Brain atrophy is currently the accepted method for measuring neurodegeneration in multiple sclerosis (MS) but is insensitive over short times and ignores changes in cellular density. Recent advances in diffusion weighted imaging provide markers of axonal fibre density and atrophy. This study aimed to study the longitudinal sensitivity of these markers in comparison to brain atrophy based on data acquired in a standard clinical MS study. Annualised within-patient change in fibre density was around seven times more sensitive than brain volume change. This supports the development of fibre density based methods for clinical monitoring of axonal loss in MS.