Voxelwise Analysis of Diffusion Tensor Imaging and Structural MR Imaging in Patients with the m.3243A>G Mutation in Mitochondrial DNA

Abstract

BACKGROUND AND PURPOSE:The m.3243AϾG mutation is the most common pathogenic mutation in mtDNA; tissues with high dependence on aerobic energy metabolism, such as the brain, heart, and skeletal muscle, are most affected by the ensuing mitochondrial dysfunction. We hypothesized that the m.3243AϾG mutation manifests as disturbances in white matter microstructural integrity and volumetric changes in the brain.

Tract-Based Spatial Statistical Analysis of Diffusion Tensor Imaging in Pediatric Patients with Mitochondrial Disease: Widespread Reduction in Fractional Anisotropy of White Matter Tracts

“…Our results overlap somewhat with the previous study by Virtanen et al, 16 which demonstrated widespread FA alterations in a group of patients characterized by m.3243AϾG mutations, characteristic of MELAS. Most interesting, in that study of adults, group differences were more striking in the posterior and caudal parts of the brain, without MD changes.…”

“…[13][14][15] In mitochondrial disease, a recent study in adults with m.3243AϾG mutations that did not meet the criteria for MELAS, except for 1 patient, demonstrated FA changes in the occipital lobes, thalami, external and internal capsules, brain stem, cerebellar peduncles, and cerebellar white matter compared with matched control subjects. 16 Because white matter lesions have been reported in patients with complex I and I/III deficiencies, we hypothesized that quantitative measures of diffusion might be sensitive for detecting subthreshold abnormalities. To test this hypothesis, we identified a group of patients at our center with complex I or I/III deficiencies having qualitatively normal-appearing white matter for age (on T1/FLAIR MR images).…”

Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease

“…The observed reduced FA in the cerebral cortex, external capsule and cerebral peduncle in Ndufs4 −/− brain, is in line with white matter diffusivity changes previously described in patients with mitochondrial disorders. Widespread reductions in FA (including the external capsule and cerebral peduncles) were found in three different clinical studies; in a group of pediatric patients, identified as having complex I or complex I/III deficits, among patients with m.3243A > G mutation and patients with OPA1 autosomal dominant optic atrophy and Leber’s hereditary optic neuropathy 61 – 63 . Not only FA was affected in the cerebral cortex and external capsule, we also found a significant increase in lipid peroxidation in these brain areas.…”

Quantitative brain MRI at 7T in healthy subjects and in metabolic diseases

“…Thus, it is reasonable to assume that myelination decreases and iron content increases as a function of mutation load but they have different dependencies on the m.3243A>G mutation load, leading to the U-shape function observed pattern for T 1 . In contrast to the observed cortical pattern, the increased cerebellar GM T 1 observed in patients compared to controls, in addition to the unchanged T 2 *, may implicate predominantly myelin loss secondary to neuronal and axonal loss (Virtanen et al, 2011;Lax et al, 2012).…”