Measuring Regional Brain Tissue Sodium Concentrations in MS

Abstract & Commentary

By Susan Gauthier, DO, MS, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Gauthier reports no financial relationships relevant to this field of study.

Synopsis: Higher tissue sodium concentrations were present in multiple sclerosis patients as compared to healthy controls. In patients, sodium levels within lesions corresponded to lesion volumes and grey matter sodium levels were negatively associated with grey matter volume.

Source: Inglese M, et al. Brain tissue sodium concentration in multiple sclerosis: A sodium imaging study at 3 telsa. Brain 2010:133; 847-857.

Changes in axonal membrane architecture have been found to occur in multiple sclerosis (MS) and may be a significant factor leading to a loss of axonal integrity. Redistribution of sodium channels occurs in demyelinated regions of the axons as part of a compensatory change to maintain proper impulse conduction.1 This process results in an increase in influx of Na+, which leads to an increase in ATP consumption. The energy depletion impairs the function of Na+/K+ ATPase causing an accumulation of axoplasmic Na+; this in turn is thought to promote the reversal of the Na+ /Ca2+ exchanger. The ultimate consequence of this process is the activation of Ca2+ dependent mechanisms that damage the axon. In this recent report by Inglese et al., a novel imaging approach has been proposed to measure regional differences in brain tissue Na+ in MS patients.

This was a pilot study of 17 relapsing-remitting (RR) MS patients and 13 age/gender matched healthy controls (HC) utilizing ultra-short TE sequences on a 3T Siemens MRI platform. In HC, the tissue sodium concentration (TSC) of grey matter was higher than that of white matter without age or gender differences; a pattern that was reproduced in RRMS patients. TSC of normal appearing white matter (NAWM) was significantly higher in RRMS patients as compared to the white matter of HC; TSC of normal appearing grey matter (NAGM) was similarly higher in patients, although the difference was less remarkable. TSC of lesions hypointense on T1-weighted images and those that enhance with gadolinium were similar, however only the TSC of hypointense lesions was higher than that of T1-isointense lesions. TSC of T1-hypointense lesions were higher than NAWM but similar to NAGM. The TSC of T1-isointense lesions and NAWM were similar, although the TSC of T1-isointense lesions was lower than that of NAGM. The average lesion TSC correlated with both T2 and T1-hypointense lesion volumes; the strongest association was between T1-hypointense lesion TSC and its corresponding lesion volume (r = 0.47, p=0.0003). Regarding a relationship with brain volume in RRMS patients, the TSC of NAGM had a negative correlation with grey matter volume (r = -0.23, p=0.0009) but this relationship was not reproduced with NAWM TSC and white matter volume. There was a positive correlation with EDSS and TSC of T1-hypointense lesions (r = 0.22, p=0.002) and TSC of NAGM (r = 0.20, p=0.002).

Commentary

The poor pathological specificity of T2-hyperintense lesions in MS has limited the acceptance of MRI as a biomarker for the disease. However, with higher resolution scanning and sequence development, the pathological specificity of MRI has the potential to significantly improve and sodium imaging represents one of many new MRI techniques under development. There were clear limitations to this study that were fully acknowledged by the authors, the most important of which was the inability to distinguish between intra and extracellular sodium. In addition, given the cross-sectional design of the study, the authors were not able to determine if T1-hypointense lesions were permanent black holes. Permanent T1-hypointense lesions are associated with more axonal loss; however if hypointense lesions are acute or subacute, the pathological specificity is less clear. This is of particular importance given that the majority of the lesions in the study were considered hypointense. There was an interesting association with grey matter TSC and volume; this corresponds well with recent work suggesting grey matter atrophy may be more prominent than white matter atrophy in MS. The modest correlation with disability underscores the complexity of the disease, but this may potentially improve with a larger sample size. Not withstanding these issues, sodium MRI has the potential to be a valuable outcome measure to test novel therapeutics targets in MS, especially for those agents that target the axon membrane architecture.

Reference

1. Dutta R, et al. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 2007;68 (Suppl 3): S22-S31.