Translational Stroke Research最新文献

Rheumatoid factor (RF), an established diagnostic biomarker for rheumatoid arthritis (RA), is associated with cardiovascular diseases, but its impact on clinical outcomes of ischemic stroke remains unclear. We aimed to investigate the observational associations between serum RF and prognosis of ischemic stroke, and further examined the genetic associations of RA and its therapeutic strategy, interleukin-6 (IL-6) inhibitor, with prognosis of ischemic stroke. We measured serum RF levels in 3474 Chinese ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset. Mendelian randomization (MR) analyses were performed to examine the associations of genetically predicted RA and IL-6 inhibition with prognosis of ischemic stroke. During 3 months of follow-up, 866 patients (25.43%) experienced death or major disability. After multivariate adjustment, RF-positive was significantly associated with a high risk of primary outcome (OR, 1.47; 95% CI, 1.08-2.00; P =0.016) compared with RF-negative. The two-sample MR analyses suggested that genetically predicted RA was associated with an increased risk of primary outcome (OR, 1.09; 95% CI, 1.01-1.18; P=0.021), while genetically predicted IL-6 inhibition was associated with a decreased risk of primary outcome (OR, 0.88; 95% CI, 0.77-0.99; P=0.041). We found that positive RF was associated with increased risks of adverse outcomes after atherosclerotic ischemic stroke, and genetically predicted RA and IL-6 inhibition increased and decreased the risks of adverse outcomes after ischemic stroke, respectively.

Canonical transient receptor potential (TRPC) non-selective cation channels, particularly those assembled with TRPC3, TRPC6, and TRPC7 subunits, are coupled to G_αq-type G protein-coupled receptors for the major classes of excitatory neurotransmitters. Sustained activation of this TRPC channel-based pathophysiological signaling hub in neurons and glia likely contributes to prodigious excitotoxicity-driven secondary brain injury expansion. This was investigated in mouse models with selective Trpc gene knockout (KO). In adult cerebellar brain slices, application of glutamate and the class I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine to Purkinje neurons expressing the GCaMP5g Ca²⁺ reporter demonstrated that the majority of the Ca²⁺ loading in the molecular layer dendritic arbors was attributable to the TRPC3 effector channels (Trpc3^KO compared with wildtype (WT)). This Ca²⁺ dysregulation was associated with glutamate excitotoxicity causing progressive disruption of the Purkinje cell dendrites (significantly abated in a GAD67-GFP-Trpc3^KO reporter brain slice model). Contribution of the G_αq-coupled TRPC channels to secondary brain injury was evaluated in a dual photothrombotic focal ischemic injury model targeting cerebellar and cerebral cortex regions, comparing day 4 post-injury in WT mice, Trpc3^KO, and Trpc1/3/6/7 quadruple knockout (Trpc^QKO), with immediate 2-h (primary) brain injury. Neuroprotection to secondary brain injury was afforded in both brain regions by Trpc3^KO and Trpc^QKO models, with the Trpc^QKO showing greatest neuroprotection. These findings demonstrate the contribution of the G_αq-coupled TRPC effector mechanism to excitotoxicity-based secondary brain injury expansion, which is a primary driver for mortality and morbidity in stroke, traumatic brain injury, and epilepsy.

Perfusion CT is established to aid selection of patients with proximal intracranial vessel occlusion for thrombectomy in the extended time window. Selection is mostly based on simple thresholding of perfusion parameter maps, which, however, does not exploit the full information hidden in the high-dimensional perfusion data. We implemented a multiparametric mass-univariate logistic model to predict tissue outcome based on data from 405 stroke patients with acute proximal vessel occlusion in the anterior circulation who underwent mechanical thrombectomy. Input parameters were acute multimodal CT imaging (perfusion, angiography, and non-contrast) as well as basic demographic and clinical parameters. The model was trained with the knowledge of recanalization status and final infarct localization. We found that perfusion parameter maps (CBF, CBV, and T_max) were sufficient for tissue outcome prediction. Compared with single-parameter thresholding-based models, our logistic model had comparable volumetric accuracy, but was superior with respect to topographical accuracy (AUC of receiver operating characteristic). We also found higher spatial accuracy (Dice index) in an independent internal but not external cross-validation. Our results highlight the value of perfusion data compared with non-contrast CT, CT angiography and clinical information for tissue outcome-prediction. Multiparametric logistic prediction has high potential to outperform the single-parameter thresholding-based approach. In the future, the combination of tissue and functional outcome prediction might provide an individual biomarker for the benefit from mechanical thrombectomy in acute stroke care.

Clinical implications of RNF213 genetic variants, other than p.Arg4810Lys, in moyamoya disease (MMD), remain unclear. This study aimed to investigate the association of RNF213 variants with clinical phenotypes in MMD. This retrospective cohort study collected data regarding the clinical characteristics of 139 patients with MMD and evaluated the angioarchitectures of 253 hemispheres using digital subtraction angiography at diagnosis. All RNF213 exons were sequenced, and the associations of clinical characteristics and angiographical findings with p.Arg4810Lys, p.Ala4399Thr, and other rare variants (RVs) were examined. Among 139 patients, 100 (71.9%) had p.Arg4810Lys heterozygote (GA) and 39 (28.1%) had the wild type (GG). Fourteen RVs were identified and detetcted in 15/139 (10.8%) patients, and p.Ala4399Thr was detected in 17/139 (12.2%) patients. Hemispheres with GG and p.Ala4399Thr presented with significantly less ischemic events and more hemorrhagic events at diagnosis (p = 0.001 and p = 0.028, respectively). In asymptomatic hemispheres, those with GG were more susceptible to de novo hemorrhage than those with GA (adjusted hazard ratio [aHR] 5.36) with an increased risk when accompanied by p.Ala4399Thr or RVs (aHR 15.22 and 16.60, respectively). Within the choroidal anastomosis-positive hemispheres, GG exhibited a higher incidence of de novo hemorrhage than GA (p = 0.004). The GG of p. Arg4810Lys was a risk factor for de novo hemorrhage in asymptomatic MMD hemispheres. This risk increased with certain other variants and is observed in choroidal anastomosis-positive hemispheres. A comprehensive evaluation of RNF213 variants and angioarchitectures is essential for predicting the phenotype of asymptomatic hemispheres in MMD.

Failure to achieve target-specific delivery to ischemic brain sites has hampered the clinical efficacy of newly developed therapies for ischemic stroke. Emodin, an active ingredient isolated from traditional Chinese medicine, has been indicated to alleviate ischemic stroke; however, the underlying mechanism remains unclear. In this study, we aimed to achieve brain-targeted delivery of emodin to maximize its therapeutic efficacy and elucidate the mechanisms by which emodin alleviates ischemic stroke. A polyethylene glycol (PEG)/cyclic Arg-Gly-Asp (cRGD)-modified liposome was used to encapsulate emodin. TTC, HE, Nissl staining, and immunofluorescence staining were employed to evaluate the therapeutic efficacy of brain-targeting emodin in MCAO and OGD/R models. Inflammatory cytokine levels were determined using ELISA. Immunoprecipitation, immunoblotting, and RT-qPCR were utilized for clarifying the changes in key downstream signaling. Lentivirus-mediated gene restoration was employed to verify the core effector of emodin for relieving ischemic stroke. Encapsulating emodin in a PEG/cRGD-modified liposome enhanced its accumulation in the infarct region and substantially raised its therapeutic efficacy. Furthermore, we demonstrated that AQP4, the most abundant water transporter subunit expressed in astrocytes, plays a crucial role in mediating the mechanisms by which emodin inhibits astrocyte swelling, neuroinflammatory blood-brain barrier (BBB) breakdown in vivo and in vitro, and brain edema in general. Our study unveiled the critical target of emodin responsible for alleviating ischemic stroke and a localizable drug delivery vehicle in the therapeutic strategy for ischemic stroke and other brain injuries.

Microglia and monocytes play a critical role in immune responses to cerebral ischemia. Previous studies have demonstrated that interferon regulatory factor 4 (IRF4) and IRF5 direct microglial polarization after stroke and impact outcomes. However, IRF4/5 are expressed by both microglia and monocytes, and it is not clear if it is the microglial (central) or monocytic (peripheral) IRF4-IRF5 regulatory axis that functions in stroke. In this work, young (8-12 weeks) male pep boy (PB), IRF4 or IRF5 flox, and IRF4 or IRF5 conditional knockout (CKO) mice were used to generate 8 types of bone marrow chimeras, to differentiate the role of central (PB-to-IRF CKO) vs. peripheral (IRF CKO-to-PB) phagocytic IRF4-IRF5 axis in stroke. Chimeras generated from PB and flox mice were used as controls. All chimeras were subjected to 60-min middle cerebral artery occlusion (MCAO) model. Three days after the stroke, outcomes and inflammatory responses were analyzed. We found that PB-to-IRF4 CKO chimeras had more robust microglial pro-inflammatory responses than IRF4 CKO-to-PB chimeras, while ameliorated microglial response was seen in PB-to-IRF5 CKO vs. IRF5 CKO-to-PB chimeras. PB-to-IRF4 or IRF5 CKO chimeras had worse or better stroke outcomes respectively than their controls, whereas IRF4 or 5 CKO-to-PB chimeras had similar outcomes compared to controls. We conclude that the central IRF4/5 signaling is responsible for microglial activation and mediates stroke outcomes.

This study aimed to identify the neuroanatomical predictors of oropharyngeal dysphagia and tube dependency in patients with supratentorial or infratentorial ischemic strokes. Patients with acute ischemic stroke were enrolled and were classified into 3 groups: right supratentorial (n = 61), left supratentorial (n = 89), and infratentorial stroke (n = 50). Dysphagia was evaluated by a modified water swallowing test and the Food Intake LEVEL Scale to evaluate oropharyngeal dysphagia and tube dependency, respectively. As two dysphagia parameters, we evaluated the durations from onset of stroke to (1) success in the modified water swallowing test and to (2) rating 7 points or above on the Food Intake LEVEL Scale: patients regained sufficient oral intake and were not tube-dependent. Voxel-based lesion-symptom mapping analysis was performed for a spatially normalized lesion map of magnetic resonance imaging to explore the anatomies that are associated with the two dysphagia parameters for each stroke group. The right precentral gyrus and parts of the internal capsule are associated with oropharyngeal dysphagia. The four supratentorial areas are associated with tube dependency. The dorsal upper medulla is associated with both oropharyngeal dysphagia and tube dependency. These results suggest that supratentorial stroke patients can be tube-dependent due to an impaired anticipatory phase of ingestion. The simultaneous damage in the four supratentorial areas: the inferior part of the precentral gyrus, lenticular nucleus, caudate head, and anterior insular cortex, predicts tube dependency. In contrast, infratentorial stroke patients can be tube-dependent due to oropharyngeal dysphagia caused by lesions in the dorsal upper medulla, damaging the swallowing-related nucleus.

There have been few reports on the risk factors for preoperative cerebral infarction in childhood moyamoya disease (MMD) in infants under 4 years. The aim of this retrospective study is to identify clinical and radiological risk factors for preoperative cerebral infarction in infants under 4 years old with MMD, and the optimal timing for EDAS was also considered. We retrospectively analyzed the risk factors for preoperative cerebral infarction, confirmed by magnetic resonance angiography (MRA), in pediatric patients aged ˂4 years who underwent encephaloduroarteriosynangiosis between April 2005 and July 2022. The clinical and radiological outcomes were determined by two independent reviewers. In addition, potential risk factors for preoperative cerebral infarction, including infarctions at diagnosis and while awaiting surgery, were analyzed using a univariate model and multivariate logistic regression to identify independent predictors of preoperative cerebral infarction. A total of 160 hemispheres from 83 patients aged <4 years with MMD were included in this study. The mean age of all surgical hemispheres at diagnosis was 2.17±0.831 years (range 0.380-3.81 years). In the multivariate logistic regression model, we included all variables with P<0.1 in the univariate analysis. The multivariate logistic regression analysis indicated that preoperative MRA grade (odds ratio [OR], 2.05 [95% confidence interval [CI], 1.3-3.25], P=0. 002), and age at diagnosis (OR, 0.61 [95% CI, 0.4-0.92], P=0. 018) were predictive factors of infarction at diagnosis. The analysis further indicated that the onset of infarction (OR, 0.01 [95% CI, 0-0.08], P<0.001), preoperative MRA grade (OR, 1.7 [95% CI, 1.03-2.8], P=0.037), and duration from diagnosis to surgery (Diag-Op) (OR, 1.25 [95% CI, 1.11-1.41], P<0.001) were predictive factors for infarction while awaiting surgery. Moreover, the regression analysis indicated that family history (OR, 8.88 [95% CI, 0.91-86.83], P=0.06), preoperative MRA grade (OR, 8.72 [95% CI, 3.44-22.07], P<0.001), age at diagnosis (OR, 0.36 [95% CI, 0.14-0.91], P=0.031), and Diag-Op (OR, 1.38 [95% CI, 1.14-1.67], P=0.001) were predictive factors for total infarction. Therefore, during the entire treatment process, careful observation, adequate risk factor management, and optimal operation time are required to prevent preoperative cerebral infarction, particularly in pediatric patients with a family history, higher preoperative MRA grade, duration from diagnosis to operation longer than 3.53 months, and aged ˂3 years at diagnosis.

Neutrophil-activating peptide 2 (NAP-2, CXCL7), a platelet-derived neutrophil chemoattractant, is involved in inflammation. We investigated associations between NAP-2 levels, neutrophil extracellular traps (NETs) formation, and fibrin clot properties in atrial fibrillation (AF). We recruited 237 consecutive patients with AF (mean age, 68 ± 11 years; median CHA₂DS₂VASc score of 3 [2-4]) and 30 apparently healthy controls. Plasma NAP-2 concentrations were measured, along with plasma fibrin clot permeability (K_s) and clot lysis time (CLT), thrombin generation, citrullinated histone H3 (citH3), as a marker of NETs formation, and 3-nitrotyrosine reflecting oxidative stress. NAP-2 levels were 89% higher in AF patients than in controls (626 [448-796] vs. 331 [226-430] ng/ml; p < 0.0001). NAP-2 levels were not associated with demographics, CHA₂DS₂-VASc score, or the AF manifestation. Patients with NAP-2 in the top quartile (> 796 ng/ml) were characterized by higher neutrophil count (+ 31.7%), fibrinogen (+ 20.8%), citH3 (+ 86%), and 3-nitrotyrosine (+ 111%) levels, along with 20.2% reduced K_s and 8.4% prolonged CLT as compared to the remaining subjects (all p < 0.05). NAP-2 levels were positively associated with fibrinogen in AF patients (r = 0.41, p = 0.0006) and controls (r = 0.65, p < 0.01), along with citH3 (r = 0.36, p < 0.0001) and 3-nitrotyrosine (r = 0.51, p < 0.0001) in the former group. After adjustment for fibrinogen, higher citH3 (per 1 ng/ml β = -0.046, 95% CI -0.029; -0.064) and NAP-2 (per 100 ng/ml β = -0.21, 95% CI -0.14; -0.28) levels were independently associated with reduced K_s. Elevated NAP-2, associated with increased oxidative stress, has been identified as a novel modulator of prothrombotic plasma fibrin clot properties in patients with AF.