Identification and validation of novel CSF biomarkers for early stages of Alzheimer's disease
Identification and validation of novel CSF biomarkers for early stages of Alzheimer's disease
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DOI：
10.1002/prca.200600999
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发表时间：
2007-11-01
影响因子：
2
通讯作者：
Holtzman, David M.
中科院分区：
文献类型：
--
作者：
Hu, Yan;Kauwe, John S. K.;Holtzman, David M.
阿尔茨海默病（AD）的病理学在临床诊断前几年就开始了。发展的先行生物标志物，表明AD病理的存在，并预测认知正常和轻度受损的个人下降的风险将是有用的，作为有效的治疗方法的开发。虽然脑脊液（CSF）标记物如淀粉样蛋白-β（AP）42和tau是有用的，但需要另外的生物标记物。为了鉴定新的标志物，我们利用2-D差异凝胶电泳（2-D DIGE）的个体CSF样品从受试者与非常轻度AD与对照组后，耗尽高丰度蛋白。用MS鉴定了两组之间显示差异丰度的蛋白质点。在18个凝胶特征中鉴定了一些候选生物标志物。使用ELISA在更大的临床组中对所选候选物进行定量。α 1-抗糜蛋白酶（ACT）、抗凝血酶III（ATIII）和锌-α 2-糖蛋白（ZAG）的平均水平在轻度AD组中显著更高，并且肌肽酶1（CNDP 1）的平均水平降低。当这些生物标志物最佳组合时，基于临床诊断的特异性和灵敏度比单独使用时更高。我们的研究结果为非常轻度和轻度AD提供了新的生物标志物候选物，可以进一步评估为临床进展的先行标志物和预测因子。
The pathology of Alzheimer's disease (AD) begins years prior to clinical diagnosis. The development of antecedent biomarkers that indicate the presence of AD pathology and predict risk for decline in both cognitively normal and mildly impaired individuals will be useful as effective therapies are developed. While cerebrospinal fluid (CSF) markers such as amyloid-beta (AP) 42 and tau are useful, additional biomarkers are needed. To identify new markers, we utilized 2-D difference gel electrophoresis (2-D DIGE) of individual CSF samples from subjects with very mild AD versus controls after depletion of high-abundant proteins. Protein spots displaying differential abundance between the two groups were identified with MS. A number of candidate biomarkers were identified in 18 gel features. Selected candidates were quantified in a larger clinical set using ELISA. The mean levels of alpha l-antichymotrypsin (ACT), antithrombin III (ATIII), and zinc-alpha 2-glycoprotein (ZAG) were significantly higher in the mild AD group, and the mean level of carnosinase 1 (CNDPl) was decreased. When these biomarkers are optimally combined, there is a strong trend toward greater specificity and sensitivity based on clinical diagnosis than when used individually. Our findings provide novel biomarker candidates for very mild and mild AD that can be further assessed as antecedent markers and predictors of clinical progression.