Current Neurovascular Research - Volume 15, Issue 4, 2018

Background: While the NOD-Like Receptor Protein-3 (NLRP3) inflammasome is involved in a variety of nervous system diseases, its role in epilepsy still needs to be further investigated. Methods: The expressions of NLRP3 inflammasome and apoptosis related proteins were examined by Western blot. MTT was used to assess cell viability. The role of NLRP3 inflammasome in epileptic neuronal apoptosis was further validated in NLRP3 knockout (KO) mice by Nissl staining. Results: Exposure of SH-SY5Y cells to free-Mg2+ solutions increased the expression of NLRP3 inflammasome with a concomitant increase in neuronal apoptosis. This effect was inhibited in cells treated with MCC950 as a common NLRP3 inhibitor, thereby implicating the role of NLRP3 inflammasome in epileptic neuronal apoptosis. In vivo relevance of this finding was further corroborated in the NLRP3 KO mice. Compared with the wild type mice, neuronal loss induced by pentylenetetrazole was significantly inhibited in the NLRP3 KO mice. Conclusion: The study presented herein demonstrates the interaction between NLRP3 inflammasome and epilepsy progression. In addition, MCC950 might represent an important therapeutic drug for the treatment of NLRP3 inflammasome driven epileptogenic activity.

Background: Grey Matter (GM) atrophy has been extensively described in Multiple Sclerosis (MS) patients, while cerebral hypoperfusion has been less consistently reported. Since hypoperfusion might be related to atrophy, we evaluated the presence of both damages. Objective: We aimed to assess if the regions of altered perfusion and atrophy overlapped with one another and if the two parameters were locally related. Method: 3D-T1 weighted and arterial spin labelling sequences were acquired using a 1.5T Magnetic Resonance Imaging scanner from 26 relapsing remitting MS patients and 26 Healthy Controls (HC). GM volume and Cerebral Blood Flow (CBF) differences and their correlation were tested with a voxel-wise approach. Results: MS patients (41.4±12.5 years; 14 females) had a median [25th-75th percentile range] Expanded Disability Status Scale of 1.0[1.0-2.4] and a median [25th-75th percentile range] disease duration of 8.0 [4.0-16.5] years. HC were age- and sex-matched (43.9±17.4 years; 11 females). GM atrophy was detected for MS group in the right parahippocampal gyrus, thalami and left caudate (pFWE≤0.05). Areas of significant (after family-wise error -FWE- correction for multiple comparisons) (pFWE≤0.05) hypoperfusion were found for MS in the anterior cingulate and paracingulate gyri, supplementary motor cortex, precentral and superior frontal gyrus. GM volume and CBF showed a significant correlation (pFWE≤0.05) in the right lateral occipital cortex and precuneus in the MS group. Conclusions: GM atrophy and hypoperfusion in MS were located in different areas. Perfusion estimate might be used as a further marker of tissue damage, in addition to GM volume.

Background: Uric Acid (UA) has been known to play a neuroprotective role in ischemic stroke patients. However, the relationship between UA levels and prognosis in patients with Cerebral Venous Thrombosis (CVT) has not been investigated. Method: A total of 228 CVT patients were retrospectively identified and were divided into three groups according to UA levels. Functional outcome was evaluated by the modified Rankin Scale (mRS). Multivariate logistic regression analysis was conducted to evaluate the relation between UA levels and functional outcome after CVT. Results: UA levels were significantly higher in male than female patients (274.5±125.9 vs. 197.4±81.6, P < 0.001). The association between UA levels and mortality was modified by sex (Pinteraction = 0.010). Multivariate logistic regression analysis indicated that a higher UA level was associated with a decreased risk of mRS of 3 to 6 in female patients (Odds Ratio [OR] = 0.204; 95% Confidence Interval [CI], 0.044-0.938), but not in male patients (OR= 0.441; 95% CI, 0.033- 5.339). Similarly, a high UA level was associated with a decreased risk of mortality in female patients (OR= 0.058; 95% CI, 0.008-0.437), but not in male patients (OR= 2.309; 95% CI, 0.057- 93.308). In addition, each 1 μmol/L increase in UA levels was also associated with a lower risk of poor clinical outcome and mortality for female patients, but not in male patients. Conclusion: Our study demonstrated that there might be a gender-specific relationship between UA levels and clinical outcome in patients with CVT. Higher UA levels were associated with better prognosis in female patients, but not in male patients.

Background: Recent studies indicated that multiple acute infarctions on Diffusion- Weighted Imaging (DWI) were associated with a higher risk of stroke. Objective: The study aims to estimate the association of different infarction patterns and ABCD2 score with the prognosis of Transient Ischemic Attack (TIA). Method: We prospectively analyzed the data from TIA database of the First Affiliated Hospital of Zhengzhou University. The predictive outcome was a 90-day ischemic stroke. Cox proportional hazards model was used to evaluate the predictive value of risk factors associated with stroke. The receiver-operating characteristics curves were plotted, and the predictive value was assessed by computing the Area Under the Curve (AUC). Results: A total of 1376 eligible patients were enrolled. DWI patterns were significant predictors for stroke (single acute infarction: hazard ratio [HR] =2.942, p <0.001; multiple acute infarctions: HR =5.552, p <0.001, in comparison with no acute infarction). Patients with both multiple infarctions and ABCD2 ≥4 were associated with approximately 15.5-fold risk of stroke at 90 days (28.8% vs. 2.1%, HR =15.455, 95% confidence interval [CI], 7.946-30.057, p <0.001), compared with those with no infarction or ABCD2 <4. The ABCD2+ DWI patterns showed a better discrimination with an AUC of 0.765 (95% CI, 0.741–0.787) than the ABCD2 score (AUC =0.651; 95% CI, 0.625-0.676; Z =4.777; p <0.0001) and ABCD3-I score (AUC =0.724; 95% CI, 0.700- 0.748; Z =2.697; p =0.007). Conclusion: Combining infarction patterns with ABCD2 score could enhance the predictive value for early stroke risk in TIA.

Background: There was a lack of studies on the association between Human Cytomegalovirus (HCMV) infection and prognosis of ischemic stroke, although it was indicated that human cytomegalovirus DNA has played a role in several cardiovascular disorders. Objective: To examine the association between HCMV IgM levels in the acute phase and death and major disability after 2 weeks of acute ischemic stroke. Methods: Serum HCMV IgM levels were measured in 1150 participants in China. Study outcome data on major disability and combined outcome of death and major disability were collected at 2 weeks after stroke onset or hospital discharge. Results: After 2 weeks of follow-up, 351 participants (30.52%) suffered from a major disability or died. Serum HCMV IgM was correlated with the combined outcome of death and major disability significantly after adjustment confounding factors. For example, the highest quartile of HCMV IgM was related to an odds ratio (95% confidence interval) of 1.84 (1.12-3.11) for the combined outcome. Risk prediction of the combined outcome was improved by the addition of serum HCMV IgM to conventional risk factors (net reclassification index 25.41%, p = 0.0002; integrated discrimination improvement 0.70%, p = 0.04377). Conclusions: Elevated serum HCMV IgM levels in the acute phase of ischemic stroke were correlated with increased risk of combined outcome of death and major disability, indicating that serum HCMV IgM could be an important predictive factor for poor prognosis of ischemic stroke.

Background: The neurovasculature dynamically responds to changes in cerebral blood flow by vascular remodeling processes. Serial imaging studies in mouse models could help characterize pathologic and physiologic flow-induced remodeling of the Circle of Willis (CoW). Method: We induced flow-driven pathologic cerebral vascular remodeling in the CoW of mice (n=3) by ligation of the left Common Carotid Artery (CCA), and the right external carotid and pterygopalatine arteries, increasing blood flow through the basilar and the right internal carotid arteries. One additional mouse was used as a wild-type control. Magnetic Resonance Imaging (MRI) at 9.4 Tesla (T) was used to serially image the mouse CoW over three months, and to obtain threedimensional images for use in Computational Fluid Dynamic (CFD) simulations. Terminal vascular corrosion casting and scanning electron microscope imaging were used to identify regions of macroscopic and microscopic arterial damage. Results: We demonstrated the feasibility of detecting and serially measuring pathologic cerebral vascular changes in the mouse CoW, specifically in the anterior vasculature. These changes were characterized by bulging and increased vessel tortuosity on the anterior cerebral artery and aneurysm- like remodeling at the right olfactory artery origin. The resolution of the 9.4T system further allowed us to perform CFD simulations in the anterior CoW, which showed a correlation between elevated wall shear stress and pathological vascular changes. Conclusion: In the future, serial high-resolution MRI could be useful for characterizing the flow environments corresponding to other pathologic remodeling processes in the mouse CoW, such as aneurysm formation, subarachnoid hemorrhage, and ischemia.

Background and Purpose: Leukocyte is currently known as a potential risk factor for symptomatic intracranial hemorrhage after reperfusion therapy, but there is little evidence on whether leukocyte is associated with the overall risk of Hemorrhagic Transformation (HT) after Acute Ischemic Stroke (AIS). Methods: Patients within seven days after stroke onset were included between January 2016 and October 2017. The laboratory data were collected within 24 hours after admission. HT was defined as hemorrhage presented on follow-up magnetic resonance imaging or Computed Tomography (CT) but not on baseline CT. The univariate analysis and multivariate logistic regression were performed to assess the association of white blood cell, neutrophil, lymphocyte, Neutrophil-To- Lymphocyte Ratio (NLR) with HT. Then the relationship between their levels and HT in different stroke subtypes was further studied. Results: We included 1233 Chinese AIS patients (mean age 64.10 ±14.53 years; 63.5% male). HT occurred in 145 patients (11.8%). After adjusting for confounders, NLR (odds ratio [OR] 1.295, 95% Confidence Interval [CI] 1.085-1.546, P=0.004) was independently associated with HT. In stroke subtypes, NLR was found to be significantly related to HT in cardio-embolic stroke (OR 1.366, 95% CI 1.019-1.830, P=0.037) but showed no significance in large-artery atherosclerosis, small-artery occlusion and undetermined etiology. Conclusions: Higher level of NLR is associated with greater risk of hemorrhagic transformation in patients with acute ischemic stroke, especially in cardio-embolic stroke. Moreover, the results suggest that therapeutic interventions that may increase the risk of bleeding should be undertaken carefully in the management of AIS patients with higher NLR.

Introduction: Parkinson’s Disease (PD) is a debilitating, age-related disorder characterized by selective degeneration of dopaminergic neurons in the midbrain substantia nigra (SNc). Dopaminergic neurons originating in the midbrain project to the striatum (Caudate-putamen-CPU). Although studies have suggested that the extracellular signal-regulated kinase ½ (ERK ½) in the brain is activated after 1-Methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) exposure, to our knowledge no study has yet been done to demonstrate whether such activation occurs in neurons or in glia. Material and Methods: In the current study, we utilized both an acute and a repeat dose mouse model of PD using the neurotoxicant MPTP as the causative agent. Immunohistochemical studies using phospho ERK ½ antibody suggested that ERK ½ activation takes place in the striatum (CPU) and SNc of both animal models. Moreover, double immunolabeling studies using phospho ERK ½ and the microglial marker, CD11b or the astrocyte marker, Glial Fibrillary Acidic Protein (GFAP) suggested that the phospho ERK ½ was present exclusively in the microglia and not in the astrocytes. Results: Western Blot results suggested that there were no alterations in ERK in either MPTPtreated animals or in control animals; however, phospho ERK ½ was found to be significantly increased in the striatum and SNc in both acute chronic mouse PD models. Tyrosine Hydroxylase (TH) immunolabeling revealed significant decreases in dopaminergic neurons in the SNc in both animal models' concomitant with activation of microglia and ERK activation. Conclusion: These observations suggest that ERK activation takes place following MPTP treatment and that activation of ERK occurs primarily in the microglia. The data provided also suggest that ERK activation may be involved in transcriptional activation of microglia following neurotoxicant insults.

Background: A number of epidemiological studies have revealed a controversial correlation between Blood Pressure (BP) and the risk of dementia, hindering translation of research into preventative practice. Objective: To meta-analyze the dose-response relationship of dementia and its subtypes to BP. Method: Relevant studies were identified via a systematic retrieval analysis in electronic databases from inception to May 1, 2017. Linear and non-linear dose-response meta-analyses were conducted to evaluate the effects of BP on dementia risk. Results: Twenty-three studies from 17 articles with 830631 participants and 4384 cases for all dementia, 17 studies from 12 articles with 1707445 participants and 3481 cases for Alzheimer’s disease (AD) and 11 studies from 8 articles with 1693690 participants and 1067 cases for Vascular Dementia (VD) were included. We identified that the associations between BP and dementia varied with population characteristics. A nonlinear relationship was found between systolic blood pressure (SBP) and all dementia risk in population-aged ≥ 65 years (pnonlinearity <0.05). SBP between 110 and 120mmHg played a protective role in population aged 62 to 82; while SBP above 162 mmHg would significantly increase the risk in those aged 70 to 86.5. It is also noteworthy that there is a linear association between diastolic blood pressure (DBP) and AD risk in the population aged ≥ 65 years, such that the risk decreased by 3% for per 10 mmHg increase in a specific range of DBP. Conclusion: These findings indicate that BP management strategy for dementia prevention might be tailored according to specific population characteristics.

Bradykinin (BK) is a major kinin substance in the Kallikrein-Kinin System (KKS) that acts in conjunction with target cell bradykinin receptors and is involved in a variety of systems and organs. Functional regulation and pathophysiological processes such as cardiovascular, renal, central nervous system regulation, glucose metabolism, cell proliferation, smooth muscle contraction, inflammation, pain, shock, and tissue damage processes, etc. The role and mechanism of receptors in the mediation of ischemic injury in tissues was reviewed.

The world's population continues to age at a rapid pace. By the year 2050, individuals over the age of 65 will account for sixteen percent of the world’s population and life expectancy will increase well over eighty years of age. Accompanied by the aging of the global population is a significant rise in Non-Communicable Diseases (NCDs). Neurodegenerative disorders will form a significant component for NCDs. Currently, dementia is the 7th leading cause of death and can be the result of multiple causes that include diabetes mellitus, vascular disease, and Alzheimer’s Disease (AD). AD may represent at least sixty percent of these cases. Current treatment for these disorders is extremely limited to provide only some symptomatic relief at present. Sirtuins and in particular, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), represent innovative strategies for the treatment of cognitive loss. New work has revealed that SIRT1 provides protection against memory loss through mechanisms that involve oxidative stress, Aβ toxicity, neurofibrillary degeneration, vascular injury, mitochondrial dysfunction, and neuronal loss. In addition, SIRT1 relies upon other avenues that can include trophic factors, such as erythropoietin, and signaling pathways, such as Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4). Yet, SIRT1 can have detrimental effects as well that involve tumorigenesis and blockade of stem cell differentiation and maturation that can limit reparative processes for cognitive loss. Further investigations with sirtuins and SIRT1 should be able to capitalize upon these novel targets for dementia and cognitive loss.