PSD-95 inhibitor Tat-NR2B9c (NA-1) protects the integrity of the blood-brain barrier after transient middle artery occlusion in rats by downregulating matrix metalloprotease-9 and upregulating endothelial nitric oxide synthase.

BACKGROUND: Protection against ischemic stroke may be most effective when multiple components of the neurovascular unit are protected, yet current treatments target mainly neurons. Here we explored whether the PSD-95 inhibitor Tat-NR2B9c (NA-1) can protect not only neurons but also the blood-brain barrier. METHODS: Adult male Sprague-Dawley rats were randomly divided into three groups, which were subjected to either sham surgery or transient cerebral ischemia-reperfusion, after which some animals were treated with Tat-NR2B9c. The therapeutic efficacy of Tat-NR2B9c was assessed in terms of the degree of neurological deficit and cerebral infarction, integrity of the blood-brain barrier, cerebral water content, as well as expression of PSD-95, nitric oxide synthase, and matrix metalloprotease-9. RESULTS: Tat-NR2B9c (NA-1) ameliorated neurofunctional deficit, reduced cerebral infarction, mitigated blood-brain barrier injury and improved its integrity following ischemia-reperfusion, leading to less cerebral edema. These improvements were associated with upregulation of tight junction proteins in the blood-brain barrier. At the same time, Tat-NR2B9c (NA-1) downregulated neuronal nitric oxide synthase and matrix metalloprotease-9, while reversing the ischemia-induced downregulation of endothelial nitric oxide synthase in brain. We report here the first evidence that PSD-95 is expressed in vascular endothelial cells in the brain. CONCLUSION: Our experiments in a rat model of transient occlusion of the middle cerebral artery suggest that Tat-NR2B9c (NA-1) can mitigate ischemic injury to the blood-brain barrier, and that it may do so by downregulating matrix metalloprotease-9 and upregulating endothelial nitric oxide synthase.

Associations between computed tomography markers of cerebral small vessel disease and hemorrhagic transformation after intravenous thrombolysis in acute ischemic stroke patients.

Background: Hemorrhagic transformation (HT) is common among acute ischemic stroke patients after treatment with intravenous thrombolysis (IVT). We analyzed potential relationships between markers of cerebral small vessel disease (CSVD) and HT in patients after IVT. Methods: This study retrospectively analyzed computed tomography (CT) data for acute ischemic stroke patients before and after treatment with recombinant tissue plasminogen activator at a large Chinese hospital between July 2014 and June 2021. Total CSVD score were summed by individual CSVD markers including leukoaraiosis, brain atrophy and lacune. Binary regression analysis was used to explore whether CSVD markers were related to HT as the primary outcome or to symptomatic intracranial hemorrhage (sICH) as a secondary outcome. Results: A total of 397 AIS patients treated with IVT were screened for inclusion in this study. Patients with missing laboratory data (n = 37) and patients treated with endovascular therapy (n = 42) were excluded. Of the 318 patients included, 54 (17.0%) developed HT within 24-36 h of IVT, and 14 (4.3%) developed sICH. HT risk was independently associated with severe brain atrophy (OR 3.14, 95%CI 1.43-6.92, P = 0.004) and severe leukoaraiosis (OR 2.41, 95%CI 1.05-5.50, P = 0.036), but not to severe lacune level (OR 0.58, 95%CI 0.23-1.45, P = 0.250). Patients with a total CSVD burden ≥1 were at higher risk of HT (OR 2.87, 95%CI 1.38-5.94, P = 0.005). However, occurrence of sICH was not predicted by CSVD markers or total CSVD burden. Conclusion: In patients with acute ischemic stroke, severe leukoaraiosis, brain atrophy and total CSVD burden may be risk factors for HT after IVT. These findings may help improve efforts to mitigate or even prevent HT in vulnerable patients.

High ratio of C-reactive protein to albumin is associated with hemorrhagic transformation and poor functional outcomes in acute ischemic stroke patients after thrombolysis.

Background: In patients with acute ischemic stroke, hemorrhagic transformation (HT) is a common complication after intravenous thrombolysis (IVT). In this study, we evaluated the relationship between the ratio of C-reactive protein to albumin (CAR) before thrombolysis, HT, and functional outcomes in patients with acute ischemic stroke. Methods: We retrospectively analyzed data from 354 patients who received thrombolytic therapy at the Second Affiliated Hospital of the Wenzhou Medical University in China between July 2014 and May 2022. CAR was measured on admission, and HT was identified by cranial computed tomography (CT) within 24-36 h after treatment. Poor outcome was defined as a score on the modified Rankin Scale (mRS) > 2 at discharge. The multivariate logistic regression model was used to investigate the association between CAR, HT, and poor outcome after thrombolysis, respectively. Results: A total of 354 patients were analyzed, and their median CAR was 0.61 (interquartile range, 0.24-1.28). CAR was significantly higher in the 56 patients (15.8%) who experienced HT than in those who did not (0.94 vs. 0.56, p < 0.001), and the 131 patients (37.0%) who experienced poor outcome than in those who did not (0.87 vs. 0.43, p < 0.001). Multivariate logistic regression indicated that CAR was an independent risk factor for both HT and poor outcome. The risk of HT was significantly higher among patients whose CAR fell in the fourth quartile than among those with CAR in the first quartile (OR 6.64, 95% CI 1.83 to 24.17, p = 0.004). Patients with CAR in the third quartile were more likely to experience poor outcome (OR 3.35, 95% CI 1.32 to 8.51, p = 0.01), as were those in the fourth quartile (OR 7.33, 95% CI 2.62 to 20.50, p < 0.001), compared to patients with CAR in the first quartile. Conclusion: High ratio of C-reactive protein to albumin in individuals with ischemic stroke is associated with an increased risk of HT and poor functional outcomes after thrombolysis.

High ratio of monocytes to high-density lipoprotein is associated with hemorrhagic transformation in acute ischemic stroke patients on intravenous thrombolysis.

Background: Hemorrhagic transformation (HT) is a frequent, serious complication in acute ischemic stroke patients on intravenous thrombolysis. Here we investigated whether risk of HT is associated with the ratio of monocyte count to high-density lipoprotein level (MHR). Materials and methods: Medical records were retrospectively examined for consecutive patients with acute ischemic stroke who received thrombolytic therapy. HT was diagnosed by computed tomography at 24-36 h after therapy. Potential association between MHR and HT was examined using logistic regression. Results: A total of 340 patients were analyzed, and their median MHR was 0.44 (0.31-0.59). MHR was higher in the 51 patients (15.0%) with HT than in those who did not suffer HT (0.53 vs. 0.42, P = 0.001). Multivariate logistic regression showed that, after adjusting for potential confounders, MHR was an independent risk factor for HT (OR 7.50, 95% CI 1.64 to 34.35, P = 0.009). Risk of HT was significantly higher among patients whose MHR fell in the third quartile (0.42-0.53) and the fourth quartile (> 0.53) than among those with MHR in the first quartile (< 0.31; OR 3.53, 95% CI 1.11 to 11.20, P = 0.032; OR 4.79, 95% CI 1.49 to 15.42, P = 0.009). Conclusion: High MHR may be independently associated with higher risk of HT in patients with acute ischemic stroke on intravenous thrombolysis.

U-Shaped Association Between Serum Uric Acid and Hemorrhagic Transformation After Intravenous Thrombolysis.

BACKGROUND: Uric acid (UA) has both antioxidative and pro-oxidative properties. The study aimed to investigate the relationship between serum UA and hemorrhagic transformation (HT) after intravenous thrombolysis in patients with acute ischemic stroke. METHODS: The patients undergoing intravenous thrombolysis from two hospitals in China were retrospectively analyzed. HT was evaluated using computed tomography images reviewed within 24- 36h after thrombolysis. Symptomatic intracranial hemorrhage (sICH) was defined as HT accompanied by worsening neurological function. Multivariate logistic regression and spline regression models were performed to explore the relationship between serum UA levels and the risk of HT and sICH. RESULTS: Among 503 included patients, 60 (11.9%) were diagnosed with HT and 22 (4.4%) developed sICH. Patients with HT had significant lower serum UA levels than those without HT (245 [214-325 vs. 312 [256-370] µmol/L, p < 0.001). Multivariable logistic regression analysis indicated that patients with higher serum UA levels had a lower risk of HT (OR per 10-µmol/L increase 0.96, 95%CI 0.92-0.99, p = 0.015). Furthermore, multiple-adjusted spline regression models showed a Ushaped association between serum UA levels and HT (p < 0.001 for non-linearity). Similar results were present between serum UA and sICH. Restricted cubic spline models predicted the lowest risk of HT and sICH when the serum UA levels were 386µmol/L. CONCLUSION: The data show the U-shaped relationship between serum UA levels and the risk of HT and sICH after intravenous thrombolysis.

Cerebral small vessel disease and prognosis in intracerebral haemorrhage: A systematic review and meta-analysis of cohort studies.

BACKGROUND AND PURPOSE: The aim was to investigate whether cerebral small vessel disease (CSVD) markers and the total CSVD burden are associated with functional outcome, mortality, stroke recurrence and haematoma expansion in patients with spontaneous intracerebral haemorrhage (ICH). METHODS: Following a previously registered protocol (PROSPERO protocol: CRD42021287743), PubMed, Web of Science and Embase were systematically searched to identify relevant literature up to November 2021. Cohort studies that examined the association between CSVD markers (white matter hyperintensity [WMH], lacune, enlarged perivascular space [EPVS], cerebral microbleed [CMB] and brain atrophy) or CSVD burden and prognosis in patients with ICH were included. The pooled estimates were calculated using random effects models. RESULTS: Forty-one studies with 19,752 ICH patients were pooled in the meta-analysis. WMH (odds ratio [OR] 1.50, 95% confidence interval [CI] 1.32-1.70), lacune (OR = 1.32, 95% CI 1.18-1.49), CMB (OR = 2.60, 95% CI 1.13-5.97) and brain atrophy (OR = 2.22, 95% CI 1.48-3.31) were associated with worse functional outcome. CSVD markers concerning increased risk of mortality were WMH (OR = 1.57, 95% CI 1.38-1.79) and brain atrophy (OR = 1.84, 95% CI 1.11-3.04), and markers concerning increased risk of stroke recurrence were WMH (OR = 1.62, 95% CI 1.28-2.04) and lacune (OR = 3.00, 95% CI 1.68-5.37). Enlarged perivascular space was not related to prognosis. There was a lack of association between CSVD markers and haematoma expansion. CSVD burden increased the risk of worse functional outcome, mortality and stroke recurrence by 57%, 150% and 44%, respectively. CONCLUSIONS: In patients with spontaneous ICH, WMH, lacune, CMB, brain atrophy and the total CSVD burden are associated with substantially increased risk of worse functional outcome, mortality or stroke recurrence.

Troponin Elevation on Admission Along With Dynamic Changes and Their Association With Hemorrhagic Transformation After Thrombolysis.

Background: Hemorrhagic transformation (HT) is a common complication of intravenous thrombolysis with alteplase. Cardiac troponin has been found to be associated with poor prognosis and cognitive impairment in acute ischemic stroke. But studies on the relationship between troponin and HT after thrombolysis are scarce. Methods: This study retrospectively analyzed thrombolytic patients from June 2015 to June 2021 in the Second Affiliated Hospital of Wenzhou Medical University. Cardiac troponin I were measured on admission and on following days to determine the presence of elevation and dynamic changes. HT within 24-36 h after treatment was identified by cranial computed tomography (CT). Besides, a score on the modified Rankin Scale (mRS) > 2 at discharge was defined as unfavorable outcome. Univariate analysis was used to explore the factors related to the troponin elevation on admission and troponin dynamic changes. Multivariate logistic regression model was used to investigated the association between troponin elevation on admission, troponin dynamic changes and HT after thrombolysis, respectively. Results: Troponin levels on admission were measured in 377 patients, and follow-up assay was performed in 292 patients (77.5%). 39 patients (10.3%) had troponin elevation on admission, and 66 patients (22.6%) had troponin dynamic changes comprising rising and falling pattern. The pre-existing heart disease, renal insufficiency and higher stroke severity are related to both troponin elevation on admission and the subsequent troponin dynamic changes. After adjusting the potential confounding factors, logistic regression model showed that patients with troponin elevation on admission had insignificant trend to develop HT (OR 2.23, 95%CI 0.96-5.21, p = 0.063), while patients with troponin dynamic changes had significantly higher risk of HT (OR 2.27, 95%CI 1.06-4.85, p = 0.034). Compared to the troponin elevation, a statistically stronger association was present between rising troponin dynamic changes and unfavorable outcome (OR 2.20, 95%CI 1.05-4.60, p = 0.037). Conclusion: Troponin dynamic changes are associated with HT after thrombolysis. Serial measurements are quite necessary in thrombolytic patients with risk factors associated with troponin dynamic changes (e.g., advanced age, pre-existing heart disease, higher NIHSS score, and troponin elevation on admission).

Low Serum Magnesium Levels Are Associated With Hemorrhagic Transformation After Thrombolysis in Acute Ischemic Stroke.

Background: In patients with acute ischemic stroke, hemorrhagic transformation is a major complication after intravenous thrombolysis. This study aimed to investigate the relationship between serum magnesium levels and hemorrhagic transformation (HT) after thrombolytic therapy. Methods: We retrospectively analyzed data from 242 patients who received thrombolytic therapy at the Second Affiliated Hospital of the Wenzhou Medical University in China. Baseline serum magnesium levels were measured before intravenous thrombolysis, and the occurrence of HT was evaluated using computed tomography images reviewed within 24-36 h after therapy. The relationship between serum magnesium levels and HT was examined using multivariate logistic regression, subgroup analysis, and restricted cubic spline models. Results: Of the 242 included patients, 43 (17.8%) developed HT. Patients with HT had significant lower serum magnesium levels than those without HT (0.81 ± 0.08 vs. 0.85 ± 0.08 mmol/L, p = 0.007). Multivariable logistic regression analysis indicated that patients with higher serum magnesium levels had lower risk of HT (OR per 0.1-mmol/L increase 0.43, 95% CI 0.27-0.73, p = 0.002). However, this association did not persist when baseline levels of serum magnesium were higher than the median value (0.85 mmol/L) in subgroup analysis (OR per 0.1-mmol/L increase 0.58, 95% CI 0.14-2.51, p = 0.47). This threshold effect was also observed in the restricted cubic spline model when serum magnesium levels were above 0.88 mmol/L. No association between symptomatic HT and serum magnesium levels was observed in our study (OR per 0.1-mmol/L increase 0.52, 95% CI 0.25-1.11, p = 0.092). Conclusions: Lower serum magnesium levels in patients with ischemic stroke are associated with an increased risk of HT after intravenous thrombolysis, but perhaps only when serum magnesium is below a certain minimal concentration.

Associations of Clinical Characteristics and Etiology With Death in Hospitalized Chinese Children After Spontaneous Intracerebral Hemorrhage: A Single-Center, Retrospective Cohort Study.

Objective: We retrospectively analyzed clinical characteristics, etiology, and mortality risk factors in pediatric cases of non-traumatic spontaneous intracerebral hemorrhage. Methods: This study involved children between 29 days and 18 years old with confirmed spontaneous intracerebral hemorrhage based on head CT or MRI at the Second Affiliated Hospital of Wenzhou Medical University and Yuying Children's Hospital from January 2008 to March 2020. Demographic and clinical characteristics, etiology, imaging, and treatment data were collected at baseline. Potential risk factors of in-hospital death were identified using univariate analysis and multivariate logistic regression. Result: A total of 200 children (126 males, median age 5 years) were included in the study. Clinical symptoms of spontaneous intracerebral hemorrhage were typically non-specific (79.5%). One third of patients (31.1%) had a Glasgow Coma Scale score (GCS) ≤ 8, and nearly two-thirds (60.5%) showed a combination of ventricular hemorrhage or subarachnoid hemorrhage. Supratentorial hemorrhage was more common. Cerebrovascular disease (37.0%) and hematological disease (33.5%) were the most frequent etiologies of spontaneous intracerebral hemorrhage. Most patients (74.5%) received non-surgical treatment, while 25.5% received surgical treatment. After an average of 12 days of treatment, 167 children (83.5%) survived and 33 (16.5%) died. Multivariate logistic regression showed herniation syndrome, and low GCS (≤ 8) to be associated with increased risk of mortality, while hemorrhage due to arteriovenous malformation was associated with lower risk of mortality. Conclusion: Our data suggest that cerebrovascular disease is the most common cause of spontaneous intracerebral hemorrhage among children, and that arteriovenous malformation is associated with lower risk of death in hospital. Conversely, the presence of herniation syndrome, low GCS (≤ 8) increase risk of in-hospital mortality. Our results underscore the importance of timely imaging and supplementary examinations in cases of suspected spontaneous intracerebral hemorrhage.