CSF Biomarkers of Antecedent AD

AD 前身的 CSF 生物标志物

• 批准号: 8287322
• 负责人: Anne Fagan
• 金额: $ 23.45万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287322
• 关键词: AP40; Address; Adult Children; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Biological Assay; Biological Markers; Biostatistics Core; Brain; Calcium Signaling; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Cessation of life; Clinical; Clinical Trials; Cognitive; Cohort Studies; Cross-Sectional Studies; Data; Dementia; Detection; Development; Diagnosis; Diagnostic; Disease; Drops; Elderly; Enzyme-Linked Immunosorbent Assay; Enzymes; Event; Evolution; Family history of; Fasting; Foundations; Functional disorder; Funding; Future; Genotype; Goals; Image; Immunosorbents; Impaired cognition; Individual; Instruction; Light; Link; Liquid substance; Longitudinal Studies; Measurement; Measures; Modality; Monitor; Nerve Degeneration; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neurons; Normalcy; Participant; Pathology; Performance; Pharmaceutical Preparations; Physicians; Pittsburgh Compound-B; Plasma; Play; Prevention; Process; Proteins; Public Health; Recruitment Activity; Role; Sampling; Signaling Molecule; Staging; Symptoms; Synapses; Technology; Testing; Therapeutic; Time; VSNL1 gene; age group; age related; base; cohort; data management; design; disease diagnosis; disorder risk; effective therapy; high risk; inflammatory marker; information gathering; insight; longitudinal design; member; neuroimaging; neuroinflammation; neuron loss; neuropathology; neuropsychological; novel marker; outcome forecast; pre-clinical; prevent; prognostic; standardize measure; tau Proteins; tool

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).

阿尔茨海默病（AD）很快将成为一个公共卫生危机。目前没有治疗方法， 延迟AD的发作或预防AD的进展，尽管一些有希望的候选药物正在开发中。 因此，重要的是要有生物标志物，可以识别高风险的个人，以靶向 他们的临床试验，疾病改善疗法和监测治疗。AD病理学（例如，A（3块斑块） 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，识别具有以下特征的个人至关重要 “临床前”AD，在明显的临床症状和神经元损失之前，因此新的疗法将具有最好的治疗效果。 保持正常大脑功能的机会。低水平的CSF AP 42已被证明是一种极好的 CSF tau/AP 42和ptau 181/AP 42比率在疾病早期是皮质淀粉样蛋白的标志物，而CSF tau/AP 42和ptau 181/AP 42比率在疾病早期是有用的。 预测未来的认知能力下降然而，目前还不清楚这种变化在疾病过程中有多早。 脑脊液变得可检测，因此正在努力研究年轻的队列，希望能识别出 受影响的人在最早的阶段。我们的长期目标是全面了解 生物标志物在AD自然病程中的变化。项目2开始着手实现这一目标。 目的1：获得在哺乳动物中Ap 40、AP 42、tau、ptau 181和新标志物YKL-40和VILIP-1的标准化测量。 使用酶联免疫吸附试验，测定了空腹CSF样本和匹配的空腹血浆样本中的API^o、Apx-40、Api ^2和APx-42。 免疫吸附测定（基于板的ELISA）和xMAP（Luminex，基于珠）技术。 目标2：在纵向研究中，评估生物标志物水平的年变化率作为家庭的函数 病史和APOE e4状态，并研究CSF AP 42水平降低或AP 42随时间下降是否预测 其它生物标志物分析物如tau、ptauISI，神经炎性标志物（例如，YKL-40），或 神经变性的推定标志物（例如，VILIP-1）。 目的3：将液体生物标志物测量（和生物标志物随时间的变化率）与未来认知功能相关联 下降（临床核心），通过PIB评估的皮质淀粉样蛋白负荷变化（项目1），神经心理学 测量（项目3）和结构/功能神经影像学测量（项目4）。