The Role of Network Connectivity and Transcriptomic Vulnerability in Shaping Grey Matter Atrophy in Multiple Sclerosis

Clinical progression is strongly linked to grey matter atrophy in multiple sclerosis (MS), detectable early on MRI and progressing non-randomly across the brain. However, the mechanisms driving its spatio-temporal progression and individual variability remain unclear. Using MRIs from 2,187 participants, alongside normative data, we systematically investigated network-based mechanisms underlying MS-related atrophy. Regional atrophy colocalised with functional cortical hubs, supporting the nodal stress hypothesis, and propagated along 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 epicentres involving the visual, sensorimotor, and temporal cortices, and the hippocampi and thalami. Network-based measures enhanced the prediction of future atrophy progression in individual with MS, providing a mechanistic framework to understand neurodegeneration in MS.