CSF complement 3 and factor H are staging biomarkers in Alzheimer's disease.
CSF complement 3 and factor H are staging biomarkers in Alzheimer's disease.
复制标题
DOI：
10.1186/s40478-016-0277-8
复制
发表时间：
2016-02-17
影响因子：
7.1
通讯作者：
Alzheimer’s Disease Neuro-Imaging Initiative
中科院分区：
文献类型：
--
作者：
Hu WT;Watts KD;Tailor P;Nguyen TP;Howell JC;Lee RC;Seyfried NT;Gearing M;Hales CM;Levey AI;Lah JJ;Lee EK;Alzheimer’s Disease Neuro-Imaging Initiative
已建立的阿尔茨海默病(AD)生物标志物的脑脊液水平在疾病进展的情况下保持稳定，而非淀粉样非tau生物标志物具有告知疾病分期和进展的潜力。我们以前发现，补体3(C3)在AD痴呆中降低，但其他人在AD早期阶段没有发现这种变化。我们假设C3和相关因子H(FH)的水平可以潜在地区分AD的轻度认知损害(MCI)和痴呆阶段，但我们也发现它们的水平受到年龄和疾病状况的影响。我们开发了一条生化/生物信息学管道，以优化在验证疾病生化标记物时变量之间复杂交互的处理。我们使用来自阿尔茨海默病神经成像倡议的数据来构建并行机器学习模型，并在从埃默里大学独立招募的 = 和轻度AD患者的测试队列(n = 73)中客观地测试了模型。虽然结合了年龄、性别、载脂蛋白ε4状态以及脑脊液淀粉样蛋白和tau水平的模型不能可靠地区分ADNI中的轻度和轻度AD，但脑脊液C3和FH水平的引入重复地改善了ADNI中两个AD阶段的区别(p <； 0.014)和Emory队列(p = 0.014)。在每个AD阶段，最终的模型还区分了快速和较慢的下降者(p <； 0.001用于轻度AD，p = 0.007用于轻度AD)，较低的C3和FH水平与更严重的疾病和更快的进展相关。我们认为，脑脊液C3和FH的改变可以反映AD的分期相关生物标志物的变化，并可以参考公开的ADNI数据库来补充临床医生对AD的诊断和分期。本文的在线版本(doi：10.1186/s40478-0160277-8)包含补充材料，授权用户可以使用。
CSF levels of established Alzheimer’s disease (AD) biomarkers remain stable despite disease progression, and non-amyloid non-tau biomarkers have the potential of informing disease stage and progression. We previously identified complement 3 (C3) to be decreased in AD dementia, but this change was not found by others in earlier AD stages. We hypothesized that levels of C3 and associated factor H (FH) can potentially distinguish between mild cognitive impairment (MCI) and dementia stages of AD, but we also found their levels to be influenced by age and disease status. We developed a biochemical/bioinformatics pipeline to optimize the handling of complex interactions between variables in validating biochemical markers of disease. We used data from the Alzheimer’s Disease Neuro-imaging Initiative (ADNI, n = 230) to build parallel machine learning models, and objectively tested the models in a test cohort (n = 73) of MCI and mild AD patients independently recruited from Emory University. Whereas models incorporating age, gender, APOE ε4 status, and CSF amyloid and tau levels failed to reliably distinguish between MCI and mild AD in ADNI, introduction of CSF C3 and FH levels reproducibly improved the distinction between the two AD stages in ADNI (p < 0.05) and the Emory cohort (p = 0.014). Within each AD stage, the final model also distinguished between fast vs. slower decliners (p < 0.001 for MCI, p = 0.007 for mild AD), with lower C3 and FH levels associated with more advanced disease and faster progression. We propose that CSF C3 and FH alterations may reflect stage-associated biomarker changes in AD, and can complement clinician diagnosis in diagnosing and staging AD using the publically available ADNI database as reference. The online version of this article (doi:10.1186/s40478-016-0277-8) contains supplementary material, which is available to authorized users.