CSF Biomarkers of Antecedent AD

阿尔茨海默病(AD)将很快成为一种公共卫生危机。目前还没有治疗方法 延缓AD的发病或防止AD的进展，尽管有几个有希望的候选药物正在开发中。 因此，重要的是要有能够识别高危个体的生物标记物，以便靶向 用于临床试验、疾病修正疗法和监测治疗。AD病理(例如，A(3个斑块)) 在认知症状出现前10-20年开始。即使是最早的临床症状 伴有神经元和突触功能障碍/死亡。因此，至关重要的是确定个人与 “临床前”阿尔茨海默病，在明显的临床症状和神经元丧失之前，因此新的治疗方法将是最好的 保存正常大脑功能的机会。低水平的脑脊液AP42已被证明是一种极好的 疾病早期皮质淀粉样蛋白的标记物，而脑脊液tau/AP42和ptau8i/AP42比值在 预测未来的认知衰退。然而，目前还不清楚这种变化在疾病过程的早期有多早。 脑脊液变得可以检测到，所以正在努力研究年轻的队列，希望能识别出 在最早的阶段就受到影响的个人。我们的长期目标是充分了解纵向 阿尔茨海默病自然病程中生物标志物的演变。项目2开始解决这一目标。 目的1：获得AP4o、AP42、tau、ptaui8i和新的标记物YKL-40、VILIP-1的标准化测量方法 禁食脑脊液样本和API^0、Apx-40、Api^2和APx-42in匹配的禁食血浆样本 免疫吸附分析(平板法)和xMAP(Luminex，珠基)技术。 目标2：在纵向研究中，评估生物标记物水平作为家庭功能的年变化率 病史和载脂蛋白e4状态，并调查低脑脊液AP42水平或AP42随时间的下降是否可以预测 其他生物标志物分析的未来变化，如tau、ptauisi、神经炎性标志物(例如YKL-40)，或 神经退行性变的假定标记物(例如，VILIP-1)。 目标3：将流体生物标记物测量方法(以及生物标记物随时间的变化率)与未来认知能力相关联 下降(临床核心)，由PIB评估的皮质淀粉样蛋白负荷的变化(项目1)，神经心理学 措施(项目3)和结构/功能神经成像措施(项目4)。

Alzheimer's disease (AD) will soon become a public health crisis. There currently are no treatments that delay the onset or prevent the progression of AD, though several promising candidates are in development. It will, therefore, be important to have biomarkers that can identify individuals at high risk in order to target them for clinical trials, disease-modifying therapies and to monitor therapy. AD pathology (e.g., A(3 plaques) begins 10-20 years before the onset of cognitive symptoms. Even the earliest clinical symptoms are accompanied by neuronal and synaptic dysfunction/death. Thus, it will be critical to identify individuals with "preclinical" AD, prior to marked clinical symptoms and neuron loss, so new therapies will have the best chance to preserve normal brain function. Low levels of CSF AP42 have been shown to be an excellent marker of cortical amyloid early in the disease, whereas CSF tau/AP42 and ptaui8i/AP42 ratios are useful in predicting future cognitive decline. It is unclear, however, how early in the disease process such changes in CSF become detectable, so efforts are being made to study younger cohorts in the hopes of identifying affected individuals at the very earliest stages. Our long term goal is to fully understand the longitudinal evolution of biomarker changes during the natural course of AD. Project 2 begins to address this goal. Aim 1: Obtain standardized measures of Ap4o, AP42, tau, ptaui8i, and novel markers YKL-40, and VILIP-1 in fasted CSF samples and APi^o, Apx-40, Api^2, and APx-42in matched, fasted plasma samples using enzymelinked immunosorbent assays (plate-based ELISA) and xMAP (Luminex, bead-based) technologies. Aim 2: In longitudinal studies, assess the annual rate of change in biomarker levels as a function of family history and APOE e4 status, and investigate whether low CSF AP42 levels, or a drop in AP42 over time, predict future change in other biomarker analytes, such as tau, ptauisi, neuroinflammatory markers (e.g.,YKL-40), or putative markers of neurodegeneration (e.g., VILIP-1). Aim 3: Correlate fluid biomarker measures (and rate of biomarker change over time) with future cognitive decline (Clinical Core), changes in cortical amyloid load as assessed by PIB (Project 1), neuropsychological measures (Project 3), and structural/functional neuroimaging measures (Project 4).