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 痴呆以及神经认知障碍起源于代谢失调。 代谢，导致将痴呆视为“3 型糖尿病”表型。广泛的基础实验 以识别精确代谢缺陷为核心的理论、基于模型系统和人体研究 的 AD/非 AD 痴呆症已经出现。试图确定代谢基础的研究的一个关键特征 神经认知功能障碍是对表型良好的代谢进行广泛评估的应用 患有痴呆症的男性队列和相关结果。作为 R01AG059729 的一部分，博士。沙阿、纽曼、穆尔蒂和 Clish 一直在健康老龄化和身体健康的混血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。家长学习的同时 包括一些神经认知测量，它仅分析 Health ABC 中的子样本的脂质和脂质代谢- diators 中，关键代谢物被认为与 AD 和相关痴呆症相关。根据数据表明 由于炎症和脂质异常在 AD 中的重要性日益凸显，研究小组正在要求补充 作为本申请的一部分，资金用于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以及 (2) 与其他代谢模式的整合 在 Health ABC 中完成，以更广泛地描述生命中重要的代谢异常- 神经认知功能障碍和 AD 的病程。我们假设脂质和脂质介质相关 具有 AD 核心的表型和表型组，可能有助于发现潜在的干预措施 AD 和 AD 相关神经认知功能障碍的核心途径。为了解决这个假设，我们将 在 Health ABC 中以更广泛的样本量对脂质（C8 阳性）和脂质介质进行代谢物分析 （C18 阴性）识别与临床和基于成像的去相关的代谢物和编码途径 心理终点。在目标 1 中，我们将识别与亚组相关的脂质和脂质介质代谢特征。 随后的认知能力下降、临床前 AD 表型和痴呆。在目标 2 中，我们将确定关联 脂质和脂质介质与先前报道的痴呆症的选定 MRI 标记。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，以及这些代谢特征如何相关 饮食、健身、活动和肥胖等关键可改变的生活方式特征与改善神经认知功能有关 。该补充品的独特之处在于它是与 Na- 充分合作构思和构建的。 国家老龄化研究所（Luigi Ferrucci 博士和 Qu Tian），老龄化和 AD 方面的专家，并大幅增强 母公司 R01 资助涵盖的代谢物分析的样本量，同时利用其大量的重新 来源。完成将为科学界提供更广泛的定量代谢表型分析 解决 AD 和 AD 相关表型，通过整合持续的努力来直接解决 NOT-AG-20-008 正在进行衰老研究，以解决与 AD 相关的神经认知终点问题。