BackgroundMultiple sclerosis (MS) is a complex chronic inflammatory and degenerative disorder of the central nervous system. Accelerated brain volume loss, or also termed atrophy, is currently emerging as a popular imaging marker of neurodegeneration in affected patients, but, unfortunately, can only be reliably interpreted at the time when irreversible tissue damage likely has already occurred. Timing of treatment decisions based on brain atrophy may therefore be viewed as suboptimal.Main bodyThis Narrative Review focuses on alternative techniques with the potential of detecting neurodegenerative events in the brain of subjects with MS prior to the atrophic stage. First, metabolic and molecular imaging provide the opportunity to identify early subcellular changes associated with energy dysfunction, which is an assumed core mechanism of axonal degeneration in MS. Second, cerebral hypoperfusion has been observed throughout the entire clinical spectrum of the disorder but it remains an open question whether this serves as an alternative marker of reduced metabolic activity, or exists as an independent contributing process, mediated by endothelin-1 hyperexpression. Third, both metabolic and perfusion alterations may lead to repercussions at the level of network performance and structural connectivity, respectively assessable by functional and diffusion tensor imaging. Fourth and finally, elevated body fluid levels of neurofilaments are gaining interest as a biochemical mirror of axonal damage in a wide range of neurological conditions, with early rises in patients with MS appearing to be predictive of future brain atrophy.ConclusionsRecent findings from the fields of advanced neuroradiology and neurochemistry provide the promising prospect of demonstrating degenerative brain pathology in patients with MS before atrophy has installed. Although the overall level of evidence on the presented topic is still preliminary, this Review may pave the way for further longitudinal and multimodal studies exploring the relationships between the abovementioned measures, possibly leading to novel insights in early disease mechanisms and therapeutic intervention strategies.