Discussion
death, myelin injury, axonal damage, NAWM, axonal loss, Neuronal loss
DISEASE, AXONAL SWELLING, PLAQUE
We present the first positive identification of an MRI correlate of therapy-induced remyelination in a clinical trial (ReBUILD) (We were able to successfully measure an improvement of the myelin content metrics in the CC NAWM of subjects enrolled in the ReBUILD trial (Since its earliest description, the primary focus in MS has been in understanding focal lesions (Importantly at a histopathological level, MS NAWM demonstrates global reduction in the intensity of myelin staining but also focal axonal swellings and axonal end bulbs. This axonal damage is more prominent around demyelinated plaques and within defined tracts emerging from the plaques. Neuronal loss in NAWM increases in progressive patients, highlighting a dynamic picture characterized by unmyelinated and damaged axons prone to cell death, opposed to the stability of the axonal loss within the plaque.As myelin is laid down and compacted water in the form of cytoplasm and extracellular water is expelled leaving only a very thin layer of cytoplasmic water (approximately 2 nm) and extracellular water (approximately 4 nm between each wrap) remaining (MWF of the NAWM was recently shown to be improved with the use of ocreluzimab in a substudy of the OPERA II trial (In conclusion, future reparative and remyelinating trials focused on restoring function should identify myelin-content–related changes on MRI within the NAWM and especially within highly myelinated coherently organized structures like the corpus callosum as imaging endpoints. Furthermore, myelin repair appears to be more robust in the NAWM than in the lesion which should focus our attention on understanding myelin injury in the NAWM and its impact on disease.