Cerebrospinal Fluid β-Amyloid and Phospho-Tau Biomarker Interactions Affecting Brain Structure in Preclinical Alzheimer Disease
Cerebrospinal Fluid β-Amyloid and Phospho-Tau Biomarker Interactions Affecting Brain Structure in Preclinical Alzheimer Disease
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DOI：
10.1002/ana.24186
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发表时间：
2014-08-01
影响因子：
11.2
通讯作者：
Lleo, Alberto
中科院分区：
文献类型：
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作者：
Fortea, Juan;Vilaplana, Eduard;Lleo, Alberto
目的：评估临床前阿尔茨海默病 (AD) 中核心脑脊液 (CSF) 生物标志物与皮质厚度 (CTh) 之间的关系。方法：在这项横断面研究中，阿尔茨海默病神经影像计划的正常对照 (n = 145) 接受了结构 3T 磁共振成像 (MRI) 和腰椎穿刺。通过 Luminex 测定法测量 CSF β-淀粉样蛋白 (1-42) (A beta) 和磷酸 tau (181p) (p-tau) 水平。使用已发布的截断值（A beta(+)/A beta(-) 和 p-tau(+)/ptau(-)）对样本进行二分。 CTh 由 Freesurfer 测量。 CTh 差异图源自相互作用和相关分析。分离出相互作用分析中的簇，通过协方差分析来分析相互作用的方向性。结果：我们发现 CSF Ab 和 CSF p-tau 水平之间存在显着的生物标志物相互作用，影响大脑结构。皮质萎缩仅发生在同时具有 A beta(+) 和 p-tau(+) 的受试者中。分层相关分析表明，p-tau 和 CTh 之间的关系受 A beta 状态的影响，A beta 和 CTh 之间的关系受 p-tau 状态的影响。在 A beta(+) 受试者的不同皮质区域发现了 p-Tau 依赖性变薄，但在 A beta(-) 受试者中没有发现。在不存在异常 p-tau 的情况下，皮质增厚与 CSF A β 值降低有关，但在 p-tau(+) 受试者中未发现相关性。 解释：我们的数据表明，AD 中生物标志物之间的相互作用导致与低 CSF A β 相关的病理性皮质增厚的两阶段现象，一旦 CSF p-tau 异常，就会出现萎缩。在临床前 AD 的临床试验中，无论是选择患者还是使用 MRI 作为疗效的替代标志物时，都应考虑这些相互作用。
Objective: To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer disease (AD).Methods: In this cross-sectional study, normal controls (n = 145) from the Alzheimer's Disease Neuroimaging Initiative underwent structural 3T magnetic resonance imaging (MRI) and lumbar puncture. CSF beta-amyloid(1-42) (A beta) and phospho-tau(181p) (p-tau) levels were measured by Luminex assays. Samples were dichotomized using published cutoffs (A beta(+)/A beta(-) and p-tau(+)/ptau(-)). CTh was measured by Freesurfer. CTh difference maps were derived from interaction and correlation analyses. Clusters from the interaction analysis were isolated to analyze the directionality of the interaction by analysis of covariance.Results: We found a significant biomarker interaction between CSF Ab and CSF p-tau levels affecting brain structure. Cortical atrophy only occurs in subjects with both A beta(+) and p-tau(+). The stratified correlation analyses showed that the relationship between p-tau and CTh is modified by A beta status and the relationship between A beta and CTh is modified by p-tau status. p-Tau-dependent thinning was found in different cortical regions in A beta(+) subjects but not in A beta(-) subjects. Cortical thickening was related to decreasing CSF A beta values in the absence of abnormal p-tau, but no correlations were found in p-tau(+) subjects.Interpretation: Our data suggest that interactions between biomarkers in AD result in a 2-phase phenomenon of pathological cortical thickening associated with low CSF A beta, followed by atrophy once CSF p-tau becomes abnormal. These interactions should be considered in clinical trials in preclinical AD, both when selecting patients and when using MRI as a surrogate marker of efficacy.