Abstract TP327: Major Inflammatory Pathways in Peripheral Blood Associate With Intracerebral Hemorrhage Volume in Human

Abstract

Objectives: Intracerebral hemorrhage (ICH) volume is a major determinant of functional outcome. The peripheral immune system plays a critical role in post-ICH damage and repair. Identifying potential modulators of ICH volume may guide the search for therapeutic targets. We performed a whole genome expression study in peripheral blood to examine the immune response following ICH with respect to ICH volume. Methods: Whole-genome RNA expression from 18 ICH subjects (14M/4F) was assessed on Affymetrix HTA 2.0 microarrays. Volumetric measurements were conducted on CT images using AnalyzePro. Multiple Regression including ICH volume while accounting for time from ICH onset to blood draw and interval between scan time and blood draw, was performed. A partial correlation between gene expression and ICH volume was calculated, with FDR p<0.3 (nominal p<0.005) and Pearson Correlation coefficient r>|0.6| considered significant. Pathway analysis and activation/suppression prediction of over-represented pathways was performed (Benjamini-Hochberg p<0.05, pathway activation/suppression Z-score >|2|). Results: Gene expression levels of 281 genes, including coding (mRNA) and non-coding RNA (i.e. several miRNAs) were associated with ICH volume. Major pathways, such as Neuroinflammation Signaling, were predicted to be activated in subjects with larger ICH volumes. So were Inflammasome Pathway, Toll-like Receptor, Leukocyte Extravasation, NF-kB signaling and FC? Receptor-Mediated Phagocytosis – some of which have been associated with poor clinical outcomes. Scavenger mechanisms, such as FC? Receptor-Mediated Phagocytosis, have been implicated in hematoma resolution. Thrombin Signaling, involved in coagulation, was also activated in subjects with larger ICH volumes. Peroxisome Proliferator-Activated Receptor (PPAR) Signaling was predicted to be suppressed in subjects with larger ICH volumes. PPAR pathway activation may have a neuroprotective effect following experimental ICH. Conclusions: We provide human data on genes and pathways associated with ICH volume. The results reveal major inflammatory pathways associated with ICH volume, which may be therapeutic targets for human ICH.

“Rogue” [DEspR+CD11b+] neutrophil subset correlates with severity in spontaneous intracerebral hemorrhage

“…The observed correlations of three different peripheral neutrophil biomarkers-DEspR+CD11b+ N counts and NET+N counts, and NLR with 90-day mRScollectively support the role of neutrophil-mediated secondary brain injury as a determinant of sICH outcome. These correlations suggest that peripheral neutrophils reflect ongoing neutrophil-mediated secondary brain injury in sICH, a notion supported by RNA-profiling data showing that peripheral neutrophils exhibit similar RNA profiles as brain neutrophil infiltrates in patients with sICH at 72 h (8). Furthermore, as our neutrophil measures were obtained on average on day 3, observed correlations with subsequent 90-day mRS suggest putative consequential role(s).…”

“…First, recent histopathology staining of postmortem sICH brain sections has confirmed neutrophil presence in the perihematomal region starting day1 post-ICH (6) and neutrophil extracellular trap (NET)-forming neutrophils at least by day 3 (7). Second, recent transcription profile analyses report that circulating neutrophils in patients with sICH differ in gene expression compared with age-matched non-ICH controls (8). Third, neutrophil-specific gene changes in the sICH brain and peripheral neutrophils are similar, indicating the pathogenic relevance of studying peripheral neutrophils (8).…”

“…Second, recent transcription profile analyses report that circulating neutrophils in patients with sICH differ in gene expression compared with age-matched non-ICH controls (8). Third, neutrophil-specific gene changes in the sICH brain and peripheral neutrophils are similar, indicating the pathogenic relevance of studying peripheral neutrophils (8). Fourth, a meta-analysis of multiple clinical studies confirmed the association of high NLR with worse outcomes in sICH (9), further supported by a recent study showing the association of elevated NLR with poor outcomes and perihematomal edema (10).…”

Age-related changes after intracerebral hemorrhage: a comparative proteomics analysis of perihematomal tissue

“…In addition, the other module from the aged-specific DEP PPI network included Spta1 (spectrin alpha chain, erythrocytic 1), Slc4a1 (band 3 anion transport protein), and Ank1 (ankyrin-1). In clinical research, the Slc4a1 and Ank1 genes from the peripheral blood of ICH patients were verified as hub genes by RNA sequence analysis, and this result implied that these genes have the potential to be used as key intervention targets in translational research [30].…”