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.

摘要 非洲裔美国人（PAA）患阿尔茨海默病和相关痴呆症（ADRD）的比例较高 肥胖率也更高。虽然整体肥胖和内脏脂肪是已知的风险， 认知障碍和ADRD的因素，我们和其他人的新证据表明，肌肉中的脂肪 在PAA患者中，肌脂肪变性对认知和脑健康具有独立的负面影响。由于肌肉脂肪变性 与其他人相比，PAA的发病率更高，我们认为， 与PAA中ADRD的相关性。 与整体或内脏肥胖相比，肌肉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， 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ADRD以来 发展缓慢，中年和随后的增加，随着时间的推移，肌肉脂肪变性可能会影响以后的大脑健康。 我们的总体假设是，PAA中的肌肉脂肪变性损害老年人的大脑健康，部分原因是由于 肌因子稳态未知，但关键是建立这种新的风险来源的基础，是是否 脂肪肌变性（目的1）和肌因子（目的2）影响晚期ADRD的临床和生物学标志物， 这些效应是否更强，是否独立于脂肪因子、其他肥胖（例如，总体、局部）。所有 假设解释了认知能力差的风险因素;特别是，但不仅仅是遗传因素（APOE 4）， 肥胖相关疾病（糖尿病、高血压、久坐行为、睡眠不良）。因为性会影响 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。 我们在托巴哥加勒比地区持续20多年的PAA纵向研究的基础上， （N~ 4 000）。在这项托巴哥大脑研究中，我们将招募1000名年龄在65岁以上的中年人， 测量：脂肪肌变性、其他肥胖、人口统计学、病史和生殖史、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储存。我们 我将重复这些措施，并新增加详细的神经心理学测试，ADRD的血浆水平 生物标志物和脂肪因子。我们在中年（使用我们现有的生物储存库）和中年（使用我们现有的生物储存库）测量肌因子。 提出新的考试。 这项研究提供了一个前所未有的机会，检查中年脂肪肌变性和相关的影响， 使用成本效益研究设计和现有NIH， 投资.我们希望确定在多大程度上， 肌因子模式独立地影响PAA患者的认知功能和ADRD生物标志物。我们的研究结果 可能导致新的亚组靶向，肌肉脂肪特异性干预措施，以降低PAA的ADRD风险。