CN113567683B - 一种用于检测轻度脑外伤的血清标记物及应用 - Google Patents
一种用于检测轻度脑外伤的血清标记物及应用 Download PDFInfo
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Abstract
本发明公开一种用于检测轻度脑外伤的血清标记物及应用,具体属于生物技术领域,所述血清标记物包括NFL、VEGF‑A、GDNF、IL‑1beta和IL‑6中至少一种,上述五种血清标记物在轻度脑外伤患者血清中的表达与非轻度脑外伤者中表达相比显著增高,选用上述的血清标记物对轻度脑外伤进行辅助诊断并预测评估颅内病变,有助于探索轻度脑损伤病理生理机制及寻求更好的治疗干预措施,并且本发明应用ROC分析进一步验证了上述血清标记物在临床诊断或辅助诊断价值。
Description
技术领域
本发明属于生物技术领域,具体属于一种用于检测轻度脑外伤的血清标记物及应用。
背景技术
脑外伤是由头部撞击、打击或震动或身体受到撞击导致头部和大脑迅速向后移动而引起的创伤性脑组织损伤。创伤性脑损伤(traumatic brain injury, TBI)是一个重要的公共卫生问题,脑外伤在45岁以下人群中致死致残率高居首位。在我国,TBI发病率超过100/10万人口,总病死率高达30%-50%。其中,据统计,世界范围内每年受到轻度脑外伤(mild traumatic brain injury, mTBI)影响的人群可以达到4200万,但由于轻度脑外伤患者中仅有少数人会选择就医,使得轻度脑外伤真实发病率远高于统计估计,超过80%脑外伤为轻度脑外伤,轻度创伤性脑损伤代表了绝大多数的头部创伤病例,可能导致严重的,有时持续的神经认知和神经行为功能障碍,超过50%存在脑外伤后遗症及精神障碍。
在临床影像表现上,超过95%的轻度脑外伤患者CT为阴性,因而造成了医疗资源的浪费和不必要的CT扫描对人体产生的辐射。找到一个客观性指标对mTBI患者大脑受损程度做出较早的诊断和评定,为临床及时治疗和司法鉴定提供可靠的依据,具有重要的社会意义和经济价值。
根据颅脑创伤患者脑监测技术中国专家共识及相关研究,目前可用于脑外伤病人诊断的指标有主要有:格拉斯哥昏迷评分(Glasgow coma scale,GCS),影像学检查、病理生理学参数监测、生化指标及生物志物检测等,但各种方法在评估轻度脑外伤上都存在其局限性和片面性,GCS评分部分依赖患者主观的回忆,往往因为创伤后的失忆、渴望返回工作以及其他原因而影响最终的结果;超过95%的轻度脑外伤患者CT为阴性,MRI可用于评估轴索损伤,检查的时间较长而患者难以维持静止不动;多种可作为重型脑外伤的诊断的生物标记物对轻度脑外伤的诊断价值还不明。
发明内容
为了解决现有技术中存在的问题,本发明提供一种用于检测轻度脑外伤的血清标记物及应用,为轻度脑外伤的早期检测提供有效的辅助检测手段。
为实现上述目的,本发明提供如下技术方案:一种检测血清标记物的试剂在制备轻度脑外伤血清分子诊断产品中的应用,所述血清标记物为NFL、VEGF-A、GDNF、IL-1beta和IL-6中的至少一种。
优选的,血清标记物VEGF-A和GDNF联合检测诊断效力最高。
本发明还提供一种轻度脑外伤血清分子诊断产品,所述产品包含检测至少一种血清标记物NFL、VEGF-A、GDNF、IL-1beta和IL-6的试剂。
进一步的,所述试剂包括免疫吸附剂、结合物、酶的底物、对照品或参考标准品、质控血清、稀释液、洗涤液和酶反应终止液。
进一步的,所述对照品为阴性对照品和阳性对照品。
进一步的,所述稀释液为结合物和标本的稀释液。
进一步的,所述试剂用于检测血清中血清标记物的含量从而判断患者是否患有轻度脑外伤。
进一步的,所述产品为试剂盒、芯片或检测平台。
与现有技术相比,本发明至少具有以下有益效果:
本发明提供一种用于检测轻度脑外伤的血清标记物及应用,通过测定了轻度脑损伤患者血清中的预选表达蛋白NFL、生长因子、炎症因子,发现NFL、VEGF-A、GDNF、IL-1beta和IL-6在轻度脑外伤患者血清中的表达与非轻度脑外伤者中表达相比显著增高,选用上述的血清标记物对轻度脑外伤进行辅助诊断并预测评估颅内病变,有助于探索轻度脑损伤病理生理机制及寻求更好的治疗干预措施,并且本发明应用ROC分析进一步验证了上述血清标记物在临床诊断或辅助诊断价值。
进一步的,本发明提供了有效的轻度脑损伤血清标记物检测方法,并应用随机森林分析发现VEGF-A和GDNF组成的分子诊断组合可作为轻度脑外伤患者的最佳血清诊断标记物组合。
进一步的,本发明提供了一种轻度脑损伤的血清标记物诊断产品,该产品可根据受试者血清中前述标记物的浓度快速检测脑受伤后是否为轻度脑损伤,为后续的诊断及治疗提供参考。
当然,实施本发明阐述的任一产品并不是一定要同时达到上述的每一项技术效果。
附图说明
图1为本发明流程示意图;
图2为NFC在轻度脑外伤与正常对照组中的组差异分析;
图3为VEGF-A和GDNF在轻度脑外伤与正常对照组中的组差异分析;
图4为IL-1beta和IL-6在轻度脑外伤与正常对照组中的组差异分析;
图5为NFC在轻度脑外伤与正常对照组中的ROC曲线分析;
图6为VEGF-A在轻度脑外伤与正常对照组中的ROC曲线分析;
图7为GDNF在轻度脑外伤与正常对照组中的ROC曲线分析;
图8为IL-1beta在轻度脑外伤与正常对照组中的ROC曲线分析;
图9为IL-6在轻度脑外伤与正常对照组中的ROC曲线分析;
图10为随机森林分析获得的最佳标记物组合的ROC曲线;
图11为在另一组小样本中验证最佳标记物组合的ROC曲线。
具体实施方式
下面结合附图和具体实施方式对本发明作进一步的说明。
本发明提出一种血清标记物在制备检测轻度脑外伤产品应用,其中血清标记物包括NFL (神经丝蛋白多肽)、炎症因子、生长因子中至少一种;
具体的,炎症因子包括IL-1beta(白细胞介素-1
β)和/或IL-6(白细胞介素-6);
生长因子包括VEGF-A(血管内皮生长因子A)和/或GDNF(胶质细胞源性的神经营养因子);
进一步的,所述标志物NFL、VEGF-A、GDNF、IL-1beta和IL-6中的一种或多种在轻度脑外伤患者血清中的表达与非轻度脑外伤者中表达相比显著增高。
本发明还公开了一种轻度脑外伤血清分子诊断产品,该产品通过检测被检者血清中上述一种或多种血清标志物的浓度,来诊断其是否患有轻度脑外伤。
可选地,该产品包含检测上述一种或多种血清标志物的试剂。
可选地,所述轻度脑外伤诊断产品可以是试剂盒、芯片或检测平台。
实施例1
如图1所示,轻度脑外伤的特异血清标记物筛选,具体步骤如下:
1、特异血清标记物包括:
1.1NFL(神经丝蛋白多肽);
1.2炎症因子:beta-NGF (β神经生长因子)、CCL2/MCP(CC趋化因子/单核细胞趋化蛋白)、NSE(神经元特异性烯醇化酶)、ICAM(细胞间黏附分子)、IL-1beta(白细胞介素-1β)、IL-4(白细胞介素-4)、IL-6(白细胞介素-6)、IL-8(白细胞介素-8)、IL-10(白细胞介素-10)、IL-12(白细胞介素-12)、INF-gamma(干扰素-γ)、Synuclein-alpha(突触核蛋白-α)、TNF-alpha(肿瘤坏死因子-α)和UCH-L1(泛素羧基末端水解酶L1);
1.3生长因子:BDNF(脑源性神经营养因子)、VEGF-A(血管内皮生长因子A)、Park7/DJ-1、GDF-15(生长分化因子-15)和GDNF(胶质细胞源性的神经营养因子)。
2、实验方法如下:
2.1、研究采集了温州医科大学第二附属医院急诊科接受脑损伤治疗并被诊断为轻度脑损伤的102例患者血清(19~65岁,伤后7天内作为轻度脑损伤组)和75例非轻度脑损伤正常人的血清(21~60岁,作为对照组)。
2.2、按标记物分为NFL(轻度脑损伤组50例,正常人44例)、生长因子(轻度脑损伤组49例,正常人43例)、炎症因子(轻度脑损伤组84例,正常人53例)三组进行检测。对每一项测得的标记物进行差异表达分析,筛选出显著的差异表达蛋白。差异分析采用双样本t检验对两组人的血清标记物数据进行分析,具体的数据范围如表1所示:
表1血清标记物检测结果
注:表1展示了NFL、VEGF-A、GDNF、IL-1beta和IL-6五种血清标记物在轻度脑损伤患者组以及非轻度脑损伤组的检测结果(均值±标准差)。
2.3对显著的差异表达蛋白进行ROC曲线分析。
实验结果:
2.3.1差异表达蛋白分析如图2、图3、图4表明:在NFL中,NFL在轻度脑损伤患者较正常人显著上升(p<0.001);在生长因子中,VEGF-A、GDNF在轻度脑损伤患者较正常人显著上升(p<0.001);在炎症因子中,IL-1beta在轻度脑损伤患者较正常人显著上升(p<0.05),IL-6在轻度脑损伤患者较正常人显著上升(p<0.001)。
2.3.2对显著的差异表达蛋白进行ROC曲线分析表明,如图4-9所示,NFL(AUC=69.5%)、VEGF-A(AUC=87.4%)、GDNF(AUC=84.4%)、IL-1beta(AUC=70.5%)以及IL-6(AUC=74.2%)综上,说明本发明的血清标记物NFL、VEGF-A、GDNF、IL-1beta和IL-6对轻度脑损伤均具有较好的诊断价值。
3、轻度脑外伤的最优特异血清标记物组合筛选
3.1实验方法如下:
(1)研究整理了前述采集了三组血清标记物的轻度脑损伤的32例患者和23例非轻度脑损伤正常人的NFL、VEGF-A、GDNF、IL-1beta和IL-6信息。
(2)对这5种显著差异表达的血清标记物进行了随机森林分析,以寻找最优的特异血清标记物组合诊断组合。
(3)对分析的标记物组合,在另一组样本(轻度脑损伤组17例,正常人21例)中进行验证,以验证该标记物组合的可重复性。
3.2实验结果:
(1)差异表达蛋白的随机森林分析结果如图10所示:在NFL、VEGF-A、GDNF、IL-1beta和IL-6的标记物组合中,VEGF-A和GDNF联合检测的诊断效力最高(AUC=97.83%)。
(2)对VEGF-A和GDNF的血清标记物组合进行验证分析的结果如图11所示,在小样本验证中AUC=84.2%。
实施例2:轻度脑损伤诊断试剂盒
试剂盒可检测血清样品中前述一种或多种mTBI血清标志物,可采用ELISA夹心法、竞争法(测定抗原)、间接法(测定抗体)或竞争法(测定小分子化合物)定量检测mTBI血清标记物的含量。
试剂盒包含:(1)已包被抗原或抗体的固相载体(免疫吸附剂);(2)酶标记的抗原或抗体(结合物);(3)酶的底物;(4)阴性对照品和阳性对照品或参考标准品和质控血清;(5)结合物及标本的稀释液;(6)洗涤液;(7)酶反应终止液。
Claims (8)
1.一种检测血清标记物的试剂在制备轻度脑外伤血清分子诊断产品中的应用,其特征在于,所述血清标记物为VEGF-A和GDNF。
2.根据权利要求1所述的一种检测血清标记物的试剂在制备轻度脑外伤血清分子诊断产品中的应用,其特征在于,所述轻度脑外伤血清分子诊断产品包含至少一种检测VEGF-A和GDNF的试剂。
3.根据权利要求2所述的一种检测血清标记物的试剂在制备轻度脑外伤血清分子诊断产品中的应用,其特征在于,所述试剂包括已包被抗原或抗体的固相载体、酶标记的抗原或抗体、酶的底物、对照品或参考标准品、质控血清、稀释液、洗涤液和酶反应终止液。
4.根据权利要求3所述的一种检测血清标记物的试剂在制备轻度脑外伤血清分子诊断产品中的应用,其特征在于,所述对照品为阴性对照品和阳性对照品。
5.根据权利要求3所述的一种检测血清标记物的试剂在制备轻度脑外伤血清分子诊断产品中的应用,其特征在于,所述稀释液为酶标记的抗原或抗体和标本的稀释液。
6.根据权利要求2所述的一种检测血清标记物的试剂在制备轻度脑外伤血清分子诊断产品中的应用,其特征在于,所述试剂用于检测血清中血清标记物的含量从而判断患者是否患有轻度脑外伤。
7.根据权利要求2所述的一种检测血清标记物的试剂在制备轻度脑外伤血清分子诊断产品中的应用,其特征在于,所述产品为试剂盒或芯片。
8.根据权利要求2所述的一种检测血清标记物的试剂在制备轻度脑外伤血清分子诊断产品中的应用,其特征在于,所述产品为检测平台。
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