Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers

Abstract

Objective: To establish cerebral metabolic features associated with the A3243G mitochondrial DNA mutation with proton magnetic resonance spectroscopic imaging ((1)H MRSI) and to assess their potential as prognostic biomarkers.

Methods: In this prospective cohort study, we investigated 135 clinically heterogeneous A3243G mutation carriers and 30 healthy volunteers (HVs) with (1)H MRSI. Mutation carriers included 45 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); 11 participants who would develop the MELAS syndrome during follow-up (converters); and 79 participants who would not develop the MELAS syndrome during follow-up (nonconverters). The groups were compared with respect to MRSI metabolic indices of 1) anaerobic energy metabolism (lactate), 2) neuronal integrity (N-acetyl-l-aspartate [NAA]), 3) mitochondrial function (NAA; lactate), 4) cell energetics (total creatine), and 5) membrane biosynthesis and turnover (total choline [tCho]).

Results: Consistent with prior studies, the patients with MELAS had higher lactate (p < 0.001) and lower NAA levels (p = 0.01) than HVs. Unexpectedly, converters showed higher NAA (p = 0.042), tCho (p = 0.004), and total creatine (p = 0.002), in addition to higher lactate levels (p = 0.032), compared with HVs. Compared with nonconverters, converters had higher tCho (p = 0.015). Clinically, converters and nonconverters did not differ at baseline. Lactate and tCho levels were reliable biomarkers for predicting the risk of individual mutation carriers to develop the MELAS phenotype.

Conclusions: (1)H MRSI assessment of cerebral metabolism in A3243G mutation carriers shows promise in identifying disease biomarkers as well as individuals at risk of developing the MELAS phenotype.

Figures

Figure 1. Representative spectra from 2 voxels of interest in the 4 diagnostic groups

Representative spectra (A) of T1-weighted brain MRIs (B) for voxels (1) in the right parietal gray matter and (2) in the lateral ventricle of, left to right, a patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); a converter; a nonconverter; and a healthy control subject. To achieve a smooth representation and drawing of the ventricular region of interest, the magnetic resonance spectroscopic imaging (MRSI) data matrix was zero-filled to 64 × 64 points along the spatial domains, which effectively halved the voxel size without increasing or decreasing information content—current information is simply replicated in twice as many voxels. Spectral resonances identified are those for total choline-containing compounds (tCho at 3.24 ppm), total creatine (tCr at 3.03 ppm), N-acetyl-l-aspartate (NAA at 2.02 ppm), and lactate (Lac at 1.33 ppm). Note a clearly visible Lac peak in the spectra from all the carrier groups but not in the spectrum from the healthy control subject. All of the spectra are plotted using the same vertical-axis scale.

Figure 2. Comparison of brain metabolite levels as measured by proton magnetic resonance spectroscopic imaging

Mean metabolite levels in institutional units (i.u.) and SDs for N-acetyl-l-aspartate (NAA), lactate (Lac), total creatine (tCr), and total choline (tCho) in the 4 diagnostic groups. Significant differences relative to the converters are marked by asterisks (*p < 0.05, **p < 0.01) and relative to the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) group by daggers (†p < 0.05, ‡p < 0.01). The black circle atop the bar for the converters emphasizes the concerted and unanticipated increases in all metabolite levels in this group.

Figure 3. Associations between magnetic resonance spectroscopy metabolites and clinical indices in mutation carriers

(A) Negative linear relationship between gray matter N-acetyl-l-aspartate (NAA) and the Global Neuropsychological score, indicating lower NAA concentrations in those individuals with higher neuropsychological dysfunction. (B) Inverse relationship between lactate levels and the neurologic status, indicating higher lactate in those with pronounced neurologic impairment.