急性缺血性脑卒中外周血生化标志物的研究进展

早期诊断急性缺血性脑卒中(acute ischemic stroke,AIS),并对其缺血性脑损伤严重性进行评估,在AIS临床十预方法的选择以及预后判断中扮演着重要角色.神经影像学检查虽然能够提供卒中定位和脑组织结构性改变的重要信息,但它对于AIS患者的脑损伤严重性判断是不允足的.     

Release of glial fibrillary acidic protein is related to the neurovascular status in acute ischemic stroke

This study aimed at an analysis of glial fibrillary acidic protein (GFAP) in acute ischemic stroke, its association with the neurovascular status and its potential value as monitoring parameter. In 53 consecutive patients, serial venous blood samples were taken on admission, 6, 12, 18, 24, 48, 72, 96, and 120 h after stroke onset. The neurovascular status was assessed by repetitive extracranial and transcranial duplex sonography. Neurologic deficits were quantified by the National Institutes of Health stroke scale, and functional outcome was assessed with the modified Rankin Scale. Mean GFAP values were elevated from admission on with highest levels 48 h after stroke onset. GFAP release was highly correlated with severity of neurologic deficits and infarct volume. In patients with persistent middle cerebral artery occlusion, GFAP increased significantly compared with patients with normal sonographic findings ( P  = 0.019) and recanalization after thrombolysis resulted in a significant reduced increase ( P  = 0.038). GFAP concentrations were associated with the functional outcome after 3 months. Release kinetics of GFAP are associated with patients clinical deficits and infarct volume, depend on the neurovascular status on admission and on early recanalization after thrombolysis, and may be used as an additional predictor of the early course and functional outcome.     

Early neurobehavioral outcome after stroke is related to release of neurobiochemical markers of brain damage.

BACKGROUND AND PURPOSE: The study aimed to investigate the predictive value of neurobiochemical markers of brain damage (protein S-100B and neuron-specific enolase [NSE]) with respect to early neurobehavioral outcome after stroke. METHODS: We investigated 58 patients with completed stroke who were admitted to the stroke unit of the Department of Neurology at Magdeburg University. Serial venous blood samples were taken after admission and during the first 4 days, and protein S-100B and NSE were analyzed by the use of immunoluminometric assays. In all patients, lesion topography and vascular supply were analyzed and volume of infarcted brain areas was calculated. The neurological status was evaluated by a standardized neurological examination and the National Institutes of Health Stroke Scale (NIHSS) on admission, at days 1 and 4 on the stroke unit, at day 10, and at discharge from the hospital. Comprehensive neuropsychological examinations were performed in all patients with first-ever stroke event and supratentorial brain infarctions. Functional outcome was measured with the Barthel score at discharge from the hospital. RESULTS: NSE and protein S-100B concentrations were significantly correlated with both volume of infarcted brain areas and NIHSS scores. Patients with an adverse neurological outcome had a significantly higher and significantly longer release of both markers. Neuropsychological impairment was associated with higher protein S-100B release, but this did not reach statistical significance. CONCLUSIONS: Serum concentrations and kinetics of protein S-100B and NSE have a high predictive value for early neurobehavioral outcome after acute stroke. Protein S-100B concentrations at days 2 to 4 after acute stroke may provide valuable information for both neurological status and functional impairment at discharge from the acute care hospital.     

Sequential analyses of neurobiochemical markers of cerebral damage in cerebrospinal fluid and serum in CNS infections

OBJECTIVE: To elucidate the relation between release patterns and cerebrospinal fluid/serum concentrations of neurobiochemical markers of cerebral damage and their potential value as monitoring parameters in central nervous system infections. METHODS: We investigated protein S-100B and neuron-specific enolase (NSE) in 102 sequential cerebrospinal fluid (CSF)-serum-pairs in patients with bacterial (n = 11) or viral (n = 13) meningitis/meningoencephalitis and neuroborreliosis (n = 8) in comparison with controls (n = 13). RESULTS: Highest S-100B values in CSF and serum were found on admission and showed a significant decrease afterwards. Comparison between disease groups revealed significant differences between bacterial and viral meningitis and neuroborreliosis for S-100B and also when compared with controls. NSE was not significantly elevated. CONCLUSIONS: S-100B is altered in CNS infection but does not provide additional benefit in the differential diagnosis when compared with standard CSF parameters. Nevertheless, S-100B values might be used as an additional monitoring parameter especially when sequential lumbar punctures are contraindicated.     

急性缺血性脑卒中患者治疗前后血清S100B蛋白变化及其意义

目的探讨急性缺血性脑卒中患者治疗前后血清S100B蛋白的变化及其临床意义。方法采用ELISA法检测86例急性缺血性脑卒中患者治疗前后及46例正常人的血清S100B蛋白水平。结果急性缺血性脑卒中患者治疗前的血清S100B蛋白水平显著高于对照组（P〈0．001），差异有统计学意义；急性缺血性脑卒中患者治疗后血清S100B蛋白水平显著下降（P〈0．001），差异有统计学意义。结论急性缺血性脑卒中发生时，患者血清S100B蛋白增高；治疗后检测急性缺血性脑卒中患者血清S100B蛋白水平有助于早期诊断、指导治疗及判断预后。     

急性缺血性脑卒中患者治疗前后血清S100B蛋白变化及其意义

目的探讨急性缺血性脑卒中患者治疗前后血清S100B蛋白的变化及其临床意义。方法采用ELISA法检测86例急性缺血性脑卒中患者治疗前后及46例正常人的血清S100B蛋白水平。结果急性缺血性脑卒中患者治疗前的血清S100B蛋白水平显著高于对照组(P<0.001),差异有统计学意义;急性缺血性脑卒中患者治疗后血清S100B蛋白水平显著下降(P<0.001),差异有统计学意义。结论急性缺血性脑卒中发生时,患者血清S100B蛋白增高;治疗后检测急性缺血性脑卒中患者血清S100B蛋白水平有助于早期诊断、指导治疗及判断预后。     

Neuron-specific enolase and tau protein as neurobiochemical markers of neuronal damage are related to early clinical course and long-term outcome in acute ischemic stroke

OBJECTIVES: Analyses of neuron-specific enolase (NSE) and tau protein in patients with hyperacute ischemic stroke, their association with infarct volume, severity of the neurological deficit, the neurovascular status and functional outcome. PATIENTS AND METHODS: In 66 consecutive patients, serial venous blood samples were taken at 3, 6, 12, 18, 24, 48, 72, 96, and 120 h after stroke onset. The neurovascular status was assessed by repetitive extra- and transcranial duplex sonography. Neurological deficits were quantified by the NIH stroke scale, and functional outcome was assessed with the modified Rankin scale (mRS). RESULTS: After a first rise within 3 h, NSE decreased followed by a secondary increase until Day 5. Tau protein concentrations showed a continuous increase from admission onward. NSE and tau release were highly correlated with severity of neurological deficits and infarct volume (P = 0.001). NSE, but not tau protein, release was associated to the neurovascular status on admission. NSE and tau protein values were significantly correlated with the functional outcome at 3 months (P < 0.001). CONCLUSION: Release kinetics of NSE and tau protein are associated with patients' clinical deficits and infarct volume, and may be used as an additional predictor of the early course and functional outcome.     

Plasma heart-type fatty acid binding protein level in acute ischemic stroke: Comparative analysis with plasma S100B level for diagnosis of stroke and prediction of long-term clinical outcome

Objectives

Heart-type fatty acid binding protein (H-FABP) is enriched in neuronal cell body as well as myocardium, and is rapidly released from damaged neuron into circulation in cerebral ischemia. We performed a comparative analysis between plasma H-FABP and S100B levels in the acute phase of ischemic stroke.

Methods

The present study included 111 consecutive patients with acute ischemic stroke and 127 control subjects. Measurement of plasma H-FABP and S100B levels was conducted during acute phase (<24 h) of stroke. Clinical severities were evaluated by the use of NIHSS scores at admission and mRS score at 3 months after symptom onset.

Results

Both the plasma H-FABP and S100B levels were significantly higher in stroke group than control group. In multiple logistic regression analysis, statistical significance of both markers remained significant after adjusting the vascular risk factors. In the receiver operator characteristic (ROC) curve analysis, neither H-FABP (area under curve [AUC] = 0.71, P < 0.001, sensitivity: 59.5%, specificity: 79.5%) nor S100B (AUC = 0.70, P < 0.001, sensitivity: 54.0%, specificity: 83.5%) showed a favorable degree of diagnostic value to discriminate stroke from stroke mimic. Plasma H-FABP (r = 0.46, P < 0.01) and S100B (r = 0.45, P < 0.01) were correlated with initial NIHSS score, and both marker were significantly higher in patients with poor clinical outcome.

Conclusion

Although plasma H-FABP is elevated in the acute phase of ischemic stroke, the diagnostic accuracy of H-FABP as a sole marker is not sufficient to be applied in the clinical setting. Plasma H-FABP can be used as a potential marker for stroke prognosis.     

Biochemical brain markers and purinergic parameters in rat CSF after seizure induced by pentylenetetrazol

Cellular and molecular mechanisms involved in the generation of seizures and the magnitude of neural cells injury are not fully understood. We evaluated astrocyte and/or neuronal injury in rats in the pentylenetetrazol model of acute seizures by measuring S100B and NSE levels in cerebrospinal fluid. Additionally, we determined ADP and GDP hydrolysis by soluble nucleoside triphosphate diphosphohydrolase in the cerebrospinal fluid, and the concentration of nucleosides adenosine, inosine and guanosine as putative markers of brain injury. After pentylenetetrazol-induced seizures: (i) S100B values increased from 10 to 30 min, returning to control levels at 24 h; NSE levels presented a biphasic increase: an increase at 10 to 30 min returning to control levels, and again at 240 min followed by a decline at 24 h; (ii) nucleotidase activities increased from 10 min, returning to control levels at 240 min; (iii) guanosine and inosine levels increased exclusively after 30 min. In summary, this study showed biochemical changes in the cerebrospinal fluid occurring after seizures induced by pentylenetetrazol. Such events may have a modulating effect upon seizure expression, particularly nucleoside triphosphate diphosphohydrolase activities and nucleoside concentrations, but are nevertheless followed by neural death as evidenced by the increase in NSE and S100B levels.     

硫酸镁对急性重型颅脑损伤患者血清S100B浓度和预后的影响

目的观察急性重型颅脑损伤(asTBI)后血清S100B浓度的变化及其与预后的关系,研究硫酸镁对asTBI患者血清S100B浓度和预后的影响。方法69例患者随机分为硫酸镁治疗组(n=34)和常规治疗对照组(n=35)。按入院时GCS评分分为特重组(GCS3～5分)和重型组(GCS6～8分),于入院时,伤后1、4、7、14天,检测血清镁、S100B浓度和GCS评分。治疗组首剂给予25%硫酸镁16ml静脉滴注,15分钟输完,继予25%硫酸镁60ml静脉滴注,匀速24h输完。对照组除未用硫酸镁外其余治疗与治疗组完全相同。伤后3个月时纪录GOS评分。结果与健康对照组比较,asTBI后血清镁离子浓度下降(P0.05),血清S100B浓度升高,特重组(ssTBI)S100B浓度高于重型组(sTBI)(P0.05)。伤后第4、7天,治疗组血清S100B浓度低于对照组(P0.05)。入院时血清S100B浓度高于1.2μg/L者预后不良,其敏感度为(sensitivity,SEN)为75.8%,特异度(specificity,SPE)为69.4%。治疗组与对照组预后的比较无统计学意义(P0.05)。结论asTBI后,血清镁离子浓度下降,血清S100B浓度升高,且伤情越重,血清S100B浓度越高,预后越差。早期应用硫酸镁提高asTBI患者血清镁离子浓度可降低伤后第4、7天血清S100B浓度,提示硫酸镁具有一定的神经保护作用,但并不能改善预后。     

Preliminary findings of the effects of autonomic dysfunction on functional outcome after acute ischemic stroke

Background and purpose

Impaired autonomic function is common in the acute poststroke phase but little is known about its effects on functional outcome after acute ischemic stroke. This study sought to investigate the impact of autonomic dysfunction by Ewing's classification on functional outcome 2 months after acute ischemic stroke.

Methods

34 consecutive acute ischemic stroke patients within 7 days after onset were enrolled. On admission, autonomic function was assessed by Ewing's battery tests. Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS), autonomy in activities of daily living by the Barthel Index (BI), and global disability by the modified Rankin Scale (mRS). BI and mRS were also evaluated 2 months after ischemic stroke onset.

Results

On admission, eight patients were diagnosed as minor autonomic dysfunction and 26 patients as relatively severe autonomic dysfunction. The prevalence of relatively severe autonomic dysfunction in ischemic stroke patients was 76.5%. There were no significant differences in baseline characteristics between the minor and severe autonomic dysfunction groups. 2 months after stroke onset, the mean BI score of patients with minor autonomic dysfunction and severe autonomic dysfunction increased from 76.3 ± 15.3 on admission to 95.0 ± 7.1, 66.5 ± 15.2 on admission to 74.8 ± 15.9 respectively. The mean BI score after 2-month stroke onset and the change in BI from admission to 2-month outcome (delta BI) in patients with severe autonomic dysfunction were lower than those in patients with minor autonomic dysfunction (all P < 0.05).

Conclusions

Autonomic dysfunction occurs in acute stroke patients. Relatively severe autonomic dysfunction is related to an unfavorable functional outcome in patients with acute ischemic stroke.     

Explorative investigation of biomarkers of brain damage and coagulation system activation in clinical stroke differentiation

Introduction   A simple and accurate method of differentiating ischemic stroke and intracerebral hemorrhage (ICH) is potentially useful to facilitate acute therapeutic management. Blood measurements of biomarkers of brain damage and activation of the coagulation system may potentially serve as novel diagnostic tools for stroke subtypes. Methods   Ninety-seven stroke patients were prospectively investigated in a multicenter design with blood levels of brain biomarkers S100B, neuron specific enolase (NSE), glial fibrillary acidic protein (GFAP) as well as a coagulation biomarker, activated protein C – protein C inhibitor complex (APC-PCI), within 24 hours of symptom onset. Results   Eighty-three patients (86 %) had ischemic stroke and fourteen patients (14 %) had ICH. There were no differences in S100B (p = 0.13) and NSE (p = 0.67) levels between patients with ischemic stroke or ICH. However, GFAP levels were significantly higher in ICH patients (p = 0.0057). APC-PCI levels were higher in larger ischemic strokes (p = 0.020). The combination of GFAP and APC-PCI levels, in patients with NIHSS score more than 3, had a sensitivity and negative predictive value of 100 % for ICH in our material (p = 0.0052). Conclusion   This exploratory study indicated that blood levels of biomarkers GFAP and APC-PCI, prior to neuroimaging, may rule out ICH in a mixed stroke population.     

急性缺血性脑卒中院前延误的研究现状和若干问题

急性缺血性脑卒中能改善预后的具有循证医学证据的治疗即为时间窗内的静脉溶栓治疗,院前延误是制约这一治疗的主要因素.决定延误是院前延误中最重要的部分,由于不同地区社会经济水平、急救医疗体系不同,研究标准也不统一,目前各家研究结果不完全一致,干预性的研究更为缺乏.我国脑卒中院前延误研究近年来逐渐引起重视,加强院前延误的研究和规范化处理,对提高静脉溶栓率,减少致残率和致死率有重大意义.     

Reappraisal of early CT signs to predict the arterial occlusion site in acute embolic stroke

OBJECTIVE: To elucidate the value of early computed tomographic (CT) signs of stroke in predicting the occlusion site in the cerebral arteries. PATIENTS: 105 consecutive patients with acute embolic stroke affecting the anterior circulation. METHODS: Four early signs were evaluated on cranial CT within six hours of stroke onset: loss of the insular ribbon (LIR); attenuation of the lentiform nucleus (ALN); hemispherical sulcus effacement (HSE); and the hyperdense middle cerebral artery sign (HMCAS). The arterial occlusion site was definitively identified on cerebral angiography within two hours of the CT examination. RESULTS: LIR was present in 55% of patients with internal carotid artery occlusion. ALN was present in 65% of patients with occlusion of the sphenoidal portion (M1) of the middle cerebral artery. HSE was present in 47% of patients with middle cerebral artery branch occlusion. LIR was related independently to internal carotid artery occlusion (odds ratio (OR) 2.8 (95% confidence interval, 1.2 to 6.8)), ALN to M1 occlusion (OR 2.9 (1.2 to 7.4)), and isolated HSE without ALN or LIR to branch occlusion (OR 12.8 (3.2 to 51.5)). The combined presence of the three signs was indicative of internal carotid artery occlusion (p < 0.05), and the presence of ALN and LIR without HSE was indicative of M1 occlusion (p < 0.05) by univariate analysis. HMCAS bore no relation to either arterial occlusion site. CONCLUSIONS: LIR, ALS, HSE, and combinations of these were useful predictors of the arterial occlusion site.     

Prognostic value of biochemical markers of brain damage and oxidative stress in post-surgical aneurysmal subarachnoid hemorrhage patients

The aim of this study is to determine effective biochemical markers and optimal sampling timing for prediction of neurological prognosis in post-surgical aneurysmal subarachnoid hemorrhage (SAH) patients. Subjects were a sequential group of SAH patients admitted to our centre who underwent aneurysm clipping before Day 3 and who received a cerebrospinal fluid (CSF) drain. CSF samples from 32 patients were collected on Days 3, 7, and 14. Neurological outcome was assessed by neurosurgeons using the Glasgow outcome scale (GOS) at 6 months after onset. CSF levels of neuron-specific enolase (NSE), S100B, and glial fibrillary acidic protein (GFAP) were determined using enzyme-linked immunosorbent assay, and the CSF concentrations of malondialdehyde (MDA) were determined using spectrophotometric assay. In univariate analysis, S100B on Days 3 and 14, GFAP on Days 3 and 7, and MDA on Day 14 were significantly higher in the poor outcome group (GOS 1-4) than in the good outcome group (GOS 5). In multivariate analysis, only MDA on Day 14 was identified as a significant predictor of poor neurological outcome at 6 months after onset. The area under the receiver-operating characteristic (ROC) curve for MDA on Day 14 was 0.841. For a threshold of 0.3 μM, sensitivity and specificity were 0.875 and 0.750, respectively. Our findings suggest that these biochemical markers, especially MDA, show significant promise as predictors of neurological outcome in clinical practice.     

Improved detection and characterization of arterial occlusion in acute ischemic stroke using contrast enhanced MRA

Background and purposeTo compare the accuracy and utility of contrast enhanced magnetic resonance angiography (MRA) (CEMRA) to Time of Flight MRA (TOF MRA) during detection and evaluation of occlusions on patients diagnosed with acute ischemic stroke (AIS).MethodsThis single-center study was approved by our local institutional research ethics board. From August 2014 to July 2016, 131 consecutive adult patients with confirmed AIS were included. Detection of an arterial occlusion and its characterization were evaluated independently with CEMRA or TOF MRA by two blinded neuroradiologists, then by consensus using all available MR sequences. A Cohen's Kappa coefficient (κ) and intra-class correlation coefficients (ICC) were used to compare the two techniques.ResultsThere was substantial concordance in the detection of arterial occlusion between CEMRA and TOF MRA (κ = 0.75). TOF MRA was more likely to show an arterial occlusion than CEMRA (63 versus 52 patients respectively). There were 13 and 1 false positive arterial occlusion with TOF MRA and CEMRA respectively, and 1 false negative with TOF MRA. There was excellent concordance between the location of arterial occlusions and CEMRA and TOF MRA [κ = 0.89 (0.72–0.97)]. CEMRA was significantly more likely to allow measurement of the thrombus than was TOF MRA [38 (75%) versus 14 (22%)] (P < 0.0001).ConclusionsOur study showed that CEMRA imaging detected arterial occlusions better than TOF MRA in AIS patients and more precisely such that thrombus length and location could be known, which improves the patient's management and care.     

Plasma levels of coagulation and fibrinolysis markers in acute ischemic stroke patients with lone atrial fibrillation

Atrial fibrillation (AF) is a well-defined risk factor for ischemic stroke. Patients with lone AF represent a subgroup of AF patients with the lowest lifelong stroke risk. Nonvalvular atrial fibrillation (NVAF) confers a hypercoagulable state resulting in an increased risk of thromboembolism. This study was performed to determine the contributory role of alteration in the hemostatic markers of thrombin generation and fibrinolysis in patients with lone AF during acute ischemic stroke episode. We studied thrombin-antithrombin complexes (TAT), prothrombin fragments 1+2 (F1+2), tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1) concentrations in patients with acute middle cerebral artery ischemic stroke due to atherosclerotic large artery disease (n=50), lone AF (n=24) and cardioembolism (n=21). The values were compared with those of age-matched control subjects with lone AF and sinus rhythm (n=21 and 15, respectively). The mean F1+2 concentration was higher in the control subjects with lone AF in comparison with those without AF (p=0.014). Patients with stroke due to possible cardioembolism, from lone AF or other causes, had higher TAT (and marginally higher F1+2) concentrations than those with atherosclerotic stroke (p<0.001). tPA concentrations were not different among groups (p=0.89). PAI-1 levels were marginally higher in stroke patients with lone AF and atherothrombotic large artery disease compared to the controls without AF (p=0.05). These results suggest that in the acute period of ischemic stroke secondary to lone AF, enhancement of the coagulatory activity occurs as a result of increased thrombin generation, similar to other possible sources of cardioembolism. Observed hemostatic alterations in acute ischemic stroke associated with lone AF may indicate some therapeutic and prognostic implications. Received: 3 April 2000 / Accepted in revised form: 20 September 2000     

Expression of S-100 protein is related to neuronal damage in MPTP-treated mice

S-100beta is a calcium-binding protein expressed at high levels in brain and is known as a marker of brain damage. However, little is known about the role of S-100beta protein during neuronal damage caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To determine whether S-100beta protein is induced in glial cells after MPTP treatment, we investigated the expression of S-100 protein immunohistochemically, using MPTP-treated mice. We also examined the change of neurons and glial cells in mice after MPTP treatment. The present study shows that tyrosine hydroxylase (TH) immunoreactivity decreased gradually in the striatum and substantia nigra from 1 day after MPTP treatment. Thereafter, TH-immunopositive cells and fibers decreased in the striatum and substantia nigra at 3 days after MPTP treatment. In contrast, S-100-immunopositive cells and glial fibrillary acidic protein (GFAP)-immunopositive cells increased markedly in the striatum and substantia nigra at 3 days after MPTP treatment. Seven days after MPTP treatment, S-100-immunopositive cells decreased in the striatum and substantia nigra. However, the number of GFAP-immunopositive cells increased in these regions. In double-labeled immunostaining with anti-S-100 and anti-GFAP antibodies, S-100 immunoreactivity was observed only in the GFAP-positive astrocytes. These results provide evidence that astrocytic activation may play a role in the pathogenesis of MPTP-induced degeneration of dopaminergic neurons. Furthermore, the present study demonstrates that S-100 protein is expressed selectively by astrocytes, but not by microglia, after MPTP treatment. These results provide valuable information for the pathogenesis of the acute stage of Parkinson's disease.     

支架技术在急性缺血性卒中合并颅内外动脉狭窄中的应用

目的探讨支架技术在急性缺血性卒中合并颅内外动脉狭窄中应用的可行性、安全性及有效性。方法回顾性纳入2014年4月至2016年10月在山东大学附属济南市中心医院神经外科就诊的29例急性缺血性卒中合并颅内外动脉狭窄的患者。经数字减影血管造影（DSA）证实责任动脉闭塞,患者取栓后仍有重度狭窄,遂行球囊扩张、支架置入血管成形术。记录患者治疗前、后7d美国国立卫生研究院卒中量表（NIHSS）评分、30d卒中或短暂性脑缺血性发作的复发率及90d改良Rankin量表评分（mRS）。临床随访分别在术后30d和90d进行。结果29例患者的技术成功率为100％,支架治疗后平均残留狭窄率为（10．4±8．1）％。所有患者均得到随访,30d内再次卒中1例。NIHSS评分：治疗前为（19．5±3．5）分,治疗后7d为（5．8±2．1）分,治疗前后的差异有统计学意义（P〈0．05）。90d患者的病死率为0％,其中28例（97％）90dmRS评分≤2分,预后良好。结论急性缺血性卒中合并颅内动脉狭窄患者应用支架技术的并发症发生率较低且安全、有效;但残余狭窄以及合并基础性疾病、医嘱依从性差被认为是卒中再发的危险因素。