Overexpression of forebrain PTP1B leads to synaptic and cognitive impairments in obesity.

Obesity has reached pandemic proportions and is a risk factor for neurodegenerative diseases, including Alzheimer's disease. Chronic inflammation is common in obese patients, but the mechanism between inflammation and cognitive impairment in obesity remains unclear. Accumulative evidence shows that protein-tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. We investigated the causal role of PTP1B in obesity-induced cognitive impairment and the beneficial effect of PTP1B inhibitors in counteracting impairments of cognition, neural morphology, and signaling. We showed that obese individuals had negative relationship between serum PTP1B levels and cognitive function. Furthermore, the PTP1B level in the forebrain increased in patients with neurodegenerative diseases and obese cognitive impairment mice with the expansion of white matter, neuroinflammation and brain atrophy. PTP1B globally or forebrain-specific knockout mice on an obesogenic high-fat diet showed enhanced cognition and improved synaptic ultrastructure and proteins in the forebrain. Specifically, deleting PTP1B in leptin receptor-expressing cells improved leptin synaptic signaling and increased BDNF expression in the forebrain of obese mice. Importantly, we found that various PTP1B allosteric inhibitors (e.g., MSI-1436, well-tolerated in Phase 1 and 1b clinical trials for obesity and type II diabetes) prevented these alterations, including improving cognition, neurite outgrowth, leptin synaptic signaling and BDNF in both obese cognitive impairment mice and a neural cell model of PTP1B overexpression. These findings suggest that increased forebrain PTP1B is associated with cognitive decline in obesity, whereas inhibition of PTP1B could be a promising strategy for preventing neurodegeneration induced by obesity.

IL-1ß/IL-1R1 signaling is involved in the propagation of α-synuclein pathology of the gastrointestinal tract to the brain.

The pathological hallmark of Parkinson's disease (PD) is the intraneuronal accumulation of misfolded alpha-synuclein (termed Lewy bodies) in dopaminergic neurons of substantia nigra par compacta (SNc). It is assumed that the α-syn pathology is induced by gastrointestinal inflammation and then transfers to the brain by the gut-brain axis. Therefore, the relationship between gastrointestinal inflammation and α-syn pathology leading to PD remains to be investigated. In our study, rotenone (ROT) oral administration induces gastrointestinal tract (GIT) inflammation in mice. In addition, we used pseudorabies virus (PRV) for tracing studies and performed behavioral testing. We observed that ROT treatments enhance macrophage activation, inflammatory mediator expression, and α-syn pathology in the GIT 6-week post-treatment (P6). Moreover, pathological α-syn was localized with IL-1R1 positive neural cells in GIT. In line with these findings, we also find pS129-α-syn signals in the dorsal motor nucleus of the vagus (DMV) and tyrosine hydroxylase in the nigral-striatum dynamically change from 3-week post-treatment (P3) to P6. Following that, pS129-α-syn was dominant in the enteric neural cell, DMV, and SNc, accompanied by microglial activation, and these phenotypes were absent in IL-1R1r/r mice. These data suggest that IL-1ß/IL-1R1-dependent inflammation of GIT can induce α-syn pathology, which then propagates to the DMV and SNc, resulting in PD.

GSDMA at the crossroads between pyroptosis and tumor immune evasion in glioma.

Pyroptosis, an inflammatory and programmed cell death process, has been controversial in its role in tumor immunity. However, as the first molecule in the gasdermin family, the mechanism of GSDMA in glioma growth is not well understood. We identified the differentially expressed gene GSDMA from Treg cells-related genes using the TCGA database. The biological functions of GSDMA and the relationship between GSDMA expression and tumor immune cell infiltration and cancer patient survival were investigated using open-source databases and platforms. Additionally, flow cytometry analysis was used to examine the effect of GSDMA on tumor immune cell infiltration. Our study showed that GSDMA expression played an important role in immune evasion in glioma. Patients with high GSDMA expression had a worse prognosis. In vivo studies demonstrated that GSDMA knockdown could enhance the infiltration level of CD8+ T cells. High GSDMA expression was also positively correlated with poor anti-PD-L1 treatment outcomes in GBM patients, suggesting that GSDMA may be a potential biomarker that should be considered in combination with anti-PD-L1 therapy for glioma patients. In conclusion, our study demonstrates that high GSDMA expression in gliomas is associated with immune-infiltrating cells CD8+ T cells and Treg cells, and indicates a worse prognosis in glioma. Therefore, GSDMA may serve as a therapeutic target for glioma progression and should be applied in immunotherapy for glioma patients.

A Chiral Nanocomplex for Multitarget Therapy to Alleviate Neuropathology and Rescue Alzheimer's Cognitive Deficits.

Alzheimer's disease (AD) is a severe neurodegenerative condition characterized by inflammation, beta-amyloid (Aß) plaques, and neurodegeneration, which currently lack effective treatments. Chiral nanomaterials have emerged as a promising option for treating neurodegenerative disorders due to their high biocompatibility, strong sustained release ability, and specific enantiomer selectivity. The development of a stimulus-responsive chiral nanomaterial, UiO-66-NH2 @l-MoS2 QDs@PA-Ni (MSP-U), for the treatment of AD is reported. MSP-U is found to stimulate neural stem cell (NSCs) differentiation, promote in situ hydrogen (H2 ) production, and clear Aß plaques. l-MoS2 QDs modified with l-Cysteine (l-Cys) effectively enhance the differentiation of NSCs into neurons through circularly polarized near-infrared radiation. Doped-phytic acid nickel (PA-Ni) improves the activity of l-MoS2 QDs in scavenging reactive oxygen species at the lesion site via photocatalytic H2 production. Loading l-MoS2 QDs with UiO-66 type metal oxide suppresses electron-hole recombination effect, thereby achieving rapid charge separation and improving transport of photogenerated electrons, leading to significantly improved H2 production efficiency. The photothermal effect of MSP-U also clears the generated Aß plaques. In vivo evaluations show that MSP-U improves spatial cognition and memory, suggesting a promising potential candidate for the treatment of AD using chiral nanomaterials.

Elevated NT-proBNP predicts unfavorable outcomes in patients with acute ischemic stroke after thrombolytic therapy.

OBJECTIVE: Few studies correlated n-terminal pro-brain natriuretic peptide (NT-proBNP) with early neurological deterioration (END) and prognosis of acute ischaemic stroke (AIS) patients with rt-PA intravenous thrombolysis. Therefore this study aimed to investigate the relationship between NT-proBNP and END, and prognosis after intravenous thrombolysis in patients with AIS. METHODS: A total of 325 patients with AIS were enrolled. We performed the natural logarithm transformation on the NT-proBNP [ln(NT-proBNP)]. Univariate and multivariate logistic regression analyses were performed to assess the relationship between ln(NT-proBNP) and END, and prognosis and receiver operating characteristic (ROC) curves were used to show the sensitivity and specificity of NT-proBNP. RESULTS: After thrombolysis, among 325 patients with AIS, 43 patients (13.2%) developed END. In addition, three months follow-up showed a poor prognosis in 98 cases (30.2%) and a good prognosis in 227 cases (69.8%). Multivariate logistic regression analysis showed that ln(NT-proBNP) was an independent risk factor for END (OR = 1.450,95%CI:1.072 ~ 1.963, P = 0.016) and poor prognosis at three months follow-up (OR = 1.767, 95%CI: 1.347 ~ 2.317, P < 0.001) respectively. According to ROC curve analysis, ln(NT-proBNP) (AUC 0.735, 95%CI: 0.674 ~0.796, P < 0.001) had a good predictive value for poor prognosis, with a predictive value of 5.12 and sensitivity and specificity of 79.59% and 60.35% respectively. When combined with NIHSS to predict END(AUC 0.718, 95%CI: 0.631 ~ 0.805, P < 0.001) and poor prognosis(AUC 0.780, 95%CI: 0.724 ~ 0.836, P < 0.001), the predictive value of the model is further improved. CONCLUSION: NT-proBNP is independently associated with END and poor prognosis in patients with AIS following intravenous thrombolysis and has a particular predictive value for END and poor prognosis.

Red blood cell distribution width to platelet ratio predicts early neurological deterioration in acute ischemic stroke patients receiving intravenous thrombolysis.

BACKGROUND: Inflammation plays a prominent role in the pathogenesis and progression of acute ischemic stroke (AIS). The red blood cell distribution width to platelet ratio (RPR) has been demonstrated as a novel biomarker to indicate the severity of inflammatory reaction. This study aimed to explore the association between RPR before intravenous thrombolysis and early neurological deterioration (END) after thrombolysis in AIS patients. METHODS: AIS patients accepting intravenous thrombolysis were recruited continuously. Postthrombolysis END was defined as death or an increase in the National Institute of Health Stroke Scale (NIHSS) score ≥4 points within 24 h after intravenous thrombolysis compared to the NIHSS score before intravenous thrombolysis. We constructed univariate and multivariate logistic regression analyses to investigate the relationship of RPR before intravenous thrombolysis to postthrombolysis END. Moreover, a receiver operating characteristic (ROC) curve was applied to examine the discriminative utility of RPR before intravenous thrombolysis in predicting postthrombolysis END. RESULTS: A total of 235 AIS patients were included, and 31 (13.19%) subjects underwent postthrombolysis END. The univariate logistic regression analysis demonstrated that RPR before intravenous thrombolysis was significantly related to postthrombolysis END (odds ratio [OR], 2.162; 95% confidence interval [CI], 1.605-2.912; P < 0.001). After adjusting for potential confounding variables with P < 0.15 in the univariate logistic regression analysis, the difference remained statistically significant (OR, 2.031; 95% CI, 1.436-2.873; P < 0.001). Furthermore, an optimal cutoff value of 7.66 for RPR before intravenous thrombolysis in predicting postthrombolysis END was observed in the ROC curve analysis, and the sensitivity and specificity were calculated as 61.3% and 81.9%, respectively (area under the curve [AUC], 0.772; 95% CI, 0.684-0.860; P < 0.001). CONCLUSIONS: RPR before intravenous thrombolysis might be an independent risk factor for postthrombolysis END in AIS patients. Elevated levels of RPR before intravenous thrombolysis may predict postthrombolysis END.

The Predictive Value of Monocyte/High-Density Lipoprotein Ratio (MHR) and Positive Symptom Scores for Aggression in Patients with Schizophrenia.

Background and Objectives: Schizophrenia with aggression often has an inflammatory abnormality. The monocyte/high-density lipoprotein ratio (MHR), neutrophil/high-density lipoprotein ratio (NHR), platelet/high-density lipoprotein ratio (PHR) and lymphocyte/high-density lipoprotein ratio (LHR) have lately been examined as novel markers for the inflammatory response. The objective of this study was to assess the relationship between these new inflammatory biomarkers and aggression in schizophrenia patients. Materials and Methods: We enrolled 214 schizophrenia inpatients in our cross-sectional analysis. They were divided into the aggressive group (n = 94) and the non-aggressive group (n = 120) according to the Modified Overt Aggression Scale (MOAS). The severity of schizophrenia was assessed using the Positive and Negative Syndrome Scale (PANSS). The numbers of platelets (PLT), neutrophils (NEU), lymphocytes (LYM), monocytes (MON) and the high-density lipoprotein (HDL) content from subjects were recorded. The NHR, PHR, MHR and LHR were calculated. We analyzed the differences between those indexes in these two groups, and further searched for the correlation between inflammatory markers and aggression. Results: Patients with aggression had higher positive symptom scores (p = 0.002). The values of PLT, MON, MHR and PHR in the aggressive group were considerably higher (p < 0.05). The NHR (r = 0.289, p < 0.01), LHR (r = 0.213, p < 0.05) and MHR (r = 0.238, p < 0.05) values of aggressive schizophrenia patients were positively correlated with the total weighted scores of the MOAS. A higher MHR (ß = 1.529, OR = 4.616, p = 0.026) and positive symptom scores (ß = 0.071, OR = 1.047, p = 0.007) were significant predictors of aggression in schizophrenia patients. Conclusions: The MHR and the positive symptom scores may be predictors of aggressive behavior in schizophrenia patients. The MHR, a cheap and simple test, may be useful as a clinical tool for risk stratification, and it may direct doctors' prevention and treatment plans in the course of ordinary clinical care.

Ginkgolide B inactivates the NLRP3 inflammasome by promoting autophagic degradation to improve learning and memory impairment in Alzheimer's disease.

The NLR family, pyrin domain containing 3 (NLRP3) inflammasome drives the progression of Alzheimer's disease (AD). Ginkgolide B (GB) is a potential anti-inflammatory compound that controls neuro-inflammation. The aim of this study was to evaluate the effect of GB on the NLRP3 inflammasome in AD. The effect of GB on the conversion between the M1 and M2 microglial phenotype was examined using quantitative real-time PCR and immunostaining. Western blotting assays and ELISA were used to detect changes in neuro-inflammation following GB treatment, including the NLRP3 inflammasome pathway and autophagy. In order to evaluate the cognitive function of male senescence-accelerated mouse prone 8 (SAMP8) mice, behavioral tests, including the Morris water maze and novel object recognition tests, were performed. GB significantly decreased the intracellular pro-inflammatory cytokine levels in lipopolysaccharide-treated BV2 cells and improved cognitive behavior in SAMP8 mice. Moreover, GB deactivated the NLRP3 inflammasome, and this effect was dependent on autophagy. Ubiquitination was associated with GB-induced autophagic NLRP3 degradation. These results were further validated in the hippocampus of SAMP8 mice. Thus, GB exerted a neuroprotective effect on the cognitive function of SAMP8 mice by suppressing the activation of NLRP3 inflammasome via autophagic degradation.

Edaravone Dexborneol Versus Edaravone Alone for the Treatment of Acute Ischemic Stroke: A Phase III, Randomized, Double-Blind, Comparative Trial.

BACKGROUND AND PURPOSE: Edaravone dexborneol, comprised of 2 active ingredients, edaravone and (+)-borneol, has been developed as a novel neuroprotective agent with synergistic effects of antioxidant and anti-inflammatory in animal models. The present clinical trial aimed at testing the effects of edaravone dexborneol versus edaravone on 90-day functional outcome in patients with acute ischemic stroke (AIS). METHODS: A multicenter, randomized, double-blind, comparative, phase III clinical trial was conducted at 48 hospitals in China between May 2015 and December 2016. Inclusion criteria included patients diagnosed as AIS, 35 to 80 years of age, National Institutes of Health Stroke Scale Score between 4 and 24, and within 48 hours of AIS onset. AIS patients were randomized in 1:1 ratio into 2 treatment arms: 14-day infusion of edaravone dexborneol or edaravone injection. The primary end point was the proportion of patients with modified Rankin Scale score ≤1 on day 90 after randomization. RESULTS: One thousand one hundred sixty-five AIS patients were randomly allocated to the edaravone dexborneol group (n=585) or the edaravone group (n=580). The edaravone dexborneol group showed significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization, compared with the edaravone group (modified Rankin Scale score ≤1, 67.18% versus 58.97%; odds ratio, 1.42 [95% CI, 1.12-1.81]; P=0.004). The prespecified subgroup analyses indicated that a greater benefit was observed in female patients than their male counterparts (2.26, 1.49-3.43 versus 1.14, 0.85-1.52). CONCLUSIONS: When edaravone dexborneol versus edaravone was administered within 48 hours after AIS, 90-day good functional outcomes favored the edaravone dexborneol group, especially in female patients. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02430350.

Ginkgolide B protects against cognitive impairment in senescence-accelerated P8 mice by mitigating oxidative stress, inflammation and ferroptosis.

Alzheimer's disease (AD) is a destructive neurodegenerative disease that currently has no effective treatment option available. Ginkgolide B (GB) is a terpene lactone derivative of Ginkgo biloba that possesses neuroprotective effects in various diseases. The aim of the present study was to investigate whether GB protects against cognitive impairment in AD by mitigating oxidative stress, inflammation and ferroptosis using senescence-accelerated P8 (SAMP8) mice. The results showed that GB improved the cognitive dysfunction of SAMP8 mice in the Morris water maze and novel object recognition test, which was associated with the attenuation of oxidative stress, inflammation and nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 (GPX4) pathway-mediated ferroptosis. Furthermore, Ras-selective lethal small molecule 3, a GPX4 inhibitor and ferroptosis inducer, compromised GB-induced cognitive performance in SAMP8 mice. These findings suggested that GB alleviated AD-induced cognitive defects by mitigating oxidative stress, neuroinflammation and ferroptosis, and that the inhibition of ferroptosis is required for GB to have beneficial effects in AD.

Prognostic value of plasma fibroblast growth factor 21 among patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: To evaluate the association between plasma fibroblast growth factor 21 (FGF-21) and clinical outcomes in patients with acute ischemic stroke. METHODS: A total of 3412 acute ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke with plasma FGF-21 measurements were included in this analysis. The primary outcome was a combination of death or major disability (modified Rankin Scale score ≥3) within 1 year after stroke. RESULTS: During the 1-year of follow-up, 745 (21.83%) patients experienced the primary outcome; 550 had a major disability and 195 died. After multivariate adjustment, higher plasma FGF-21 was significantly associated with increased risk of the primary outcome (odds ratio = 1.52, 95% confidence interval = 1.11-1.29). Each 1-SD increase of log-transformed FGF-21 (0.67 pg/ml) was associated with 19%, 3%, and 33% increased risk of the primary outcome, major disability, and death, respectively. The addition of FGF-21 to the conventional risk factors significantly improved prediction of the primary outcome in ischemic stroke patients (net reclassification index = 10.8%, p = 0.011; integrated discrimination improvement = 0.3%, p = 0.038). CONCLUSIONS: Higher plasma FGF-21 was associated with poor prognosis in acute ischemic stroke patients, suggesting that FGF-21 may be a prognostic marker for ischemic stroke.

Predictive Value of Cystatin C for Stroke Recurrence in Patients With Acute Ischemic Stroke.

BACKGROUND: This study explored the value of cystatin C (CysC) in predicting stroke recurrence in patients with acute ischemic stroke.Methods and Results:This was a post hoc analysis of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) on 3,474 acute ischemic stroke patients with documented serum CysC and high-sensitivity C-reactive protein (hsCRP) concentrations. Study outcomes included stroke recurrence and combined vascular events within 2 years after stroke. In stroke patients with higher (i.e., ≥4.8ng/mL), but not lower, hsCRP concentrations, a higher CysC concentration (i.e., ≥0.78 mg/L) was associated with a 2.48-fold increase in the risk of recurrent stroke (95% confidence interval [CI] 1.37-4.51; P=0.003) and a 2.04-fold increase in the risk of vascular events (95% CI 1.27-3.28; P=0.003). Serum hsCRP concentrations significantly modified the association of serum CysC with recurrent stroke (Pinteraction=0.001) and vascular events (Pinteraction=0.007). Moreover, CysC may improve reclassification of stroke recurrence (net reclassification improvement [NRI] 42.9%, P=0.001; integrated discrimination improvement [IDI] 1.2%, P=0.001) and vascular events (NRI 35.8%, P=0.001; IDI 1.1%, P=0.004). CONCLUSIONS: In ischemic stroke patients with high hsCRP concentrations, higher CysC concentrations increased the risk of stroke recurrence and vascular events. This indicates that the predictive value of CysC on stroke recurrence may depend on the inflammation status of patients.

The cognitive impairment and risk factors of the older people living in high fluorosis areas: DKK1 need attention.

OBJECTIVE: To evaluate cognitive impairment and risk factors of elders in high fluoride drinking water areas and investigate whether DKK1 is involved in this disorder. METHODS: MoCA-B and AD-8 were used to measure the cognitive functions of 272 and 172 subjects over the age of 60 came from the high and normal fluoride drinking water areas respectively, general information and peripheral blood were collected, the level of SOD, GSH and MDA were measured, mRNA level of DKK1, the concentration of blood fluoride and the polymorphism of APOE were tested. RESULTS: The blood fluoride concentration, mRNA level of DKK1 and ratio of abnormal cognitive function of subjects in high fluorine drinking water areas were higher than those in normal areas. The level of SOD of subjects in high fluorine drinking water was low compared with those in normal areas. The level of MDA and GSH had no difference between the two crowds in different fluorine drinking water areas. There were differences in cigarette smoking, education, dental status, hypertension, hyperlipidaemia and APOE results between the two crowds in different fluorine drinking water areas. The mRNA level of DKK1 and the level of cognitive function showed a positive correlation and DKK1 was one of five risk factors involved in cognitive impairment of older people living in high fluorosis areas. CONCLUSIONS: The cognitive functions could be impaired in the older people living in high fluoride drinking water areas, and DKK1 may as a potential intervention point of this brain damage process need attention.

White Matter Hyperintensity, Immediate Antihypertensive Treatment, and Functional Outcome After Acute Ischemic Stroke.

Background and Purpose- It remains unknown that whether white matter hyperintensity (WMH) severity influences the effect of antihypertensive treatment in acute ischemic stroke. We aimed to investigate the effects of early antihypertensive treatment on death and disability among patients with acute ischemic stroke according to WMH severities. Methods- This study was a secondary analysis of the data from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). Severity of WMH was evaluated using Fazekas rating scale score among 303 participants with available magnetic resonance imaging data and was categorized into none-mild WMH (Fazekas score 0-2) and moderate-severe WMH (Fazekas score 3-6). Functional outcome was death or major disability (modified Rankin Scale score of ≥3) at 14 days or hospital discharge and within 3 months. Results- WMH severity was significantly associated with an increased risk of death or major disability. Each 1 score increase in Fazekas score was associated with an adjusted odds ratio (95% CI) of 1.25 (1.03-1.51) for 14 days or hospital discharge and 1.39 (1.12-1.72) for 3-month functional outcome. There were no significant interactions between antihypertensive treatment and WMH severity (both P>0.1) on functional outcome at 14 days or hospital discharge and within 3 months. The neutral effects of immediate antihypertensive treatment were observed both in patients with moderate-severe WMH and none-mild WMH. Conclusions- Participants with higher WMH burden had increased risk of death or major disability after acute ischemic stroke. Early antihypertensive treatment had a neutral effect on clinical outcomes among acute ischemic stroke patients with a variety of WMH severities. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

DNAzyme-Powered Three-Dimensional DNA Walker Nanoprobe for Detection Amyloid ß-Peptide Oligomer in Living Cells and in Vivo.

Amyloid ß-peptide oligomer (AßO) is widely acknowledged as the promising biomarker for the diagnosis of Alzheimer's disease (AD). In this work, we designed a three-dimensional (3D) DNA walker nanoprobe for AßO detection and real-time imaging in living cells and in vivo. The presence of AßO triggered the DNAzyme walking strand to cleave the fluorophore (TAMRA)-labeled substrate strand modified on the gold nanoparticle (AuNP) surface and release TAMRA-labeled DNA fragment, resulting in the recovery of fluorescent signal. The entire process was autonomous and continuous, without external fuel strands or protease, and finally produced plenty of TAMRA fluorescence, achieving signal amplification effect. The nanoprobe enabled the quantitative detection of AßO in vitro, and the limit of detection was 22.3 pM. Given the good biocompatibility of 3D DNA walker nanoprobe, we extended this enzyme-free signal amplification method to real-time imaging of AßO. Under the microscope, nanoprobe accurately located and visualized the distribution of AßO in living cells. Moreover, in vivo imaging results showed that our nanoprobe could be used to effectively distinguish the AD mice from the wild-type mice. This nanoprobe with the advantages of great sensitivity, high specificity, and convenience, provides an outstanding prospect for AD's early diagnosis development.

Serum dickkopf-3 is associated with death and vascular events after ischemic stroke: an observational study from CATIS.

BACKGROUND: Dickkopf-3 (Dkk-3) is implicated in the progression of atherosclerosis. This study aimed to investigate the association between serum Dkk-3 and the prognosis of ischemic stroke. METHODS: We measured serum Dkk-3 levels in 3344 ischemic stroke patients from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). The primary outcome was a combination of death and vascular events within 3 months after ischemic stroke. RESULTS: During 3 months of follow-up, the cumulative incidence rates of primary outcome among ischemic stroke patients in five quintiles of serum Dkk-3 (from low to high) were 4.49%, 3.74%, 2.54%, 5.23%, and 6.73%, respectively (log-rank p = 0.004). Multivariable Cox proportional hazards regression analyses showed that compared with the third quintile of serum Dkk-3, the adjusted hazard ratios (95% confidence intervals) associated with the first and fifth quintile were 3.49 (1.46-8.34) and 4.23 (1.86-9.64) for primary outcome, 3.47 (1.06-11.36) and 5.30 (1.81-15.51) for death, and 2.66 (1.01-7.01) and 3.35 (1.33-8.40) for vascular events, respectively. Multivariable-adjusted Cox proportional hazards regression model with restricted cubic splines showed a U-shaped association between serum Dkk-3 and the risk of primary outcome (p for nonlinearity = 0.030). Moreover, adding serum Dkk-3 to conventional risk factors could improve the predictive power for primary outcome (net reclassification improvement 28.44%, p < 0.001; integrated discrimination improvement 0.48%, p = 0.001). CONCLUSIONS: Both low and high serum Dkk-3 levels are associated with increased risks of death and vascular events within 3 months after ischemic stroke, indicating that serum Dkk-3 may have a special effect on the prognosis of ischemic stroke. We also found that serum Dkk-3 might be a prognostic biomarker for ischemic stroke. Further studies are needed to replicate our findings and to determine the optimal levels of serum Dkk-3.

Dectin-1/Syk signaling triggers neuroinflammation after ischemic stroke in mice.

BACKGROUND: Dendritic cell-associated C-type lectin-1 (Dectin-1) receptor has been reported to be involved in neuroinflammation in Alzheimer's disease and traumatic brain injury. The present study was designed to investigate the role of Dectin-1 and its downstream target spleen tyrosine kinase (Syk) in early brain injury after ischemic stroke using a focal cortex ischemic stroke model. METHODS: Adult male C57BL/6 J mice were subjected to a cerebral focal ischemia model of ischemic stroke. The neurological score, adhesive removal test, and foot-fault test were evaluated on days 1, 3, 5, and 7 after ischemic stroke. Dectin-1, Syk, phosphorylated (p)-Syk, tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) expression was analyzed via western blotting in ischemic brain tissue after ischemic stroke and in BV2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro. The brain infarct volume and Iba1-positive cells were evaluated using Nissl's and immunofluorescence staining, respectively. The Dectin-1 antagonist laminarin (LAM) and a selective inhibitor of Syk phosphorylation (piceatannol; PIC) were used for the intervention. RESULTS: Dectin-1, Syk, and p-Syk expression was significantly enhanced on days 3, 5, and 7 and peaked on day 3 after ischemic stroke. The Dectin-1 antagonist LAM or Syk inhibitor PIC decreased the number of Iba1-positive cells and TNF-α and iNOS expression, decreased the brain infarct volume, and improved neurological functions on day 3 after ischemic stroke. In addition, the in vitro data revealed that Dectin-1, Syk, and p-Syk expression was increased following the 3-h OGD and 0, 3, and 6 h of reperfusion in BV2 microglial cells. LAM and PIC also decreased TNF-α and iNOS expression 3 h after OGD/R induction. CONCLUSION: Dectin-1/Syk signaling plays a crucial role in inflammatory activation after ischemic stroke, and further investigation of Dectin-1/Syk signaling in stroke is warranted.

Prognostic Metrics Associated with Inflammation and Atherosclerosis Signaling Evaluate the Burden of Adverse Clinical Outcomes in Ischemic Stroke Patients.

BACKGROUND: Conventional prognostic risk factors can only partly explain the adverse clinical outcomes after ischemic stroke. We aimed to establish a set of prognostic metrics and evaluate its public health significance on the burden of adverse clinical outcomes of ischemic stroke. METHODS: All patients were from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). We established prognostic metrics of ischemic stroke from 20 potential biomarkers in a propensity-score-matched extreme case sample (n = 146). Pathway analysis was conducted using Ingenuity Pathway Analysis. In the whole CATIS population (n = 3575), we evaluated effectiveness of these prognostic metrics and estimated their population-attributable fractions (PAFs) related to the risk of clinical outcomes. The primary outcome was a composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 months after stroke. RESULTS: Matrix metalloproteinase-9 (MMP-9), S100A8/A9, high-sensitivity C-reactive protein (hsCRP), and growth differentiation factor-15 (GDF-15) were selected as prognostic metrics for ischemic stroke. Pathway analysis showed significant enrichment in inflammation and atherosclerosis signaling. All 4 prognostic metrics were independently associated with poor prognosis of ischemic stroke. Compared with patients having 1 or 0 high-level prognostic metrics, those with 4 had higher risk of primary outcome (OR: 3.84, 95%CI: 2.67-5.51; PAF: 37.4%, 95%CI: 19.5%-52.9%). CONCLUSION: The set of prognostic metrics, enriching in inflammation and atherosclerosis signaling, could effectively predict the prognosis at 3 months after ischemic stroke and would provide additional information for the burden of adverse clinical outcomes among patients with ischemic stroke.

Plasma S100A8/A9 Concentrations and Clinical Outcomes of Ischemic Stroke in 2 Independent Multicenter Cohorts.

BACKGROUND: S100A8/A9 is implicated in inflammation mechanisms related to atherosclerosis and plaque vulnerability, but it remains unclear whether S100A8/A9 is associated with the prognosis of ischemic stroke. The aim of this study was to investigate these associations in 2 independent multicenter cohorts. METHODS: Plasma S100A8/A9 concentrations at baseline were measured among 4785 patients with ischemic stroke from 2 independent cohorts: Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke (IIPAIS) and China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a composite outcome of death or major disability at 3 months after ischemic stroke. Secondary outcomes were major disability, death, and a composite outcome of death or vascular events. RESULTS: Among the combined participants of IIPAIS and CATIS, the adjusted odds ratios associated with the highest quartile of plasma S100A8/A9 were 2.11 (95% CI, 1.66-2.68) for the primary outcome and 1.62 (95% CI, 1.27-2.07) for the secondary outcome of major disability; adjusted hazard ratios were 4.14 (95% CI, 2.10-8.15) for the secondary outcome of death and 2.08 (95% CI, 1.38-3.13) for the composite outcome of death or vascular events. Each SD increase of log-transformed S100A8/A9 was associated with 28% (95% CI, 18%-39%; P < 0.001) increased risk of the primary outcome. Multivariable-adjusted spline regression analyses showed a linear association between plasma S100A8/A9 concentrations and primary outcome (P < 0.001 for linearity). Subgroup analyses further confirmed these associations. CONCLUSIONS: High plasma S100A8/A9 concentrations at baseline were independently associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that S100A8/A9 might have a role as a prognostic marker of ischemic stroke.

Serum Dkk-1 (Dickkopf-1) Is a Potential Biomarker in the Prediction of Clinical Outcomes Among Patients With Acute Ischemic Stroke.

Objective- Serum Dkk-1 (dickkopf-1) level has been shown to be elevated in patients with ischemic stroke, but its impact on clinical outcomes of ischemic stroke remains unclear. The aim of this study is to investigate the association between serum Dkk-1 and prognosis of ischemic stroke. Approach and Results- We measured serum Dkk-1 levels in 3178 patients with ischemic stroke from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). The primary outcome was a combination of all-cause mortality and major disability (modified Rankin scale score, ≥3) at 1 year after stroke. Secondary outcomes were stroke recurrence and vascular events. After multivariate adjustment, elevated Dkk-1 levels were associated with an increased risk of primary outcome (odds ratio, 1.40; 95% CI, 1.03-1.89; Ptrend=0.015) when 2 extreme quartiles were compared. Each SD increase of log-transformed Dkk-1 was associated with 12% (95% CI, 1%-24%) increased risk of primary outcome. Multiple-adjusted spline regression model showed a linear association between serum Dkk-1 and risk of primary outcome ( P for linearity, 0.039). Subgroup analyses further confirmed these associations. The addition of serum Dkk-1 to conventional risk factors improved the predictive power for primary outcome (net reclassification improvement: 10.11%, P=0.029; integrated discrimination improvement: 0.21%, P=0.028). Conclusions- High serum Dkk-1 levels at baseline were associated with poor prognosis at 1 year after ischemic stroke, suggesting that serum Dkk-1 may be a potential prognostic biomarker for ischemic stroke. Further studies from other samples of patients with ischemic stroke are needed to replicate our findings and to clarify the potential mechanisms.