ADNI 队列中生物标志物阳性和阴性受试者：临床特征。
Biomarker positive and negative subjects in the ADNI cohort: clinical characterization.
机构信息
Department of Biostatistics, School of Public Health, 1665 University Blvd, University of Alabama at Birmingham, Birmingham, AL, USA.
出版信息
Curr Alzheimer Res. 2012 Dec;9(10):1135-41. doi: 10.2174/156720512804142976.
BACKGROUND
The Alzheimer's Disease Neuroimaging Initiative (ADNI) was created to develop standards for brain imaging and biomarkers for diagnosis and treatment trials. Using the ADNI dataset, experts have found that low cerebrospinal fluid amyloid-β1-42 (CSF Aβ1-42) concentration and high total-tau/Aβ1-42 ratio are highly predictive of progression in amnestic mild cognitive impairment (aMCI), and recommended these biomarkers to support the diagnosis of prodromal Alzheimer's disease and select patients for clinical trials. However, biomarker selection criteria may introduce systematic bias that undermines their utility.
METHODS
We tested for systematic biases among individuals undergoing lumbar puncture in the ADNI dataset who fulfilled the following entry criteria: (1) aMCI with CSF Aβ1-42 ≤ 192 pG/mL, compared to aMCI with Aβ1-42 > 192 pG/mL, and (2) aMCI with total-tau/Aβ1-42 > 0.39, compared to aMCI with total-tau/Aβ1-42 ≤ 0.39, as well as comparisons between participants with aMCI with and without lumbar puncture.
FINDINGS
Individuals with low CSF Aβ1-42 scored significantly poorer than individuals with high Aβ1-42 on several baseline measures of disease severity, including Logical Memory II (3.24 vs 4.73; p < 0.001), Functional Activities Questionnaire (4.30 vs 2.37; p < 0.001), and Alzheimer's Disease Assessment Scale-cognitive (12.23 vs 10.09; p=0.002). Similar results were found using high total-tau/Aβ1-42. No differences were found for individuals with and without lumbar puncture except for marital status.
INTERPRETATIONS
Individuals with aMCI with low Aβ1-42 in the ADNI dataset appear to have more advanced disease than those with high Aβ1-42. Selection criteria based on ADNI, as well as design of future studies, must account for potential confounds between biomarker status and disease severity to ensure that the former, and not the latter, is the true determinant of predictive accuracy.
背景
阿尔茨海默病神经影像学倡议（ADNI）旨在为脑成像和生物标志物的诊断和治疗试验制定标准。利用 ADNI 数据集，专家们发现脑脊液中淀粉样蛋白-β1-42（CSF Aβ1-42）浓度低和总 tau/Aβ1-42 比值高可高度预测遗忘型轻度认知障碍（aMCI）的进展，并推荐这些生物标志物来支持前驱期阿尔茨海默病的诊断和选择患者进行临床试验。然而，生物标志物选择标准可能会引入系统偏差，从而削弱其效用。
方法
我们在 ADNI 数据集中检测了符合以下入组标准的接受腰椎穿刺的个体中的系统偏差：（1）与 CSF Aβ1-42＞192pg/mL 的 aMCI 相比，CSF Aβ1-42≤192pg/mL 的 aMCI，以及（2）与总 tau/Aβ1-42≤0.39 的 aMCI 相比，总 tau/Aβ1-42＞0.39 的 aMCI，以及 aMCI 患者与未接受腰椎穿刺患者之间的比较。
发现
与 CSF Aβ1-42 高的个体相比，CSF Aβ1-42 低的个体在疾病严重程度的几个基线测量中得分明显较低，包括逻辑记忆 II（3.24 对 4.73；p＜0.001）、功能活动问卷（4.30 对 2.37；p＜0.001）和阿尔茨海默病评估量表认知（12.23 对 10.09；p=0.002）。使用高总 tau/Aβ1-42 也得到了类似的结果。除了婚姻状况外，接受和未接受腰椎穿刺的个体之间没有差异。
解释
ADNI 数据集中的 aMCI 个体，其 CSF Aβ1-42 水平较低的患者，似乎比 CSF Aβ1-42 水平较高的患者疾病更为严重。基于 ADNI 的选择标准以及未来研究的设计，必须考虑生物标志物状态和疾病严重程度之间的潜在混杂因素，以确保前者，而不是后者，是预测准确性的真正决定因素。
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