Inflammatory And Neurodegenerative Gene Expression Changes Occur Longterm After ICH

Objective: There is a high prevalence of progressive cognitive impairment in intracerebral hemorrhage (ICH) survivors. We sought to identify gene expression changes, in association with long-term neurodegeneration, among patients 12-24 months post-ICH. Methods: The Recovery and Outcomes from StrokE (ROSE) study prospectively recruits patients with spontaneous, supratentorial ICH, collecting baseline peripheral blood samples and MRI with diffusion tract imaging (DTI). The Recovery of StrokE-Longitudinal Assessment with Neuroimaging (ROSE-LAWN) study performs long term follow-up at 12-24 months on cases enrolled in ROSE. We report on the first five cases enrolled in the ROSE-LAWN study from December 2020 to March 2021. Controls were matched to an overall ICH population by age, sex, and race. RNA-sequencing, aligned to human genome assembly GRCh38, was tested for differential gene expression. Canonical pathway enrichment and network analyses were computed for differentially expressed genes using Ingenuity Pathway Analysis, STRING and MCODE. Results: RNA-seq analysis of 5 ICH cases [male, 80%; median age, 61 (45 - 73); black, 40%; ICH volume, 14.88cc ± 13.07] and 13 controls [male, 54%; median age, 74 (69 - 79); black, 15%] identified 554 differentially expressed genes (genomic control adjusted p < 0.01), of which 24 met the false discovery rate correction for multiple comparisons (FDR < 0.05). The most significant difference was observed in hypoxia up-regulated 1 ( HYOU1), a heat shock protein related gene (p = 2.64E-11). Pathway analysis identified enrichment of dopamine and serotonin receptor signaling (p = 8.74E-03, 2.23E-02), cell cycle regulation (p = 1.75E-02) and agranulocyte adhesion pathways (p = 2.18E-02). Comparison of baseline and follow-up MRI DTI demonstrated extensive cortical tract degeneration, beyond the initial injury. Conclusion: These results provide novel evidence of significant gene expression changes occurring years after the initial ICH. Despite resolution of the ICH, persistent inflammation may correlate with progressive neurodegeneration and subsequent cognitive impairment in ICH survivors. Future studies with greater sample sizes are supported by this work.