An Observation of Interest Relative to the Practice of Spectroscopic Measurements in Multiple Sclerosis

In recent years, new advanced MR techniques, such as magnetization transfer imaging, diffusion tensor imaging, and functional and spectroscopic images (MR spectroscopy), have provided us with the possibility of detecting and quantifying neural damage related to multiple sclerosis (MS), monitoring the disease progression over time, and assessing the effects of therapeutic intervention. MR spectroscopy has been especially relevant in the investigation of the pathologic changes in early forms of the disease, when immunomodulators and neuroprotective agents might be more effective. In MS lesions, axonal function and neural viability seem to be compromised by inflammatory substances that activate immune and glial cells, whereas in normal-appearing white matter (NAWM), wallerian degeneration of the transected axons within distant MS lesions has been proposed as the mechanism of axonal dysfunction

A meta-analysis was recently performed on the results of 75 comparisons from 30 peer-reviewed publications that reported on the use of MR spectroscopy to quantify metabolic changes in the brain tissues of patients with MS. N-acetylaspartate (NAA), which has a role in neural viability, is mainly found in neurons and axons of the mature brain. This meta-analysis verifies that metabolic changes occur in lesional tissue and NAWM of MS and concludes that though the level of NAA can be statistically equivalent, it is usually decreased in MS brain tissue relative to non-MS tissue.¹ The concentration of creatine (Cr) is significantly increased in lesional white matter (WM) of patients with MS but has been detected at increased, unchanged, or, in some cases, decreased levels in nonlesional WM.¹ This variability in the Cr value seems to be the result of various amounts of reactive gliosis, astrocytic proliferation, and oligodendroglial loss and is in good correlation with histopathologic findings; however, the NAA/Cr ratio has been universally accepted as a valid measure of neuroaxonal damage. A change in the NAA and the NAA/Cr ratio was concordant in 84% of reported measurements; therefore, it is also possible that the NAA/Cr ratio could remain unchanged if the NAA and Cr simultaneously decrease at similar levels and that the brain NAA/Cr ratio could decrease when NAA remains constant if Cr increases. Reduced Cr values in NAWM have been reported previously^2,3 and no change in the NAA/Cr ratio, together with a significant decrease in the NAA/ choline (Cho) ratio, has also been reported in a group of patients with a clinically isolated syndrome suggestive of MS.⁴ Some authors have already suggested that NAA quantification, as determined by evaluating the NAA/Cr and assuming that Cr is constant, can introduce more variability than it prevents in most cases. Meanwhile, Cho is a useful metabolite that has a role in the metabolism of phospholipids, indicative of a rise in membrane turnover upon increased Cho expression. Its expression level is usually increased in subacute and acute MS lesions.⁵ An increase in the amount of Cho-containing compounds has been detected in prelesional NAWM, at least 12 months before lesions became visible by conventional MR imaging as a result of early myelin membrane pathology.⁶ It is noteworthy that Cho seems to be relatively stable outside of MS lesions. We think that this metabolite should be considered a reference for evaluating NAA values, possibly in combination with Cr determination, and that Cho could become a useful alternative biomarker to Cr in nonlesional WM. In a previous report, our group also found a significant decrease in NAA in NAWM without a concomitant decrease of the NAA/Cr ratio.³ Conflicting results have been published regarding the Cr concentration in MS lesions.

In our opinion, the determination of more than one ratio by spectroscopy, including NAA/Cr and NAA/Cho, could be more beneficial than evaluating a single ratio, would allow for a better understanding of the pathophysiologic mechanisms of MS, and, if there is agreement between the results, would lend consistency to the spectroscopic data.

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