Total Brain Sodium on MRI Linked to More Severe MS

Total sodium concentration in the brain, measured by sodium magnetic resonance imaging (MRI), is linked to disability and a progressive course in multiple sclerosis (MS), according to findings of a cross-sectional study reported in the July issue of Brain (Paling et al., 2013). Changes in sodium concentration within and outside of nerve cells may reflect neurophysiological changes in MS.

“Neuroaxonal loss is a major substrate of irreversible disability in [MS], however, its cause is not understood,” wrote David Paling, MB ChB, of the NMR Research Unit, Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, University College London Institute of Neurology and colleagues. “In [MS] 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 [MRI] … could investigate this neuroaxonal dysfunction and loss in vivo.”

Participants were 27 healthy controls, 27 patients with relapsing-remitting MS (RRMS), 23 with secondary progressive MS (SPMS), and 20 with primary progressive MS (PPMS). In SPMS, disability gradually accumulates independent of relapses, and in PPMS, disability gradually accumulates from disease onset. During remissions, patients with RRMS have fewer or no symptoms.

Compared with controls, all MS subgroups had significantly higher cortical sodium concentrations, and patients with primary and secondary progressive MS had higher sodium concentrations in deep gray matter and in normal-appearing white matter. Compared with patients with RRMS, those with SPMS had significantly higher sodium concentrations in cortical gray matter, in normal-appearing white matter, and in deep gray matter.

Sodium concentrations were significantly higher in brain areas affected by MS lesions seen on MRI than in apparently normal brain tissue. Specifically, they were higher in T1 isointense (44.6 + 7.2 mM) and T1 hypointense lesions (46.8 + 8.3 mM) than in normal-appearing white matter (34.9 + 3.3 mM). In T1 hypointense lesions, sodium concentration was significantly higher in secondary progressive (49.0 + 7.0 mM) and primary progressive (49.3 + 8.0 mM) than in RRMS (43.0 + 8.5 mM).

Furthermore, sodium concentration in the deep gray matter was significantly and independently associated with functional ability measured by the Expanded Disability Status Score (coefficient 0.24) and timed 25-foot walking speed (coefficient -0.24). Similarly, sodium concentration in T1 lesions was significantly linked to neuropsychological function (z-scores of the nine hole peg test [coefficient -0.12] and paced auditory serial addition test [coefficient = -0.081]).

“Sodium concentration is increased within lesions, normal appearing white matter and cortical and deep grey matter in [MS], with higher concentrations seen in secondary-progressive MS and in patients with greater disability,” the study authors wrote. “Increased total sodium concentration is likely to reflect neuroaxonal pathophysiology leading to clinical progression and increased disability.”

Study limitations include cross-sectional design and older age in patients with primary and secondary progressive MS than in the other groups. However, controlling for age did not affect the findings. A technical limitation of sodium MRI is that inherently low signal potentially induces partial volume effects, particularly when including voxels that partially contain cerebrospinal fluid, which has a much higher sodium concentration than brain tissue.

“Further longitudinal studies are needed to elucidate the evolution of sodium accumulation at different stages of the disease,” the study authors concluded. “[Such studies] could clarify whether tissue sodium concentrations help predict the future clinical course of [MS] and potentially identify patients most likely to benefit from therapeutic neuroprotective interventions before the onset of irreversible tissue damage.”

Key open questions

• What changes in sodium accumulation occur at different stages of MS?
• Could brain sodium concentrations be of diagnostic and prognostic value?
• What sodium MRI techniques would be most useful to enhance the diagnostic and prognostic value of this test in MS, and to directly distinguish between intracellular sodium accumulation and increase in extracellular volume?

Disclosures

The National Institute for Health Research University College London Hospitals Biomedical Research Centre funded this study. The Multiple Sclerosis Society of Great Britain and Northern Ireland, Philips Healthcare, and the National Institute for Health Research University College London Hospitals Biomedical Research Centre supported the NMR unit where this study was performed.