Discovery and Confirmation of Diagnostic Serum Lipid Biomarkers for Alzheimer's Disease Using Direct Infusion Mass Spectrometry
Discovery and Confirmation of Diagnostic Serum Lipid Biomarkers for Alzheimer's Disease Using Direct Infusion Mass Spectrometry
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DOI：
10.3233/jad-170035
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发表时间：
2017-01-01
影响因子：
4
通讯作者：
Graves, Steven W.
中科院分区：
文献类型：
--
作者：
Anand, Swati;Barnes, Justin M.;Graves, Steven W.
阿尔茨海默病(AD)是一种缺乏早期生化诊断和治疗的神经退行性疾病。脂质与包括阿尔茨海默病在内的神经退行性疾病有关。采用鸟枪式脂质组学方法来确定是否存在能够区分AD病例和对照组的脂质生物标志物。这项发现研究涉及29例不同阶段AD患者和32名对照的血清。用有机溶剂进行脂类提取，样品直接输入飞行时间质谱仪。检测AD患者和对照组之间的差异，发现87个有统计学意义的血脂候选标志物。在涉及27例患者和30名对照的第二次验证性研究中，对这些潜在的血脂标志物进行了重新评估。在第一项研究的87名候选人中，35名在第二组验证性研究中继续具有统计学意义。进行了串联MS研究，并对几乎所有已确认的标记进行了表征和分类。在确认的标记上使用贝叶斯套索概率回归模型，建立了AUC=0.886的多标记集，将AD的所有阶段与对照进行比较。此外，使用确认的生物标记物，针对每个特定的AD临床痴呆症分级与对照组，包括AD的最早阶段，开发了AUC>；0.90的多标记集。更保守和可能更现实的统计分析仍然发现了似乎对诊断AD有用的多标记集。最后，使用序数模型开发了一组标记物，该标记物在70%的时间内准确地分期AD，p=0.0079。这些结果表明，这些血清脂质生物标志物可能有助于AD的诊断，甚至可能有助于AD的分期。
Alzheimer's disease (AD) is a neurodegenerative disorder lacking early biochemical diagnosis and treatment. Lipids have been implicated in neurodegenerative disorders including AD. A shotgun lipidomic approach was undertaken to determine if lipid biomarkers exist that can discriminate AD cases from controls. The discovery study involved sera from 29 different stage AD cases and 32 controls. Lipid extraction was performed using organic solvent and the samples were directly infused into a time-of-flight mass spectrometer. Differences between AD cases and controls were detected with 87 statistically significant lipid candidate markers found. These potential lipid markers were reevaluated in a second confirmatory study involving 27 cases and 30 controls. Of the 87 candidates from the first study, 35 continued to be statistically significant in the second confirmatory set. Tandem MS studies were performed and almost all confirmed markers were characterized and classified. Using a Bayesian lasso probit regression model on the confirmed markers, a multi-marker set with AUC = 0.886 was developed comparing all stages of AD with controls. Additionally, using confirmed biomarkers, multi-marker sets with AUCs >0.90 were developed for each specific AD Clinical Dementia Rating versus controls, including the earliest stage of AD. More conservative and likely more realistic statistical analyses still found multi-marker sets that appeared useful in diagnosing AD. Finally, using ordinal modeling a set of markers was developed that staged AD accurately 70% of the time, p = 0.0079. These results suggest that these serum lipidomic biomarkers may help diagnose and perhaps even stage AD.