Identification of potential CSF biomarkers in ALS
Identification of potential CSF biomarkers in ALS
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DOI：
10.1212/01.wnl.0000203129.82104.07
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发表时间：
2006-04-25
期刊：
影响因子：
9.9
通讯作者：
Ho, L
中科院分区：
文献类型：
--
作者：
Pasinetti, GM;Ungar, LH;Ho, L
背景：ALS的临床诊断完全基于临床特征。鉴定ALS的生物标志物对诊断很重要，也可能提供发病机制的线索。目的：确定脑脊液中是否存在一种特殊的蛋白谱，以区分ALS患者与纯运动周围神经病变（PN）患者和健康对照者。方法：采用表面增强激光解吸/电离飞行时间质谱蛋白质组学技术对ALS患者、疾病对照（其他神经系统疾病患者）和正常人的脑脊液进行分析。采用受试者工作特征曲线法计算生物标志物的敏感性和特异性。利用质谱定向肽测序技术对ALS生物标志物进行纯化和序列鉴定。结果：在最初的蛋白质组学发现研究中，发现了三种蛋白（4.8,6.7和13.4 kda）在ALS患者（n = 36）脑脊液中的浓度显著低于正常对照（n = 21）。三种蛋白的组合（“三蛋白”模型）正确识别ALS患者，与对照组相比，准确率为95%，灵敏度为91%，特异性为97%。使用ALS （n = 13）、健康对照（n = 25）和PN （n = 7）受试者的单独队列进行的独立验证研究证实了这三种CSF蛋白能够将ALS患者与其他疾病区分开来。蛋白质序列分析鉴定出13.4 kda的蛋白种为胱抑素C， 4.8 kda的蛋白种为神经分泌蛋白VGF的肽片段。结论：将“三蛋白”生物标志物模型进一步应用于当前的诊断标准，可能提供一种客观的生物标志物模式，以帮助识别ALS患者。
Background: The clinical diagnosis of ALS is based entirely on clinical features. Identification of biomarkers for ALS would be important for diagnosis and might also provide clues to pathogenesis. Objective: To determine if there is a specific protein profile in the CSF that distinguishes patients with ALS from those with purely motor peripheral neuropathy (PN) and healthy control subjects. Methods: CSF obtained from patients with ALS, disease controls ( patients with other neurologic disorders), and normal controls were analyzed using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry proteomics technique. Biomarker sensitivity and specificity was calculated with receiver operating characteristic curve methodology. ALS biomarkers were purified and sequence identified by mass spectrometry-directed peptide sequencing. Results: In initial proteomic discovery studies, three protein species (4.8-, 6.7-, and 13.4-kDa) that were significantly lower in concentration in the CSF from patients with ALS (n = 36) than in normal controls (n = 21) were identified. A combination of three protein species (the "three-protein" model) correctly identified patients with ALS with 95% accuracy, 91% sensitivity, and 97% specificity from the controls. Independent validation studies using separate cohorts of ALS (n = 13), healthy control (n = 25), and PN (n = 7) subjects confirmed the ability of the three CSF protein species to separate patients with ALS from other diseases. Protein sequence analysis identified the 13.4-kDa protein species as cystatin C and the 4.8-kDa protein species as a peptic fragment of the neurosecretory protein VGF. Conclusion: Additional application of a "three-protein" biomarker model to current diagnostic criteria may provide an objective biomarker pattern to help identify patients with ALS.