Transcriptomic characterization of MRI contrast with focus on the T1-w/T2-w ratio in the cerebral cortex

Abstract

Magnetic resonance (MR) images of the brain are of immense clinical and research utility. At the atomic and subatomic levels, the sources of MR signals are well understood. However, at the macromolecular scale, we lack a comprehensive understanding of what determines MR signal contrast. To address this gap, we used genome-wide measurements to correlate gene expression with MR signal intensity across the cortex in the Allen Human Brain Atlas. We focused on the ratio of T1-weighted and T2-weighted intensities (T1-w/T2-w) which is considered to be a useful proxy for myelin content. Positive correlations between myelin-associated genes and the ratio supported its use as a myelin marker. However, stronger correlations were observed for neurofilaments, and genes linked to the production of formaldehyde (which cross-links protein to create larger molecules). There was also an association with protein mass, with genes coding for heavier proteins expressed in regions with high T1-w/T2-w values. Oligodendrocyte gene markers were strongly correlated but this was not driven by myelin-associated genes, suggesting this signal is from non-myelinating satellite oligodendrocytes. We find the strongest support for the previous finding of high aerobic glycolysis in regions with low T1-w/T2-w ratio. Specifically, many mitochondrial genes were negatively correlated with T1-w/T2-w ratio. Genes up-regulated by pH in the brain were also highly correlated with the ratio, suggesting the pH gradient in mitochondria may explain the aerobic glycolysis association. Expression of protease subunit genes was also inversely associated with the ratio, in agreement with the protein mass correlation. While we corroborate associations with myelin and synaptic plasticity, differences in the T1-w/T2-w ratio appear to be more attributable to molecule size, satellite oligodendrocyte proportion, mitochondrial number, alkalinity, and axon caliber. Using disease-associated gene lists, we observed an enrichment of negative T1-w/T2-w ratio correlations with human immunodeficiency virus (HIV) associated genes. Expanding our analysis to the whole brain results in strong positive T1-w/T2-w associations for immune system, inflammatory disease, and microglial genes. In contrast, neuron markers and synaptic plasticity genes are negatively enriched. Lastly, our results vary little when our analysis is performed on T1-w or inverted T2-w intensities alone, possibly because the noise reduction properties of the ratio are not needed for postmortem brain scans. These results provide a molecular characterization of MR contrast that will aid interpretation of future MR studies of the brain.