Brain frailty associated with stroke events in anterior circulation large artery occlusion.

OBJECTIVE: To investigate the factors associated with brain frailty and the effect of brain frailty in patients with anterior circulation large artery occlusion (AC-LAO). METHODS: 1100 patients with AC-LVO consecutively admitted to the Second Hospital of Hebei Medical University, North China between June 2016 and April 2018 were retrospectively analyzed. The variables associated with brain frailty and stroke outcome were analyzed by ANOVA analysis, the Mann-Whitney U test and multiple linear regression. Based on previous research. Brain frailty score comprises 1 point each for white matter hyperintensity (WMH), old infarction lesions, and cerebral atrophy among 983 participants with baseline brain magnetic resonance imaging or computed tomography. RESULTS: Among AC-LAO participants, baseline brain frailty score ≥ 1 was common (750/983, 76.3%). Duration of hypertension > 5 years (mean difference [MD] 0.236, 95% CI 0.077, 0.395, p = 0.004), multiple vessel occlusion (MD 0.339, 95% CI 0.068, 0.611, p = 0.014) and basal ganglia infarction (MD -0.308, 95% CI -0.456, -0.160, p < 0.001) were independently associated with brain frailty score. Brain frailty score was independently associated with stroke events, and higher brain frailty scores were associated with higher rates of stroke events (p < 0.001). However, brain frailty has no independent effect on short-term outcome of ACI in AC-LAO patients. CONCLUSIONS: In AC-LAO patients, older age, duration of hypertension > 5 years, and multiple vessel occlusion influenced the brain frailty score. Brain frailty score was independently associated with the occurrence of stroke events in AC-LAO patients.

Automatic segmentation of hemispheric CSF on MRI using deep learning: Quantifying cerebral edema following large hemispheric infarction.

Background and objective: Cerebral edema (CED) is a serious complication of acute ischemic stroke (AIS), especially in patients with large hemispheric infarction (LHI). Herein, a deep learning-based approach is implemented to extract CSF from T2-Weighted Imaging (T2WI) and evaluate the relationship between quantified cerebrospinal fluid and outcomes. Methods: Patients with acute LHI who underwent magnetic resonance imaging (MRI) were included. We used a deep learning algorithm to segment the CSF from T2WI. The hemispheric CSF ratio was calculated to evaluate its relationship with the degree of brain edema and prognosis in patients with LHI. Results: For the 93 included patients, the left and right cerebrospinal fluid regions were automatically extracted with a mean Dice similarity coefficient of 0.830. Receiver operating characteristic analysis indicated that hemispheric CSF ratio was an accurate marker for qualitative severe cerebral edema (area under receiver-operating-characteristic curve 0.867 [95% CI, 0.781-0.929]). Multivariate logistic regression analysis of functional prognosis showed that previous stroke (OR = 5.229, 95% CI 1.013-26.984), ASPECT≤6 (OR = 13.208, 95% CI 1.136-153.540) and low hemispheric CSF ratio (OR = 0.966, 95% CI 0.937-0.997) were significantly associated with higher chances for unfavorable functional outcome in patients with LHI. Conclusions: Automated assessment of CSF volume provides an objective biomarker of cerebral edema that can be leveraged to quantify the degree of cerebral edema and confirm its predictive effect on outcomes after LHI.

Recurrent Cerebral Infarction Due to Moyamoya Disease Complicated With Systemic Lupus Erythematosus: A Case Report and Literature Review.

INTRODUCTION: We report a rare case of moyamoya disease caused by an RNF213 mutation, complicated with systemic lupus erythematosus. CASE REPORT: A 32-year-old woman experienced 4 cerebral ischemia stroke events within 6 months. The main symptom was left limb weakness with blurred vision in the right eye. Results of digital subtraction angiography conducted at another hospital were consistent with moyamoya disease. On genetic testing, we found that the patient carried 2 mutations in the moyamoya disease-related gene RNF213 (p.R4810K, p.T1727M). On the basis of the laboratory immunologic indicators, such as positive antibodies and abnormal immunoglobulin levels and imaging examinations, the patient was finally diagnosed as moyamoya disease complicated with systemic lupus erythematosus. She was treated with aspirin, butylphthalide, urinary kallidinogenase, and sodium methylprednisolone. CONCLUSIONS: This was a 32-year-old young patient diagnosed with moyamoya disease carrying RNF213 gene mutation and accompanied by lupus with cerebral ischemic event as the first occurrence. The patient's condition was complex; therefore, comprehensive analysis and in-depth consideration were needed to avoid a missed diagnosis and misdiagnosis. When the primary disease cannot be identified, genetic testing can help to clarify the diagnosis of moyamoya disease.

Plaque enhancement predicts recurrence in acute ischemic stroke patients with large artery intracranial atherosclerosis.

BACKGROUND: The association between the degree of plaque enhancement and ischemic brain stroke recurrence remains unclear. We aimed to establish models to predict plaque enhancement and stroke recurrence. METHODS: Seventy-eight participants with acute ischemic brain stroke due to intracranial arterial stenosis were recruited and divided into high enhancement (HE) and non-HE groups. The relationship between imaging characteristics (degree of stenosis, minimal lumen area, intraplaque hemorrhage, and plaque burden) and the degree of plaque contrast enhancement was analyzed. Inflammatory cytokine expression was examined by flow cytometry. Independent predictors of stroke recurrence were investigated via multivariate Cox proportional hazards regression analysis. Nomogram was used to construct a prediction model. Harrell's concordance indices (c-indices) and calibration curves were used to assess the discrimination of the nomogram. A risk prediction nomogram for prognosis was constructed. RESULTS: Thirty-three participants were assigned to the HE group and 45 to the non-HE group. The degree of stenosis and plaque burden in the HE group was higher than that in the non-HE group (P<0.05). Multiple linear regression analysis showed the degree of stenosis was associated with HE (ß=0.513; P=0.000). After adjusting for confounding factors, age (HR=1.115; 95%CI=1.034-1.203, P=0.005) and HE plaques (HR=10.457; 95%CI=1.176-93.018; P=0.035) were independent risk factors of stroke recurrence, whereas cytokine levels were not statistically significant between two group. CONCLUSIONS: HE of intracranial atherosclerosis plaques is an independent factor for ischemic brain stroke recurrence.

Receptor-Interacting Protein 3/Calmodulin-Dependent Kinase II/Proline-Rich Tyrosine Kinase 2 Pathway is Involved in Programmed Cell Death in a Mouse Model of Brain Ischaemic Stroke.

Neuronal necroptosis and apoptosis are the most important pathways for programmed cell death after brain ischaemic stroke. Although apoptosis signalling pathways have been extensively studied, molecular mechanisms underlying necroptosis remain unclear. In this study, we found that receptor-interacting protein 3 (RIP3) deficiency reduced cerebral infarction volume, neurological deficits, and neuronal ultrastructural damage in a mouse model of brain ischaemic stroke by inhibiting programmed cell death. RIP3 deficiency inhibited the activation of both calmodulin-dependent kinase II (CaMKII) and proline-rich tyrosine kinase 2 (Pyk2) cascade, decreased the expression of classic necroptotic and apoptotic proteins, and ultimately decreased neuronal necroptosis and apoptosis. We further confirmed that RIP3 deficiency inhibited the decrease of mitochondrial membrane potential, the increase of calcium influx and reactive oxygen species (ROS) production. In addition, compared with WT primary cortical neurons, the decreased expression of CaMKII and Pyk2 was further verified in a Ripk3-/- primary cortical neurons underlying oxygen and glucose deprivation/reoxygenation (OGD/R) model. In conclusion, we first identified that the RIP3/CaMKII/Pyk2 pathway is involved in programmed cell death after brain ischaemic stroke, which suggests it is a promising therapeutic target in ischaemia-induced neuronal injury.

Machine Learning-Based Model for Predicting Incidence and Severity of Acute Ischemic Stroke in Anterior Circulation Large Vessel Occlusion.

Objectives: Patients with anterior circulation large vessel occlusion are at high risk of acute ischemic stroke, which could be disabling or fatal. In this study, we applied machine learning to develop and validate two prediction models for acute ischemic stroke (Model 1) and severity of neurological impairment (Model 2), both caused by anterior circulation large vessel occlusion (AC-LVO), based on medical history and neuroimaging data of patients on admission. Methods: A total of 1,100 patients with AC- LVO from the Second Hospital of Hebei Medical University in North China were enrolled, of which 713 patients presented with acute ischemic stroke (AIS) related to AC- LVO and 387 presented with the non-acute ischemic cerebrovascular event. Among patients with the non-acute ischemic cerebrovascular events, 173 with prior stroke or TIA were excluded. Finally, 927 patients with AC-LVO were entered into the derivation cohort. In the external validation cohort, 150 patients with AC-LVO from the Hebei Province People's Hospital, including 99 patients with AIS related to AC- LVO and 51 asymptomatic AC-LVO patients, were retrospectively reviewed. We developed four machine learning models [logistic regression (LR), regularized LR (RLR), support vector machine (SVM), and random forest (RF)], whose performance was internally validated using 5-fold cross-validation. The performance of each machine learning model for the area under the receiver operating characteristic curve (ROC-AUC) was compared and the variables of each algorithm were ranked. Results: In model 1, among the included patients with AC-LVO, 713 (76.9%) and 99 (66%) suffered an acute ischemic stroke in the derivation and external validation cohorts, respectively. The ROC-AUC of LR, RLR and SVM were significantly higher than that of the RF in the external validation cohorts [0.66 (95% CI 0.57-0.74) for LR, 0.66 (95% CI 0.57-0.74) for RLR, 0.55 (95% CI 0.45-0.64) for RF and 0.67 (95% CI 0.58-0.76) for SVM]. In model 2, 254 (53.9%) and 31 (37.8%) patients suffered disabling ischemic stroke in the derivation and external validation cohorts, respectively. There was no difference in AUC among the four machine learning algorithms in the external validation cohorts. Conclusions: Machine learning methods with multiple clinical variables have the ability to predict acute ischemic stroke and the severity of neurological impairment in patients with AC-LVO.

Human urinary kininogenase reduces the endothelial injury by inhibiting Pyk2/MCU pathway.

The injury of endothelial cells is one of the initiating factors in restenosis after endovascular treatment. Human urinary kallidinogenase (HUK) is a tissue kallikrein which is used for ischemia-reperfusion injury treatment. Studies have shown that HUK may be a potential therapeutic agent to prevent stenosis after vascular injury, however, the precise mechanisms have not been fully established. This study is to investigate whether HUK can protect endothelial cells after balloon injury or H2O2-induced endothelial cell damage through the proline-rich tyrosine kinase 2 (Pyk2)/mitochondrial calcium uniporter (MCU) pathway. Intimal hyperplasia, a decrease of pinocytotic vesicles and cell apoptosis were found in the common carotid artery balloon injury and H2O2-induced endothelial cell damage, Pyk2/MCU was also up-regulated in such pathological process. HUK could prevent these injuries partially via the bradykinin B2 receptor by inhibiting Pyk2/MCU pathway, which prevented the mitochondrial damage, maintained calcium balance, and eventually inhibited cell apoptosis. Furthermore, MCU expression was not markedly increased if Pyk2 was suppressed by shRNA technique in the H2O2 treatment group, and cell viability was significantly better than H2O2-treated only. In short, our results indicate that the Pyk2/MCU pathway is involved in endothelial injury induced by balloon injury or H2O2-induced endothelial cell damage. HUK plays an protective role by inhibiting the Pyk2/MCU pathway in the endothelial injury.

Pyk2/MCU Pathway as a New Target for Reversing Atherosclerosis.

Objective: Multiple mechanisms including vascular endothelial cell damage have a critical role in the formation and development of atherosclerosis (AS), but the specific molecular mechanisms are not exactly clarified. This study aims to determine the possible roles of proline-rich tyrosine kinase 2 (Pyk2)/mitochondrial calcium uniporter (MCU) pathway in AS mouse model and H2O2-induced endothelial cell damage model and explore its possible mechanisms. Approach and Results: The AS mouse model was established using apolipoprotein E-knockout (ApoE-/-) mice that were fed with a high-fat diet. It was very interesting to find that Pyk2/MCU expression was significantly increased in the artery wall of atherosclerotic mice and human umbilical vein endothelial cells (HUVECs) attacked by hydrogen peroxide (H2O2). In addition, down-regulation of Pyk2 by short hairpin RNA (shRNA) protected HUVECs from H2O2 insult. Furthermore, treatment with rosuvastatin on AS mouse model and H2O2-induced HUVEC injury model showed a protective effect against AS by inhibiting the Pyk2/MCU pathway, which maintained calcium balance, prevented the mitochondrial damage and reactive oxygen species production, and eventually inhibited cell apoptosis. Conclusion: Our results provide important insight into the initiation of the Pyk2/MCU pathway involved in AS-related endothelial cell damage, which may be a new promising target for atherosclerosis intervention.

Evaluating the cerebrospinal fluid ctDNA detection by next-generation sequencing in the diagnosis of meningeal Carcinomatosis.

BACKGROUND: Meningeal carcinomatosis (MC) is the most severe form of brain metastasis and causes significant morbidity and mortality. Currently, the diagnosis of MC is routinely confirmed on the basis of clinical manifestation, positive cerebrospinal fluid (CSF) cytology, and/or neuroimaging features. However, negative rate of CSF cytology and neuroimaging findings often result in a failure to diagnose MC from the patients who actually have the disease. Here we evaluate the CSF circulating tumor DNA (ctDNA) in the diagnosis of MC. METHODS: A total of 35 CSF samples were collected from 35 patients with MC for CSF cytology examination, CSF ctDNA extraction and cancer-associated gene mutations detection by next-generation sequencing (NGS) at the same time. RESULTS: The most frequent primary tumor in this study was lung cancer (26/35, 74%), followed by gastric cancer (2/35, 6%), breast cancer (2/35, 6%), prostatic cancer (1/35, 3%), parotid gland carcinoma (1/35, 3%) and lymphoma (1/35, 3%) while no primary tumor could be found in the remaining 2 patients in spite of using various inspection methods. Twenty-five CSF samples (25/35; 71%) were found neoplastic cells in CSF cytology examination while all of the 35 CSF samples (35/35; 100%) were revealed having detectable ctDNA in which cancer-associated gene mutations were detected. All of 35 patients with MC in the study underwent contrast-enhanced brain MRI and/or CT and 22 neuroimaging features (22/35; 63%) were consistent with MC. The sensitivity of the neuroimaging was 88% (95% confidence intervals [95% CI], 75 to 100) (p = 22/25) and 63% (95% CI, 47 to 79) (p = 22/35) compared to those of CSF cytology and CSF ctDNA, respectively. The sensitivity of the CSF cytology was 71% (95% CI, 56 to 86) (n = 25/35) compared to that of CSF ctDNA. CONCLUSIONS: This study suggests a higher sensitivity of CSF ctDNA than those of CSF cytology and neuroimaging findings. We find cancer-associated gene mutations in ctDNA from CSF of patients with MC at 100% of our cohort, and utilizing CSF ctDNA as liquid biopsy technology based on the detection of cancer-associated gene mutations may give additional information to diagnose MC with negative CSF cytology and/or negative neuroimaging findings.

The therapeutic value of cerebrospinal fluid ctDNA detection by next-generation sequencing for meningeal carcinomatosis: a case report.

BACKGROUND: It is usually very complicated to treat meningeal carcinomatosis, and it is important to treat it as soon as possible. CASE PRESENTATION: The 19-Del mutation was found in the exon for the epidermal growth factor receptor gene in the pleural effusion of a patient on March 11th, 2015. He took 250 mg of oral gefitinib once a day for 11 months beginning in December of 2015. On the 3rd of November 2016, he arrived at the hospital and presented with dizziness, headache and transient blurred vision. At this time, he began to take 4 mg of oral zoledronic acid once a month to prevent bone metastases. The result of a cytology exam of the cerebrospinal fluid showed that the man had meningeal carcinomatosis. The 19-Del mutation and the 20-T790 M mutation in the exon of the epidermal growth factor receptor gene was found by the next generation sequencing of the CSF. Then, he discontinued taking gefitinib and began to take 90-100 mg of oral AZD9291 once a day in November 2016. After adjusting the medication dose based on the NGS, his headache was noticeably reduced, and his condition gradually stabilized. CONCLUSIONS: Cerebrospinal fluid ctDNA detection by next generation sequencing may become a suitable biomarker to monitor clinical treatment response in meningeal carcinomatosis.

The gamma-aminobutyric acid-B receptor (GABAB) encephalitis: clinical manifestations and response to immunotherapy.

PURPOSE: We report 11 patients diagnosed with GABAB receptor (GABABR) antibodies encephalitis in China and aim to analyze the clinical characteristics, laboratory and imaging findings, therapeutic modalities and outcomes. METHODS: Clinical data from patients diagnosed with anti-GABAB receptor encephalitis in the Second Affiliated Hospital of Hebei Medical University from February 2016 to October 2016 January were retrospectively collected and evaluated. RESULTS: Of the 11 patients, seven were males, and a mean age at presentation of 63 years (range: 47-79 years). The major clinical features include cognitive decline (9/11), epilepsy (10/11), mental and behavioral disorders (6/11), involuntary movement (4/11), sleep disorders (2/11), hearing loss (1/11), disturbance of consciousness (4/11) and fever (3/11). GABA-B receptor antibody was positive in serum and/or cerebrospinal fluid in 11 patients. Small-cell lung cancer was detected in five patients. Electroencephalogram monitoring demonstrated abnormal discharge in 10 cases. Epileptiform activities were found in five patients. Four patients showed abnormality in hippocampal region, parahippocampal gyrus, temporal and occipital lobe on magnetic resonance imaging. Ten patients accepted first-line immune therapy. Five patients with small-cell lung cancer received oncologic treatment. During a median follow-up of 11 months, eight patients showed a good outcome, two patients (cases 8 and 9) with tumors had a poor one and one patient (case 10) died of status epilepticus. CONCLUSION: Anti-GABAB receptor encephalitis is an uncommon autoimmune disease, which has been known to be often associated with cancer. Generally, patients associated with GABABR GABA-B receptor antibody encephalitis respond well to immunotherapy, especially if started early.