Background Radial Diffusivity (RD) has been suggested as a promising biomarker associated with the level of myelination in MS lesions. However, the level of RD within the lesion is affected not only by loss of myelin sheaths, but also by the degree of tissue destruction. This may lead to exaggeration of diffusivity measures, potentially masking the effect of remyelination. Objective To test the hypothesis that the T2 hyperintense lesion edge that extends beyond the T1 hypointense lesion core is less affected by tissue loss, and therefore a more appropriate target for imaging biomarker development targeting de- and re-myelination. Method Pre- and post-gadolinium (Gd) enhanced T1, T2 and DTI images were acquired from 75 consecutive RRMS patients. The optic radiation (OR) was identified in individual patients using a template-based method. T2 lesions were segmented into T1-hypointense and T1-isointense areas and lesion masks intersected with the OR. Average Radial, Axial and Mean diffusivity (RD, AD and MD) and fractional anisotropy (FA) were calculated for lesions of the entire brain and the OR. In addition, Gd enhancing lesions were excluded from the analysis. Results 86% of chronic T2 lesions demonstrated hypointense areas on T1-weighted images, which typically occupied the central part of each T2 lesion, taking about 40% of lesional volume. The T1-isointense component of the T2 lesion was most commonly seen as a peripheral ring of relatively constant thickness (“T2-rim”). While changes of diffusivity between adjacent normal appearing white matter and the “T2-rim” demonstrated a disproportionally high elevation of RD compare to AD, the increase of water diffusion was largely isointense between the “T2-rim” and T1-hypointense parts of the lesion. Conclusion Distinct patterns of diffusivity within the central and peripheral components of MS lesions suggest that axonal loss dominates in the T1 hypointense core. The effects of de/remyelination may be more readily detected in the “T2-rim”, where there is relative preservation of structural integrity. Identifying and separating those patterns has an important implication for clinical trials of both neuroprotective and, in particular, remyelinating agents.