PROJECT SUMMARY Multiple sclerosis (MS) is a chronic inflammatory-demyelinating and neurodegenerative disease of the central nervous system that affects 400.000 people in US. While it only slightly shortens life expectancy, MS is the leading cause of non-traumatic neurological disability in young adults. There is ever-growing evidence that neuro-axonal degeneration is the main pathological correlate of clinical disability. Despite its clinical relevance little is known about the mechanisms leading to axonal degeneration due to the lack of methods for exact identification and quantification of neurodegeneration in vivo and due to the paucity of neuropathological data. It has been suggested that the accumulation of intra-axonal sodium ions represents a key factor in the degenerative process and that partial blockade of sodium channels protects axons from degeneration in experimental models of MS. Changes in the intracellular sodium content (ISC) lead to changes in the total tissue sodium concentration (TSC) that can be measured in vivo by single quantum Sodium MR Imaging (23Na MRI). The application of triple quantum sodium filtration, allows an improvement in the specificity of TSC by measuring ISC and neglecting most of the signal contributions from the extra-cellular sodium content. Therefore, we propose that (a) excess brain sodium accumulation plays an important role in neuro-axonal injury in MS contributing to brain damage and accumulation of clinical disability; (b) changes in brain total sodium concentration (TSC) as well as in ISC can be measured in vivo with single and triple quantum 23Na MRI; (c) combined use of sodium and diffusion basis spectrum imaging (DBSI) can help better characterize the changes in TSC in lesions and normal-appearing white matter. Initially, we will measure and compare brain TSC and ISC values in MS patients with relapsing-remitting MS and healthy controls at baseline and at short- and long-term follow-up. Then, we will correlate 23Na MRI metrics with DBSI metrics of tissue damage, neurological and cognitive impairment at baseline and follow-up. This research is innovative because it uses a newly developed cutting-edge technology to discover the mechanisms that bridge the gap from inflammation to irreversible disability in MS. The proposed research is significant because it will advance our understanding of the pathophysiology of neurodegeneration in MS, and will help identify potential novel outcome measures of disease progression, thus improving the clinical management of patients with MS.