A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology
A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology
复制标题
DOI：
10.1038/tp.2016.194
复制
发表时间：
2016-11-15
影响因子：
6.8
通讯作者：
Schott, J. M.
中科院分区：
文献类型：
--
作者：
Paterson, R. W.;Heywood, W. E.;Schott, J. M.
阿尔茨海默病（AD）是痴呆症最常见的原因。需要生物标志物来识别临床前阶段的个体，解释表型多样性，测量进展和估计预后。开发用于验证候选生物标志物的检测方法既昂贵又耗时。靶向蛋白质组学是一种有吸引力的量化脑脊液和其他液体中新蛋白质的方法，并有可能帮助克服生物标志物开发中的这一瓶颈。我们使用先前验证的多路复用10分钟靶向蛋白质组学分析来评估两个独立队列中的54个候选脑脊液（CSF）生物标志物，这些队列包括神经退行性痴呆患者和健康对照者。根据使用酶联免疫吸附法测量的脑脊液T-tau和淀粉样蛋白A β 1-42谱，将个体分类为“AD”或“非AD”；使用单变量和多变量分析比较感兴趣的生物标志物。总之，队列1中有35/31人和队列2中有46/36人分别符合AD/非AD概况CSF的标准。经过多次比较调整后，在两个队列中，与非AD CSF相比，AD CSF中有5种蛋白显著升高：苹果酸脱氢酶；总载脂蛋白e;几丁质酶3样蛋白1 (YKL-40)；在独立的多变量正交投影到潜在结构判别分析（OPLS-DA）中，这些蛋白也被确定为两个队列中AD和非AD区分的主要因素。独立于CSF A β 1-42和tau，这些生物标志物的组合区分AD和非AD，曲线下面积(AUC) = 0.88。这种基于靶向蛋白质组学多反应监测（MRM）的检测方法可以同时快速测量多种候选CSF生物标志物。将这项技术应用于阿尔茨海默病，我们证明了参与葡萄糖代谢和神经炎症的蛋白质的差异，这些蛋白质共同具有潜在的临床诊断价值。
Alzheimer's disease (AD) is the most common cause of dementia. Biomarkers are required to identify individuals in the preclinical phase, explain phenotypic diversity, measure progression and estimate prognosis. The development of assays to validate candidate biomarkers is costly and time-consuming. Targeted proteomics is an attractive means of quantifying novel proteins in cerebrospinal and other fluids, and has potential to help overcome this bottleneck in biomarker development. We used a previously validated multiplexed 10-min, targeted proteomic assay to assess 54 candidate cerebrospinal fluid (CSF) biomarkers in two independent cohorts comprising individuals with neurodegenerative dementias and healthy controls. Individuals were classified as ` AD' or ` nonAD' on the basis of their CSF T-tau and amyloid A beta 1-42 profile measured using enzyme-linked immunosorbent assay; biomarkers of interest were compared using univariate and multivariate analyses. In all, 35/31 individuals in Cohort 1 and 46/36 in Cohort 2 fulfilled criteria for AD/non-AD profile CSF, respectively. After adjustment for multiple comparisons, five proteins were elevated significantly in AD CSF compared with non-AD CSF in both cohorts: malate dehydrogenase; total APOE; chitinase-3-like protein 1 (YKL-40); osteopontin and cystatin C. In an independent multivariate orthogonal projection to latent structures discriminant analysis (OPLS-DA), these proteins were also identified as major contributors to the separation between AD and non-AD in both cohorts. Independent of CSF A beta 1-42 and tau, a combination of these biomarkers differentiated AD and non-AD with an area under curve (AUC) = 0.88. This targeted proteomic multiple reaction monitoring (MRM)-based assay can simultaneously and rapidly measure multiple candidate CSF biomarkers. Applying this technique to AD we demonstrate differences in proteins involved in glucose metabolism and neuroinflammation that collectively have potential clinical diagnostic utility.