profiles of disease epicenters involving the visual, sensorimotor, and temporal cortices, as well as the hippocampi, amygdalae, and thalami. Network-based measures enhanced the explanation of future atrophy progression in people with MS, providing a mechanistic framework to understand neurodegeneration in MS.