Xu Jing, Ma Feiqiang, Yan Wei, Qiao Sen, Xu Shengquan, Li Yi, Luo Jianhong, Zhang Jianmin, Jin Jinghua
Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310002, China.
Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, 866 Yuhangtang Rd, Hangzhou, Zhejiang, 310058, China.
BMC Neurol. 2015 Mar 5;15:23. doi: 10.1186/s12883-015-0282-8.
Subarachnoid hemorrhage caused by a ruptured intracranial aneurysm (RIA) is a devastating condition with significant morbidity and mortality. Despite the fact that RIAs can be prevented by microsurgical clipping or endovascular coiling, there are no reliable means of effectively predicting IA patients at risk for rupture. The purpose of our study was to discover differentially-expressed glycoproteins in IAs with or without rupture as potential biomarkers to predict rupture.
Forty age/gender-matched patients with RIA, unruptured IA (UIA), healthy controls (HCs) and disease controls (DCs) (discovery cohort, n = 10 per group) were recruited and a multiplex quantitative proteomic method, iTRAQ (isobaric Tagging for Relative and Absolute protein Quantification), was used to quantify relative changes in the lectin-purified glycoproteins in CSF from RIAs and UIAs compared to HCs and DCs. Then we verified the proteomic results in an independent set of samples (validation cohort, n = 20 per group) by enzyme-linked immunosorbent assay. Finally, we evaluated the specificity and sensitivity of the candidate marker with receiver operating characteristic (ROC) curve methods.
The proteomic findings identified 294 proteins, 40 of which displayed quantitative changes unique to RIA, 13 to UIA, and 20 to IA. One of these proteins, receptor tyrosine kinase Axl, was significantly increased in RIA, as confirmed in CSF from the discovery cohort as well as in CSF and plasma from the validation cohort (p <0.05). Spearman's correlation analysis revealed that the CSF and plasma Axl levels were strongly correlated (r = 0.93, p <0.0001). The ROC curve indicated an optimal CSF Axl threshold of 0.12 nM for discriminating RIA from UIA with corresponding sensitivity/specificity of 73.33%/90% and an area under the curve (AUC) of 0.89 (95% CI: 0.80-0.97, p < 0.0001). The optimal threshold for plasma Axl was 1.7 nM with corresponding sensitivity/specificity of 50%/80% and an AUC of 0.71 (95% CI: 0.54-0.87, p = 0.027).
Both CSF and plasma Axl levels are significantly elevated in RIA patients. Axl might serve as a promising biomarker to predict the rupture of IA.
颅内动脉瘤破裂（RIA）导致的蛛网膜下腔出血是一种具有严重发病率和死亡率的毁灭性疾病。尽管RIA可通过显微外科夹闭术或血管内栓塞术预防，但目前尚无有效预测有破裂风险的颅内动脉瘤（IA）患者的可靠方法。我们研究的目的是发现破裂或未破裂IA中差异表达的糖蛋白，作为预测破裂的潜在生物标志物。
招募了40名年龄/性别匹配的RIA患者、未破裂IA（UIA）患者、健康对照（HC）和疾病对照（DC）（发现队列，每组n = 10），并采用多重定量蛋白质组学方法iTRAQ（相对和绝对蛋白质定量的等压标记），定量RIA和UIA患者脑脊液中凝集素纯化糖蛋白相对于HC和DC的相对变化。然后，我们通过酶联免疫吸附测定法在一组独立样本（验证队列，每组n = 20）中验证蛋白质组学结果。最后，我们用受试者工作特征（ROC）曲线方法评估候选标志物的特异性和敏感性。
蛋白质组学研究发现了294种蛋白质，其中40种在RIA中呈现独特的定量变化，13种在UIA中呈现独特的定量变化，20种在IA中呈现独特的定量变化。其中一种蛋白质，受体酪氨酸激酶Axl，在RIA中显著增加，这在发现队列的脑脊液以及验证队列的脑脊液和血浆中均得到证实（p <0.05）。Spearman相关性分析显示，脑脊液和血浆中的Axl水平高度相关（r = 0.93，p <0.0001）。ROC曲线表明，区分RIA和UIA的脑脊液Axl最佳阈值为0.12 nM，相应的敏感性/特异性为73.33%/90%，曲线下面积（AUC）为0.89（95%CI：0.80 - 0.97，p <0.0001）。血浆Axl的最佳阈值为1.7 nM，相应的敏感性/特异性为50%/80%，AUC为0.71（95%CI：0.54 - 0.87，p = 0.027）。
RIA患者的脑脊液和血浆Axl水平均显著升高。Axl可能是预测IA破裂的一种有前景的生物标志物。
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