Schematic approach for whole-brain cells proportions vulnerability analysis in neurodegeneration. (A) Gene expression levels in the AHBA were derived from 3072 distinct tissue samples of six post-mortem human brains. (B) Microarray gene expression data was inferred for each unsampled GM voxel and together with AHBA data was mapped into volumetric MNI space resulting in the brain-wide transcriptional atlas. Deconvolution machine learning algorithm for bulk RNA expression levels was applied to the transcriptional atlas with using well-known cell-type-specific gene markers. (C) Comprehensive volumetric maps showing reconstructed distributions of six canonical cell-types, including neurons, astrocytes, microglia, endothelial cells, oligodendrocytes and OPCs, across all gray matter voxels in the brain (see Materials and Methods, Cell-type proportion estimation subsection). At each voxel, red and blue colors indicate high and low proportion densities, respectively. (D) Associations between cell-types proportions from each density map and atrophy values in eleven neurodegenerative conditions were analysed in 118 predefined by the AAL atlas regions. Created with BioRender.com

Spatial associations between tissue integrity and cell-types proportions for eleven neurodegenerative conditions. A-K) Strongest Spearman correlations for EOAD, LOAD, DLB, PS1, 3RTau, 4RTau, TDP43A, TDP43C, FTD, PD, and ALS, respectively. L) All pairwise cells-diseases correlation values. In A-K, each dot represents a GM region from the AAL atlas (Table S1; see Fig. S1 for equivalent results for the DKT parcellation). Lower tissue integrity score indicates greater GM loss/atrophy. Notice how astrocyte density significantly correlates with increase in tissue loss in EOAD, DLB, PS1, TDP43C, and FTD (A, C, D, H, I; P < 0.001). Tissue loss was also associated with increase in microglial proportion in LOAD, 3RTau, 4RTau, and TDP43A (B, E, F, G; P < 0.001), and increase in oligodendrocytes in PD (J; p < 0.001). Increase in neuronal proportion showed association with decrease in atrophy and tissue enrichment in ALS (K; p < 0.001).

Cells and diseases similarities based on shared distributions. A) Dendrogram and unsupervised hierarchical clustering heatmap of Spearman’s correlations between cell-type proportions and atrophy patterns of the eleven neurodegenerative diseases. B) Cell-cell associations based on regional vulnerabilities to tissue loss across neurodegenerative conditions. C) Disease-disease similarities across cell-types. In A), red color corresponds to strong positive correlations between cells and diseases, white to no correlation, and dark blue to strong negative correlation.