ANTECEDENT BIOMARKERS FOR AD; THE ADULT CHILDREN STUDY

AD 的先行生物标志物；

• 批准号: 8476417
• 负责人: JOHN MORRIS
• 金额: $ 24.73万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8476417
• 关键词: ATP phosphohydrolase; Address; Adult; Adult Children; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Attention; Biological Markers; Blood Circulation; Blood Glucose; Blood flow; Brain; Chronology; Clinical; Clinical assessments; Consumption; Data; Dementia; Deposition; Development; Diagnostic; Disease; Disease Progression; Energy Metabolism; Excitatory Synapse; Exhibits; Failure; Family; Functional disorder; Gender; Genotype; Glucose; Glutamates; Health; Human; Image; Impaired cognition; Individual; Intercellular Fluid; Knowledge; Laboratories; Measurement; Measures; Metabolism; Mitochondria; Modification; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Pathogenesis; Pathology; Patients; Positron-Emission Tomography; Preventive; Psychometrics; Recording of previous events; Reporting; Rest; Risk; Risk Factors; Site; Staging; Symptoms; Synapses; Time; Transgenic Mice; Universities; Washington; Work; aerobic glycolysis; arm; brain circulation; brain metabolism; design; glucose metabolism; improved; neurotransmission; novel; pre-clinical; synaptic function; uptake; young adult

DESCRIPTION (provided by applicant): This proposal will pursue in cognitively normal individuals from the Adult Children Study (ACS; POI AG026276) detailed, quantitative cross-sectional and longitudinal measurements of regional brain circulation, oxygen consumption and glucose use (total as well as the fraction devoted to aerobic glycolysis (AG; glucose use outside of oxidative phosphorylation)), and compare for the first time these more comprehensive measurements of brain circulation and metabolism with state-of-the-art biomarkers and clinical assessments in the same individuals. This work is motivated by our observation that while AG represents about 15% of the total glucose metabolized by the normal adult human brain it is strikingly nonuniform in its distribution being highest the brain's default mode network (DMN). The DMN is noteworthy from a disease perspective in that it represents a primary site of beta-amyloid (A¿) plaque accumulation in Alzheimer's disease (AD). This apparent association between AG and AD prompted us to explore further this relationship in transgenic mice where we found that AG (but not total glucose consumption) and AP vary together not only regionally but with changes in synaptic activity. Furthermore, reducing synaptic activity chronically not only reduces AG and A¿ levels but also retards plaque deposition. Here we propose measuring for the first time AG in individuals in whom A¿ plaque distribution will be assessed with [11C]PIB PET imaging along with other state-of-the-art biomarkers and clinical assessments. The overarching aim of this application is to substantially enhance our knowledge of the pathophysiology of preclinical AD and specifically to more fully characterize AG as a biomarker of synaptic activity, a potential aggravating factor in the development of AD pathology. We will determine the chronology (cross-sectionally and longitudinally) of changes in AG and its relationship to clinical assessments and other biomarkers of AD. This project will not only provide novel and important information about development of preclinical AD and its transition to clinical stages, but also may provide a useful marker of the efficacy of anti-Abeta treatments especially those designed to modify synaptic function.

描述（由申请人提供）：本提案将对成年儿童研究（ACS；POI AG026276）中认知正常的个体进行区域脑循环、耗氧量和葡萄糖消耗（总消耗量和葡萄糖消耗量）的详细、定量横断面和纵向测量。用于有氧糖酵解的部分（AG；氧化磷酸化之外的葡萄糖使用）），并首次将这些更全面的大脑循环和代谢测量与最先进的测量进行比较这项工作的动机是我们观察到，虽然 AG 约占正常成人大脑代谢的总葡萄糖的 15%，但其分布在大脑默认模式网络 (DMN) 中的分布却非常不均匀。从疾病角度来看，DMN 值得注意，因为它代表了阿尔茨海默病 (AD) 中 β-淀粉样蛋白 (A¿) 斑块积累的主要位点，AG 和 AD 之间的这种明显关联促使我们进一步探索转基因中的这种关系。我们在小鼠中发现 AG（但不是总葡萄糖消耗）和 AP 不仅在区域上变化，而且随着突触活动的变化而变化。此外，突触活动不仅长期减少。 AG 减少并且 A¿水平，但也延缓斑块沉积，在这里我们建议首次测量 A¿将使用 [11C]PIB PET 成像以及其他最先进的生物标志物和临床评估来评估斑块分布。该应用的首要目标是大幅增强我们对临床前 AD 病理生理学的了解，特别是更全面地了解。将 AG 描述为突触活动的生物标志物，突触活动是 AD 病理学发展的潜在加重因素。我们将确定 AG 变化的时间顺序（横向和纵向）及其与临床评估和其他的关系。该项目不仅将提供有关临床前 AD 的发展及其向临床阶段过渡的新颖且重要的信息，而且还可能提供抗 Abeta 治疗（尤其是旨在改变突触功能的治疗）功效的有用标记。