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

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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.