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.

阿尔茨海默氏症型（AD）和非AD痴呆症和神经认知障碍起源于失调 Tabolism，导致将痴呆视为“ 3型糖尿病”表型。各种各样的基本实验 保守党，基于模型的系统和人类投资围绕确定精确的代谢缺陷为核心 出现了广告/非AD痴呆症。试图确定代谢基础的研究的关键特征 神经认知功能障碍是对新陈代谢的广泛评估的应用 与痴呆症和相关结果的人队列。作为R01AG059729的一部分，Drs。 Shah，Newman，Murthy和 克里什（Clish 位置研究（Health ABC）确定与健康衰老有关的代谢途径。父母学习 包括一些神经认知措施，它仅测定健康ABC中的子样本的脂质和脂质me- 养子，关键的代谢产物认为与AD和相关痴呆症有关。根据暗示的数据 研究小组的新兴感染和脂质异常的重要性是要求补充 资金作为本申请的一部分，以完成脂质和脂质中间代谢物分析以促进（1）Wilder AD和AD相关表型中的科学发现以及（2）与其他代谢物模式的整合 在卫生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 具有AD中心的表型和表型组，并可能有助于发现潜在的可干预 AD核心和与AD相关的神经认知功能障碍的途径。为了解决这一假设，我们将 在健康ABC中，对脂质（C8阳性）和脂质介质进行代谢物分析，以更广泛的样本量进行 （C18负）确定与临床和基于成像的DE-相关的代谢物和编码途径 精神病终点。在AIM 1中，我们将确定与子 - 依次的认知下降，临床前AD表型和痴呆症。在AIM 2中，我们将确定 先前报道的具有痴呆症的精选MRI标记的脂质和脂质介质。在AIM 3中，我们将测试如何 与种族和性别不同的痴呆症与痴呆症相关的代谢途径以及这些代谢物特征如何相关 为了饮食，健身，活动和肥胖，关键的可修改生活方式特征与改善神经认知功能有关 tion。这种补充是独一无二的 衰老学院（Luigi Ferrucci博士和Qu Tian博士），衰老和广告专家 代谢物分析的样本量由父级R01赠款涵盖，同时利用其大量重新 来源。完成将为科学界提供更广泛的定量代谢表型 为了解决AD和与广告相关的表型，通过将努力整合到Ongo中直接解决非AG-20-008 衰老研究以解决与AD相关的神经认知终点。