SERPINA3: A novel inflammatory biomarker associated with cerebral small vessel disease burden in ischemic stroke

Abstract

Background and ObjectiveInflammation has emerged as a prominent risk factor for cerebral small vessel disease (CSVD). However, the specific association between various inflammatory biomarkers and the development of CSVD remains unclear. Serine proteinase inhibitor A3 (SERPINA3), Matrix metalloproteinase‐9 (MMP‐9), Tissue inhibitor metalloproteinase‐1 (TIMP‐1), Monocyte Chemoattractant Protein‐1 (MCP‐1) are several inflammatory biomarkers that are potentially involved in the development of CSVD. In this present study, we aimed to investigate the relationship between candidate molecules and CSVD features.MethodThe concentration of each biomarker was measured in 79 acute ischemic stroke patients admitted within 72 h after symptom onset. The associations between blood levels of inflammatory markers and CSVD score were investigated, as well as each CSVD feature, including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (EPVS).ResultsThe mean age was 69.0 ± 11.8 years, and 65.8% of participants were male. Higher SERPINA3 level (>78.90 ng/mL) was significantly associated with larger WMH volume and higher scores on Fazekas's scale in all three models. Multiple regression analyses revealed the linear association between absolute WMH burden and SERPINA3 level, especially in model 3 (β = 0.14; 95% confidence interval [CI], 0.04–0.24p ). Restricted cubic spline regression demonstrated a dose–response relationship between SERPINA3 level and larger WMH volume (p nonlineariy = 0.0366 and 0.0378 in model 2 and mode 3, respectively). Using a receiving operating characteristic (ROC) curve, plasma SERPINA3 level of 64.15 ng/mL distinguished WMH >7.8 mL with the highest sensitivity and specificity (75.92% and 60%, respectively, area under curve [AUC] = 0.668, p = 0.0102). No statistically significant relationship has been found between other candidate biomarkers and CSVD features.ConclusionIn summary, among four inflammatory biomarkers that we investigated, SERPINA3 level at baseline was associated with WMH severity, which revealed a novel biomarker for CSVD and validated its relationship with inflammation and endothelial dysfunction.

Prediction Value of Initial Serum Levels of SERPINA3 in Intracranial Pressure and Long-Term Neurological Outcomes in Traumatic Brain Injury

“…Furthermore, insights reveal a connection between SERPINA3 and cardiovascular diseases, such as its correlation with the progression of coronary artery disease [ 24 ], and its significant correlation with the clinical outcomes in myocardial infarction as well as non-ischemic cardiomyopathies [ 43 ], suggesting its utility as a biomarker. Additionally, SERPINA3’s involvement in inflammation and immune regulation has emerged as a significant area of interest, exemplified by its elevated expression in stroke patients, correlating with cerebral small vessel disease and validating its relationship with inflammation and endothelial dysfunction [ 23 ]. These investigations provide crucial insights into the biological functions of SERPINA3 and its mechanistic roles in disease progression, laying the groundwork for the development of future therapeutic modalities and diagnostic tools.…”

“…Future studies should aim to include a larger sample size and perform multiple comparisons to yield more comprehensive and generalizable conclusions. Secondly, SERPINA3 expression is not exclusively specific to TBI cases [ 16 , 18 , 22 , 23 , 43 ], and more complex situations, such as polytrauma cases, are common in many moderate to severe TBI patients, which could complicate the large-scale use of SERPINA3 as a biomarker. Future research should investigate the effects of SERPINA3 in a polytrauma cohort.…”

“…Patients were divided into a high-SERPINA3 group and low-SER-PINA3 group based on the median SERPINA3 concentration in our study. ICP peaks were categorized as moderately elevated (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) or severely elevated (>40 mmHg). The Glasgow Outcome Scale (GOS) score [26,27] criteria consist of 5 points for well-recovered individuals returning to normal life despite mild impairment, 4 points for those with mild disability who are disabled but can live independently and work with support, 3 points for severe disability where the individual is awake but reliant on others for daily activities, 2 points for vegetative survival with minimal response like eye opening during cycles of sleep and wakefulness, and 1 point for death.…”

“…SerpinA3 has been shown to be involved in several pathologies, including cancers, Alzheimer’s disease, neuropathic pain, and stroke [ 18 , 19 , 20 , 21 ]. Previous research reported that SERPINA3 is a biomarker involved in diabetic nephropathy renal tubular injury, cerebral small vessel disease, and coronary artery disease [ 22 , 23 , 24 ]. However, whether or not SERPINA3 could serve as a biomarker for TBI progression and prognosis has not been clearly investigated.…”