MRS in Mitochondrial Diseases: Lactate and NAA changes
Mitochondrial disease represents a particularly prominent set of diseases that show MRS changes due to the consequences of impaired OXPHOS. The disruption of the ETC and consequent depletion of NAD+ and NADP+ shifts metabolism from the tricarboxylic acid cycle to glycolysis. The glycolytic by-product lactate is the primary abnormality detected in mitochondrial disease. This can then be measured along with numerous markers of cellular integrity and energetics (e.g. myo-inositol, choline, creatine, and NAA). In mitochondrial diseases, lactate elevations are suggested to range from 3−11 mM (Wilchowski et al., 1999) with other studies reporting average levels of approximately 6 mM (Saitoh et al., 1998; Isobe et al., 2007).
The most consistent MRS change accompanying increased lactate in mitochondrial disease is decreased NAA, suggestive of cellular compromise. While elevations in lactate and decreases in NAA occur in other diseases, for example stroke and seizures (Kingsley et al., 2006), such diseases are typically distinct in clinical work-up and MRI abnormalities. In the following summary, owing to the preponderance of lactate and NAA changes in mitochondrial disease, these metabolites are summarized first, followed by a detailed discussion of myo-inositol, choline, and creatine, with a brief discussion of future studies increasing specificity of measurement. Next, a very specific MRS biomarker in complex II disease, succinate, is described, followed by a summary of how MRS-visible biomarkers may be used to monitor therapeutic interventions in these heterogeneous diseases.
The phenotypic heterogeneity of mitochondrial patients can result in some patients not demonstrating marked lactate elevations (Lin et al., 2003; Bianchi et al., 2003), due to variability in disease state and regional sampling. There is the possibility that variability in regional sampling limits detection in some subjects. In some cases, propan-1,2-diol, localized at 1.1 ppm, can be mistaken for lactate (Figure 7; Cady et al., 1994).