Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly.
Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly.
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DOI：
10.3233/jad-151155
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发表时间：
2016-03-29
期刊：
影响因子：
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通讯作者：
Lovestone S
中科院分区：
文献类型：
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作者：
Westwood S;Leoni E;Hye A;Lynham S;Khondoker MR;Ashton NJ;Kiddle SJ;Baird AL;Sainz-Fuertes R;Leung R;Graf J;Hehir CT;Baker D;Cereda C;Bazenet C;Ward M;Thambisetty M;Lovestone S
阿尔茨海默病（AD）的临床试验越来越多地在疾病阶段的早期进行，并使用体内淀粉样蛋白PET成像或CSF tau和Aβ测量来量化病理学的生物标志物确认。然而，进行这样的临床前AD诊断相对昂贵，并且筛选失败率可能很高。拥有一种基于血液的标记物，可以通过识别可能患有临床前AD的潜在参与者来降低此类成本并加速临床试验，这将是一个重大的进步。为了寻找这样的候选生物标志物，使用2DGE和无凝胶LC-MS/MS对高分子量和低分子量分析物进行发现阶段蛋白质组学分析，这些分析物是在12年期间从显示淀粉样蛋白负荷的一系列11 C-PiB PET测量的非痴呆老年个体中收集的纵向血浆样本。然后，我们试图通过在一个独立的队列中调查我们的候选生物标志物是否也与疾病中的脑淀粉样蛋白负荷相关来扩展我们的发现。七种血浆蛋白，包括A2 M、Apo-A1和多种补体蛋白，被鉴定为淀粉样蛋白负荷的临床前生物标志物，并且在三个时间点上是一致的（p < 0.05）。这些蛋白质中的五种也与疾病不同阶段的脑淀粉样蛋白测量相关（q < 0.1）。在这里，我们表明，有可能在临床疾病表现发作之前很久的阶段检测指示AD病理学的基于血浆的生物标志物特征。在以前的研究中，急性期反应物和炎症标志物占主导地位。
Increasingly, clinical trials for Alzheimer’s disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p < 0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q < 0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.