Myosteatosis, Cognition and Blood Biomarkers of Alzheimer's Disease in Persons of African Ancestry

非洲血统人群阿尔茨海默病的肌肉脂肪变性、认知和血液生物标志物

• 批准号: 10447294
• 负责人: IVA MILJKOVIC
• 金额: $ 321.2万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447294
• 关键词: Address; Adipose tissue; Adult; Affect; African ancestry; Age; Aging; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Animals; Biochemical; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; CCL2 gene; Caribbean region; Clinical; Clinical Markers; Cognition; Development; Diabetes Mellitus; Elderly; Epidemic; Fatty acid glycerol esters; Foundations; Funding; GDF8 gene; Genetic; Health; Homeostasis; Human; Hypertension; Impaired cognition; Impairment; Individual; Inflammatory; Interleukin-6; Intervention; Investments; Knowledge; Lead; Leptin; Life; Lipids; Longitudinal Studies; Measures; Mediating; Mediator of activation protein; Medical History; Metabolic Pathway; Metabolism; Minority Groups; Muscle; Neuropsychological Tests; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Obesity; Organ; Outcome; Participant; Pattern; Persons; Pharmacology; Plasma; Prevalence; Public Health; Race; Regimen; Reproductive History; Research Design; Risk; Risk Factors; Role; Severities; Source; Structure; Subgroup; Testing; Time; Tobago; United States National Institutes of Health; Visceral; Visceral fat; Vulnerable Populations; Woman; adipokines; adiponectin; aged; apolipoprotein E-4; biobank; brain health; brain parenchyma; circulating biomarkers; clinical care; cognitive function; cohort; cost effective; cytokine; dementia risk; demographics; endothelial dysfunction; follow-up; high risk; human old age (65+); inhibitor; men; middle age; neurotransmission; novel; poor sleep; recruit; relating to nervous system; sedentary lifestyle; sex; strength training; tau Proteins

ABSTRACT Persons of African Ancestry (PAA) have higher rates of Alzheimer's Disease and Related Dementias (ADRD) and higher rates of adiposity, compared to other races. While overall adiposity and visceral fat are known risk factors for cognitive impairment and ADRD, emerging evidence by us and others suggests that fat in muscle (myosteatosis) has independent negative effects on cognition and brain health among PAA. Since myosteatosis is greater in PAA compared to others, we propose that myosteatosis may be a novel risk factor with special relevance for ADRD in PAA. Compared to overall or visceral adiposity, myosteatosis could be more harmful to the brain; while adipose tissue in muscle and elsewhere releases adipokines with pro-inflammatory effects, myosteatosis also damages muscle and impairs release of myokines, which are largely beneficial to metabolism and neural health. Since ADRD develops slowly, midlife and subsequent increase in myosteatosis over time may influence later brain health. Our overarching hypothesis is that myosteatosis in PAA harms brain health in older age, in part, by compromising myokine homeostasis. Unknown, but key to establishing the foundation for this novel source of risk, is whether myosteatosis (Aim 1) and myokines (Aim 2) influence clinical and biological markers of ADRD late in life, and whether these effects are stronger and independent of adipokines, other adiposity (e.g. total, regional). All hypotheses account for risk factors for poor cognition; especially, but not only, genetic factors (APOe4), and adiposity-related conditions (diabetes, hypertension, sedentary behavior, poor sleep). Since sex affects the prevalence of ADRD and myosteatosis, we test whether associations vary by sex. We build on our ongoing NIH-funded 20+year longitudinal studies of PAA in the Tobago Caribbean region (N~4,000). For this Tobago Brain Study, we will recruit 1000 of them who are aged 65+, with existing midlife measures of: myosteatosis, other adiposity, demographics, medical and reproductive history, circulating biomarkers of metabolism (HOMA-IR, lipids, etc), subclinical vascular measures, and blood biorepository. We will repeat these measures, and newly add detailed neuropsychological tests, plasma levels of ADRD biomarkers, and adipokines. We measure myokines both at mid-life (using our existing biorepository) and at the proposed new exam. This study provides an unprecedented opportunity to examine the influence of midlife myosteatosis and related myokines on brain health in a minority population using a cost-effective study design and existing NIH investments. We expect to determine the extent to which myosteatosis and specific myosteatosis-related myokine patterns contribute independently to cognitive function and biomarkers of ADRD in PAA. Our findings could lead to novel subgroup-targeted, muscle fat-specific interventions to reduce ADRD risk in PAA.

抽象的 非洲血统 (PAA) 的人患阿尔茨海默病和相关痴呆症 (ADRD) 的比例较高 与其他种族相比，肥胖率更高。虽然整体肥胖和内脏脂肪是已知的风险 我们和其他人的新证据表明，肌肉中的脂肪 （肌肉脂肪变性）对 PAA 的认知和大脑健康有独立的负面影响。由于肌脂肪变性 与其他因素相比，PAA 更大，我们认为肌脂肪变性可能是一种具有特殊特征的新危险因素。 PAA 中 ADRD 的相关性。 与整体或内脏肥胖相比，肌脂肪变性对大脑的危害更大。而脂肪组织 在肌肉和其他地方释放具有促炎作用的脂肪因子，肌脂肪变性也会损害肌肉 并损害肌因子的释放，而肌因子在很大程度上有益于新陈代谢和神经健康。自从 ADRD 中年时期发展缓慢，随着时间的推移，肌脂肪变性的增加可能会影响以后的大脑健康。 我们的首要假设是，PAA 中的肌脂肪变性会损害老年人的大脑健康，部分原因是损害 肌因子稳态。未知，但为这种新的风险来源奠定基础的关键是： 肌脂肪变性（目标 1）和肌因子（目标 2）影响晚年 ADRD 的临床和生物学标志物，并且 这些影响是否更强并且独立于脂肪因子、其他肥胖（例如总体肥胖、局部肥胖）。全部 假设解释了认知不良的风险因素；尤其是但不仅限于遗传因素 (APOe4)，以及 肥胖相关疾病（糖尿病、高血压、久坐行为、睡眠不佳）。由于性别会影响 为了了解 ADRD 和肌脂肪变性的患病率，我们测试了相关性是否因性别而异。 我们以 NIH 资助的多巴哥加勒比地区 PAA 20 多年纵向研究为基础 （N~4,000）。对于这项多巴哥大脑研究，我们将招募 1000 名 65 岁以上、已步入中年的人 衡量指标：肌脂肪变性、其他肥胖、人口统计、医疗和生殖史、循环 代谢生物标志物（HOMA-IR、脂质等）、亚临床血管测量和血液生物样本库。我们 将重复这些措施，并新添加详细的神经心理学测试、ADRD 血浆水平 生物标志物和脂肪因子。我们在中年（使用我们现有的生物样本库）和成年时测量肌动蛋白 提议的新考试。 这项研究提供了一个前所未有的机会来检查中年肌脂肪变性和相关的影响 使用具有成本效益的研究设计和现有的 NIH 来研究肌动蛋白对少数群体大脑健康的影响 投资。我们期望确定肌脂肪变性和特定肌脂肪变性相关的程度 肌因子模式独立地影响 PAA 中的认知功能和 ADRD 生物标志物。我们的发现 可能会导致新的针对亚组、针对肌肉脂肪的干预措施，以降低 PAA 的 ADRD 风险。