Predictive value of longitudinal changes of serum matrix metalloproteinase-9 and brain-derived neurotrophic factor in acute ischemic stroke

Abstract

Background: Matrix metalloproteinase-9 (MMP-9) and brain-derived neurotrophic factor (BDNF) have documented roles in the inflammatory injury cascade of neurovascular units following ischemic brain injury. However, their dynamic changes and predictive values after acute ischemic stroke (AIS) have not been well elucidated.

Objective: To investigate the temporal profiles of serum MMP-9 and BDNF concentrations and their relationship with the prognosis in patients with AIS.

Methods: MMP-9 and BDNF levels were measured in 42 AIS patients in prospectively collected blood samples, which were taken on the first day (Day 1), the second day (Day 2), and the fifth day (Day 5) after admission. Healthy subjects (n = 40) were used as controls. The AIS patients were divided into groups of good functional prognosis (n = 24) and poor prognosis (n = 18) according to their modified Rankin Scale score at 3 months. Longitudinal analysis of MMP-9 and BDNF and their association with neurological prognosis was performed using repeated measurement ANOVA.

Results: At baseline (Day 1), the levels of serum MMP-9 and BDNF were significantly higher in the AIS group than in the normal control group (P < 0.01). Repeated measurement ANOVA showed a significant main effect and interaction of MMP-9 between good prognosis and the poor group (P < 0.05). Further simple-effect analysis showed that the MMP-9 level was significantly increased in the poor prognosis group compared with the good prognosis group at T5 (P < 0.05). There were no significant time-dependent or the interaction effect (all P > 0.05), but a main effect (P < 0.05) for BDNF. Compared with the poor prognosis group, the simple-effect results indicated that the BDNF level of the good prognosis group was lower at Day 1, while the same was reversed for expression at Day 5 (P < 0.05).

Conclusion: MMP-9 and BDNF are closely related to the prognosis of patients with AIS in a time-dependent manner. The dynamic changes of the two biomarkers are superior to baseline levels in predicting the prognosis of AIS patients. A sustained decrease in MMP-9 and an increase in BDNF levels in AIS patients after several days of treatment implied a favourable prognosis.

Keywords: acute ischemic stroke; brain-derived neurotrophic factor; matrix metalloproteinase-9; neuroinflammation; serum biomarkers.

FIGURE 1

The flow chart of the current study protocol is shown. DWI, diffusion weighted image.

FIGURE 2

Comparison of baseline serum MMP-9 (A) and BDNF (B) levels between the AIS group and the healthy control group at baseline. A 42 patients in the AIS group and 40 participants in the health control group were used for the analysis. AIS, acute ischemic stroke; data represent as mean ± SD, ****P < 0.001.

FIGURE 3

The longitudinal changes of MMP-9 and BDNF over the acute stage of ischemic stroke between good prognosis group and poor prognosis group. (A) Mean serum MMP-9 levels changes at Day 1, Day 2, and Day 5 time points between good prognosis group and poor prognosis group. (B) Mean serum BDNF levels at Day 1, Day 2, and Day 5 time points between good prognosis group and poor prognosis group. Error bars indicate 95% CI of the mean.

FIGURE 4

Average serum MMP-9 and BDNF levels of AIS patients with or without thrombolysis at Day 1, Day 2, and Day 5 time points. (A) Bar graph shows quantitative analysis for serum MMP-9 of patients with non-thrombolysis between good prognosis group (n = 15) and poor prognosis group (n = 8). (B) Bar graph shows quantitative analysis for serum BDNF of patients with non-thrombolysis between good prognosis group (n = 9) and poor prognosis group (n = 10). (C) Bar graph shows quantitative analysis for serum MMP-9 of patients with thrombolysis between good prognosis group (n = 15) and poor prognosis group (n = 8). (D) Bar graph shows quantitative analysis for serum BDNF of patients with thrombolysis between good prognosis group (n = 9) and poor prognosis group (n = 10). Data represent as mean ± SD, *P < 0.05, ^**P < 0.01 vs. Day 1 time points, ^ΔP < 0.05, ^ΔΔP < 0.01 vs. group with good prognosis.