Blood Base Bioenergetic Profiling: A Novel Approach for Identifying Alzheimer's Disease Risk and Pathology

血基生物能量分析：识别阿尔茨海默病风险和病理学的新方法

• 批准号: 9383242
• 负责人: ANTHONY J MOLINA
• 金额: $ 76.63万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383242
• 关键词: Address; Adult; Advanced Development; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid deposition; Apolipoprotein E; Bioenergetics; Biological Markers; Blood; Blood Cells; Blood Platelets; Blood specimen; Brain; Brain imaging; Cell Respiration; Cerebrospinal Fluid; Cerebrum; Citrate (si)-Synthase; Clinic; Clinical; Cognitive; Cost Measures; Data; Dementia; Detection; Development; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Exhibits; Functional disorder; Funding; Genotype; Goals; Hippocampus (Brain); Impaired cognition; Individual; Inflammation; Insulin Resistance; Interdisciplinary Study; Longitudinal Studies; Lymphocyte; Machine Learning; Magnetic Resonance Imaging; Measurable; Measures; Memory; Memory impairment; Metabolic; Metabolism; Methodology; Mitochondria; Mitochondrial DNA; Modeling; Nervous System Trauma; Neurofibrillary Tangles; Participant; Pathologic; Pathologic Processes; Pathology; Patients; Pattern; Performance; Peripheral Blood Mononuclear Cell; Persons; Pilot Projects; Play; Positron-Emission Tomography; Prediabetes syndrome; Predisposition; Prevention; Prevention strategy; Reporter; Reporting; Research; Research Personnel; Resources; Respiration; Risk; Risk Factors; Role; Severity of illness; Specificity; Sum; Symptoms; Testing; Time; Work; base; cell type; cognitive performance; cognitive testing; cohort; community setting; cost effective; cytokine; density; follow-up; forest; glucose metabolism; high risk; improved; insight; ketogenic diet; mild cognitive impairment; minimally invasive; mitochondrial dysfunction; monocyte; nonhuman primate; novel strategies; respiratory; screening; stem; symposium; tau Proteins; tool; treatment strategy

7. Project Summary/Abstract In Alzheimer's disease (AD), irreversible neurological damage takes place years before the onset of clinical symptoms. Therefore, it is recognized that the development of AD dementia treatment and prevention strategies relies on the early detection of presymptomatic pathology. Previous studies demonstrate that mitochondrial dysfunction plays a key role in the pathophysiology of AD and precedes the formation of plaques and tangles that are hallmarks of this disease. The premise of this study is based on the unique sensitivity of the brain to systemic bioenergetic decline due to its exceptionally high metabolic demand. We hypothesize that bioenergetic capacity is related to early AD pathology and that bioenergetic decline is associated with the long term progression and severity of this disease. Recent work by our group and others demonstrate that blood- based bioenergetic profiling, utilizing cellular respirometry, provides a reliable measure of systemic mitochondrial function. The proposed study will determine whether blood cell bioenergetics is related to AD risk, pathology, cognitive performance, and changes in these parameters over time. Our long term goal is to develop a minimally invasive screening tool that can be used in a clinic/community setting to identify candidates for more intensive diagnostic testing, such as CSF biomarker analysis and brain imaging. This project will be completed in an efficient and cost-effective manner by leveraging resources provided by the NIA-funded Wake Forest Alzheimer' Disease Center Clinical Core (ADCCC). Participants in the ADCCC represent a spectrum of AD risk and disease progression and are being extensively characterized for AD pathologies at baseline and 3 year follow ups. Our preliminary data from ADCCC participants indicate that bioenergetic capacity, measured in blood cells, is lower in participants with mild cognitive impairment. Moreover, our data suggest that bioenergetic deficits are already apparent in cognitively normal participants at high risk for AD. The aims of the proposed study are: 1) To determine bioenergetic profiles most strongly associated with AD risk and reporters of AD pathology (cognitive performance, CSF Aβ42/tau, hippocampal volume, brain amyloid, and cerebral glucose metabolism); 2) To determine the changes in bioenergetic profiles related to the 3 year progression of cognitive decline and reporters of AD pathology; and, 3) To determine the relationships of mitochondrial content and inflammation with bioenergetic capacity, and reporters of AD pathology at baseline and at follow-up. A central goal of the proposed study is to determine the specific bioenergetic parameters that are most closely associated with AD risk and pathology. Therefore, in addition to convention analytical approaches, we will employ state of the art Machine Learning analyses to identify individual parameters or multivariate signatures that are most closely associated with AD risk and pathology. Completion of this project can impact the detection of presymptomatic AD, provide insights into mechanisms underlying bioenergetic decline associated with AD, and broadly advance translational bioenergetics research.

7。项目摘要/摘要 在阿尔茨海默氏病（AD）中，不可逆转的神经系统损害发生在几年前 临床症状。因此，人们认识到AD痴呆症治疗和预防的发展 策略依赖于早期检测到头脑病理学。以前的研究表明 线粒体功能障碍在AD的病理生理学中起关键作用，并在斑块的形成之前 和缠结是这种疾病的标志。这项研究的前提是基于 由于其异常高的代谢需求，大脑降低了全身生物能的下降。我们假设这一点 生物能能力与早期AD病理有关，并且生物能下降与长期有关 该疾病的期限进展和严重程度。我们小组和其他人最近的工作表明，血液 - 使用细胞呼吸测定法基于基于的生物能分析，可靠地测量全身性 线粒体功能。拟议的研究将确定血细胞生物能是否与AD有关 随着时间的推移，这些参数的风险，病理，认知表现以及这些参数的变化。我们的长期目标是 开发一种微创筛查工具，可在诊所/社区环境中使用以识别 候选者进行更深入的诊断测试，例如CSF生物标志物分析和大脑成像。 该项目将通过利用资源以有效且具有成本效益的方式完成 由NIA资助的Wake Forest Alzheimer疾病中心临床核心（ADCCC）提供。参与者 ADCCC代表了广告风险和疾病进展的一部分，并且正在广泛地表征 对于基线和3年随访的广告病理。我们来自ADCCC参与者的初步数据表明 在患有轻度认知障碍的参与者中，在血细胞中测量的生物能力较低。 此外，我们的数据表明，生物能定义在认知正常参与者中已经显而易见 广告的高风险。拟议的研究的目的是：1）最强烈确定生物能曲线 与AD病理学的AD风险和记者有关（认知性能，CSFAβ42/TAU，海马 体积，脑淀粉样蛋白和脑葡萄糖代谢）； 2）确定生物能曲线的变化 与认知能力下降的3年进展和AD病理记者有关； 3）确定 线粒体含量和炎症与生物能力的关系以及AD的记者 基线和随访时的病理学。拟议的研究的一个核心目标是确定特定 与AD风险和病理最密切相关的生物能参数。因此，除了 惯例分析方法，我们将采用艺术机器学习分析来识别 与AD风险和病理最密切相关的个体参数或多元特征。 该项目的完成可能会影响对抑制性广告的检测，提供有关机制的见解 与AD相关的生物能下降的根本下降，并广泛提高了翻译生物能力研究。