Implications of metabolism on healthy aging in African and Caucasian Americans: the Health ABC study

新陈代谢对非洲裔和白种裔美国人健康老龄化的影响：Health ABC 研究

• 批准号: 10118476
• 负责人: Venkatesh Locharla Murthy
• 金额: $ 23.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10118476
• 关键词: Address; Adult; African American; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Amino Acids; Bile Acids; Biological Assay; Biological Models; Body Composition; Brain; Cardiovascular Diseases; Clinical; Cognitive; Collaborations; Communities; Coronary artery; Data; Defect; Deltastab; Dementia; Development; Diabetes Mellitus; Diet; Disease; Disease Pathway; Female; Framingham Heart Study; Functional disorder; Funding; Genetic Transcription; Grant; Health; Heart; Human; Image; Impaired cognition; Impairment; Individual; Inflammation; Institutes; Insulin; Insulin Resistance; Investigation; Laboratories; Life Cycle Stages; Life Style; Link; Lipids; Longevity; Longterm Follow-up; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Memory; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic Pathway; Metabolism; Modality; Morbidity - disease rate; Motor; National Heart, Lung, and Blood Institute; National Institute on Aging; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neurons; Obesity; Outcome; Parents; Pathway interactions; Phenotype; Plasma; Psychosocial Stress; Race; Reporting; Resources; Risk; Sample Size; Sampling; Source; Structural defect; System; Testing; Time; Work; Youth; age related; base; biracial; caucasian American; clinical phenotype; cognitive function; cohort; comorbidity; diet and fitness; disease phenotype; healthy aging; improved; insulin sensitivity; lifestyle factors; lipid mediator; man; metabolic phenotype; middle age; nonalzheimer dementia; pre-clinical; sex; small molecule; white matter

Alzheimer-type (AD) and non-AD dementias and neurocognitive impairment have origins in dysregulated me- tabolism, leading to consideration of dementia as a “type 3 diabetes” phenotype. A wide array of basic labora- tory, model systems-based, and human investigations around identifying precise metabolic defects as the core of AD/non-AD dementias have emerged. A critical feature of studies attempting to identify a metabolic basis of neurocognitive dysfunction is the application of a broad assessment of metabolism to a well phenotyped hu- man cohort with dementia and related outcomes. As part of R01AG059729, Drs. Shah, Newman, Murthy and Clish have been performing metabolite profiling in a biracial subsample of the Healthy Aging and Body Com- position Study (Health ABC) to identify metabolic pathways relevant to healthy aging. While the parent study includes some neurocognitive measures, it only assays a subsample within Health ABC for lipid and lipid me- diators, the key metabolites felt to be relevant to AD and related dementias. Based on data suggesting the emerging importance of inflammation and lipid abnormalities in AD, the study team is requesting supplemental funds as part of this application to complete lipid and lipid intermediate metabolite profiling to facilitate (1) wider scientific discovery in AD and AD-related phenotypes and (2) integration with other metabolite modes already completed in Health ABC to provide a wider description of the metabolic abnormalities important in the life- course of neurocognitive dysfunction and AD. We hypothesize that lipid and lipid mediators will be associated with phenotypes and phenotypic groups central to AD and may facilitate discovery of potentially intervenable pathways at the heart of AD and AD-related neurocognitive dysfunction. To address this hypothesis, we will perform metabolite profiling in a wider sample size in Health ABC for lipid (C8 positive) and lipid mediators (C18 negative) to identify metabolites and encoded pathways associated with clinical and imaging-based de- mentia endpoints. In Aim 1, we will identify lipid and lipid mediator metabolite signatures associated with sub- sequent cognitive decline, preclinical AD phenotypes, and dementia. In Aim 2, we will identify association of lipid and lipid mediators with selected MRI markers of dementia previously reported. In Aim 3, we will test how metabolic pathways linked to dementia differ by race and sex and how these metabolite signatures are related to diet, fitness, activity, and adiposity, key modifiable lifestyle features linked to improved neurocognitive func- tion. This supplement is unique in that it has been conceived and constructed in full collaboration with the Na- tional Institutes of Aging (Dr. Luigi Ferrucci and Qu Tian), experts in aging and AD and substantially augments the sample size for metabolite profiling covered by the parent R01 grant, while leveraging its substantial re- sources. Completion would afford the scientific community a wider array of quantitative metabolic phenotyping to address AD and AD-related phenotypes, directly addressing NOT-AG-20-008 by integrating efforts in ongo- ing studies of aging to address neurocognitive endpoints relevant to AD.

阿尔茨海默型（AD）和非AD痴呆和神经认知功能障碍起源于调节失调的代谢， 禁忌症，导致将痴呆症视为“3型糖尿病”表型。一系列的基础实验- 以识别精确的代谢缺陷为核心， AD/非AD痴呆的发病率。试图确定代谢基础的研究的一个关键特征是， 神经认知功能障碍是广泛评估代谢对良好表型的人的应用， 老年痴呆症男性队列及相关结果。作为R 01 AG 059729的一部分，Shah、纽曼、Murthy和 克利什一直在健康老龄化和身体委员会的一个双胞胎子样本中进行代谢物分析， 定位研究（健康ABC），以确定与健康老龄化相关的代谢途径。当父母学习 包括一些神经认知的措施，它只分析了健康ABC中的一个子样本的脂质和脂质代谢， 扩张剂，被认为与AD和相关痴呆相关的关键代谢物。根据数据显示， 由于炎症和脂质异常在AD中的重要性日益显现，研究小组要求补充 基金作为此应用程序的一部分，以完成脂质和脂质中间代谢物分析，以促进（1）更广泛的 AD和AD相关表型的科学发现和（2）与其他代谢模式的整合已经 在健康ABC中完成，以提供对生活中重要的代谢异常的更广泛描述- 神经认知功能障碍和AD的过程。我们假设脂质和脂质介质将与 表型和表型组是AD的核心，可能有助于发现潜在的可干预的 AD和AD相关的神经认知功能障碍的核心途径。为了解决这个问题，我们将 在Health ABC中对脂质（C8阳性）和脂质介质进行更大样本量的代谢物分析 (C18阴性），以鉴定与临床和基于成像的去甲肾上腺素相关的代谢物和编码途径， 精神终点。在目标1中，我们将鉴定与亚- 认知能力下降、临床前AD表型和痴呆。在目标2中，我们将确定 脂质和脂质介质与先前报道的痴呆的选定MRI标记物。在目标3中，我们将测试如何 与痴呆症相关的代谢途径因种族和性别而异，以及这些代谢物特征如何相关 饮食，健身，活动和肥胖，与改善神经认知功能相关的关键可改变的生活方式特征， 是的。这个补充是独一无二的，因为它已经构思和建设与纳充分合作， 国家老龄化研究所（Luigi Ferrucci博士和Qu Tian），衰老和AD专家， 父R 01资助涵盖的代谢物分析样本量，同时利用其实质性的重新评估， 源完成后将为科学界提供更广泛的定量代谢表型 解决AD和AD相关表型，通过整合ongo- 研究衰老，以解决与AD相关的神经认知终点。