Given the great therapeutic need, why are Phase II trials of neuroprotective agents in MS, especially in progressive MS, not proceeding? A major reason is the lack of validated biomarkers for neurodegeneration. Such biomarkers would avoid the need to test candidates in large Phase III trials first up, by allowing the design of efficient Phase II trial programs. In due course, this would then lead to judicious agent selection for Phase III trials focusing on clinical endpoints, replicating the well-established paradigm for RRMS trials. In this issue, we wish to focus on two approaches to this problem, which are rapidly gaining momentum in the eye and in the blood.

The last decade has witnessed a great expansion in our knowledge of MS neuropathology, suggesting several pathogenetic mechanisms in progressive MS that may represent therapeutic targets. Firstly, slowly progressive neurodegeneration has been highlighted as key feature in progressive MS. Secondly, increasing evidence points to the innate immune system, as effectors of ongoing neurodegeneration, particularly in nonlesional white matter.

The eye. The retina is the only place of the body, where nerves can be seen in vivo. The invention of in vivo assessment and quantification of the retinal nerve fibre layer (RNFL) has stimulated research on this biomarker as a surrogate for neurodegeneration in MS. Studies have correlated RNFL thickness with clinical disability and MRI evidence of optic nerve and brain atrophy.

The blood. Serum biomarkers of neurodegeneration allow for quantification of minute amounts of CNS proteins released during structural disintegration of the neuroaxonal, potentially preceding the development of atrophy in the eye and in the brain.

The main focus of this issue will be on new and exciting translational studies linking structure and function, the two-key components of neurodegeneration in MS. We invite both reviews and original articles on:

• Rating scales for visual function and cognitive processing in MS and NMO
• Studies on structural and functional plasticity of the visual system in MS and NMO
• MRI and other imaging studies of neurodegeneration in the retina, visual pathways, and visual cortex
• Electrophysiological studies of the visual system assessing axonal degeneration
• OCT and other retinal imaging technologies relevant for understanding neurodegeneration
• Biomarkers of neurodegeneration in blood and cerebrospinal fluid (CSF)
• Evaluation of axonal degeneration biomarkers for use in Phase II clinical trials

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