Multiple sclerosis as a neurodegenerative disease: pathology, mechanisms and therapeutic implications

Multiple sclerosis (MS) treatments targeting the inflammatory nature of the disease have become increasingly effective in recent years. However, our efforts at targeting the progressive disease phase have so far been largely unsuccessful. This has led to the hypothesis that disease mechanisms independent of an adaptive immune response contribute to disease progression and closely resemble neurodegeneration.

Nonfocal, diffuse changes in the MS brain, especially axonal loss and mitochondrial dysfunction, prove better correlates of disability than total lesion load and have been associated with disease progression. Molecular changes in nondemyelinated MS tissue also suggest that alterations in the MS brain are widespread and consist of pro-inflammatory as well as anti-inflammatory responses. However, local lymphocytic inflammation and microglial activation are salient features of the chronic disease, and T-cell-mediated inflammation contributes to tissue damage. In addition, neuroaxonal cytoskeletal alterations have been associated with disease progression.

Our knowledge of the molecular mechanisms leading to neuroaxonal damage and demise in MS is steadily increasing. Experimental therapies targeting neuroaxonal ionic imbalances and energy metabolism in part show promising results. A better understanding of the molecular mechanisms underlying chronic progression will substantially aid the development of new treatment strategies.