Transcriptome wide correlations with neuropathological hallmarks in the frontal cortex of FTLD patients

Background A key pathological event in frontotemporal lobar degeneration (FTLD) is the alteration of the RNA metabolism. Despite this, no study has characterized the diversity of RNA species using high‐throughput sequencing approaches and correlated them with the main neuropathological hallmarks across FTLD subtypes. Method Total and small RNA sequencing was performed in the frontal cortex of patients neuropathologically diagnosed with FTLD‐TDP (including non‐mutation carriers [sFTLD‐TDP;n = 9], and carriers of the C9orf72 repeat expansion [FTLD‐C9;n = 11]), FTLD‐tau (n = 13, six carrying the p.P301L mutation in MAPT) and controls without neuropathological alterations in the same brain region (n = 7). Gene and miRNA co‐expression modules were identified using WGCNA. Cell‐type proportions were estimated through cell‐type deconvolution using MuSiC. Gene ontology enrichment analyses were performed using Metascape. We assessed in the frontal cortex the presence of pTDP43 (in sFTLD‐TDP and FTLD‐C9), dipeptide repeats and RNA foci (in FTLD‐C9), and tau aggregates (in FTLD‐tau) through quantitative immunohistochemistry and correlated their density with transcriptome‐wide RNA alterations. Result Our results indicate statistically significant correlations between gene and miRNA co‐expression modules, neuropathological changes and cell‐type proportions specific for each FTLD subtype. The most significant findings include: in sFTLD‐TDP, the density of pTDP43 positively correlated with a gene co‐expression module (R = 0.9,p = 0.04) enriched with splicing functions (p