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

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 cerebral 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. We found enrichment of positive correlations between myelin-associated genes and the ratio, supporting its use as a myelin marker. However, stronger correlations were observed in many other gene sets. For example, we observed opposing associations between proteasome subunits and genes linked to the production of endogenous formaldehyde (which cross-links protein to create larger molecules). Genome-wide, 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 with the T1-w/T2-w ratio but this was not driven by myelin-associated genes, suggesting this signal is from non-myelinating satellite oligodendrocytes. Mitochondrial genes have the strongest relationship with high expression in regions with low T1-w/T2-w ratio. This may be due to the pH gradient in mitochondria as genes up-regulated by pH in the brain were also highly correlated with the ratio. While we corroborate associations with myelin and synaptic plasticity, differences in the T1-w/T2-w ratio across the cortex are more strongly linked to molecule size, oligodendrocyte markers, mitochondria, and pH. 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 correlations for immune system, inflammatory disease, and microglia marker genes. In contrast, neuron markers and synaptic plasticity genes are enriched for negative correlations in the whole brain analysis. 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.<br>