Relationship between sodium and diffusion MRI metrics in multiple sclerosis

Abstract

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.

Keywords: diffusion MRI; intra-cellular and extra-cellular sodium concentration; multiple sclerosis; sodium MRI.

Graphical Abstract

Figure 1

Examples of the MRI sequences and metrics analysed in this study. (A) Shows the T1-weighted and FLAIR images used to identify MS lesion. (B) The ²³Na extracted maps are represented, including TSC, ISC and ISVF. (C and D) Show the DBSI maps (fibre fraction, hindered fraction and restricted fraction) and NODDI maps (OD, ISOVF and ICVF), respectively. In the selected images, 2 examples of MS lesions ≥0.41 cm³ are shown. FLAIR = fluid attenuated inversion recovery; TSC = total sodium concentration; ISC = intracellular sodium concentration; ISVF = intracellular sodium volume fraction; OD = orientation dispersion; ISOVF = isotropic volume fraction; ICVF = intracellular volume fraction.

Figure 2

Sodium concentration values for HCs and PwMS. The violin plot combines the summary statistics of a box plot with the density estimation of the data distribution. The black box represents the interquartile range (25%–75% of the values), while the white points indicate the median of mean TSC (A), ISC (B) and ISVF (C). The width of the violin shows the kernel density estimation of the data. The asterisks indicate the significant differences obtained by the ANCOVA analysis (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001). The figure legend reports the sample size for each statistical test. HCs = healthy control subjects; PwMS = patients with multiple sclerosis; TSC = total sodium concentration; ISC = intracellular sodium concentration; ISVF = intracellular sodium volume fraction.

Figure 3

Correlation matrix between sodium and dMRI metrics within T2-hyperintense MS lesions. Spearman correlation coefficients were computed for sodium and dMRI metrics. The colour map represents the correlation coefficient, with the numerical value within each coloured box indicating the corresponding P-value. MS = multiple sclerosis, TSC = total sodium concentration; ISC = intracellular sodium concentration; ISVF = intracellular sodium volume fraction; OD = orientation dispersion; ISOVF = isotropic volume fraction; ICVF = intracellular volume fraction.

Figure 4

Example of voxel-wise analysis of the sodium (yellow bar) and dMRI metrics (red bar). (A) The decrease in ISVF and the increase in ISOVF in the PwMS compared to HCs; (B) The increase in TSC and hindered fraction in the PwMS compared to HCs. The alteration maps are overlaid on a T1-weighted MNI template. The colour bar indicates the P-values (TFCE, P < 0.05 corrected for family-wise error). PwMS = patients with multiple sclerosis; TFCE = threshold-free cluster enhancement.