Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI.
Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI.
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DOI：
10.1007/s00401-011-0808-0
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发表时间：
2011-05
影响因子：
12.7
通讯作者：
Alzheimer's Disease Neuroimaging Initiative
中科院分区：
文献类型：
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作者：
Shaw LM;Vanderstichele H;Knapik-Czajka M;Figurski M;Coart E;Blennow K;Soares H;Simon AJ;Lewczuk P;Dean RA;Siemers E;Potter W;Lee VM;Trojanowski JQ;Alzheimer's Disease Neuroimaging Initiative
死前脑脊液 (CSF) 淀粉样蛋白-β1-42 (Aβ1-42) 浓度异常低与淀粉样蛋白成像测量的斑块负荷之间以及脑脊液 tau 病理性升高水平与 MRI 测量的神经变性程度之间的密切相关性，使人们越来越有兴趣使用这些生物标志物来预测 AD 斑块和缠结的存在 病理学。广泛使用这些脑脊液生物标志物面临的挑战是用于测量这些分析物的测定的高度可变性，这归因于多个分析前和分析测试性能因素。为了应对这一挑战，作为阿尔茨海默病神经影像计划 (ADNI) 的一部分，我们对脑脊液总 tau (t-tau)、磷酸化 tau (p-tau181) 和 Aβ1-42 进行了一项七中心实验室间标准化研究。由多个老年对照 (n = 3) 和 AD 患者 (n = 2) 组成的五个 CSF 池制备的等分试样是参与实验室在 Luminex 分析平台上使用同一批次研究仅使用免疫测定试剂（INNO-BIA AlzBio3，xMAP 技术，来自 Innogenics）在 3 次分析运行中每一次进行分析的主要测试样本。为了解释对 CSF 样本总体精度（固定效应）、不同实验室和分析运行（随机效应）的综合影响，通过混合效应模型对这些数据进行了分析，结果如下：CSF Aβ1-42 的中心 %CV 95% CI 值（平均值）为 4.0-6.0% (5.3%)； t-tau 为 6.4–6.8% (6.7%)，p-tau181 为 5.5–18.0% (10.8%)，中心间 %CV 95% CI 范围为：Aβ1–42 为 15.9–19.8% (17.9%)，t-tau 为 9.6–15.2% (13.1%)， 11.3–18.2% (14.6%) 为 p-tau181。 ADNI 生物标志物核心实验室的长期经验复制了这种中心内精度。 Aβ1-42 的诊断阈值 CSF 浓度和 t-tau/Aβ1-42 比率是在 ADNI 独立的、尸检确认的 AD 队列中确定的，从该队列中获得了生前 CSF，临床定义的认知正常对照 (NC) 组对 ADNI 研究中从 MCI 进展为 AD 的患者进行了统计学上的显着区分。这些数据表明，对认知障碍个体进行生前脑脊液检查以确定 t-tau、p-tau181 和 Aβ1-42 的水平，再加上 MRI 和淀粉样蛋白成像生物标志物，可以在不久的将来取代尸检确认 AD 斑块和缠结病理学，成为诊断明确 AD 的“金标准”。
The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ1–42) and plaque burden measured by amyloid imaging as well as between pathologically increased levels of CSF tau and the extent of neurode-generation measured by MRI has led to growing interest in using these biomarkers to predict the presence of AD plaque and tangle pathology. A challenge for the wide-spread use of these CSF biomarkers is the high variability in the assays used to measure these analytes which has been ascribed to multiple pre-analytical and analytical test performance factors. To address this challenge, we conducted a seven-center inter-laboratory standardization study for CSF total tau (t-tau), phospho-tau (p-tau181) and Aβ1–42 as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Aliquots prepared from five CSF pools assembled from multiple elderly controls (n = 3) and AD patients (n = 2) were the primary test samples analyzed in each of three analytical runs by the participating laboratories using a common batch of research use only immunoassay reagents (INNO-BIA AlzBio3, xMAP technology, from Innogenetics) on the Luminex analytical platform. To account for the combined effects on overall precision of CSF samples (fixed effect), different laboratories and analytical runs (random effects), these data were analyzed by mixed-effects modeling with the following results: within center %CV 95% CI values (mean) of 4.0–6.0% (5.3%) for CSF Aβ1–42; 6.4–6.8% (6.7%) for t-tau and 5.5–18.0% (10.8%) for p-tau181 and inter-center %CV 95% CI range of 15.9–19.8% (17.9%) for Aβ1–42, 9.6–15.2% (13.1%) for t-tau and 11.3–18.2% (14.6%) for p-tau181. Long-term experience by the ADNI biomarker core laboratory replicated this degree of within-center precision. Diagnostic threshold CSF concentrations for Aβ1–42 and for the ratio t-tau/Aβ1–42 were determined in an ADNI independent, autopsy-confirmed AD cohort from whom ante-mortem CSF was obtained, and a clinically defined group of cognitively normal controls (NCs) provides statistically significant separation of those who progressed from MCI to AD in the ADNI study. These data suggest that interrogation of ante-mortem CSF in cognitively impaired individuals to determine levels of t-tau, p-tau181 and Aβ1–42, together with MRI and amyloid imaging biomarkers, could replace autopsy confirmation of AD plaque and tangle pathology as the “gold standard” for the diagnosis of definite AD in the near future.
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