Brain tissue sodium concentration in multiple sclerosis: a sodium imaging study at 3 tesla

Abstract

Neuro-axonal degeneration occurs progressively from the onset of multiple sclerosis and is thought to be a significant cause of increasing clinical disability. Several histopathological studies of multiple sclerosis and experimental autoimmune encephalomyelitis have shown that the accumulation of sodium in axons can promote reverse action of the sodium/calcium exchanger that, in turn, leads to a lethal overload in intra-axonal calcium. We hypothesized that sodium magnetic resonance imaging would provide an indicator of cellular and metabolic integrity and ion homeostasis in patients with multiple sclerosis. Using a three-dimensional radial gradient-echo sequence with short echo time, we performed sodium magnetic resonance imaging at 3 T in 17 patients with relapsing-remitting multiple sclerosis and in 13 normal subjects. The absolute total tissue sodium concentration was measured in lesions and in several areas of normal-appearing white and grey matter in patients, and corresponding areas of white and grey matter in controls. A mixed model analysis of covariance was performed to compare regional tissue sodium concentration levels in patients and controls. Spearman correlations were used to determine the association of regional tissue sodium concentration levels in T(2)- and T(1)-weighted lesions with measures of normalized whole brain and grey and white matter volumes, and with expanded disability status scale scores. In patients, tissue sodium concentration levels were found to be elevated in acute and chronic lesions compared to areas of normal-appearing white matter (P < 0.0001). The tissue sodium concentration levels in areas of normal-appearing white matter were significantly higher than those in corresponding white matter regions in healthy controls (P < 0.0001). The tissue sodium concentration value averaged over lesions and over regions of normal-appearing white and grey matter was positively associated with T(2)-weighted (P < or = 0.001 for all) and T(1)-weighted (P < or = 0.006 for all) lesion volumes. In patients, only the tissue sodium concentration value averaged over regions of normal-appearing grey matter was negatively associated with the normalized grey matter volume (P = 0.0009). Finally, the expanded disability status scale score showed a mild, positive association with the mean tissue sodium concentration value in chronic lesions (P = 0.002), in regions of normal-appearing white matter (P = 0.004) and normal-appearing grey matter (P = 0.002). This study shows the feasibility of using in vivo sodium magnetic resonance imaging at 3 T in patients with multiple sclerosis. Our findings suggest that the abnormal values of the tissue sodium concentration in patients with relapsing-remitting multiple sclerosis might reflect changes in cellular composition of the lesions and/or changes in cellular and metabolic integrity. Sodium magnetic resonance imaging has the potential to provide insight into the pathophysiological mechanisms of tissue injury when correlation with histopathology becomes available.

Figures

Figure 1

Location of the white matter and grey matter regions of interest on selected TSC maps in a healthy volunteer. (A) White matter of cerebellar lobes. (B) Grey matter of frontal, parietal and occipital lobes. (C) Periventricular white matter, splenium of the corpus callosum, white matter of the frontal and occipital lobes. (D) Grey matter of parietal lobes. See the text for further details.

Figure 2

Box plots displaying the 25–75% values (boxes) ± 95% values (whiskers), median values (horizontal lines within boxes) and outliers (asterisk) of the mean TSC value distribution in regions of white matter and grey matter among healthy controls (A, empty box) and in corresponding normal-appearing white matter (NAWM) and normal-appearing grey matter (NAGM) regions among patients with relapsing–remitting multiple sclerosis (B, hatched box). cc = corpus callosum.

Figure 3

Selected brain axial proton density (A), T1-weighted (B), 23Na images (C) and corresponding TSC map (D) from a 29-year-old patient with multiple sclerosis. The colour bar indicates the TSC values (mM). Note the higher TSC value in the periventricular lesion that appears hypointense (arrow) on the T1-weighted image (B).

Figure 4

Box plots displaying the 25–75% values (boxes) ± 95% values (whiskers), median values (horizontal lines within boxes) and outliers (asterisk) of the mean TSC value distribution in Gd-enhancing (Gd 1; 4), hypointense (Hypo 1; 67), isointense (Iso 1; 25) lesions and in normal-appearing white matter (NAWM) and normal-appearing grey matter (NAGM) regions among patients with multiple sclerosis (hatched box) and in the corresponding white matter (WM) and grey matter (GM) regions among healthy controls (empty box). Note that the TSC level of Gd-enhancing and hypointense lesions was statistically indistinguishable. The TSC level in hypointense lesions was significantly higher than that in isointense lesions (P < 0.0001) and that in regions of normal-appearing white matter (P < 0.0001) but not different from that of normal-appearing grey matter regions (P = 0.1). In contrast, the TSC level of isointense lesions was significantly lower than that of normal-appearing grey matter regions (P < 0.0001) but not statistically distinguishable from that of TSC averaged over normal-appearing white matter regions after Tukey’s adjustment for multiple comparisons (P = 0.1).