Amyloid-Beta Metabolism in Familial Adult Children Study

描述（由申请人提供）：有大量证据表明，常染色体显性阿尔茨海默病（ADAD）是由A 42相对于A 40的过量产生引起的，并且与晚发型阿尔茨海默病（AD）共享最终共同途径。AD引起突变的病理生理学可通过CSF A？代谢研究在人体中直接测量。ADAD A？将代谢结果与其他测试相结合将有助于更好地了解ADAD患者大脑的病理生理学、A？沉积（PET PIB）、结构（MRI）和功能变化（临床和神经心理测量学）。这些信息可能会导致改善诊断测试和更精确的疾病修饰治疗的药效学测试。目的：将招募36名年龄在21岁至74岁之间的症状前受试者，并进行CSF A？代谢研究以及ACS PPG研究，包括PET/PIB（项目1）、CSF生物标志物（项目2）、注意力神经心理测量学（项目3）和结构MRI（项目4）。通过这些数据，我们将实现三个具体目标。目的1：确定ADAD突变携带者与对照组的A <$40、A <$42和A <$总产生率和清除率。直接测量ADAD中人类A？代谢的病理生理学变化将提供AD潜在致病原因所需的生物标志物（生物标志物）。华盛顿大学开发的一种新技术可以直接测量人体内A？的产生和清除率（Bateman等人，2006年）。目的2：确定与对照组相比，ADAD中CSF中A？物种绝对水平的变化和变异模式。A42是AD的重要生物标志物，已被证明是敏感和特异的。正常参与者的A水平在数小时内发生显著变化，但这种正常的变化模式可能在AD病理学中被破坏。目标3：确定初始CSF中生物标志物（A0、tau和其他）总水平的变化、PET PIB中A1的病理性沉积（病理学）、MRI上的结构变化（病理学）以及ADAD与对照组相比的神经心理测量学变化。除了临床评价（CDR）以确定任何临床相关的认知变化外，还将对每名受试者进行这些正在进行的ACS PPG研究。这项研究将测量认知，成像，生理学和生物标志物的变化，在人的致病突变，导致阿尔茨海默病。这些信息将为开发更好的阿尔茨海默病测试提供重要数据。它还可能有助于开发可能改变疾病进程的阿尔茨海默病新疗法。

DESCRIPTION (provided by applicant): There is substantial evidence that Autosomal Dominant Alzheimer Disease (ADAD) is caused by over- production of A¿42 relative to A¿40, and shares a final common pathway with later onset Alzheimer Disease (AD). The pathophysiology of AD causing mutations can be directly measured in humans with CSF A¿ metabolism studies. ADAD A¿ metabolism results with other testing will allow for better understanding of the pathophysiology, A¿ deposition (PET PIB), structural (MRI) and functional changes (clinical and neuropsychometrics) of the brain in ADAD. This information will likely lead to improved diagnostic testing and more precise pharmacodynamic testing of disease modifying treatments. Aims: 36 pre-symptomatic participants between the age of 21 and 74 will be recruited and undergo CSF A¿ metabolism studies in addition to ACS PPG studies including PET/PIB (project 1), CSF biomarkers (project 2), attentional neuropsychometrics (project 3) and structural MRI (project 4). With these data we will achieve 3 specific aims. Aim 1: To determine A¿40, A¿42, and A¿Total production and clearance rates in ADAD mutation carriers versus controls. Direct measurement of the pathophysiological changes of A¿ metabolism in humans in ADAD would provide a needed biological marker (biomarker) of a potential pathogenic cause of AD. A novel technique, developed at Washington University, allows for the direct measurement of production and clearance rates of A¿ in humans(Bateman et al. 2006). Aim 2: To determine changes in absolute levels of A¿ species in CSF and variability patterns in ADAD vs. controls. A¿42 is an important biomarker for AD and has been demonstrated to be sensitive and specific. A¿ levels change significantly over hours in normal participants, but this normal pattern of variation may be disrupted in AD pathology. Aim 3: To determine changes in total levels biomarkers from initial CSF (A0, tau, and others), pathological deposition of A¿ by PET PIB (pathology), structural changes on MRI (pathology), and neuropsychometric changes in ADAD versus controls. These ongoing studies of the ACS PPG will be performed with each participant, in addition to a clinical evaluation (CDR) to determine any clinically relevant cognitive changes. This study will measure cognitive, imaging, physiology, and bio-marker changes in people with a causative mutation that leads to Alzheimer disease. This information will provide important data to develop better tests for Alzheimer disease. It will also likely assist in developing new treatments for Alzheimer disease that may change the course of the disease.