| 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 healthy human brains. Microarray gene expression data were inferred for each unsampled grey matter voxel using Gaussian process regression. and together with AHBA data were mapped into volumetric MNI space, resulting in the brain-wide transcriptional atlas. Deconvolution algorithm for bulk RNA expression levels was applied to the transcriptional atlas with using well-known cell-type-specific gene markers. Comprehensive volumetric maps showing reconstructed distributions of six canonical cell-types across all grey matter voxels in the brain were created (see Materials and Methods, Cell-type proportion estimation subsection). (B) Voxel-wise cortical surface visualization (lateral, dorsal, and ventral views) of cell abundance maps for neurons, astrocytes, microglia, endothelial cells, oligodendrocytes, and OPCs. At each voxel, red and blue colors indicate high and low proportion densities, respectively. (C) Associations between cell-types proportions from each density map and atrophy values in thirteen neurodegenerative conditions were analysed in 118 grey matter regions predefined by the AAL atlas. Created with BioRender.com

© 2024, BioRender Inc. Any parts of this image created with BioRender are not made available under the same license as the Reviewed Preprint, and are © 2024, BioRender Inc.

| Spatial associations between tissue integrity and cell-types proportions for thirteen neurodegenerative conditions illustrated in the scatterplots and surface maps (left hemisphere; lateral view) of regional measures. A-M) Strongest Spearman’s correlations for EOAD, LOAD, DLB, PS1, FTLD-3Rtau, FTLD-4Rtau, FTLD-TDP43A, FTLD-TDP43C, PD, ALS, bvFTD, nfvPPA, and svPPA, respectively. Atrophy and cell-type density measures were averaged across 118 grey matter regions and projected to the cortical surface of the fsaverage template. Each dot in the scatterplots represents a GM region from the AAL atlas (Table S1; see Fig. S1 for equivalent results for the DKT parcellation). Lower tissue integrity score in the scatterplots indicates greater GM loss/atrophy. For a better visual comparison of patterns in atrophy and cell abundance, the atrophy scale was reversed, with higher t-statistic values indicating greater atrophy in the surface plots. Thus, the first color bar ranging from 0 is universal for all cell maps and pathologically confirmed dementia conditions (A-H). Second color bar captures the tissue enlargement in PD, ALS, and variants of FTD (I-M). Notice how astrocyte density significantly correlates with increase in tissue loss in EOAD, DLB, PS1, FTLD-TDP43C, and nfvPPA (A, C, D, H, L; p < 0.001). Tissue loss was also associated with increase in microglial proportion in LOAD, FTLD-3Rtau, FTLD-4Rtau, FTLD-TDP43A, bvFTD, and svPPA (B, E, F, G, K, M; p < 0.001), and increase in oligodendrocytes in PD (I; p < 0.001). Increase in neuronal proportion showed association with decrease in atrophy and tissue enrichment in ALS (J; p < 0.001).

| Cells and disorders 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 thirteen neurodegenerative conditions. B) Cell-cell associations based on regional vulnerabilities to tissue loss across neurodegenerative conditions. C) Disorder-disorder similarities across cell-types. In A), red color corresponds to strong positive correlations between cells and disorders, white to no correlation, and dark blue to strong negative correlations.

Spatial associations between tissue integrity and cell-types proportions for thirteen neurodegenerative conditions in GM regions from the DKT parcellation (equivalent to main results from the AAL atlas in Figure 2).

Cortical and subcortical regions from the AAL atlas.

Origin of each disorder-associated t-statistic map.

Eighty cell-type related gene markers provided by the BRETIGEA R package.