1H-MRS quantification of tNA and tCr in patients with multiple sclerosis: a meta-analytic review

Meta-analysis was performed on the results of 75 comparisons from the 30 peer-reviewed publications that used proton magnetic resonance spectroscopy (1H-MRS) or spectroscopic imaging to (i) quantify the mean concentrations of total creatine (tCr, found in neurons, astrocytes and oligodendrocytes), and/or total N-acetyl groups (tNA, found only in neurons), in the lesional and/or non-lesional white matter (WM) and/or the grey matter (GM) of patients with multiple sclerosis (MS) and (ii) compare these values with those in the homologous tissues of normal controls (NC). For mean [tNA] values, there was (i) a large-effect-sized overall decrease in patients' lesional WM relative to NC WM (25 comparisons), (ii) a medium-effect-sized overall decrease in patients' non-lesional WM relative to NC WM (36 comparisons) and (iii) a medium-effect-sized overall decrease in patients' GM relative to NC GM (14 comparisons). Patients' mean [tNA] values were sometimes statistically normal but were never statistically increased. For mean [tCr] values, there was (i) no statistically significant overall change in the patients' lesional WM relative to NC WM (24 comparisons), although statistically significant increases and decreases were sometimes found, (ii) a medium-effect-sized overall increase in patients' non-lesional WM relative to NC WM (33 comparisons) and (iii) no statistically significant overall change in patients' GM relative to NC GM (12 comparisons), although a significant decrease was found in one comparison. Of 41 comparisons with statistically significant changes, 38 combined in a way that would probably result in decreased mean [tNA]/[tCr] ratios such that (i) 66% had statistically decreased mean [tNA] and statistically unchanged mean [tCr] values, (ii) 13% had statistically decreased mean [tNA] and statistically increased mean [tCr] values and (iii) 21% had statistically unchanged mean [tNA] values and statistically increased mean [tCr] values. Of the 25 comparisons that came from studies that also analysed [tNA]/[tCr] ratios, the direction of change in mean [tNA] values and mean [tNA]/[tCr] ratios was concordant in 84%. In comparisons that quantified both [tNA] and [tCr], there was a similar amount of variability in both measures in each of the different tissue types studied, both in patients and NCs. Together, these results suggest that within-voxel tNA/tCr ratios can be interpreted as valid and accurate surrogate measures of 'cerebral tissue integrity'-with decreased tNA/tCr ratios indicating some combination of neuroaxonal disturbance, oligodendroglial disturbance, and astrocytic proliferation. These results also suggest that, although within-voxel tNA/tCr ratios are not perfect indicators of [tNA] content, they do represent a practical compromise to acquiring surrogate measures of within-voxel neuroaxonal integrity.