Quantifying the Metabolic Signature of Multiple Sclerosis by in vivo Proton Magnetic Resonance Spectroscopy: Current Challenges and Future Outlook in the Translation From Proton Signal to Diagnostic Biomarker

Abstract

Proton magnetic resonance spectroscopy (1H-MRS) offers a growing variety of methods for querying potential diagnostic biomarkers of multiple sclerosis in living central nervous system tissue. For the past three decades, 1H-MRS has enabled the acquisition of a rich dataset suggestive of numerous metabolic alterations in lesions, normal-appearing white matter, gray matter, and spinal cord of individuals with multiple sclerosis, but this body of information is not free of seeming internal contradiction. The use of 1H-MRS signals as diagnostic biomarkers depends on reproducible and generalizable sensitivity and specificity to disease state that can be confounded by a multitude of influences, including experiment group classification and demographics; acquisition sequence; spectral quality and quantifiability; the contribution of macromolecules and lipids to the spectroscopic baseline; spectral quantification pipeline; voxel tissue and lesion composition; T1 and T2 relaxation; B1 field characteristics; and other features of study design, spectral acquisition and processing, and metabolite quantification about which the experimenter may possess imperfect or incomplete information. The direct comparison of 1H-MRS data from individuals with and without multiple sclerosis poses a special challenge in this regard, as several lines of evidence suggest that experimental cohorts may differ significantly in some of these parameters. We review the existing findings of in vivo 1H-MRS on central nervous system metabolic abnormalities in multiple sclerosis and its subtypes within the context of study design, spectral acquisition and processing, and metabolite quantification and offer an outlook on technical considerations, including the growing use of machine learning, by future investigations into diagnostic biomarkers of multiple sclerosis measurable by 1H-MRS.

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

“…In general, approximately 25 additional compounds can be assessed throughout the brain: aspartate, glutathione, taurine, ethanolamine, histidine, glycogen, lactate (detectable only during pathological increment), or mobile lipids (i.e., triacylglycerol and cholesterol esters accumulated in lipid droplets) [ 26 , 37 , 38 , 39 , 40 ]. These are difficult to detect routinely; furthermore, only rarely are they suggestive of MS manifestations [ 3 , 41 ].…”

“…The integral of tCr is widely used to evaluate relative metabolites ratios [ 37 , 41 ]; nevertheless, inconsistencies in the reported increased, decreased, and absent tCr alternations in the lesions and NAWM of MS patients are apparent [ 25 , 51 ]. Therefore, one technique increasingly being used for absolute metabolite quantification employs the water peak as a standard of known concentration [ 3 , 26 ]. Another challenge is the evaluation of several small molecules that, by standard 1 H MRS examination, are difficult to distinguish in MR spectra, although they might be clinically useful as diagnostic biomarkers.…”

“…In general, T 2 relaxation times in healthy brain tissue ( Figure 6 ) have been demonstrated to vary depending on the ratio of WM (~75 ms at 1.5T/~60 ms at 3T) to GM (~95 ms at 1.5T/~80 ms at 3T) or cerebrospinal fluid (~220 ms at 1.5T/~200 ms at 3T) [ 192 , 195 , 196 ]. The typical finding in MS, namely myelin loss, can be observed in T 2 -weighted MRI scans as hyperintense areas (lesions, plaques) that are characterized by prolonged T 2 relaxation times [ 3 , 197 , 198 ]. The prolongation of T 2 relaxation in MS lesions is thought to be caused by increased extracellular space and by larger cellular water intake in the less hydrophobic environment triggered by demyelination in WM [ 3 , 27 ].…”

“…The typical finding in MS, namely myelin loss, can be observed in T 2 -weighted MRI scans as hyperintense areas (lesions, plaques) that are characterized by prolonged T 2 relaxation times [ 3 , 197 , 198 ]. The prolongation of T 2 relaxation in MS lesions is thought to be caused by increased extracellular space and by larger cellular water intake in the less hydrophobic environment triggered by demyelination in WM [ 3 , 27 ]. Although prolonged T 2 relaxation times have been found in several CNS regions, including the NAWM of MS patients [ 198 , 199 , 200 ], other research reports indicate that NAWM water T 2 relaxation times are correlated with the tNAA concentration in RRMS patients [ 198 , 201 ], suggesting that an increase in lesion water reflects the degree of local demyelination, even before MS lesions are formed.…”

“…Multiple sclerosis (MS) is a multifactorial neurodegenerative disease that affects over 2.5 million individuals worldwide [ 1 , 2 ]. It is the most common cause of neurologic disability in young adults [ 3 , 4 ]. The traditional “outside-in” hypothesis of MS etiology is based on an autoimmune provenance whereby dysregulated auto-reactive T cells in the periphery cross into the central nervous system (CNS) and, together with macrophages and B cells, proceed to attack predominantly myelin elements [ 1 , 5 , 6 ].…”