Relationship between sodium and diffusion MRI metrics in multiple sclerosis

Sodium MRI can measure in vivo sodium concentrations in people with multiple sclerosis, but the extent to which these alterations reflect metabolic dysfunction in the absence of tissue damage or neuroaxonal loss remains uncertain. Increases in total sodium concentration and extracellular sodium concentration are believed to be indicative of tissue disruption and extracellular space expansion. Conversely, increase in intracellular sodium concentration may represent early and transient responses to neuronal insult, preceding overt tissue damage. Here, we explored the relationship between total sodium concentration, intracellular sodium concentration and intracellular sodium volume fraction, which reflects extracellular sodium concentration, against histology-validated microstructural metrics obtained using diffusion MRI. Fifty-two individuals with multiple sclerosis and 26 healthy controls underwent ¹H/²³Na MRI. Microstructural parameters were derived using Diffusion Basis Spectrum Imaging and Neurite Orientation Dispersion and Density-Imaging models. A progressive worsening in total sodium concentration and intracellular sodium volume fraction was observed from HCs white matter to normal-appearing white matter and further into T2-hyperintense and T1-hypointense lesions. Both total sodium concentration and intracellular sodium volume fraction, but not intracellular sodium concentration, correlated with Neurite Orientation Dispersion and Density Imaging and Diffusion Basis Spectrum Imaging metrics within multiple sclerosis lesions. Our findings confirm the utility of total sodium concentration and extracellular sodium concentration as indicators of extracellular expansion and axonal loss and underscore intracellular sodium concentration as a valuable biomarker for metabolic dysfunction in multiple sclerosis.