What can sodium MRI reveal about sodium accumulation in the brain: implications for multiple sclerosis

Multiple sclerosis: needs for biomarkers of neuronal injury Multiple sclerosis (MS) is a chronic disease of the CNS, representing the leading cause of neuro­ logical disability in young adults. Focal inflam­ matory and demyelinating lesions disseminated in the cerebral white matter have been considered for several decades to be the main feature of MS. However, recent histological studies have also demonstrated the presence of diffuse and progressive damage in cerebral white and gray matter, leading to neuronal injury [1–3]. While neuronal injury is known to occur progressively from the onset of MS and is thought to be a significant cause of increasing clinical disability, the mechanisms underlying neuronal injury are still poorly understood. Furthermore, the conventional MRI metrics lack the specificity required to depict this pathological process, so noninvasive and in vivo biomarkers of neuronal injury are needed. Recently, several experimental studies have highlighted the potential key role of sodium accumulation leading to the pathogenesis of neuronal injury [4–7]. It appears that occurrence of demyelination is followed by upregulation and redistribution of sodium channels along the entire demyelinated axolemna [4,8,9]. The increased number of sodium channels enhances the amount of energy required from the Na/K ATPase. Concomitantly, soluble mediators of inflammation disturb the functional integrity of mitochondria, resulting in decreased ATP production [5,10]. All of these mechanisms driven by mitochondrial energy failure result in axonal sodium accumulation, which leads to reversed activity of the Na/Ca exchanger and axonal calcium import. This calcium overload stimulates a variety of toxic calcium­dependent enzymes, causing structural and functional axonal injury [6,10]. Brain sodium MrI: a unique noninvasive tool to depict accumulation of sodium in Ms Sodium (Na) MRI appears to be the unique noninvasive way to detect and quantify in vivo the sodium concentration in the brain based on the magnetic properties of the Na nucleus [11–13]. In the human brain, sodium is distributed in two compartments; the intracellular and the extracellular compartments. The concentration gradient between the two compartments is kept constant through the effect of the sodium–potassium pump. The total sodium concentration measured by sodium MRI is the average sodium concentration between the two compartments. Sodium MRI is a promising diagnostic tool since pathological processes can alter this ion gradient. This technique has already been used to investigate strokes and brain tumors [14]. However, sodium MRI remains a challenging technique due to several limitations. A major problem of sodium MRI is related to the very short transverse relaxation time (T 2 ) of Na (<2 ms) that requires the use of imaging sequences with very short echo times (<200 μs), generally not provided by the manufacturers to detect the MR signal. The second major limitation of sodium MRI is related to its very low in vivo sensitivity, 20,000­times lower, compared with proton and leading to poor signal­to­noise ratio [15]. To date, only two studies have been per­ formed in MS that examine the total sodium concentration accumulation in lesions and normal appearing brain tissue [16,17]. Both studies demonstrated significant accumulation of total sodium concentration inside white matter lesions, normal appearing white matter and gray matter compartments. In patients with early stage relapsing–remitting MS, Zaaraoui et al. found that sodium MRI revealed abnormally high concentrations of sodium in specific brain