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，并且与晚发性阿尔茨海默病（AD）具有最终的共同途径。通过脑脊液A代谢研究，可以直接测量AD引起突变的病理生理学。ADAD A¿代谢结果与其他测试将允许更好地理解病理生理，A¿沉积（PET PIB），结构（MRI）和功能变化（临床和神经心理测量学）的大脑。这一信息将可能导致改进的诊断测试和更精确的药效学测试疾病修饰治疗。目的：将招募36名年龄在21至74岁之间的症状前参与者，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（项目3）和结构MRI（项目4）。有了这些数据，我们将实现3个具体目标。目的1：测定ADAD突变携带者与对照组相比，A¿40、A¿42和A¿的总产量和清除率。直接测量ADAD患者A¿代谢的病理生理变化将为AD的潜在致病原因提供所需的生物标志物（biomarker）。华盛顿大学开发的一项新技术可以直接测量人体中A¿的产生和清除率（Bateman等人，2006年）。目的2：确定ADAD患者脑脊液中A¿物种绝对水平的变化以及与对照组相比的变异模式。A¿42是AD的重要生物标志物，已被证明具有敏感性和特异性。在正常参与者中，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病理中被破坏。目的3：确定初始脑脊液生物标志物（A0， tau等）总水平的变化，PET PIB的A¿病理沉积（病理），MRI的结构变化（病理），以及ADAD与对照组的神经心理测量变化。这些正在进行的ACS PPG研究将在每个参与者身上进行，除了临床评估（CDR）以确定任何临床相关的认知变化。这项研究将测量导致阿尔茨海默病的致病突变患者的认知、成像、生理学和生物标志物的变化。这一信息将为开发更好的阿尔茨海默病检测方法提供重要数据。它还可能有助于开发阿尔茨海默病的新疗法，可能会改变这种疾病的病程。

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.