Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A>G patients

Abstract

Mutations of the mitochondrial DNA (mtDNA) are an important cause of inherited diseases that can severely affect the tissue’s homeostasis and integrity. The m.3243A>G mutation is the most commonly observed across mitochondrial disorders and is linked to multisystemic complications, including cognitive deficits. In line with in vitro experiments demonstrating the m.3243A>G’s negative impact on neuronal energy production and integrity, m.3243A>G patients show cerebral gray matter tissue changes. However, its impact on the most neuron-dense, and therefore energy-consuming brain structure – the cerebellum – remains elusive. In this work, we used high resolution structural and functional data acquired using 7 Tesla MRI to characterize the neurodegenerative and functional signatures of the cerebellar cortex in m.3243A>G patients. Our results reveal altered tissue integrity within distinct clusters across the cerebellar cortex, apparent by their significantly reduced volume and longitudinal relaxation rate compared to healthy controls, indicating macroscopic atrophy and microstructural pathology. Spatial characterization reveals that these changes occur especially in regions related to the frontoparietal brain network that is involved in information processing and selective attention. In addition, based on resting-state fMRI data, these clusters exhibit reduced functional connectivity to frontal and parietal cortical regions, especially in patients characterized by (i) a severe disease phenotype and (ii) reduced information processing speed and attention control. Combined with our previous work, these results provide crucial insights into the neuropathological changes and a solid base to guide longitudinal studies aimed to track disease progression.

Visual memory failure presages conversion to MELAS phenotype

“…Similarly, the MRS data collected in the temporal lobe did not clearly focus on the brain regions (i.e., mesial temporal lobe) that subserve verbal memory and therefore could not be analyzed specifically as a comparison to the occipital lobe voxel that subserves aspects of visual memory. Recent studies have also demonstrated that high resolution 7 T imaging shows that carriers of the m.3243A > G mutation have widespread cortical thinning and gray matter volume loss in areas such as the temporal lobes 46,47 . Given that the temporal lobes subserve aspects of memory, the relationships between the biomarkers we studied (i.e., visual memory performance and brain metabolites) and possible subtle changes identified on 7 T imaging should be explored in future studies.…”

“…Recent studies have also demonstrated that high resolution 7 T imaging shows that carriers of the m.3243A > G mutation have widespread cortical thinning and gray matter volume loss in areas such as the temporal lobes. 46,47 Given that the temporal lobes subserve aspects of memory, the relationships between the biomarkers we studied (i.e., visual memory performance and brain metabolites) and possible subtle changes identified on 7 T imaging should be explored in future studies. Another limitation of our study is the significant demographic differences between our control group and the MELAS and carrier groups.…”