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.

DESCRIPTION (provided by application): 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 deployed to aerobic glycolysis (AG; glucose use outside of oxide phosphorylation)), and compare for the首次通过最新的生物标志物和同一个人的临床评估对大脑循环和代谢进行了更全面的测量。这项工作是由我们的观察结果激发的，尽管AG约占正常成年人大脑代谢的总葡萄糖的15％，但它的分布非常明显，其分布是大脑的默认模式网络（DMN）。从疾病的角度来看，DMN是值得注意的，因为它代表了阿尔茨海默氏病（AD）中β-淀粉样蛋白（a。）斑块积累的主要部位。 AG与AD之间的明显关联促使我们在转基因小鼠中进一步探索这种关系，在那里我们发现AG（但不是总葡萄糖消耗）和AP不仅在区域上而且随着突触活动的变化而变化。此外，在长期降低合成活性不仅在长期上 降低Ag和A水平，但也降低了斑块沉积。在这里，我们提出了第一次测量AG的个人，其中将通过[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A斑块分布。该应用的总体目的是实质上增强了我们对临床前AD的病理生理学的了解，特别是将AG作为突触活动的生物标志物，这是AD病理发展的潜在汇总因素。我们将确定Ag变化的时间（横截面和纵向）及其与AD的临床评估和其他生物标志物的关系。该项目不仅将提供有关临床前AD开发及其过渡到临床阶段的新颖和重要信息，而且还可以为抗Abeta处理的有效性提供有用的标志，特别是设计用于修改突触功能的有效性。