Current Neurovascular Research - Volume 20, Issue 5, 2023

Background: Studies about the association between bilirubin and migraine were few. Therefore, the purpose of this study was to investigate the association between serum total bilirubin and the prevalence of severe headaches or migraine. Methods: A multivariable logistic regression was used to assess the association between serum total bilirubin concentration and severe headaches or migraine. We also performed stratified analyses, interaction analyses and multiple interpolations in the sensitivity analysis. Results: This cross-sectional study included 12,552 adults from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. The overall incidence of migraine was 19.99% (2,509/12,552). With every 1 mg/dl increase in bilirubin, the prevalence of migraine decreased by 23% (95% CI: 0.64, 0.93) after adjustment of all related covariates. Similarly, the risk of migraine was reduced by 17% (95% CI: 0.72, 0.97) in the Q4 group (the fourth quartile, highest serum total bilirubin level) compared with the Q1 group (the lowest level). Furthermore, interaction effects by age groups were significant in this relationship (P for interaction = 0.0004). In the Q4 group compared with Q1, inverse associations were observed in those aged ≥40 years (OR: 0.71,95% CI: 0.59, 0.85) in the stratified analysis. Conclusion: These findings support an association between serum total bilirubin and severe headaches or migraine, revealing an inverse association between serum total bilirubin quartiles and severe headaches or migraine in American adults. Age could play an important role in this association.

Background: The common and internal carotid arteries are the upstream vessels of the small cerebral vessels. The relationship between hemodynamic changes in the significant cervical vessels and cerebral small vessel disease (CSVD) remains uncertain. This research sought to analyze the correlation between carotid blood flow velocity and the total magnetic resonance imaging (MRI) burden of CSVD in patients with recent small subcortical infarcts (RSSIs). Methods: Data were gathered from individuals diagnosed with RSSIs admitted to Changzhou Second People's Hospital between January 2022 and June 2023. Brain MRI was performed on every patient to determine the overall MRI burden of CSVD, along with carotid duplex ultrasound to evaluate carotid blood flow velocity and pulsatility index (PI) of the common carotid (CCA) and internal carotid (ICA) arteries. The association between carotid blood flow velocity and the total MRI load of CSVD was examined using univariate and multivariate analyses. Results: For our investigation, 272 individuals with RSSIs were screened. 82 individuals had a moderate to severe load of CSVD, while 190 participants showed a mild burden. Patients with moderate to severe burden of CSVD had lower end-diastolic velocity (EDV) and higher PI in CCA and ICA than those with mild load (P < 0.001). After adjusting for variables like age, hypertension, systolic blood pressure, and blood homocysteine levels, multivariate logistic regression analysis showed that EDV in CCA (OR, 0.894; P = 0.011), PI in CCA (OR, 5.869; P = 0.017), EDV in ICA (OR, 0.909; P = 0.008), and PI in ICA (OR, 5.324; P = 0.041) were independently related to moderate to severe CSVD burden. Spearman correlation analysis showed that EDV in CCA and ICA was negatively related to the total MRI load of CSVD in patients with RSSIs (P < 0.001). PI in CCA and ICA was positively associated with the whole MRI load of CSVD (P < 0.001). Conclusion: Low carotid blood flow velocity and high carotid pulsatility index are independently associated with moderate to severe burden of CSVD.

Aims: To investigate the factors of postoperative malignant brain edema (MBE) in patients with acute ischemic stroke (AIS) treated with endovascular treatment (EVT). Background: MBE is a severe complication following EVT for AIS, and it is essential to identify risk factors early. Peripheral arterial lactate (PAL) levels may serve as a potential predictive marker for MBE. Objective: To determine whether immediate postoperative PAL levels and the highest PAL level within 24 hours of EVT are independently associated with MBE development in AIS patients. Methods: We retrospectively analyzed patients with AIS who underwent EVT from October 2019 to October 2022. Arterial blood was collected every 8 h after EVT to measure PAL, and record the immediate postoperative PAL and the highest PAL level within 24 h. Brain edema was evaluated using brain computed tomography scans within 7 days of EVT. Results: The study included 227 patients with a median age of 71 years, of whom 59.5% were male and MBE developed in 25.6% of patients (58/227). Multivariate logistic regression analysis showed that the immediate postoperative PAL (odds ratio, 1.809 [95% confidence interval (CI), 1.215-2.693]; p = 0.004) and the highest PAL level within 24 h of EVT (odds ratio, 2.259 [95% CI, 1.407-3.629]; p = 0.001) were independently associated with MBE. The area under the curve for predicting MBE based on the highest PAL level within 24 hours of EVT was 0.780 (95% CI, 0.711-0.849). Conclusion: Early increase in PAL levels is an independent predictor of MBE after EVT in AIS patients.

Objective: Diffusion-weighted imaging (DWI) is commonly detected after spontaneous intracerebral hemorrhage (sICH) and is associated with poor functional outcomes. However, the etiology and significance of DWI lesions remain unclear. Thus, our study aimed to explore the prevalence and risk factors of acute ischemic lesions in sICH and discussed the possible mechanisms. Methods: We conducted a retrospective review of a consecutive cohort of 408 patients from June 2013 to October 2019 with sICH, who had brain computed tomography (CT) and magnetic resonance imaging (MRI) within 14 days of symptoms onset. Acute ischemic lesions were assessed on MRI using DWI lesions. We compared the clinical and imaging characteristics of patients with and without DWI lesions. The data were analyzed by univariate and multivariate logistic regression. Results: Among the enrolled 408 patients, the mean age was 56.8 ± 14.5 years, 68 (16.7%) of them had been diagnosed with diabetes mellitus (DM). DWI lesions were observed in 89 (21.8%) patients, and most of them had a history of lacunar infarctions, which were located in cortical or subcortical. In multivariate logistic regression analysis, DM (odds ratio (OR) 3.962, p <0.001), severe deep white matter hypertensities (DWMH) (OR 2.463, p =0.001) and severe centrum semiovale enlarged perivascular spaces (CSO-EPVS) (OR 2.679, p =0.001) were independently associated with the presence of DWI lesions. Conclusion: In our cohort, we found DM, severe DWMH and severe CSO-EPVS were the independent risk factors in sICH patients with DWI lesions.

Background: High brain-derived neurotrophic factor (BDNF) concentrations have been found to be associated with a decreased risk of Alzheimer’s disease (AD) in observational studies, but the causality for this association remains unclear. Therefore, we aimed to examine the association between genetically determined plasma BDNF levels and AD using a two-sample Mendelian randomization (MR) method. Methods: Twenty single-nucleotide polymorphisms associated with plasma BDNF concentrations were identified as genetic instruments based on a genome-wide association study with 3301 European individuals. Summary-level data on AD were obtained from the International Genomics of Alzheimer's Project, involving 21,982 AD cases and 41,944 controls of European ancestry. To evaluate the relationship between plasma BDNF concentrations and AD, we employed the inverse-variance weighted method along with a series of sensitivity analyses. Results: The inverse-variance weighted MR analysis showed that genetically determined BDNF concentrations were associated with a decreased risk of AD (odds ratio per SD increase, 0.91; 95% confidence interval, 0.86-0.96; p =0.001). The association between plasma BDNF concentrations and AD was further confirmed through sensitivity analyses using different MR methods, and MR-Egger regression suggested no directional pleiotropy for this association. Conclusion: Genetically determined BDNF levels were associated with a decreased risk of AD, suggesting that BDNF was implicated in the development of AD and might be a promising target for the prevention of AD.

Introduction: Treatment of anterior cerebral artery (ACA) aneurysms is still not well established. The Leo stent with blood flow direction is a retrievable stent for intracranial aneurysms, whereas it needs to be studied clearly in patients with ACA aneurysms. Methods: Consecutive patients with ACA aneurysms were retrospectively enrolled in three neurosurgical centers between January 2016 and October 2021. The data on demographics, aneurysm characteristics, symptom resolution, and postoperative course were collected and analyzed. The aneurysm occlusion status was appraised by Raymond-Ray Occlusion Class (RROC). Results: A total of 57 patients with ACA aneurysms were included in our study. Immediate postprocedural angiograms showed that 20 aneurysms (35.1%) were in complete occlusion (RROC 1), 26 aneurysms (45.6%) were in near-complete occlusion (RROC 2), 11 aneurysms (19.3%) were in incomplete occlusion (RROC 3). The angiographic follow-up found that the rate of complete occlusion increased to 57.9%, and near-completion and incomplete occlusion dropped to 29.8% and 12.3%, respectively. The angiographic result of the last follow-up improved significantly (Z=- 2.805, P=0.005). Univariate analysis indicated that distal location of aneurysms (Z=4.538, P=0.033) and ruptured aneurysms (χ2=.6120, P=0.032) were potential risk factors for intra-parent artery narrowing. Furthermore, multivariate logistic regression analysis found that A3 aneurysms (95% CI 1.427~32.744, P=0.016) are the key risk factor for intra-parent artery narrowing. Conclusions: The Leo stent is safe and effective for aneurysms located in ACA circulations. The overall occlusion degree improved during follow-up. A distal, small artery was the risk factor for intra-parent artery narrowing.

Background: Cerebral small vessel disease (CSVD) is a common chronic progressive disease. It remains unclear whether high gait variability is a marker of cognitive cortical dysfunction. Methods: This study included 285 subjects (aged from 60 to 85 years, 60.3% female) including 37 controls, 179 presented as Fazekas II, and 69 presented as Fazekas III. The severity of white matter hyperintensities was assessed by the Fazekas Rating Scale. Gait parameters were assessed using a vision-based artificial intelligent gait analyzer. Cognitive function was tested by MMSE, MoCA, DST, and VFT. Results: Three gait parameters including gait speed, gait length, and swing time were associated with cognitive performance in patients with CSVD. Gait speed was associated with cognitive performance, including MMSE (β 0.200; 95%CI 1.706-6.018; p <.001), MoCA (β 0.183; 95%CI 2.047-7.046; p <.001), DST (order) (β 0.204; 95%CI 0.563-2.093; p =.001) and VFT (β 0.162; 95%CI 0.753-4.865; p =.008). Gait length was associated with cognitive performance, including MMSE (β 0.193; 95%CI 3.475-12.845; p =.001), MoCA (β 0.213; 95%CI 6.098-16.942; p <.001), DST (order) (β 0.224; 95%CI 1.056-4.839; P <.001) and VFT (β 0.149; 95%CI 1.088- 10.114; p =.015). Swing time was associated with cognitive performance, including MMSE (β - 0.242; 95%CI -2.639 to -0.974; p<.001), MoCA (β -0.211; 95%CI -2.989 to -1.034; p <.001) and DST (reverse order) (β -0.140; 95%CI -0.568 to -0.049; p =.020). Conclusion: This study revealed that the relationship between gait parameters and cognitive performance in patients with CSVD and the deteriorated gait parameters can reflect cognitive impairment and even dementia in older people with CSVD.

Background: Pneumonia causes significant morbidity and mortality and has been associated with cardiovascular complications. Our study aimed to investigate the incidence of ischemic and hemorrhagic strokes following bacterial pneumonia. Methods: Between 1997 and 2012, 10,931 subjects with bacterial pneumonia and 109,310 controls were enrolled from the Taiwan National Health Insurance Research Database, and were followed up to the end of 2013. The risk of stroke was estimated in Cox regression analyses with hazard ratios (HRs) and 95% confidence intervals (CIs). Results: When compared to the control group, subjects in the bacterial pneumonia group had a higher incidence of developing ischemic stroke (2.7% versus 0.4%, p <0.001) and hemorrhagic stroke (0.7% versus 0.1%, p <0.001). The risk of stroke increases with repeated hospitalizations due to bacterial pneumonia. Across bacterial etiologies, bacterial pneumonia was a significant risk factor among 775 subjects who developed ischemic stroke (HR, 5.72; 95% CI, 4.92-6.65) and 193 subjects who developed hemorrhagic stroke (HR, 5.33; 95% CI, 3.91-7.26). Conclusion: The risks of developing ischemic stroke and hemorrhagic stroke are significant following bacterial pneumonia infection. The risk factors, clinical outcomes, and the disease course should also be profiled to better inform the monitoring of stroke development and the clinical management of bacterial pneumonia patients.

Background: Major depression has a complex and multifactorial etiology constituted by the interaction between genetic and environmental factors in its development. Objective: The aim of this study was to evaluate the effects of sodium butyrate (SD) on epigenetic enzyme alterations in rats subjected to animal models of depression induced by maternal deprivation (MD) or chronic mild stress (CMS). Methods: To induce MD, male Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, rats were subjected to the CMS for 40 days. Adult rats were then treated with daily injections of SD for 7 days. Animals were subjected to the forced swimming test (FST), and then, histone deacetylase (HDAC), histone acetyltransferase (HAT), and DNA methyltransferase (DNMT) activities were evaluated in the brain. Results: MD and CMS increased immobility time in FST and increased HDAC and DNMT activity in the animal brains. SD reversed increased immobility induced by both animal models and the alterations in HDAC and DNMT activities. There was a positive correlation between enzyme activities and immobility time for both models. HDAC and DNMT activities also presented a positive correlation between themselves. Conclusion: These results suggest that epigenetics can play an important role in major depression pathophysiology triggered by early or late life stress and its treatment.

Background: Cardiac valve calcification predisposes patients to a higher risk of adverse cardiovascular events. This study aimed to investigate the association between cardiac valve calcification and 1-year mortality in diabetic patients after lower-extremity amputation. Methods: This was a retrospective study conducted on the clinical data of diabetic patients who underwent lower-extremity amputation admitted to the Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China for diabetic foot ulcers needed lower extremity amputation surgery between July 2017 and March 2021. Detailed preoperative medical assessments were performed and recorded. Cardiac valve calcification was assessed using echocardiography at baseline. Oneyear follow-up assessments were conducted and included clinical visits, hospital record assessments, and telephone reviews to obtain the survival status of patients. Results: Ninety-three diabetic patients participated in the study. The 1-year follow-up mortality rate after amputation was 24.7%. Compared to the survival group, the prevalence of cardiac valve calcification and the Revised Cardiac Risk Index (RCRI) were higher in the mortality group. In the Cox regression analysis, cardiac valvular calcification (HR=3.427, 95% CI=1.125- 10.443, p =0.030) was found to be an independent predictor of all-cause mortality after amputation. In addition, the patients with both aortic valve calcification and mitral annular calcification had a higher all-cause mortality rate (50%). Receiver operator characteristic curve analysis showed a stronger predictive ability when using a combination of calcified valve number and RCRI (AUC=0.786 95%, CI=0.676-0.896, p =0.000). Conclusion: In diabetic patients after lower-extremity amputation, cardiac valve calcification was associated with all-cause mortality during 1-year follow-up. Combination of calcified valve number and RCRI score showed a stronger predictive value for mortality.

Background: Stroke-Induced Immunodepression (SIID) is characterized by apoptosis in blood immune populations, such as T cells, B cells, NK cells, and monocytes, leading to the clinical presentation of lymphopenia. Disulfidptosis is a novel form of programmed cell death characterized by accumulating disulfide bonds in the cytoplasm, resulting in cellular dysfunction and eventual cell death. Objective: In this study, we investigated the association between disulfidptosis and stroke by analyzing gene sequencing data from peripheral blood samples of stroke patients. Methods: Differential gene expression analysis identified a set of disulfidptosis-related genes (DRGs) significantly associated with stroke. Initial exploration identified 32 DRGs and their interactions. Our study encompassed several analyses to understand the molecular mechanisms of DRGs in stroke. Weighted Gene Co-Expression Network Analysis (WGCNA) uncovered modules of co-expressed genes in stroke samples, and differentially expressed gene (DEG) analysis highlighted 1643 key genes. Results: These analyses converged on four hub genes of DRGs (SLC2A3, SLC2A14, SLC7A11, NCKAP1) associated with stroke. Immune cell composition analysis indicated positive correlations between hub genes and macrophages M1, M2, and neutrophils and negative associations with CD4+ and CD8+ T cells, B cells, and NK cells. Sub-cluster analysis revealed two distinct clusters with different immune cell expression profiles. Gene Set Enrichment Analysis (GSEA) demonstrated enrichment of apoptosis-related pathways, neurotrophin signaling, and actin cytoskeleton regulation. Associations between hub genes and apoptosis, necroptosis, ferroptosis, and cuproptosis, were also identified. Conclusion: These results suggest that the DRG hub genes are interconnected with various cell death pathways and immune processes, potentially contributing to stroke pathological development.

Background: Cerebral hyperperfusion syndrome (CHS) is known as a complication after bypass surgery for Moyamoya disease (MMD). However, the incidence of CHS has not been accurately reported, and there is no consensus on the risk factors associated with it. Aim: The aim of this study was to determine the risk factors associated with postoperative CHS after surgical combined revascularization used to treat adult patients with MMD. Objective: To assess the frequency and characteristics of CHS in patients with MMD after revascularization operations. Methods: Patients who received combined revascularization from Jan 2021 to Nov 2022 were retrospectively reviewed. Preoperative clinical characteristics and radiographic features were recorded. Postoperative CHS after surgery were examined. Multivariate logistic regression analyses were performed to identify the risk factors for CHS. Results: A total of 133 patients (141 hemispheres) were included in this study. Postoperative CHS were observed in 28 hemispheres (19.8%), including focal cerebral hyperperfusion syndrome (FCHS) in 20 hemispheres (14.2%), hemorrhage in 4 (2.8%) hemispheres, seizures in 4 (2.8%) hemispheres. The results of multivariate logistic regression analysis indicated that preoperative hypertension (OR 4.705, 95% CI 1.323 ~ 12.554, p = 0.014), cerebral hemorrhage onset (OR 5.390, 95% CI 1.408 ~ 20.642, p = 0.014) and higher Hct level (OR 1.171, 95% CI 1.051 ~ 1.305, p = 0.004) were significantly associated with CHS after combined revascularization. Conclusions: Preoperative hypertension, cerebral hemorrhage onset, and higher Hct level were independent risk factors for CHS after combined revascularization.