Sodium accumulation is associated with disability and a progressive course in multiple sclerosis

Abstract

Neuroaxonal loss is a major substrate of irreversible disability in multiple sclerosis, however, its cause is not understood. In multiple sclerosis there may be intracellular sodium accumulation due to neuroaxonal metabolic dysfunction, and increased extracellular sodium due to expansion of the extracellular space secondary to neuroaxonal loss. Sodium magnetic resonance imaging measures total sodium concentration in the brain, and could investigate this neuroaxonal dysfunction and loss in vivo. Sodium magnetic resonance imaging has been examined in small cohorts with relapsing-remitting multiple sclerosis, but has not been investigated in patients with a progressive course and high levels of disability. We performed sodium magnetic resonance imaging in 27 healthy control subjects, 27 patients with relapsing-remitting, 23 with secondary-progressive and 20 with primary-progressive multiple sclerosis. Cortical sodium concentrations were significantly higher in all subgroups of multiple sclerosis compared with controls, and deep grey and normal appearing white matter sodium concentrations were higher in primary and secondary-progressive multiple sclerosis. Sodium concentrations were higher in secondary-progressive compared with relapsing-remitting multiple sclerosis in cortical grey matter (41.3 ± 4.2 mM versus 38.5 ± 2.8 mM, P = 0.008), normal appearing white matter (36.1 ± 3.5 mM versus 33.6 ± 2.5 mM, P = 0.018) and deep grey matter (38.1 ± 3.1 mM versus 35.7 ± 2.4 mM, P = 0.02). Higher sodium concentrations were seen in T₁ isointense (44.6 ± 7.2 mM) and T1 hypointense lesions (46.8 ± 8.3 mM) compared with normal appearing white matter (34.9 ± 3.3 mM, P < 0.001 for both comparisons). Higher sodium concentration was observed in T₁ hypointense lesions in secondary-progressive (49.0 ± 7.0 mM) and primary-progressive (49.3 ± 8.0 mM) compared with relapsing-remitting multiple sclerosis (43.0 ± 8.5 mM, P = 0.029 for both comparisons). Independent association was seen of deep grey matter sodium concentration with expanded disability status score (coefficient = 0.24, P = 0.003) and timed 25 ft walk speed (coefficient = -0.24, P = 0.01), and of T1 lesion sodium concentration with the z-scores of the nine hole peg test (coefficient = -0.12, P < 0.001) and paced auditory serial addition test (coefficient = -0.081, P < 0.001). Sodium concentration is increased within lesions, normal appearing white matter and cortical and deep grey matter in multiple sclerosis, with higher concentrations seen in secondary-progressive multiple sclerosis and in patients with greater disability. Increased total sodium concentration is likely to reflect neuroaxonal pathophysiology leading to clinical progression and increased disability.

Cortical grey matter sodium accumulation is associated with disability and secondary progressive disease course in relapse-onset multiple sclerosis

“…Tissue mask were resampled using a point-spread-function scaling factor into sodium space to calculate the TSC (in mM) for each tissue 25. Using the probabilistic masks partial volume correction was performed for each voxel 8. Finally, using a voxel-wise partition-based correction method, we removed CSF contamination 8…”

“…Previous 23 Na-MRI studies have found evidence of increased TSC in white matter (WM) lesions and normal-appearing tissues in MS,6–10 reflecting either increased intracellular sodium, expansion of the extracellular space (due to neuroaxonal loss) or both. In cross-sectional studies, increases in TSC are most marked in progressive MS8 and in patients with greater physical disability7 8 and cognitive impairment 10…”

Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis

“…In line with this proposed mechanism, sodium imaging of multiple sclerosis patients' brains by 7 Tesla magnetic resonance imaging revealed that the intracellular sodium concentration within gray and white matter was increased compared with healthy controls and that increased intracellular sodium concentrations correlated with disease duration and degree of clinical disability (10,11). Moreover, the relevance of neuroaxonal sodium homeostasis in inflammatory neurodegeneration is supported by circumstantial evidence in EAE studies indicating that treatment with nonselective VGSC blockers can improve the clinical course (12)(13)(14).…”

Secondary Progressive Multiple Sclerosis: Definition and Measurement

“…These processes induce a modification of sodium content in the CNS that can be studied with a relatively recent MRI technique called sodium (23Na) MRI [133]. Demyelinating lesions, normal-appearing white matter and grey matter in MS all have higher concentrations of sodium and there is correlation with clinical disability, supporting its application as a future possible outcome measure in SPMS trials [134][135][136].…”

“…It can measure the thickness of the retinal nerve fibre layer and the ganglion cell layer. Retinal axonal loss, regardless of clinical history of optic neuritis, may be a good marker of clinical disability in MS [135][136][137][138][139] and correlates with brain atrophy [140,141].…”