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, we lack a comprehensive understanding of the macromolecular correlates of 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 (AHBA). We focused on the ratio of T1-weighted and T2-weighted intensities (T1-w/T2-w ratio image), which is considered to be a useful proxy for myelin content. As expected, we found enrichment of positive correlations between myelin-associated genes and the ratio image, supporting its use as a myelin marker. Genome-wide, there was 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. Mitochondrial genes exhibit the strongest relationship, showing higher 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. We evaluate correlations between AHBA transcriptomic measurements and a group averaged T1-w/T2-w ratio image, showing agreement with in-sample results. 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. Genes with negative correlations were enriched for neuron markers and synaptic plasticity genes. Lastly, our findings are similar when performed on T1-w or inverted T2-w intensities alone. These results provide a molecular characterization of MR contrast that will aid interpretation of future MR studies of the brain.

Keywords: Cortex; Gene expression; Molecular neuroanatomy; Myelin map; Transcriptomics.

Fig. 1.

Overview of the correlation analysis. MR intensities are extracted from the images on the left, depicted as a single grayscale vector which each bar corresponding to an Allen Atlas sample. The colored bar on top visualizes the expression matrix with samples as rows and genes as columns. Each gene/column forms an expression profile across the cortex (outlined in red) and is correlated with the grayscale intensity vector. Genes are then sorted from strong positive to strong negative correlation for gene set enrichment analysis to test if a particular set is enriched for positive or negative correlations. VAMP1 (high positive correlation), TREML1 (no correlation), and SCARA5 (strong negative correlation) provide examples across the correlation range using data from donor H0351.2001.

Fig. 2.

Sample-wise plots of T1-w/T2-w ratio and SCARA5 gene expression. Each donor represented as a single scatter plot of samples. To visualize the rank correlation, monotonically decreasing constrained splines are plotted in black (knots = 10). Samples are colored by their cortical lobe/division.

Fig. 3.

Associations with T1-w/T2-w ratio intensities for selected myelin-related GO groups. (A) ROC curves for GO groups selected from Table 1. The curves show the proportion of GO group genes that overlap (y-axis, true positive fraction) in varying lengths of the T1-w/T2-w gene ranking (approximated by the x-axis, false positive fraction). Colored lines mark genes in different GO groups. (B) Distributions of the three significant GO groups across the T1-w/T2-w associated gene ranking with each annotated gene representing a single colored line.

Fig. 4.

Selected GO groups with high enrichment of T1-w/T2-w ratio associations in the cortex. (A) ROC curves for GO groups selected from Tables 2 and 3 The curves show the proportion of GO group genes that overlap (y-axis, true positive fraction) in varying lengths of the T1-w/T2-w gene ranking (approximated by the x-axis, false positive fraction). Colored lines mark genes in different GO groups. (B) Distributions of the five significant GO groups across the T1-w/T2-w associated gene ranking with each annotated gene representing a single colored line.

Fig. 5.

Associations with T1-w/T2-w ratio intensities for Zeisel cell type marker genes. (A) ROC curves showing the proportion of marker genes that overlap (y-axis, true positive fraction) in varying lengths of the T1-w/T2-w gene ranking (approximated by the x-axis, false positive fraction). Colored curves mark genes in different cell type marker lists. (B) Distributions of the cell type markers across the T1-w/T2-w associated gene ranking. Each marker gene is represented by a single colored line.

Fig. 6.

Distributions of the Darmanis cell type markers across the T1-w/T2-w associated gene ranking. Each marker gene is represented by a single colored line. The endothelial and neuron marker list are not significantly enriched after test correction.

Fig. 7.

Barplot of enrichment in the T1-w/T2-w associated gene ranking across the He et al. laminar markers. ** indicates pfwer < 0.0005.