Parenchymal pericytes are not the major contributor of extracellular matrix in the fibrotic scar after stroke in male mice

Scar formation after injury of the brain or spinal cord is a common event. While glial scar formation by astrocytes has been extensively studied, much less is known about the fibrotic scar, in particular after stroke. Platelet-derived growth factor receptor ß-expressing (PDGFRß⁺) pericytes have been suggested as a source of the fibrotic scar depositing fibrous extracellular matrix (ECM) proteins after detaching from the vessel wall. However, to what extent these parenchymal PDGFRß⁺ cells contribute to the fibrotic scar and whether targeting these cells affects fibrotic scar formation in stroke is still unclear. Here, we utilize male transgenic mice that after a permanent middle cerebral artery occlusion stroke model have a shift from a parenchymal to a perivascular location of PDGFRß⁺ cells due to the loss of regulator of G-protein signaling 5 in pericytes. We find that only a small fraction of parenchymal PDGFRß⁺ cells co-label with type I collagen and fibronectin. Consequently, a reduction in parenchymal PDGFRß⁺ cells by ca. 50% did not affect the overall type I collagen or fibronectin deposition after stroke. The redistribution of PDGFRß⁺ cells to a perivascular location, however, resulted in a reduced thickening of the vascular basement membrane and changed the temporal dynamics of glial scar maturation after stroke. We demonstrate that parenchymal PDGFRß⁺ cells are not the main contributor to the fibrotic ECM, and therefore targeting these cells might not impact on fibrotic scar formation after stroke.     

Profilin 1 knockdown prevents ischemic brain damage by promoting M2 microglial polarization associated with the RhoA/ROCK pathway

Microglial polarization to the anti-inflammatory M2 phenotype is essential in resolving neuroinflammation, making it a promising therapeutic strategy for stroke intervention. The actin cytoskeleton is known to be important for the physiological functions of microglia, including migration and phagocytosis. Profilin 1 (PFN1), an actin-binding protein, is involved in the dynamic transformation and reorganization of actin. However, the role of PFN1 in microglial polarization and ischemia/reperfusion injury is unclear. The role of PFN1 on microglial polarization was examined in vitro in BV2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGDR) and in vivo in male mice after transient middle cerebral artery occlusion (MCAO). Knockdown of PFN1 inhibited M1 microglial polarization and promoted M2 microglia polarization 48 hr after OGDR stimulation in BV2 cells and 7 days after MCAO-induced injury in male mice. RhoA/ROCK pathway was involved in the regulation of PFN1 during microglial polarization. Knockdown of PFN1 also significantly attenuated brain infarcts and edema, improved cerebral blood flow and neurological deficits in MCAO-injured mice. Inhibition of PFN1 effectively protected the brain against ischemia/reperfusion injuries by promoting M2 microglial polarization in vitro and in vivo.     

A thread of hope for successful revascularization for acute embolic basilar artery occlusion due to miserable vertebral artery stump syndrome. A technical report

Acute basilar artery occlusion (BAO) is associated with major morbidities and a high mortality rate. The prevalence of acute BAO is 10.4% among patients treated with thrombectomy for acute large vessel occlusion. Vertebral artery stump syndrome (VASS) reportedly causes ischemic stroke with tandem occlusions as vertebral artery (VA) origin occlusion and BAO. The pathogenesis of ischemic stroke due to VASS can be attributed to thrombi or emboli. Acute embolic BAO due to VASS accounted for 2 of 25 cases (8.0%) of BAO treated using thrombectomy between April 2014 and May 2019 in our registry. VASS must be considered as one cause of BAO. With the initial Magnetic resonance angiography on arrival, it is difficult to distinguish between BAO due to simple cardiogenic embolus and due to embolus caused by VASS rapidly. In patients suffering from acute embolic BAO due to VASS, the presence of VA origin occlusion makes endovascular therapy (EVT) difficult to perform. Here, we report consecutive cases of thrombectomy for acute embolic BAO due to VASS, showing markedly different outcomes. VA origin occlusion severely limits the technical options for EVT. Visualization or conjecture of the origin of both or dominant VAs conceivably offers the possibility of successful EVT and may allow good outcomes.     

Collateral augmentation treatment with a combination of acetazolamide and head-down tilt in a rat ischemic stroke model

Cerebral collaterals is crucially important in the pathophysiology of acute ischemic stroke and associated with outcome after reperfusion therapy. We explored the effectiveness of collateral augmentation treatment with a combination of acetazolamide (ACZ) and head-down tilt (HDT) in the transient middle cerebral artery occlusion (MCAO) rat model. Transient MCAO was induced in all animals for 1.5 h, followed by reperfusion for 22.5 h. Seventy-two male Wistar rats were divided into four treatment groups: control, ACZ, HDT, and combination. Twenty sham rats, which underwent surgery, were randomly allocated to these groups. Twenty-four hours after MCAO or sham surgery, we measured the infarction volume, brain edema (aquaporin-4 [AQP4], and brain water content), and neurological deficits (Garcia and Longa tests). Collateral augmentation treatments were associated with reduced infarction volume, less brain edema, and better neurological outcomes compared with untreated animals. More specifically, ACZ and HDT treatments resulted in small infarction volumes, and HDT was associated with a low AQP4 expression and improved neurological score, while the combination of ACZ and HDT improved neurological scores and reduced brain water content. This study shows that collateral augmentation treatments are associated with a better stroke prognosis compared with untreated animals after transient MCAO. The combination of ACZ and HDT seems to have some synergistic effect, but was not proven to be superior to HDT treatment alone.     

Thrombolysis safety and effectiveness in acute ischemic stroke patients with pre-morbid disability

IntroductionRecombinant tissue plasminogen activator (rt-PA) is the first-line therapy demonstrated to be safe and effective in acute ischemic stroke. People with pre-existing severe dementia or physical disability are usually excluded from rt-PA. The aim of our study was to investigate rt-PA safety and effectiveness in acute stroke with pre-existing disability (mRS ≥ 2).MethodsThe study encompassed 35 acute ischemic stroke patients with mRS ≥ 2 treated with rt-PA. In order to assess the differences in clinical outcome in three disability groups (mRS = 2; 3; 4/5), the following parameters were evaluated: intracerebral hemorrhage, mortality, NIHSS, ΔNIHSS and mRS.ResultsBaseline-NIHSS and age were not significantly different among groups. Mortality was higher in the pre-morbid mRS 4/5 group (44%) than in the pre-morbid mRS 2 (16.7%) and mRS 3 groups (21.4%). In survived patients, median ΔNIHSS% was higher in the mRS 2 and 3 groups (-63.3% and −92.3%, respectively) than in the mRS 4/5 group (−9.1%). The 247 rt-PA treated subjects with mRS < 2 in the same period showed lower mortality rate (4.7%), lower sICH (5%), lower mRS at discharge (median 1; range 0–6) and similar ΔNIHSS% (−75%).ConclusionPatients with mRS 2 and 3 may benefit from rt-PA with a moderate risk of sICH and mortality.     

进展性卒中危险因素的研究现状

脑卒中是全球重要的致死、致残性疾病,是中国第一大致死原因和主要的致残原因,而缺血性卒中约占80%。进展性卒中是急性缺血性卒中发病几天内出现的神经功能的恶化,临床中约1/3的患者经历卒中进展,是脑卒中预后不良的重要原因。本文就进展性卒中的概念、发病机制、危险因素及影像学特征进行系统综述,旨在探讨进展性卒中科学的诊断标准、早期预防措施及治疗方法,以期降低脑血管疾病的致死、致残率。     

血清β2-微球蛋白水平与急性缺血性脑卒中发病风险的相关性研究

目的 探讨血清β₂-微球蛋白(β₂-microglobulinm,β₂-MG)水平与急性缺血性脑卒中发病风险的相关性。方法 选取2001年3月-2014年12月本院收治的302例新发的急性缺血性脑卒中患者作为研究对象进行巢式病例对照研究。另选取同等数量年龄与性别相匹配的非脑卒中个体作为对照,比较血清β₂-MG水平及脑卒中常见危险因素暴露与急性缺血性脑卒中发病的风险。结果 单因素分析显示,血清β₂-MG水平、心脏病史、高血压病史、脑卒中家族史与急性缺血性脑卒中的发病风险显著相关[OR(95%CI)分别为6.74(3.92～11.61)、1.77(1.00～3.09)、3.43(2.00～5.89)、2.04(1.11～3.71),P均<0.05]。此外,血清β₂-MG水平的升高与急性缺血性脑卒中的发病风险具有显著的剂量反应关系(χ2=48.47,P<0.05)。多因素Logistic回归分析显示,血清β₂-MG水平与急性缺血性脑卒中的发生独立相关[OR(95%CI)=6.11(3.46～10.77),P<0.05]。结论 血清β₂-MG水平升高与急性缺血性脑卒中的发病风险密切相关,可作为其发病的独立预测因子。     

急性缺血性脑卒中血管介入治疗方法和装置的研究进展

机械血栓切除术可治疗伴大血管闭塞的前循环和后循环急性缺血性脑卒中。机械血栓切除术失败后仍应进行支架植入术;接触抽吸术与支架取栓术的优劣难分仲伯;伴大血管闭塞的动脉粥样硬化性前循环急性缺血性脑卒中,血管成形术和(或)支架置入术要优于支架取栓术;支架取栓术加动脉内溶栓治疗有叠加效应,但机械血栓切除术加静脉溶栓则无叠加效应;远程缺血预处理和替罗非班有减少手术并发症的功效;紫杉醇洗脱支架和新型支架是值得推广的新型血管内治疗装置。     

Brain oscillatory activity as a biomarker of motor recovery in chronic stroke

In the present work, we investigated the relationship of oscillatory sensorimotor brain activity to motor recovery. The neurophysiological data of 30 chronic stroke patients with severe upper‐limb paralysis are the basis of the observational study presented here. These patients underwent an intervention including movement training based on combined brain–machine interfaces and physiotherapy of several weeks recorded in a double‐blinded randomized clinical trial. We analyzed the alpha oscillations over the motor cortex of 22 of these patients employing multilevel linear predictive modeling. We identified a significant correlation between the evolution of the alpha desynchronization during rehabilitative intervention and clinical improvement. Moreover, we observed that the initial alpha desynchronization conditions its modulation during intervention: Patients showing a strong alpha desynchronization at the beginning of the training improved if they increased their alpha desynchronization. Patients showing a small alpha desynchronization at initial training stages improved if they decreased it further on both hemispheres. In all patients, a progressive shift of desynchronization toward the ipsilesional hemisphere correlates significantly with clinical improvement regardless of lesion location. The results indicate that initial alpha desynchronization might be key for stratification of patients undergoing BMI interventions and that its interhemispheric balance plays an important role in motor recovery.     

Game theoretical mapping of white matter contributions to visuospatial attention in stroke patients with hemineglect

White matter bundles linking gray matter nodes are key anatomical players to fully characterize associations between brain systems and cognitive functions. Here we used a multivariate lesion inference approach grounded in coalitional game theory (multiperturbation Shapley value analysis, MSA) to infer causal contributions of white matter bundles to visuospatial orienting of attention. Our work is based on the characterization of the lesion patterns of 25 right hemisphere stroke patients and the causal analysis of their impact on three neuropsychological tasks: line bisection, letter cancellation, and bells cancellation. We report that, out of the 11 white matter bundles included in our MSA coalitions, the optic radiations, the inferior fronto‐occipital fasciculus and the anterior cingulum were the only tracts to display task‐invariant contributions (positive, positive, and negative, respectively) to the tasks. We also report task‐dependent influences for the branches of the superior longitudinal fasciculus and the posterior cingulum. By extending prior findings to white matter tracts linking key gray matter nodes, we further characterize from a network perspective the anatomical basis of visual and attentional orienting processes. The knowledge about interactions patterns mediated by white matter tracts linking cortical nodes of attention orienting networks, consolidated by further studies, may help develop and customize brain stimulation approaches for the rehabilitation of visuospatial neglect.