Dominantly Inherited Alzheimer Network: Biomarker Core

核心E：生物标志物项目总结/摘要 阿尔茨海默病（AD）如果不及时治疗，将在不久的将来成为一个公共卫生危机。有 目前还没有经过证实的治疗方法可以延迟AD的发作或预防AD的进展，尽管有几种治疗方法， 有希望的候选人正在接受考验。在治疗开发过程中，关键是要有生物标志物， 识别AD高危个体，以便针对他们进行临床试验并监测治疗。 常染色体显性AD（ADAD）占所有AD病例的比例很小（<1%），但 神经病理学特征和临床特征与更常见的散发性迟发性形式相似 （加载）。具有AD突变的个体注定会发展这种疾病，并且在相对较低的发病率下， 可预测的年龄，从而提供了一个独特的队列，在其中调查的轨迹/时间的基础 AD病理，尤其是从临床前/无症状阶段过渡到症状阶段。 在DIAN的最初资助期间，生物标志物核心分析了获得的CSF和血浆样本， 从基线的参与者，包括突变携带者（MC）和非携带者（NC），下降沿着广泛 症状发作估计年数谱（EYO）。横断面分析显示， CSF tau和ptau181是神经元损伤和/或神经元缠结的标志物，在神经元损伤前约10 - 20年， 症状发作的估计年龄（EYO-10至-20）。CSF A β 1 - 42水平低，是β淀粉样蛋白的标志物 在~EYO-10时首次在MC中观察到斑块，但水平似乎开始下降要早得多（~EYO -25）从最初高于NC的水平。有趣的是，最近对纵向样本的分析显示， 在症状性MC（EYO> 0）中，CSF tTau增加的减缓和pTau水平的实际降低超过 时间，可能反映了其在脑中的缠结中的隔离，如在治疗期间观察到的CSF A β 1 - 42。 斑块的发展。这些结果强调了纵向的、个人内部评估的重要性 在疾病的自然过程中模拟生物标志物轨迹时。尚待确定的是 是MC内生物标志物从无症状进展为有症状时的变化轨迹 阶段这些信息对于设计和评价旨在预防疾病的临床试验至关重要。 在由于AD而具有发展痴呆风险的个体中认知下降的开始。 在本申请中，我们将通过四个具体目标来建立我们的成功：目标1）保持和 培养DIAN CSF和血浆样本的生物储存库，并协调样本的分配， 获得批准的科学研究的合格研究者;目的2）获得已建立的生物标志物的测量值 使用下一代高性能Lumipulse®检测CSF中的分析物（A β 1 - 40、A β 1 - 42、t-Tau、p-Tau181） 自动化分析平台，以支持DIAN核心和项目的目标;目标3）维护21 C.F.R.§ 11涉及电子数据的所有生物标志物核心功能的合规性;以及目标4）执行质量 CSF生物标志物测定严格性（精密度和准确度）和再现性的对照评价。

Core E: Biomarker PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) will become a public health crisis in the very near future if left untreated. There are currently no proven treatments that delay the onset or prevent the progression of AD, although several promising candidates are being tested. During therapy development, it will be critical to have biomarkers that identify individuals at high risk for AD in order to target them for clinical trials and to monitor therapy. Autosomal-dominant AD (ADAD) accounts for a very small proportion of all AD cases (<1%) but the neuropathologic hallmarks and clinical features are similar to the more common sporadic, late-onset form (LOAD). Individuals possessing AD mutations are destined to develop the disease and at a relatively predictable age, thus providing a unique cohort in which to investigate the trajectories/timing of underlying AD pathologies, especially as one transitions from the preclinical/asymptomatic to the symptomatic stage. During the initial funding periods of DIAN, the Biomarker Core analyzed CSF and plasma samples obtained from participants at baseline, including mutation carriers (MC) and non-carriers (NC) that fell along a wide spectrum of estimated years to symptom onset (EYO). Cross-sectional analyses demonstrated elevated CSF tau and ptau181, markers of neuronal injury and/or neurofibrillary tangles, ~10-20 years prior to the estimated age of symptom onset (EYO -10 to -20). Low levels of CSF Aβ1-42, a marker of β-amyloid plaques, were first observed in MC at ~EYO -10, but levels appeared to start to decline much earlier (~EYO -25) from levels initially higher than NC. Interestingly, more recent analyses of longitudinal samples revealed a slowing of the increase in CSF tTau and an actual reduction in pTau levels in symptomatic MC (EYO>0) over time, perhaps reflecting its sequestration into tangles in the brain as is observed for CSF Aβ1-42 during the development of plaques. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the natural course of the disease. What remains to be determined is the trajectory of biomarker changes within MC as they progress from the asymptomatic to the symptomatic stages. Such information will be critical for the design and evaluation of clinical trials intended to prevent the onset of cognitive decline in individuals at risk for developing dementia due to AD. In the present application, we will build upon our success through four Specific Aims: Aim 1) Maintain and grow the biorepository of DIAN CSF and plasma samples and coordinate the distribution of samples to qualified investigators for approved scientific studies; Aim 2) Obtain measures of established biomarker analytes in CSF (Aβ1-40, Aβ1-42, t-Tau, p-Tau181) using the next generation, high-performance Lumipulse® automated assay platform in order to support the aims of the DIAN cores and projects; Aim 3) Maintain 21 C.F.R. § 11 compliance for all Biomarker Core functions involving electronic data; and Aim 4) Perform quality control evaluation of CSF biomarker assay rigor (precision and accuracy) and reproducibility.