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 5 0.01) than HVs. Unexpectedly, converters showed higher NAA (p 5 0.042), tCho (p 5 0.004), and total creatine (p 5 0.002), in addition to higher lactate levels (p 5 0.032), compared with HVs. Compared with nonconverters, converters had higher tCho (p 5 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. Neurology ® 2014;82:798-805 GLOSSARY CNS 5 Columbia Neurological Score; GNP 5 Global Neuropsychological; 1 H MRSI 5 proton magnetic resonance spectroscopic imaging; HV 5 healthy volunteer; MELAS 5 mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MRS 5 magnetic resonance spectroscopy; NAA 5 N-acetyl-L-aspartate; tCho 5 total choline; tCr 5 total creatine.

Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes (MELAS): A Case Report and Critical Reappraisal of Treatment Options

“…26 This speculation, if true, may contribute to the pathophysiology of stroke-like episode and explain the decrease in brain N -acetylaspartate seen in the MELAS brain as the disease progresses. 8 …”

“…8 MELAS is characterized by elevated ventricular lactate that increases as the disease progresses signifying a progressive shift of the oxidation-reduction (redox) potential. 9 Stroke-like episodes represent the clinical signature of MELAS, manifested by a mixture of features including altered consciousness, seizures, imaging abnormalities and transient focal deficits.…”

Assessment of glutamate in striatal subregions in obsessive-compulsive disorder with proton magnetic resonance spectroscopy

“…For normalization of levels across subjects, the glutamate peak areas were expressed in institutional units (i.u.) as ratios relative to the root-mean-square (rms) of the background noise in each voxel (i.e., as signal-to-noise ratios) – an approach that we have used previously in a number of publications (Kaufmann et al, 2004; Mathew et al, 2009; Weiduschat et al, 2014; Weiduschat et al, 2013). …”

Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia

“…For normalization of levels across subjects, the lactate peak areas were expressed in institutional units (i.u.) as ratios relative to the root-mean-square (rms) of the background noise in each spectrum – an approach that we have used previously in a number of studies [8, 14, 15]. …”