<p>In Multiple Sclerosis, inflammation and neurodegeneration disrupt structural and functional brain networks. While the association between structural connectivity and disability is rather clear, functional connectivity changes are not yet characterised as a physiological response to the disease, as functionally meaningful adaptation or as a deceptive response. We explored the topology of brain networks of 65 Multiple Sclerosis patients over up to seven years in comparison to 59 controls. Connectomes based on probabilistic tractography from diffusion weighted imaging and resting-state MRI, were analysed with graph theory. The hub disruption index estimated connectivity perturbation in relation to the network hierarchy. In controls, we observed a transient increase in functional hub connectivity in the 5th and 6th age decade as a response to a subtle diffuse loss of structural connectivity, before structural and functional connectomes show a pronounced loss of hub connectivity. In Multiple Sclerosis, structural hub disruption was present from the disease onset while the transient upregulation of functional hub connectivity in the middle age was lacking. Patients seem to transition directly into an exhausted hub connectivity configuration. However, we observed the transient functional reorganisation of hubs in the first years after disease onset. Multiple Sclerosis patients present a probable physiological response to structural connectivity loss very early in the disease, potentially leading to an accelerated hub overload with accelerated neurodegeneration. The onset of chronic progression in the 5th age decade might be partially driven by the absence of the physiological increased hub connectivity observed in healthy individuals.</p>