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 非洲血统的人（PAA）的阿尔茨海默氏病和相关痴呆症的率较高（ADRD） 与其他种族相比，肥胖率更高。总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 （Myosteatosis）对PAA的认知和大脑健康具有独立的负面影响。自肌生肌病变以来 与其他人相比，PAA的PAA更大，我们建议肌toposisosis可能是特殊的新风险因素 与PAA中的ADRD相关性。 与整体或内脏肥胖相比，肌萎缩症可能对大脑有害。而脂肪组织 在肌肉和其他地方释放脂肪因子具有促炎作用的脂肪因子，肌动症也会损害肌肉 并损害肌动物的释放，这在很大程度上对代谢和神经健康有益。自adrd 随着时间的流逝，肌达丝病随后慢慢发展可能会影响以后的大脑健康。 我们的总体假设是，PAA中的肌topososisosis在某种程度上损害了大脑健康，部分原因是 肌动稳定率。未知，但要建立这种新颖风险来源的基础的关键是，是否是 Myosteatosis（AIM 1）和肌动物（AIM 2）影响生命后期Adrd的临床和生物学标志物，以及 这些作用是否更强，独立于脂肪因子，其他肥胖（例如总区域）。全部 假设是认知不良的危险因素；特别是，但不仅是遗传因素（APOE4）和 与肥胖相关的疾病（糖尿病，高血压，久坐行为，睡眠不佳）。由于性影响 ADRD和Myosteatosis的患病率，我们测试关联是否因性别而异。 我们以NIH资助的20+20年纵向研究为基础 （n〜4,000）。对于Tobago Brago的研究，我们将招募其中1000名65岁以上的人，现有中年 措施：Myosteatosis，其他肥胖，人口统计学，医学和生殖历史，循环 代谢（HOMA-IR，脂质等），亚临床血管测量和血液生物座的生物标志物。我们 将重复这些措施，并新添加详细的神经心理学测试，血浆ADRD水平 生物标志物和脂肪因子。我们在中年（使用现有的生物库）和 拟议的新考试。 这项研究提供了一个前所未有的机会，可以检查中年肌toposisosis及相关的影响 使用经济有效的研究设计和现有NIH 投资。我们期望确定肌toposisosis和特定的肌toposisosis的程度 肌动物模式对PAA中ADRD的认知功能和生物标志物有独立的贡献。我们的发现 可能导致新颖的亚组靶向肌肉脂肪特异性干预措施，以降低PAA的ADRD风险。