Abstract
PURPOSE: It has remained a mystery why some genetic mitochondrial disorders affect predominantly specific cell types such as the retinal ganglion cell. This is particularly intriguing concerning retinal and cortical function since they are tightly linked in health and disease. Autosomal dominant optic neuropathy (ADOA) is a mitochondrial disease that affects the ganglion cell. However, it is unknown whether alterations are also present in the visual cortex, namely in excitation/inhibition balance. METHODS: In this study, we performed in vivo structural and biochemical proton magnetic resonance imaging in 14 ADOA and 11 age-matched control participants focusing on the visual cortex, with the aim of establishing whether in this genetically determined disease an independent cortical neurochemical phenotype could be established irrespective of a putative structural phenotype. Cortical thickness of anatomically defined visual areas was estimated, and a voxel-based morphometry approach was used to assess occipital volumetric changes in ADOA. Neurochemical measurements were focused on γ-aminobutyric acid (GABA) and glutamate, as indicators of the local excitatory/inhibitory balance. RESULTS: We found evidence for reduced visual cortical GABA and preserved glutamate concentrations in the absence of cortical or subcortical atrophy. These changes in GABA levels were explained by neither structural nor functional measures of visual loss, suggesting a developmental origin. CONCLUSIONS: These results suggest that mitochondrial disorders that were previously believed to only affect retinal function may also affect cortical physiology, especially the GABAergic system, suggesting reduced brain inhibition vs. excitation. This GABA phenotype, independent of sensory loss or cortical atrophy and in the presence of preserved glutamate levels, suggests a neurochemical developmental change at the cortical level, leading to a pathophysiological excitation/inhibition imbalance.