Dominantly Inherited Alzheimer Network: Biomarker Core

核心E：生物标记物项目摘要/摘要 阿尔茨海默病(AD)如果不加以治疗，在不久的将来将成为一种公共卫生危机。确实有 目前还没有得到证实的延缓AD发病或防止AD进展的治疗方法，尽管有几种 有前途的候选人正在接受测试。在治疗发展过程中，拥有生物标记物将是至关重要的 确定阿尔茨海默病的高危人群，以便针对他们进行临床试验和监测治疗。 常染色体显性阿尔茨海默病(ADAD)在所有AD病例中只占很小的比例(1%)，但 神经病理特征和临床特征类似于更常见的散发性晚发型 (加载)。携带AD突变的个体注定会患上这种疾病，并处于相对较低的水平 可预测的年龄，从而提供了一个独特的队列，在其中调查潜在的 AD病理学，尤指当一个人从临床前/无症状过渡到有症状阶段时。 在DIAN的最初资助期间，Biomarker Core分析了获得的脑脊液和血浆样本 来自基线的参与者，包括突变携带者(MC)和非携带者(NC) 出现症状的估计年限(EYO)。横断面分析显示隆起 脑脊液tau和ptau181，神经元损伤和/或神经原纤维缠结的标志物，大约10-20年前 估计出现症状的年龄(Eyo-10至-20)。低水平脑脊液Aβ1-42，β-淀粉样蛋白的标志物 斑块，在~Eyo-10时首次在MC中观察到，但水平似乎开始下降得更早(~Eyo -25)从最初高于NC的水平开始。有趣的是，最近对纵向样本的分析揭示了 症状MC(EYO&GT；0)的脑脊液tTau增加减缓，ptau水平实际降低。 时间，可能反映了它在大脑中被隔离成缠结，就像在脑脊液Aβ1-42中观察到的那样 斑块的形成。这些结果强调了纵向、面对面评估的重要性。 在对疾病自然过程中的生物标记物轨迹进行建模时。还有什么有待确定 MC内生物标记物的变化轨迹是从无症状发展到有症状 各阶段。这些信息对于设计和评估临床试验至关重要，这些试验旨在防止 阿尔茨海默病易患痴呆症的个体认知能力下降。 在本申请中，我们将通过四个具体目标建立我们的成功：目标1)维护和 培养代氏脑脊液和血浆样本的生物库，并协调样本的分配到 经批准的科学研究的合格调查人员；目的2)获得已建立的生物标志物的测量 脑脊液中的分析物(Aβ1-40、Aβ1-42、t-Tau、p-Tau181)使用新一代高性能Lumipulse® 自动化化验平台，以支持DIAN核心和项目的目标；目标3)维护21 C.F.R.§11所有涉及电子数据的Biomarker核心功能的合规性；以及Aim 4)执行质量 对照评价脑脊液生物标记物测定的严格性(精密度和准确性)和重复性。

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.