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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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，不可逆的神经损伤发生在发病前数年。因此，人们认识到AD痴呆的治疗和预防的发展。先前的研究表明，策略依赖于症状前病理学的早期检测。线粒体功能障碍在 AD 的病理生理学中起着关键作用，并且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。生物能能力与早期 AD 病理有关，生物能下降与长期 AD 相关。我们小组和其他人最近的工作表明，这种疾病的长期进展和严重程度。基于生物能量分析，利用细胞呼吸测量法，提供了可靠的全身测量拟议的研究将确定血细胞生物能学是否与 AD 相关。我们的长期目标是：风险、病理、认知表现以及这些参数随时间的变化。开发一种微创筛查工具，可用于诊所/社区环境中以识别适合进行更深入的诊断测试，例如脑脊液生物标志物分析和脑成像。该项目将利用资源以高效且具有成本效益的方式完成由 NIA 资助的维克森林阿尔茨海默病中心临床核心 (ADCCC) 参与者提供。 ADCCC 代表了一系列 AD 风险和疾病进展，并且正在被广泛表征我们来自 ADCCC 参与者的初步数据表明 AD 病理的基线和 3 年随访。以血细胞测量的生物能量能力在患有轻度认知障碍的参与者中较低。此外，我们的数据表明，在认知正常的参与者中，生物能量缺陷已经很明显拟议研究的目的是：1）最有力地确定生物能特征。与 AD 风险和 AD 病理学产生相关（认知表现、CSF Aβ42/tau、海马 2) 确定生物能谱的变化与认知衰退的 3 年进展和 AD 病理的产生有关；以及，3) 确定线粒体含量和炎症与生物能能力的关系以及 AD 的产生拟议研究的中心目标是确定基线和随访时的具体病理学。因此，除了与 AD 风险和病理学最密切相关的生物能量参数。传统的分析方法，我们将采用最先进的机器学习分析来识别与 AD 风险和病理学最密切相关的单个参数或多变量特征。该项目的完成可以影响症状前 AD 的检测，提供对机制的见解与 AD 相关的潜在生物能下降，并广泛推进转化生物能学研究。