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.项目总结/摘要 在阿尔茨海默病（AD）中，不可逆的神经损伤在阿尔茨海默病（AD）发作前数年发生。 临床症状。因此，人们认识到，开发AD痴呆的治疗和预防 这些策略依赖于症状前病变的早期检测。先前的研究表明， 线粒体功能障碍在AD的病理生理学中起关键作用，并先于斑块的形成 和缠结是这种疾病的标志。这项研究的前提是基于独特的敏感性 大脑由于其异常高的代谢需求而导致全身生物能量下降。我们假设 生物能量能力与早期AD病理学有关，生物能量下降与长期AD相关。 这种疾病的长期进展和严重程度。我们小组和其他人最近的工作表明，血液- 基于生物能量分析，利用细胞呼吸测定法，提供了一个可靠的测量系统 线粒体功能这项拟议的研究将确定血细胞生物能量学是否与AD有关 风险、病理学、认知表现以及这些参数随时间的变化。我们的长期目标是 开发一种可用于诊所/社区环境的微创筛查工具， 更密集的诊断测试的候选人，如CSF生物标志物分析和脑成像。 将利用资源，以高效率和高成本效益的方式完成这一项目 由美国国立卫生研究院资助的维克森林阿尔茨海默病中心临床核心（ADCCC）提供。参与者 ADCCC代表了AD风险和疾病进展谱，且正在被广泛表征 在基线和3年随访时的AD病理学。来自ADCCC参与者的初步数据表明， 在轻度认知障碍的参与者中，以血细胞为单位测量的生物能量能力较低。 此外，我们的数据表明，在认知正常的参与者中， AD的高风险。本研究的目的是：1）确定最强的生物能量分布 与AD风险和AD病理学报告相关（认知表现、CSF Aβ42/tau、海马 体积、脑淀粉样蛋白和脑葡萄糖代谢）; 2）确定生物能量谱的变化 与认知衰退的3年进展和AD病理学的报告者相关;以及，3）为了确定 线粒体含量和炎症与生物能量能力的关系，以及AD的报告基因 基线和随访时的病理学。拟议研究的一个中心目标是确定 与AD风险和病理学最密切相关的生物能量参数。因此除了 传统的分析方法，我们将采用最先进的机器学习分析，以确定 与AD风险和病理学最密切相关的个体参数或多变量特征。 该项目的完成可以影响症状前AD的检测， 与AD相关的潜在生物能量下降，并广泛推进转化生物能量学研究。