Current Neurovascular Research - Volume 18, Issue 2, 2021

Background: Cerebral Cavernous Malformations (CCM) predispose patients to a lifetime risk of seizures and symptomatic hemorrhage. Only a small percentage of people affected will develop clinical symptoms and the molecular mechanisms underlying lesional activity remain unclear. We analyzed a panel of Single Nucleotide Polymorphisms (SNPs) in CCM patients. We looked for plasmatic inflammatory cytokines, checking for a pattern of plasma expression heterogeneity and any correlation with genetic variations identified with different CCM clinical phenotypes. Methods: This was a case-control study from a long-term follow-up cohort including 23 CCM patients, of which 16 were symptomatic, and 7 were asymptomatic. A 200-SNP panel was considered through next-generation sequencing and 18 different plasma molecules were assessed through a suspension array system. Results: Fcγ receptor IIa rs1801274 (FCGR2A) and protein tyrosine phosphatase non-receptor type 2 rs72872125 PTPN2 were statistically different between groups. Patients who had a combination of the presence of FCGR2A and the absence of PTPN2 also had symptoms earlier in life. The combination of genetic polymorphisms and serum level of GM-CSF showed the best diagnostic biomarker to distinguish symptomatic patients as formulated: [0.296*(FCGR2A)] + [-0.788*(PTPN2)] + [-0.107*(GM-CSF)]. Conclusion: We have shown that SNPs in inflammation genes might be related to a symptomatic phenotype in CCM. We also demonstrated that a formula based on two of these polymorphisms (FCGR2A+ and PTPN2+) is possibly capable of predicting a symptomatic phenotype during a patient’s lifetime.

Background: Many factors including genetic and environmental are responsible for the incidence of Age-related Macular Degeneration (AMD). However, its pathogenesis has not been clearly elucidated yet. Objective: This study aimed to estimate the Age-Related Maculopathy Susceptibility 2 (ARMS2), Collagen type VIII Alpha 1 chain (COL8A1), Rad 51 paralog(RAD51B), and Vascular Endothelial Growth Factor (VEGF) protein levels in serum of AMD and control participants and to further investigate their correlation to understand AMD pathogenesis. Methods: For this case-control study, 31 healthy control and 57 AMD patients were recruited from Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India. A blood sample was taken and serum was isolated from it. ELISA (enzyme-linked immunosorbent assay) was used for the estimation of proteins in the serum of patients. Results: ARMS2 and COL8A1 levels were significantly elevated in the AMD group than in the control group. The highest levels of ARMS2, COL8A1, and VEGF proteins were recorded for the wet AMD sub-group. The study results endorsed significant positive correlation between these following molecules; ARMS2 and COL8A1 (r = 0.933, p < 0.0001), ARMS2 and RAD51B (r = 0.704, p < 0.0001), ARMS2 and VEGF (r = 0.925, p < 0.0001), COL8A1 and RAD51B (r = 0.736, p < 0.0001), COL8A1 and VEGF (r = 0.879, p < 0.0001), and RAD51B and VEGF (r = 0.691, p < 0.0001). Conclusion: The ARMS2 and COL8A1 levels were significantly higher and RAD51B was significantly lower in the AMD group than controls. Also, a significant statistical correlation was detected between these molecules, indicating that their interaction may be involved in the pathogenesis of AMD.

Background: Cerebral ischemia-reperfusion injury is caused by a blood reperfusion injury in the ischemic brain and usually occurs in the treatment stage of ischemic disease, which can aggravate brain tissue injury. Objective: Curcumin was reported to exert a good therapeutic effect on neural cells against ischemia- reperfusion injury, However, the mechanism is not clear. Methods: In this study, Oxygen-Glucose Deprivation (OGD) model of fetal rat cerebral cortical neurons and the Middle Cerebral Artery Occlusion (MCAO) model of rats were employed to mimic cerebral ischemia-reperfusion injury in vitro and in vivo, respectively. Results: We confirmed that curcumin has a promotive effect on neuronal proliferation and an inhibitory effect on neuronal pyroptosis. Furthermore, we found that curcumin could improve cerebral infarction. The results of western blotting showed that curcumin down-regulated the expression of nucleotide-binding oligomerization domain-containing protein-, leucine-rich repeats-, and pyrin domain-containing protein 1 (NLRP1), cysteinyl aspartate-specific protease 1 (caspase-1), gasdermin D (GSDMD), IL-1β, IL-6, TNF-α, and iNOS proteins in OGD and MCAO models. NLRP1- dependent neuronal pyroptosis played an important role in cerebral ischemia-reperfusion injury. Conclusion: Curcumin could effectively inhibit NLRP1-dependent neuronal pyroptosis by suppressing the p38 MAPK pathway and therefore exerted neuroprotective effects against cerebral ischemia- reperfusion injury.

Background: Few studies have investigated the association between plasma Homocysteine (Hcy) levels in patients with recanalization after acute Basilar Artery Occlusion (BAO). Objective: This study investigated the predictive value of Hcy on the clinical prognosis of patients with recanalization after acute BAO. Methods: Altogether, 829 participants were recruited from the standard medical treatment plus endovascular treatment group of the Acute Basilar Artery Occlusion Study (BASILAR). Hcy levels were measured the morning after admission. The primary outcome was a combination of death and major disability (modified Rankin Scale score 4-6) at 90 days, and the secondary outcome was the mortality of patients with recanalization after acute BAO within 90 days. We used multivariable logistic regression modeling to estimate the association between Hcy and prognosis in our participants at 90 days. Results: Altogether, 647 patients were assessed, and 302 patients were included in this study. The median was 12.88 μmol/L, and the mean Hcy concentration was 15.49 μmol/L. Elevated plasma Hcy levels (Hcy >12.88 μmol/L) were associated with poor functional outcomes (adjusted odds ratio 1.922, 95% confidence interval (CI) 1.048-3.528, P=0.035), but not with mortality (adjusted odds ratio 1.605, 95% CI 0.986-2.489, P=0.058). In further subgroup analysis, the conclusion was consistent in all predefined subgroups. Conclusion: Our analysis suggests that elevated plasma Hcy levels have a predictive value for functional outcomes in patients with recanalization after acute BAO during the 90-day follow-up period, but not for mortality.

Background: Increasing evidences suggest that Neutrophil-to-Lymphocyte Ratio (NLR) is an independent predictor of poor prognosis in patients with cardiovascular disease. However, the relationship between NLR and prognosis in patients with Cerebral Venous Thrombosis (CVT) has not been studied. Methods: Consecutive CVT patients from November 2011 through April 2019 were retrospectively identified. Poor outcome was defined as a modified Rankin Scale (mRS) of 3-6. Multivariate regression analysis was conducted to assess the relationship between total and differential leukocyte counts, NLR and clinical outcome in CVT patients. The Receiver Operating Characteristic (ROC) analysis was further performed to evaluate the ability to predict mortality, and subgroup analysis was conducted to explore the potential interaction effects. Results: A total of 360 CVT patients were included, and the median duration of follow-up was 9.0 months. Multivariate logistic regression analysis suggested that NLR value, as a continuous variable, was significantly associated with a high risk of poor outcome (adjusted odds ratio [OR]=1.06, 95% confidence intervals [CI] 1.01-1.11, P = 0.013) and mortality (adjusted OR = 1.08; 95% CI, 1.03-1.14; P = 0.002). Compared with the total and differential leukocyte counts, the best discriminating variable to predict the risk of mortality was NLR, and the area under the receiver operating curve was 0.81. The optimal cut-off value of NLR to predict mortality was 5.6 (sensitivity 84.2%, specificity 69.9%). Multivariate Cox regression analysis indicated that the mortality rate was significantly higher in patients with a high NLR level group (>5.6) (adjust hazard ratio=5.65, 95% CI 2.33-12.73, P<0.001). There was no potential heterogeneity in the further subgroup analysis across age (above vs. below 45 years old), sex, history of infections and pregnancy/postpartum, presence of coma and intracerebral hemorrhage. Conclusion: Elevated NLR value is associated with a high risk of poor outcomes in CVT patients.

Background: Ischemic Stroke (IS) is a serious cerebrovascular disease, which leads to irreversible damage or death of brain cells. Effective control of stroke risk factors can effectively reduce the incidence of IS. However, there was an “obesity paradox” about the relationship between obesity and the prognosis of IS, in which obesity would not bring worse outcomes than non-obese IS patients. Objective: Herein, we aimed to investigate the transcriptional response to IS in obese and nonobese mice brain via RNA-Seq technology. The datasets of obese and non-obese mice with/without IS were obtained from the Gene Expression Omnibus (GEO) database. Methods: Differentially expressed genes (DEGs) between Control and Obesity (DEGsObesity) and between Obesity and Obese-Stroke (DEGsObese-Stroke) were identified. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Protein-Protein Interaction (PPI) network analysis were performed to predict the function of DEGs. 28 and 109 DEGs were screened in DEGsObesity and DEGsObese-Stroke, respectively. Results: Significantly, in the top 10 key-genes of DEGsObese-Stroke (Tnf, Lgals3, Serpinb2, Ly6c2, Chil3, Clec4e, Mmp3, Mefv, Spn, Tlr8), Tnf and Mefv were involved in the NOD-like receptor signaling pathway, which was consistent with KEGG pathway enrichment results. And Chil3, as a mononuclear cell marker, was significantly elevated in Obese-Stroke compared with Stroke, suggesting mononuclear cell, rather than other peripheral immune cells, infiltrated into the brain of Obese-stroke. Conclusion: Hence, we concluded that obesity could affect the brain microenvironment at the transcriptome level and Stroke after obesity could lead to more changes in NOD-like receptor signaling pathway and monocyte infiltration, compared with non-obese Stroke.

Aims: Brain vascular endothelial cell dysfunction after rtPA treatment is a significant factor associated with poor prognosis, suggesting that alleviation of rtPA-related endothelial cell injury may represent a potential beneficial strategy along with rtPA thrombolysis. Background: Thrombolysis with recombinant tissue plasminogen activator (rtPA) is beneficial for acute ischemic stroke but may increase the risk of Hemorrhagic Transformation (HT), which is considered ischemia-reperfusion injury. The underlying reason may contribute to brain endothelial injury and dysfunction related to rtPA against ischemic stroke. As previous studies have demonstrated that transiently blocked Cx43 using peptide5 (Cx43 mimetic peptide) during retinal ischemia reduced vascular leakage, it is necessary to know whether this might help decrease side effect of rtPA within the therapeutic time window. Objective: This study aims to investigate the effects of peptide5 on rtPA-related cell injury during hypoxia/reoxygenation (H/R) within the therapeutic time window. Methods: In this study, we established a cell hypoxia/reoxygenation H/R model in cultured primary Rat Brain Microvascular Endothelial Cells (RBMECs) and evaluated endothelial cell death and permeability after rtPA treatment with or without transient peptide5. In addition, we also investigated the potential signaling pathway to explore the underlying mechanisms preliminarily. Results: The results showed that peptide5 inhibited rtPA-related endothelial cell death and permeability. It also slightly increased tight junction (ZO-1, occluding, claudin-5) and β-catenin mRNA expression, demonstrating that peptide5 might attenuate endothelial cell injury by regulating the Wnt/ β-catenin pathway. The following bioinformatic exploration from the GEO dataset GSE37239 was also consistent with our findings. Conclusion: This study showed that the application of peptide5 maintained cell viability and permeability associated with rtPA treatment, revealing a possible pathway that could be exploited to limit rtPA-related endothelial cell injury during ischemic stroke. Furthermore, the altered Wnt/β- catenin signaling pathway demonstrated that signaling pathways associated with Cx43 might have potential applications in the future. This study may provide a new way to attenuate HT and assist the application of rtPA in ischemic stroke.

Objective: To investigate the factors related to the prognosis of Neuromyelitis Optica Spectrum Disorder (NMOSD) in cerebrospinal fluid and peripheral blood examination. Methods: In this study, we enrolled 111 patients who were admitted to the First Affiliated Hospital of Zhengzhou University between January 2016 and January 2018 and diagnosed with NMOSD. The patients were divided into the relapse group (n = 48) and remission group (n = 67). Before treatment, all the patients underwent a routine Cerebrospinal Fluid (CSF) and peripheral blood test on the second morning of admission. The association between laboratory data and disease prognosis was evaluated. Results: The immunoglobulin G (IgG) level in the serum showed a strong correlation with the relapse of patients, especially in the aquaporin-4-Antibody (AQP4-Ab) positive group (p < 0.01). A high level of serum IgG concentration was associated with the relapse of NMOSD, especially in the anti-AQP4 positive group. The area under the Receiver Operating Characteristic (ROC) curve of serum IgG level was 0.888 (p<0.001, 95%CI: 0.808-0.968). The ratio of Neutrophils to Lymphocytes (NLR) was associated with the disability degree of NMOSD patients in 3 years. The NLR value was a linear correlation with final Expanded Disability Status Scale (EDSS) scores; patients with a high level of NLR value presented an increased degree of disability in the following three years (R² = 0.053, p= 0.015). Conclusion: The serum IgG level and NLR of first-attack patients were correlated with the prognosis of NMOSD.

Background: The role of inflammation in the prognosis of cerebral venous sinus thrombosis (CVST) has been demonstrated in a small number of studies. The platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII) have been studied as prognostic inflammatory biomarkers in numerous thrombo-embolic diseases. However, the number of studies evaluating the relationship between these parameters and CVST is very low. Objective: The purpose of this retrospective study was to investigate the relationship between PLR, NLR, and SII values on admission and long-term prognosis in patients with CVST in the acute-subacute period. Methods: Fifty-one patients diagnosed with CVST and 51 healthy controls were included in the study. The patient and control groups were compared in terms of NLR, PLR, and SII values. Patients were classified into good and poor prognosis groups based on sixth-month modified Rankin scale scores (mRS) (0-2: good prognosis, 3-6: poor prognosis). Clinical and radiological features and PLR, NLR, and SII values were compared between the good and poor prognosis groups. Multivariate logistic regression analysis was used to identify independent prognostic factors for poor prognosis. The Receiver Operating Curve (ROC) was used to demonstrate the predictive power of PLR, NLR, and SII. Results: Higher NLR and SII emerged as independent factors for poor prognosis in patients with CVST. NLR was the strongest parameter in predicting poor prognosis in CVST (AUC: 0.817, 95% CI: 0.63-1.00, sensitivity 70%, specificity 92.7%, p:0.002). Conclusion: Higher NLR and SII on admission may be a predictor of long-term poor prognosis in patients with acute-subacute CVST.

Background: Posture Instability (PI) is known to be a severe complication in Parkinson’s Disease (PD), and its mechanism remains poorly understood. Our study aims to explore the changes of brain network in PI of PD, and further investigate the role of peripheral inflammation on activities of different brain regions in PD with PI. Methods: 167 individuals were recruited, including 36 PD cases with PI and 131 ones without PI. We carefully assessed the status of motor and cognitive function, measured serum inflammatory factors, and detected the dopaminergic pathways and the metabolism of different brain regions by Positron Emission Tomography (PET). Data analysis was conducted by variance, univariate analysis, chi-square analysis, logistic regression, and partial correlation. Results: No difference was found for age or onset age between the two groups (P>0.05). Female patients were susceptible to posture impairment and had a 2.14-fold risk for PI compared with male patients in PD (P<0.05). Patients with PI had more severe impairment of motor and cognitive function for a longer duration than those without PI (P<0.05). The mean uptake ratios of presynaptic vesicular monoamine transporter (VMAT2), which were detected in the caudate nucleus and putamen, were lower in PI group than those without PI (P<0.05). There were lower activities of the midbrain, caudate nucleus, and anterior medial temporal cortex in PI group than those in the non-PI group (P<0.05). Although serum concentrations of immunoglobulins (IgG, IgM, and IgA) and complements (C3, C4) were higher in the PI group than those in the non-PI group, only serum IgM concentration had a significant difference between the two groups (P<0.05). We further explored significant inverse correlations of IgG, IgM, IgA, and C4 with activities of some cerebral cortex in PI of PD (P<0.05). Conclusion: Female patients were susceptible to posture instability and had a 2.14-fold risk for PI of PD. Patients with PI had more severe impairments of motor and cognitive function for a longer duration than those without PI. PI was associated with a dopamine drop of the nigrostriatal system and lower activities of the limbic cortex in PD. Peripheral inflammation may be involved in degeneration of the cerebral cortex in PD combined with PI.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive damage of mesencephalic dopaminergic neurons of the substantia nigra and the striatal projections. Recent studies suggest that estrogen and estrogen-like chemicals have beneficial effects on neurodegenerative diseases, particularly PD. Animal studies demonstrate that estrogen influences dopamine’s synthesis, release, and metabolism. In vivo studies have also shown the significant beneficial effects of estrogen in shielding the brain from neurodegenerative processes like PD. Moreover, the expression and function of dopamine receptors can be modified by estrogen. Phytoestrogens are non-steroidal compounds derived from plants present in a large spectrum of foods, most specifically soy and in numerous dietary supplements. Phytoestrogens share structural and functional similarities with 17β-estradiol and can be used as an alternative treatment for PD because of estrogen’s undesirable effects, such as the increased risk of breast and endometrial cancer, ischemic disorders, and irregular bleeding. Despite the beneficial effects of phytoestrogens, their impact on human health may depend on age, health status, and even the presence or absence of specific gut microflora. In addition to their antioxidant properties, soy products or phytoestrogens also exhibit neuroprotective activity in patients with PD via the interaction with estrogen receptors (ER) α and β, with a higher affinity for ERβ. Phytoestrogens offer a valuable model for fully exploring the biological effects of endocrine disruptors in general. However, observational studies and randomized controlled trials in humans have resulted in inconclusive findings within this domain. This review considered the evidence in animal models and human epidemiological data as to whether developmental exposure to various phytoestrogen classes adversely or beneficially impacts the neurobehavioral programming in PD.