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

¹Centre de Résonance Magnétique Biologique et Médicale, Unité Mixte de Recherche 7339, Aix-Marseille Université, Centre National de Recherche Scientifique, 13005, Marseille, France

²Centre de Résonance Magnétique Biologique et Médicale, Unité Mixte de Recherche 7339, Aix-Marseille Université, Centre National de Recherche Scientifique, 13005, Marseille, France

³Centre de Résonance Magnétique Biologique et Médicale, Unité Mixte de Recherche 7339, Aix-Marseille Université, Centre National de Recherche Scientifique, 13005, Marseille, France

Corresponding Author:

Wafaa Zaaraoui
Centre de Résonance Magnétique Biologique et Médicale
Unité Mixte de Recherche 7339
Aix-Marseille Université
Centre National de Recherche Scientifique
13005, Marseille, France
Tel: +33 4 91 38 84 66
Fax: +33 4 91 38 84 61
E-mail: wafaa.zaaraoui@univ-amu.fr

Abstract

Keywords

brain ▪ disability ▪ multiple sclerosis ▪ neuronal injury ▪ sodium MRI

Multiple sclerosis: needs for biomarkers of neuronal injury

Multiple sclerosis (MS) is a chronic disease of the CNS, representing the leading cause of neurological disability in young adults. Focal inflammatory 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⁺/Ca²⁺ exchanger and axonal calcium import. This calcium overload stimulates a variety of toxic calcium-dependent enzymes, causing structural and functional axonal injury [6,10].

Brain sodium MRI: a unique noninvasive tool to depict accumulation of sodium in MS

Sodium (²³Na) 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 23Na 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 (T2) of 23Na (<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, 20,000-times lower, compared with proton and leading to poor signal-to-noise ratio [15].

To date, only two studies have been performed 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 regions, including the brainstem, cerebellum and temporal pole. In the advanced-stage relapsing–remitting MS patients, abnormally high sodium accumulation was widespread throughout the whole brain, including in normal-appearing brain tissue. Another striking point of this study was that the amount of sodium accumulation in gray matter associated with the motor system was directly correlated with the degree of patient disability [17].

The abnormal sodium accumulation in macroscopic white matter lesions may be related to increases in sodium concentration inside the extracellular and/or intracellular compartments. The increase of sodium concentration in the extracellular compartment, if present, would probably be related to edema as encountered in acute lesions or loss of tissues in chronic lesions. On the other hand, the increase in sodium concentration in the intracellular compartment may be explained by demyelination or gliosis processes. In the normal-appearing brain tissues, the diffuse sodium accumulation may reflect the progressive axonal injury present outside macroscopic lesions in patients with longer disease duration. The progressive axonal injury may also result from macroscopic white matter lesions that induce distant brain injury secondary to Wallerian degeneration [17].

“...a combination of proton and sodium MRI techniques in parallel with the assessment of clinical disability would allow the better depiction of the occurrence and degree of axonal injury.”

Zaaraoui et al. hypothesized that sodium accumulation in the brain detected by sodium MRI may be a biomarker for the degeneration of nerve cells that occurs in patients with MS. Therefore, sodium MRI may help to monitor the occurrence of tissue injury and disability. To reach this goal, further studies need to be performed on larger groups of patients and during longitudinal follow-up to better depict and understand the patterns of brain sodium accumulation and their clinical impact during the course of MS [17].

The view of physicians & the future of sodium MRI in MS

Conventional and advanced proton MRI techniques are powerful tools used daily by physicians in the diagnosis and monitoring of the evolution of MS. However, these MR techniques suffer from a lack of specificity in identifying and quantifying neuronal injury in vivo, especially in the early stages of the disease. In the near future, proton MRI techniques will probably be combined with sodium MRI, which is more prone to detect the occurrence and to monitor the evolution of neuronal injury. On an individual level, longitudinal studies involving a combination of proton and sodium MRI techniques in parallel with the assessment of clinical disability would allow the better depiction of the occurrence and degree of axonal injury. Furthermore, these combined tools would allow the assesment of new drugs for neuroprotection such as sodium-channel blockers to prevent or repair accumulation of disability. Recently, a Phase 2 trial study was performed in patients with secondary progressive MS to assess whether the sodium-channel blocker lamotrigine is neuroprotective, as found in experimental models of MS [18]. The study failed to demonstrate an effect of neuroprotection. It can be assumed that the use of sodium MRI in the upcoming studies may be of paramount interest to depict and quantify the degree of neuroprotection of these drugs more accurately.

While the feasibility of using sodium MRI to examine the human brain was first demonstrated in 1985 [12], its application in clinical research has been limited for two decades due to methodological drawbacks. Nowadays, the increasing availability of high-field (≥3 Tesla) and ultra-high-field MR scanners (≥7 Tesla) contribute to improving the sensitivity of sodium MRI by offering better signal-to-noise ratio, higher spatial resolution and shorter acquisition time. Moreover, the emergence of promising techniques, such as inversion recovery and triple quantum-filtered sodium imaging [19], enable the selective measurement of different sodium compartments. Several progresses are still required. For example, the assessment of the in vivo longitudinal and transverse sodium relaxation times and the assessment of the nonuniform B1 magnetic fields have to be taken into account to improve the sodium absolute quantification.

Conclusion

In conclusion, brain sodium MRI is an emerging tool that enables depiction of cerebral sodium accumulation related to neuronal injury as evidenced in MS [16,17] and also in brain tumors, stroke [14] and Huntington’s disease [20]. Sodium MRI may be useful when applied to other neurological diseases, such as epilepsy, or channelopathies to monitor the occurrence of tissue injury and disability.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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