Amyloid-Beta Metabolism in Familial Adult Children Study

家族成年儿童研究中的淀粉样蛋白代谢

• 批准号: 7304012
• 负责人: JOHN MORRIS
• 金额: $ 25.47万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7304012
• 关键词: Adult Children; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease risk; Amino Acids; Amyloid beta-Protein; Animal Model; Attention; Biochemical; Biochemical Genetics; Biological Markers; Biostatistics Core; Brain; Brain Injuries; Budgets; Cerebrospinal Fluid; Cerebrum; Clinical; Clinical assessments; Clinical dementia rating scale; Cognitive; Counseling; DNA Library; Data; Dementia; Deposition; Development; Diagnosis; Diagnostic tests; Disease; Early Diagnosis; Employee Strikes; Enrollment; Family; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Genes; Genetic; Genetic screening method; Goals; Hour; Human; Image; Imaging Techniques; In Vitro; Individual; Inherited; Knowledge; Label; Late Onset Alzheimer Disease; Lead; Letters; Leucine; Magnetic Resonance Imaging; Measurement; Measures; Memory Loss; Metabolic Clearance Rate; Metabolism; Methods; Molecular Biology; Mutation; Nature; Neuraxis; Parents; Participant; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Personality; Persons; Pharmaceutical Preparations; Pharmacodynamics; Physiology; Pittsburgh Compound-B; Plasma; Population; Positron-Emission Tomography; Prevalence; Principal Investigator; Production; Program Research Project Grants; Proteins; Public Health; Rate; Recruitment Activity; Relative (related person); Research; Research Infrastructure; Resources; Risk; Severities; Siblings; Structure; Symptoms; Techniques; Testing; Time; United States; Universities; Variant; Washington; abeta accumulation; amyloid imaging; clinical Diagnosis; clinically relevant; cognitive change; cognitive function; disease mechanisms study; disease-causing mutation; early onset; improved; in vivo; insight; kindred; metabolic abnormality assessment; mutation carrier; neuron loss; novel; prevent; programs; research clinical testing; tau Proteins

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.

描述(由申请人提供)：有大量证据表明，常染色体显性遗传性阿尔茨海默病(ADAD)是由A？42相对于A？40的过度产生引起的，并与晚发型阿尔茨海默病(AD)共享最终的共同途径。AD导致突变的病理生理学可以通过脑脊液A代谢研究在人类中直接测量。ADAD的代谢结果和其他测试将有助于更好地了解ADAD患者大脑的病理生理、A？沉积(PET PIB)、结构(MRI)和功能变化(临床和神经心理计量学)。这些信息可能会导致改进的诊断测试和更精确的疾病修改治疗的药效学测试。目的：36名年龄在21岁到74岁之间的有症状前期的参与者将被招募，在接受包括PET/PIB(项目1)、脑脊液生物标记物(项目2)、注意力神经心理计量学(项目3)和结构磁共振(项目4)在内的ACS PPG研究的基础上，进行脑脊液A代谢研究。有了这些数据，我们将实现三个具体目标。目的1：测定ADAD基因突变携带者与对照组的A？40、A？42和A？总产量和清除率。直接测量ADAD患者体内Aβ代谢的病理生理变化，将为AD的潜在致病因素提供必要的生物标记物。华盛顿大学开发的一项新技术允许直接测量人类A型肝炎的产生和清除率(贝特曼等人)。2006)。目的2：确定脑脊液中A物种绝对水平的变化以及ADAD与对照组之间的变异模式。A？42是AD的重要生物标志物，已被证明是敏感和特异的。在正常受试者中，A？水平随着时间的推移发生显著变化，但这种正常的变化模式可能会在AD病理中被破坏。目的：测定ADAD患者初始脑脊液(A0、tau等)的总水平、PET PIB的病理沉积(病理)、MRI的结构变化(病理)以及神经心理计量学的变化。除了进行临床评估(CDR)以确定任何与临床相关的认知变化外，还将对每个参与者进行这些正在进行的关于ACS PPG的研究。这项研究将测量患有导致阿尔茨海默病的致病突变的人的认知、成像、生理学和生物标志物的变化。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治疗阿尔茨海默病的新疗法，可能会改变疾病的进程。