Stroke and Vascular Cognitive Impairment: The Role of Intestinal Microbiota Metabolite TMAO.

The gut microbiome interacts with the brain bidirectionally through the microbiome-gutbrain axis, which plays a key role in regulating various nervous system pathophysiological processes. Trimethylamine N-oxide (TMAO) is produced by choline metabolism through intestinal microorganisms, which can cross the blood-brain barrier to act on the central nervous system. Previous studies have shown that elevated plasma TMAO concentrations increase the risk of major adverse cardiovascular events, but there are few studies on TMAO in cerebrovascular disease and vascular cognitive impairment. This review summarized a decade of research on the impact of TMAO on stroke and related cognitive impairment, with particular attention to the effects on vascular cognitive disorders. We demonstrated that TMAO has a marked impact on the occurrence, development, and prognosis of stroke by regulating cholesterol metabolism, foam cell formation, platelet hyperresponsiveness and thrombosis, and promoting inflammation and oxidative stress. TMAO can also influence the cognitive impairment caused by Alzheimer's disease and Parkinson's disease via inducing abnormal aggregation of key proteins, affecting inflammation and thrombosis. However, although clinical studies have confirmed the association between the microbiome-gut-brain axis and vascular cognitive impairment (cerebral small vessel disease and post-stroke cognitive impairment), the molecular mechanism of TMAO has not been clarified, and TMAO precursors seem to play the opposite role in the process of poststroke cognitive impairment. In addition, several studies have also reported the possible neuroprotective effects of TMAO. Existing therapies for these diseases targeted to regulate intestinal flora and its metabolites have shown good efficacy. TMAO is probably a new target for early prediction and treatment of stroke and vascular cognitive impairment.

Comparison of seven surrogate insulin resistance indexes for predicting the prevalence of carotid atherosclerosis in normal-weight individuals.

Introduction: The aim of this study was to assess the correlation between surrogate insulin resistance (IR) indexes and carotid atherosclerosis (CA) in normal-weight populations, as well as compared their ability to predict CA. Method: A total of 26,795 middle-aged and older adult individuals with normal body weights were included. Triglyceride-glucose index (TyG), TyG-body mass index, TyG-waist circumference (TyG-WC), TyG-waist-to-height ratio (TyG-WHtR), visceral adiposity index, Chinese VAI (CVAI) and lipid accumulation product (LAP) were determined using established formulas. The associations between these surrogate indexes and CA were assessed using logistic regression models and restricted cubic spline (RCS) analysis. Receiver operating characteristic curves were utilized to compare the performance of these indexes for predicting CA. Result: The levels of all seven surrogate indexes of IR were significantly higher in normal-weight individuals with CA than in those without CA (p < 0.001). In the full-adjusted model, only CVAI, TyG-WC, TyG-WHtR and LAP were significantly associated with CA, with the adjusted odds ratios (95% CI) of CA being 1.25 (1.20-1.30), 1.18 (1.14-1.23), 1.20 (1.16-1.25) and 1.25 (1.18-1.32) for each one standard deviation increase in CVAI, TyG-WC, TyG-WHtR and LAP, respectively. RCS analysis revealed a significant increase in the prevalence of CA among normal-weight individuals with CVAI >89.83, LAP >28.91, TyG-WHtR >4.42 and TyG-WC >704.93. The area under the curve for CVAI was significantly greater than for other indexes (p < 0.001). Conclusion: CVAI, TyG-WC, TyG-WHtR and LAP were independently associated with the prevalence of CA. Specifically, CVAI may be the most appropriate predictor of CA in normal-weight individuals.

The association between neutrophil counts and neutrophil-to-lymphocyte ratio and stress hyperglycemia in patients with acute ischemic stroke according to stroke etiology.

Background and purpose: Stress hyperglycemia ratio (SHR), which is used to assess stress hyperglycemia, is associated with the functional outcome of ischemic stroke (IS). IS can induce the inflammatory response. Neutrophil counts and neutrophil-to-lymphocyte ratio (NLR) as good and easily available inflammatory biomarkers, the relationship between neutrophil counts and NLR and SHR were poorly explored in IS. We aimed to systemically and comprehensively explore the correlation between various blood inflammation markers (mainly neutrophil counts and NLR) and SHR. Methods: Data from 487 patients with acute IS(AIS) in Xiangya Hospital were retrospectively reviewed. High/low SHR groups according to the median of SHR (≤1.02 versus >1.02). Binary logistic regression analysis was used to evaluate the correlation between neutrophil counts and NLR and high SHR group. Subgroup analyses were performed in the TOAST classification and functional prognosis. Results: The neutrophil counts and NLR were all clearly associated with SHR levels in different logistic analysis models. In the subgroup analysis of TOAST classification, the higher neutrophil counts and NLR were the independent risk factors for high SHR patients with large-artery atherosclerosis (LAA) (neutrophil: adjusted OR:2.047, 95% CI: 1.355-3.093, P=0.001; NLR: adjusted OR:1.315, 95% CI: 1.129-1.530, P<0.001). The higher neutrophil counts were the independent risk factor for high SHR patients with cardioembolism (CE) (adjusted OR:2.413, 95% CI: 1.081-5.383, P=0.031). ROC analysis showed that neutrophil counts was helpful for differentiating high SHR group with CE and low SHR group with CE (neutrophil: AUC =0.776, P=0.002). However, there were no difference in levels of neutrophil counts and NLR between patients with SVO and without SVO. The higher neutrophil counts and NLR independently associated with high SHR patients with mRS ≤2 at 90 days from symptom onset, (neutrophil: adjusted OR:2.284, 95% CI: 1.525-3.420, P<0.001; NLR: adjusted OR:1.377, 95% CI: 1.164-1.629, P<0.001), but not in patients with mRS >2. Conclusions: This study found that the neutrophil counts and NLR are positively associated with SHR levels in AIS patients. In addition, the correlation between neutrophil counts and NLR and different SHR levels are diverse according to TOAST classification and functional prognosis.

PD-L1-related IncRNAs are associated with malignant characteristics and immune microenvironment in glioma.

BACKGROUND: The expression of long non-coding RNA (lncRNA) can function as diagnostic and therapeutic biomarker for tumors. This research explores the role of PD-L1-related lncRNAs in affecting malignant characteristics and the immune microenvironment of glioma. METHODS: Downloading gene expression profiles and clinicopathological information of glioma from TCGA and CGGA databases, 6 PD-L1-related lncRNAs were identified through correlation analysis, Cox and LASSO regression analysis, establishing the risk score model based on them. Bioinformatics analysis and cell experiments in vitro were adopted to verify the effects of LINC01271 on glioma. RESULTS: Risk scores based on 6 PD-L1-related lncRNAs (AL355974.3, LINC01271, AC011899.3, MIR4500HG, LINC02594, AL357055.3) can reflect malignant characteristics and immunotherapy response of glioma. Patients with high LINC01271 expression had a worse prognosis, a higher abundance of M1 subtype macrophages in the immune microenvironment, and a higher degree of tumor malignancy. Experiments in vitro confirmed its positive regulatory effect on the proliferation and migration of glioma cells. CONCLUSIONS: The risk score model based on 6 PD-L1-related lncRNAs can reflect the malignant characteristics and prognosis of glioma. LINC01271 can independently be used as a new target for prognosis evaluation and therapy.

Stroke-associated infection in patients with co-morbid diabetes mellitus is associated with in-hospital mortality.

Background and objective: The association between infection and acute ischemic stroke (AIS) with diabetes mellitus (DM) remains unknown. Therefore, this study aimed to explore the effect of infection on AIS with DM. Materials and methods: The data of patients with AIS and DM were extracted from the Chinese Stroke Center Alliance (CSCA) database from August 2015 to July 2019. The association between infections [pneumonia or urinary tract infection (UTI)] and in-hospital mortality was analyzed. Logistic regression models were used to identify the risk factors for in-hospital mortality of patients with infection. Results: In total, 1,77,923 AIS patients with DM were included in the study. The infection rate during hospitalization was 10.5%, and the mortality rate of infected patients was 3.4%. Stroke-associated infection was an independent risk factor for an early poor functional outcome [odds ratio (OR) = 2.26, 95% confidence interval (CI): 1.97-2.34, P < 0.0001] and in-hospital mortality in AIS patients with DM. The in-hospital mortality after infection was associated with age (OR = 1.02, 95% CI: 1.01-1.03, P < 0.0001), male (OR = 1.39, 95% CI: 1.13-1.71, P = 0.0018), reperfusion therapy (OR = 2.00, 95% CI: 1.56-2.56, P < 0.0001), and fasting plasma glucose at admission (OR = 1.05, 95% CI: 1.03-1.08, P < 0.0001). In contrast, antiplatelet drug therapy (OR = 0.63, 95% CI: 0.50-0.78, P < 0.0001) and hospital stay (OR = 0.96, 95% CI: 0.94-0.97, P < 0.0001) were independent protecting factors against in-hospital mortality of patients with infection. Conclusion: Infection is an independent risk factor of in-hospital mortality for patients with AIS and DM, and those patients require strengthening nursing management to prevent infection.

Molecular Biomarkers Associated with Early-Onset Symptomatic Intracranial Atherosclerosis.

PURPOSE: Previous studies have shown a rising incidence of early-onset symptomatic intracranial atherosclerosis (sICAS), which has brought a severe economic burden to social development. This study aimed to evaluate the molecular biomarkers associated with early-onset sICAS and to seek possible intervention strategies for early prevention. PATIENTS AND METHODS: We consecutively recruited patients with sICAS and divided them into two groups based on age: early-onset sICAS group as age ≤60 years old and late-onset sICAS group as age >60 years old. We collected and compared the demographic data and laboratory results of each group. A bivariate logistic regression model was applied to evaluate the independent molecular biomarkers of early-onset sICAS. RESULTS: A total of 1007 subjects with sICAS were enrolled in this study, comprising 519 patients in the early-onset sICAS group and 488 patients in the late-onset sICAS group. Bivariate logistic regression analysis demonstrated an increased level of white blood cell, platelet, albumin globulin ratio, free triiodothyronine, and a decreased level of total bile acid, urea nitrogen, high-density lipoprotein, homocysteine, and fibrinogen in the early-onset sICAS group when compared to the late-onset group. CONCLUSION: Our study showed the relevance between early sICAS and circulating levels of different molecular biomarkers. Detection of these related molecular biomarkers may provide a simple way for early sICAS preventions in the future.

Neutrophil-to-Lymphocyte Ratio as a Predictive Biomarker for Stroke Severity and Short-Term Prognosis in Acute Ischemic Stroke With Intracranial Atherosclerotic Stenosis.

Background: Neutrophil-to-lymphocyte ratio (NLR) is an indicator of poor prognosis in acute ischemic stroke (AIS), but associations between NLR with stroke severity and prognosis of intracranial atherosclerotic stenosis (ICAS)-related ischemic events have not been well-elucidated; therefore, we aimed to evaluate whether admission NLR levels correlate with the early stroke severity and short-term functional prognosis in patients with symptomatic intracranial atherosclerotic stenosis (sICAS). Methods: This retrospective study enrolled 899 consecutive patients with AIS attributed to ICAS at Xiangya Hospital stroke center between May 2016 and September 2020. The initial stroke severity was rated by the admission National Institutes of Health Stroke Scale (NIHSS) scores, and the short-term prognosis was evaluated using the 14-day modified Rankin Scale (mRS) scores after stroke onset. A severe stroke was defined as NIHSS >8; an unfavorable functional outcome was defined as mRS scores of 3-6. Admission NLR was determined based on circulating neutrophil and lymphocyte counts. Results: The median admission NLR of all patients was 2.80 [interquartile range (IQR), 2.00-4.00]. In univariate analysis, admission NLR was significantly elevated in patients with severe stroke and poor short-term prognosis. After multivariate adjustment, admission NLR levels were significantly correlated with severe stroke [odds ratio (OR), 1.132; 95% confidence interval (95% CI), 1.038-1.234; P = 0.005] and unfavorable short-term prognosis (OR, 1.102; 95% CI, 1.017-1.195; P = 0.018) in Model 1. In Model 2, the highest NLR tertile (≥3.533) remained an independent predictor of severe stroke (OR, 2.736; 95% CI, 1.590-4.708; P < 0.001) and unfavorable functional outcome (OR, 2.165; 95% CI, 1.416-3.311; P < 0.001) compared with the lowest NLR tertile (<2.231). The receiver operating characteristic (ROC) curves showed the predictability of NLR regarding the stroke severity [area under the curve (AUC), 0.659; 95% CI, 0.615-0.703; P < 0.001] and short-term prognosis (AUC, 0.613; 95% CI, 0.575-0.650; P < 0.001). The nomograms were constructed to create the predictive models of the severity and short-term outcome of sICAS. Conclusions: Elevated admission NLR levels were independently associated with the initial stroke severity and could be an early predictor of severity and poor short-term prognosis in AIS patients with ICAS, which might help us identify a target group timely for preventive therapies.