Current Neurovascular Research - Volume 16, Issue 1, 2019

Introduction: Endoplasmic reticulum (ER) stress induced the mobilization of two protein breakdown routes, the proteasomal- and autophagy-associated degradation. During ERassociated degradation, unfolded ER proteins are translocated to the cytosol where they are cleaved by the proteasome. When the accumulation of misfolded or unfolded proteins excels the ER capacity, autophagy can be activated in order to undertake the degradative machinery and to attenuate the ER stress. Autophagy is a mechanism by which macromolecules and defective organelles are included in autophagosomes and delivered to lysosomes for degradation and recycling of bioenergetics substrate. Materials and Methods: Autophagy upon ER stress serves initially as a protective mechanism, however when the stress is more pronounced the autophagic response will trigger cell death. Because autophagy could function as a double edged sword in cell viability, we examined the effects autophagy modulation on ER stress-induced cell death in HT22 murine hippocampal neuronal cells. We investigated the effects of both autophagy-inhibition by 3-methyladenine (3-MA) and autophagy-activation by trehalose on ER-stress induced damage in hippocampal HT22 neurons. We evaluated the expression of ER stress- and autophagy-sensors as well as the neuronal viability. Results and Conclusion: Based on our findings, we conclude that under ER-stress conditions, inhibition of autophagy exacerbates cell damage and induction of autophagy by trehalose failed to be neuroprotective.

Background: Intracranial aneurysms (IAs) are life-threatening lesions known within the literature to be found incidentally during routine angiographic workup for carotid artery stenosis (CAS). As IAs are associated with vascular shear stress, it is reasonable to expect that altered flow demands within the anterior circulation, such as with CAS, increase compensatory flow demands via the Circle of Willis (COW) and may induce similar stress at the basilar apex. Objective: We present a series of nine unruptured basilar apex aneurysms (BAA) with CAS and a comparative radiographic analysis to BAA without CAS. Methods: Twenty-three patients with BAA were retrospectively identified using records from 2011 to 2016. CAS by North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria, morphology of BAA, competency of COW, and anatomic relationships within the posterior circulation were examined independently by a neuroradiologist using angiographic imaging. Results: Nine (39%) of the twenty-three BAA patients had CAS, with six having stenosis ≥50%. Four (67%) of the patients with ≥50% CAS demonstrated aneurysm flow angles contralateral to the side with highest CAS. Additionally, the angle between the basilar artery (BA) trajectory and aneurysm neck was observed to be smaller in patients with ≥50% CAS (61 vs 74 degrees). No significant differences in COW patency, posterior circulation morphology, and degree of stenosis were observed. Conclusion: Changes in the cervical carotid arteries may lead to blood flow alterations in the posterior circulation that increase the propensity for BAA formation. Posterior circulation imaging can be considered in CAS patients to screen for BAA.

Background: Endothelial Progenitor Cells (EPCs) are important players in neovascularization, mobilized through signalling by Angiogenic Growth Factors (AGFs) such as Vascular Endothelial Growth Factor (VEGF) and fibroblast growth factor (FGF). In vitro, inflammatory parameters impair the function and influence of EPCs on AGFs. However, this connection is not clear in vivo. To understand the mechanisms of augmented arteriogenesis and angiogenesis in acute ischemic stroke (AIS) patients, we investigated whether circulating stem cells (CD133+), early endothelial progenitor cells (CD133+/VEGFR2+), and endothelial cells (ECs; CD34¯/CD133¯/VEGFR2+) were increasingly mobilized during AIS, and whether there were correlations between EPC levels, growth factor levels and inflammatory parameters. Methods: Data on demographics, classical vascular risk factors, neurological deficit information (assessed using the National Institutes of Health Stroke Scale), and treatment were collected from 43 consecutive AIS patients (group I). Risk factor control patients (group II) included 22 nonstroke subjects matched by age, gender, and traditional vascular risk factors. EPCs were measured by flow cytometry and the populations of circulating stem cells (CD133+), early EPCs (CD133+/VEGFR2+), and ECs (CD34¯/CD133¯/VEGFR2+) were analysed. Correlations between EPC levels and VEGF and FGF vascular growth factor levels as well as the influence of inflammatory parameters on EPCs and AGFs were assessed. Results: Patient ages ranged from 54 to 92 years (mean age 75.2 ± 11.3 years). The number of circulating CD34¯/CD133¯/VEGF-R2+ cells was significantly higher in AIS patients than in control patients (p < 0.05). VEGF plasma levels were also significantly higher in AIS patients compared to control patients on day 7 (p < 0.05). FGF plasma levels in patients with AIS were significantly higher than those in the control group on day 3 (p < 0.05). There were no correlations between increased VEGF and FGF levels and the number of CD133+, CD133+/VEGFR2+, or CD34¯/CD133¯/VEGFR2+ cells. Leukocyte levels, FGF plasma levels, and the number of early EPCs were negatively correlated on day 3. High sensitivity C-reactive protein levels and the number of CD133+ and CD133+/VEGFR2+ cells were negatively correlated on day 7. In addition, there was a negative correlation between fibrinogen levels and FGF plasma levels as well as the number of early EPCs (CD133+/VEGFR2+). Conclusion: AIS patients exhibited increased numbers of early EPCs (CD133+/VEGFR2+) and AGF (VEGF and FGF) levels. A negative correlation between inflammatory parameters and AGFs and EPCs indicated the unfavourable influence of inflammatory factors on EPC differentiation and survival. Moreover, these correlations represented an important mechanism linking inflammation to vascular disease.

Introduction: Cerebral hypoperfusion has been considered as major risk factor for Vascular Dementia (VaD). The present study shows the potential of Tadalafil, a phosphodiesterase-5 inhibitor, in bilateral common carotid artery occlusion (BCCAo) induced VaD in rats. Materials and Methods: BCCAo procedure was performed under anesthesia in wistar rats to induce VaD. Morris Water-Maze (MWM) parameter was employed on 7th day post-surgery to determine learning and memory. Escape latency time, time spent in target quadrant, Path length and average swim speed taken as important parameters in MWM. Endothelial dysfunction was assessed in isolated aorta by observing endothelial dependent vasorelaxations and levels of serum nitrite. Various biochemical and histopathological estimations were also performed. Results: BCCAo produced significant impairment in endothelium dependent vasorelaxation and a decrease in serum nitrite levels indicating endothelial dysfunction. Further poor performance on MWM represents impairment of learning and memory. There was a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid reactive species and decrease in reduced glutathione levels). Increase in brain acetylcholinesterase activity; brain myloperoxidase activity and brain neutrophil infiltration (as marker of inflammation) were also observed. Treatment of Tadalafil (5 & 10 mg/kg, p. o.)/Donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated BCCAo induced endothelial dysfunction; memory deficits; biochemical and histopathological changes in a significant manner. Conclusion: It may be concluded that Tadalafil has shown efficacy in rat model of BCCAo induced VaD and that phosphodiesterase-5 can be considered as an important therapeutic target for the treatment of VaD.

Background and Purpose: Hyperglycemia is reported to be associated with poor outcome in patients with spontaneous Intracerebral Hemorrhage (ICH), but the association between blood glucose level and outcomes in Primary Intraventricular Hemorrhage (PIVH) remains unclear. We sought to identify the parameters associated with admission hyperglycemia and analyze the impact of hyperglycemia on clinical outcome in patients with PIVH. Methods: Patients admitted to Department of Neurosurgery, West China Hospital with PIVH between 2010 and 2016 were retrospectively included in our study. Clinical, radiographic, and laboratory data were collected. Univariate and multivariate logistic regression analyses were used to identify independent predictors of poor outcomes. Results: One hundred and seventy patients were included in the analysis. Mean admission blood glucose level was 7.78±2.73 mmol/L and 10 patients (5.9%) had a history of diabetes mellitus. History of diabetes mellitus (P = 0.01; Odds Ratio [OR], 9.10; 95% Confidence Interval [CI], 1.64 to 50.54) was independent predictor of admission critical hyperglycemia defined at 8.17 mmol/L. Patients with admission critical hyperglycemia poorer outcome at discharge (P < 0.001) and 90 days (P < 0.001). After adjustment, admission blood glucose was significantly associated with discharge (P = 0.01; OR, 1.30; 95% CI, 1.06 to 1.59) and 90-day poor outcomes (P = 0.03; OR, 1.27; 95% CI, 1.03 to 1.58), as well as mortality at 90 days (P = 0.005; OR, 1.41; 95% CI, 1.11 to 1.78). In addition, admission critical hyperglycemia showed significantly increased the incidence rate of pneumonia in PIVH (P = 0.02; OR, 6.04; 95% CI 1.27 to 28.80) even after adjusting for the confounders. Conclusion: Admission blood glucose after PIVH is associated with discharge and 90-day poor outcomes, as well as mortality at 90 days. Admission hyperglycemia significantly increases the incidence rate of pneumonia in PIVH.

Background: Although several studies have evaluated the change of cognitive performance after severe carotid artery stenosis, the results still remain elusive. The objective of this study was to assess changes in cognitive function, depressive symptoms and Health Related Quality of Life (HRQoL) after carotid stenosis revascularisation and Best Medical Treatment (BMT). Methods: Study involved 213 patients with ≥70% carotid stenosis who underwent assessment of cognitive function using Montreal Cognitive Assessment scale (MoCA), depressive symptoms - using Patient Health Questionnaire-9 (PHQ-9) and HRQoL - using Medical Outcome Survey Short Form version 2 (SF-36v2). The assessment was performed before and at 6 and 12 months followup periods in patients who had Carotid Endarterectomy (CEA), Carotid Artery Stenting (CAS) or received BMT only. Results: Improvement in the total MoCA scores was observed after 6 and 12 months (p<0.001, Kendall's W=0.28) in the CEA group. In the CAS group - after 12 months (p=0.01, Kendall's W=0.261) whereas in the BMT group - no significant changes (p=0.295, Kendall's W=0.081) were observed. Reduction of depressive symptoms was not found in any of the study groups. Comparing mean SF-36v2 scores in the CEA group, there was no significant difference in any of 10 subscales. Likewise in the CAS group - no significant difference in 9 of 10 subscales (p=0.028, η2=0.343) was observed. Three subscales worsened in the BMT group during the 1-year follow-up period. Conclusion: Patients with severe carotid stenosis who underwent revascularisation enhanced their cognitive performance without exerting significant change of depressive symptoms. Preoperative HRQoL may be maintained for at least one year in the CEA group.

Background: The exact causes of intracranial aneurysms (IAs) are still unknown. However, certain diseases are known to be associated with IAs. Objective: To analyze the differences in IA characteristics in the general population and in individuals with sickle-cell disease (SCD). Methods: We systematically searched PubMed, Scopus, Web of Science, and Cochrane Library for Data on SCD patients with IAs. We compared IA characteristics of SCD patients with those from 2451 healthy IA carriers from our observational cohort. Results: 129 SCD patients with IAs were identified in 42 studies. The SCD patient cohort was characterized by younger age (mean 27.1 vs 54.9 years, p<0.0001) and lower female prevalence (57.7% vs 68.4%, p=0.0177). The prevalence (47% vs 34.5%, p=0.004) and the number (3.02 vs 2.56 IAs/patient, p=0.004) of multiple IAs were also higher in the SCD cohort. Unruptured IAs (3.27 vs 6.16 mm, p<0.0001), but not ruptured IAs (7.8 vs 7.34 mm, p=0.9086) were significantly smaller in the SCD cohort. In addition, IAs were more frequently located in the internal carotid artery (45% vs 29%, p<0.0001) or posterior circulation (43% vs 20%, p<0.0001). Higher age (≥30 years, p=0.007), IA size ≥7 mm (p=0.008), and location in posterior circulation (p=0.01) were independently associated with subarachnoid hemorrhage in SCD. Conclusion: There is a distinct demographic and radiographic pattern of IA in SCD. Risk factors for IA rupture in SCD are mostly congruent with those in healthy individuals.

Background and Purpose: Cerebral Venous Sinus Stenosis (CVSS) usually results in severe Intracranial Hypertension (IH), which can be corrected by stenting immediately. However, there is a lack of evidence of the long-term good outcomes in patients with CVSS who underwent stenting. Methods: A total of 62 patients with imaging confirmed non-thrombotic and non-external compression CVSS were enrolled into this single center real-world cohort study after undergoing stenting, and were continuously followed up for more than 12 years. The symptoms and signs of IH prior to stenting and post-stenting and the incidence of restenosis after stenting were analyzed. Results: The mean age of the 62 patients (range, 13 to 62) was 40 years old, and the mean body mass index was 26 (range 23 to 40). Females accounted for 67.7% (42/62). Headache was the most common symptom (79%). Transient visual obscurations occurred in 69% of the patients. 42% of the patients suffered from visual loss, 11.3% pulsatile tinnitus, and 96.8% Papilledema before stenting. The mean trans-stenotic pressure gradients were 6~43 mmHg prior to stenting and returned to 0~4 mmHg after stent placement. During the following 12~126 months (the median was 62) after stenting of the follow-up, 91.9% (57/62) of the patients obtained good outcomes. Headaches disappeared in 96% (47/49) of the patients and papilledema was attenuated in 98.3% (59/60). However, There were still 8.0 % (5/62) of the patients with poor outcomes, including optic disc atrophy in 3 patients and stent-interior thrombosis in 2 patients, which occurred 6.3 months after stenting. Conclusion: Our data suggest that stenting may be a promising therapy for CVSS correcting. Patients with CVSS may get long-term benefit from stenting, especially when they are accompanied with severe IH.

Background: Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms have been reported to be associated with ischemic stroke. However, the association between serum MTHFR level and ischemic stroke has not yet been studied. We aimed to examine the association between them in patients with large-artery atherosclerotic stroke and community-based healthy controls. Methods: This study includes three hundred ninety-five patients with large-artery atherosclerotic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and 395 age- and sex-matched healthy controls from Chinese communities. Serum MTHFR concentrations were examined and some conventional risk factors of stroke were collected. The association between serum MTHFR and large-artery atherosclerotic stroke was evaluated. Results: A U-shaped association of serum MTHFR level with large-artery atherosclerotic stroke was observed (p for nonlinearity =0.008). After multivariate adjustment, the odds ratios (95% confidence intervals) of large-artery atherosclerotic stroke associated with the first, second, fourth, and fifth quintiles of MTHFR were 5.62 (1.10-28.87), 2.13 (0.51-8.99), 1.08 (0.21-5.56), and 2.31 (0.57-9.34), respectively, compared with the third quintiles of MTHFR. Adding MTHFR quintiles to a model containing conventional risk factors improved the predictive power for large-artery atherosclerotic stroke (continuous net reclassification improvement=63.78%, p<0.001; categorical net reclassification improvement=2.54%, p=0.012). Conclusion: There is a significant U-shaped relationship between serum MTHFR levels and largeartery atherosclerotic stroke. Our findings raise the possibility that serum MTHFR may have a potential role in the pathogenesis of large-artery atherosclerotic stroke.

Objective: With the aging of the world population, the number of elderly patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) is gradually growing. We aim to investigate the potential association between plasma ALT level and clinical complications of elderly aSAH patients, and explore its predictive value for clinical outcomes of elderly aSAH patients. Methods: Between January 2013 and March 2018, 152 elderly aSAH patients were analyzed in this study. Clinical information, imaging findings and laboratory data were reviewed. According to the Glasgow Outcome Scale (GOS), clinical outcomes at 3 months were classified into favorable outcomes (GOS 4-5) and poor outcomes (GOS 1-3). Logistic regression analysis was used to assess the indicators associated with poor outcomes, and receiver curves (ROC) and corresponding area under the curve (AUC) were used to detect the accuracy of the indicator. Results: A total of 48 (31.6 %) elderly patients with aSAH had poor outcome at 3 months. In addition to ICH, IVH, Hunt-Hess 4 or 5 Grade and Modified Fisher 3 or 4 Grade, plasma ALT level was also strongly associated with poor outcome of elderly aSAH patients. After adjusting for other covariates, plasma ALT level remained independently associated with pulmonary infection (OR 1.05; 95% CI 1.00–1.09; P = 0.018), cardiac complications (OR 1.05; 95% CI 1.01–1.08; P = 0.014) and urinary infection (OR 1.04; 95% CI 1.00–1.08; P = 0.032). Besides, plasma ALT level had a predictive ability in the occurrence of systemic complications (AUC 0.676; 95% CI: 0.586– 0.766; P<0.001) and poor outcome (AUC 0.689; 95% CI: 0.605–0.773; P<0.001) in elderly aSAH patients. Conclusion: Plasma ALT level of elderly patients with aSAH was significantly associated with systemic complications, and had additional clinical value in predicting outcomes. Given that plasma ALT levels on admission could help to identify high-risk elderly patients with aSAH, these findings are of clinical relevance.

Carotid Artery Stenosis (CAS) is a marker of systemic atherosclerosis and patients with CAS are at high risk of vascular events in multiple vascular locations, including ipsilateral ischemic stroke. Both medical and surgical therapies have been demonstrated effective in reducing this risk. The optimal management for patients with asymptomatic carotid artery stenosis remains controversial. In patients with symptomatic CAS ≥70%, CEA has been demonstrated to reduce the risk of stroke. With the risk of recurrent stroke being particularly high in the first 2 weeks after the first event, Carotid Endarterectomy (CEA) or carotid angioplasty with stenting provides maximal benefits to patients with symptomatic CAS ≥70% if performed within this «2-week» target. Several large ongoing trials are currently comparing the risks and benefits of carotid revascularization versus medical therapy alone.