Betaine alleviates cognitive impairment induced by homocysteine through attenuating NLRP3-mediated microglial pyroptosis in an m6A-YTHDF2-dependent manner.

Dementia, with homocysteine (Hcy) as an important risk factor, is a severe public health problem in the aging society. Betaine serves as a methyl donor and plays an important role in reducing Hcy. However, the effects and mechanisms of betaine on Hcy-induced cognitive impairment remain unclear. Firstly, SD rats were injected with Hcy (400 µg/kg) through vena caudalis, and betaine (2.5 % w/v) was supplemented via drinking water for 14 days. Betaine supplementation could attenuate Hcy-induced cognitive impairment in the Y maze and novel object recognition tests by repairing brain injury. Meanwhile, microglial activation was observed to be inhibited by betaine supplementation using immunofluorescence and sholl analysis. Secondly, HMC3 cells were treated with betaine, which was found to decrease the ROS level, ameliorate cell membrane rupture, reduce the release of LDH, IL-18 and IL-1ß, and attenuate the damage of microglia to neurons. Mechanistically, betaine alleviates cognitive impairment by inhibiting microglial pyroptosis via reducing the expressions of NLRP3, ASC, pro-caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, IL-18 and IL-1ß. Betaine treatment can increase SAM/SAH ratio, confirming its enhancement on methylation capacity. Furthermore, betaine treatment was found to enhance N6-methyladenosine (m6A) modification of NLRP3 mRNA, and reduced the NLRP3 mRNA stability through increasing the expression of the m6A reader YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Finally, silencing YTHDF2 could reverse the inhibitory effect of betaine on pyroptosis. Our data demonstrated that betaine attenuated Hcy-induced cognitive impairment by suppressing microglia pyroptosis via inhibiting the NLRP3/caspase-1/GSDMD pathway in an m6A-YTHDF2-dependent manner.

Predicting the severity of white matter lesions among patients with cerebrovascular risk factors based on retinal images and clinical laboratory data: a deep learning study.

Background and purpose: As one common feature of cerebral small vascular disease (cSVD), white matter lesions (WMLs) could lead to reduction in brain function. Using a convenient, cheap, and non-intrusive method to detect WMLs could substantially benefit to patient management in the community screening, especially in the settings of availability or contraindication of magnetic resonance imaging (MRI). Therefore, this study aimed to develop a useful model to incorporate clinical laboratory data and retinal images using deep learning models to predict the severity of WMLs. Methods: Two hundred fifty-nine patients with any kind of neurological diseases were enrolled in our study. Demographic data, retinal images, MRI, and laboratory data were collected for the patients. The patients were assigned to the absent/mild and moderate-severe WMLs groups according to Fazekas scoring system. Retinal images were acquired by fundus photography. A ResNet deep learning framework was used to analyze the retinal images. A clinical-laboratory signature was generated from laboratory data. Two prediction models, a combined model including demographic data, the clinical-laboratory signature, and the retinal images and a clinical model including only demographic data and the clinical-laboratory signature, were developed to predict the severity of WMLs. Results: Approximately one-quarter of the patients (25.6%) had moderate-severe WMLs. The left and right retinal images predicted moderate-severe WMLs with area under the curves (AUCs) of 0.73 and 0.94. The clinical-laboratory signature predicted moderate-severe WMLs with an AUC of 0.73. The combined model showed good performance in predicting moderate-severe WMLs with an AUC of 0.95, while the clinical model predicted moderate-severe WMLs with an AUC of 0.78. Conclusion: Combined with retinal images from conventional fundus photography and clinical laboratory data are reliable and convenient approach to predict the severity of WMLs and are helpful for the management and follow-up of WMLs patients.

Evaluation of extent vs velocity of cortical venous filing in stroke outcome after endovascular thrombectomy.

PURPOSE: Abnormal venous drainage may affect the prognosis of patients undergoing endovascular reperfusion therapy (ERT). Herein, time-resolved dynamic computed tomography arteriography (dCTA) was applied to evaluate the relationship between the velocity and extent of cortical venous filling (CVF), collateral status and outcomes. METHODS: Thirty-five consecutive patients with acute anterior circulation occlusion who underwent ERT within 24 h of onset and successfully recanalized were enrolled. All patients underwent dCTA before ERT. Slow first or end of CVF was considered to occur when the time point of CVF appearance or disappearance on the affected side occurred after than that on the healthy side, whereas an equal CVF, a CVF reduced by ≤ 50%, or by > 50% on the affected side, were considered good, intermediate, and poor CVF extent, respectively. RESULTS: Slow first CVF (29 patients, 82.8%), slow end of CVF (29, 85.7%), and intermediate extent of CVF (7, 20.0%) were not associated with collateral status or outcomes. Poor extent of CVF (6, 17.1%) was associated with poor collateral status, higher proportion of midline shift, larger final infarct volume, higher modified Rankin Scale (mRS) score at discharge, and higher proportion of in-hospital mortality. All patients with transtentorial herniation had poor extent of CVF, and those with poor CVF extent had an mRS score ≥ 3 at discharge. CONCLUSION: Poor CVF extent, as assessed by dCTA, is a more accurate and specific marker than slow CVF to identify patients at high risk for poor outcomes after ERT.

Poor Internal Jugular Venous Outflow Is Associated with Poor Cortical Venous Outflow and Outcomes after Successful Endovascular Reperfusion Therapy.

Many patients show poor outcomes following endovascular reperfusion therapy (ERT), and poor cortical venous outflow is a risk factor for these poor outcomes. We investigated the association between the outflow of the internal jugular vein (IJV) and baseline cortical venous outflow and the outcomes after ERT. We retrospectively enrolled 78 patients diagnosed with an acute anterior circulation stroke and successful ERT. Poor IJV outflow on the affected side was defined as stenosis ≥50% or occlusion of ipsilateral IJV, and poor outflow of bilateral IJVs was defined as stenosis ≥50% or occlusion of both IJVs. Poor cortical venous outflow was defined as a cortical vein opacification score (COVES) of 0 on admission. Multivariate analysis showed that poor outflow of IJV on the affected side was an independent predictor for hemorrhagic transformation. The poor outflow of bilateral IJVs was an independent risk factor for poor clinical outcomes. These patients also had numerical trends of a higher incidence of symptomatic intracranial hemorrhage, midline shift >10 mm, and in-hospital mortality; however, statistical significance was not observed. Additionally, poor IJV outflow was an independent determinant of poor cortical venous outflow. For acute large vessel occlusion patients, poor IJV outflow is associated with poor baseline cortical venous outflow and outcomes after successful ERT.

Association between serum bilirubin and asymptomatic intracranial atherosclerosis: results from a population-based study.

INTRODUCTION: The effects of bilirubin on asymptomatic intracranial atherosclerosis (aICAS) remain uncertain. OBJECTIVES: To investigate the association between bilirubin and aICAS in rural-dwelling Chinese people. METHODS: This population-based study included 2013 participants from the Kongcun Town Study, which aimed to investigate the prevalence of aICAS in people aged ≥ 40 years who were free of stroke and hepatic and gall disease history. Baseline data were collected via interviews, clinical examinations, and laboratory tests. Total bilirubin (Tbil), direct bilirubin (Dbil), and indirect bilirubin (Ibil) levels were divided into high-concentration group and low-concentration group, respectively. We diagnosed aICAS and moderate-to-severe aICAS (m-saICAS) (≥ 50% stenosis) by integrating transcranial Doppler ultrasound with magnetic resonance angiography. The association between bilirubin and aICAS, as well as m-saICAS, was analyzed using logistic regression. RESULTS: Of the 2013 participants, those in the high-concentration group of Tbil (odds ratio (OR), 0.50; 95% confidence interval (CI), 0.42-0.87), Dbil (OR 0.60, 95%CI 0.41-0.87), and Ibil (OR 0.67; 95%CI 0.47-0.97) had a lower risk of aICAS than those in the low-concentration group after adjusting all confounders. The high concentrations of Tbil, Dbil, and Ibil were also negatively associated with m-saICAS. After stratification according to age, Tbil, Dbil, and Ibil were significantly negatively associated with aICAS among participants aged ≥ 60 years. CONCLUSION: Tbil, Dbil, and Ibil might be independent protective factors for aICAS and moderate-to-severe aICAS in rural-dwelling Chinese people, especially among older participants aged ≥ 60 years.