Temporal profile of soluble Toll-like receptor 4 in serum and its association with hematoma expansion in intracerebral hemorrhage: a retrospective study

Abstract

Background and purpose: Intracerebral hemorrhage (ICH) is the most devastaing subtype of stroke, with poorly understood mechanisms and no effectve treatment. Hematoma expansion (HE) occurs in about one in five patents and is the only modifiable predictor of poor outcome, but trials targetng HE have not improved outcomes due to challenges in patient selecton. Blood biomarkers could be early prognostic tools and guide treatment by reflecting the pathophysiological processes behind HE and secondary brain injury (SBI). Toll-like receptor 4 (TLR4) plays a role in post-ICH SBI and neuroinflammation, and its soluble form, sTLR4, has been proposed as a biomarker for poor clinical outcomes. Elucidating the association between TLR4 and HE may provide insights into the molecular mechanisms underlying HE. Objectives: To compare baseline sTLR4 levels between ICH patients and individuals without stroke; to evaluate the temporal profile of serum sTLR4 levels in patients with ICH; and to assess their potential as a prognostic biomarker for HE. Materials and methods: We conducted a retrospective study on a cohort of 101 patients with ICH within 12 hours from symptom onset, admiked to Hospital Doctor Josep Trueta between 2017 and 2022. Samples and data from ICH patients and non-stroke controls were obtained from the IDIBGI Biobank (ICTUS and IMAGENOMA collections). Serum sTLR4 levels were measured at admission, 24 hours, 72 hours, and 3 months, using ELISA. HE was defined as an increase in hematoma volume of >6mL and/or >33% between admission and 24-hour followup CT scans, assessed by semi-automated planimetric methods. Results: Pa]ents with ICH exhibited significantly higher serum sTLR4 levels compared to individuals without stroke (p=0.027). sTLR4 levels showed a significant decrease from baseline to 24 hours (p=0.05) and to 72 hours (p=0.006). The overall comparison across time points was statistically significant (p=0.007). Patients who experienced HE exhibited persistently higher serum sTLR4 concentrations. In a multivariate model including age, baseline NIHSS and baseline sTLR4 levels, the laker two variables remained in the model as independent predictors of HE. ROC curve analyses showed that the combined NIHSS + sTLR4 model had a higher positive predictive value for HE than ICH volume alone (62.3% vs. 58.9%). Conclusions: Serum sTLR4 levels are significantly higher in ICH patients compared to individuals without stroke. sTLR4 levels in ICH patients decrease from baseline to 24 hours, 72 hours, and 3 months. sTLR4 levels in the hyperacute and acute phases of ICH might serve as a prognostic biomarker for HE

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