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 非洲血统的人(PAA)阿尔茨海默病和相关痴呆症(ADRD)的发病率较高 与其他种族相比，肥胖率更高。虽然总体肥胖和内脏脂肪是已知的风险 认知障碍的因素和ADRD，我们和其他人的新证据表明，肌肉中的脂肪 (肌骨病)在PAA中对认知和脑健康有独立的负面影响。自肌骨瘤病以来 我们认为，肌瘤病可能是一种新的具有特殊意义的危险因素。 在PAA中与ADRD的相关性。 与全身或内脏肥胖相比，骨质疏松症对大脑的危害更大；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，肌肉骨瘤病也会损害肌肉 并损害肌动蛋白的释放，这在很大程度上有利于新陈代谢和神经健康。自ADRD以来 发展缓慢，随着时间的推移，中年和随之而来的肌肉瘤病的增加可能会影响后来的大脑健康。 我们的主要假设是，PAA中的肌瘤病损害了老年人的大脑健康，部分原因是 肌动因子动态平衡。未知，但为这种新的风险来源奠定基础的关键是 肌骨病(Aim 1)和肌肉激动素(Aim 2)影响ADRD晚年的临床和生物标志，以及 这些影响是否更强，是否独立于脂肪因子、其他肥胖症(例如，完全、区域性)。全 假说解释了认知不良的风险因素；特别是但不仅是遗传因素(ApoE4)，以及 肥胖相关疾病(糖尿病、高血压、久坐不动、睡眠不佳)。由于性会影响 ADRD和肌瘤病的患病率，我们测试相关性是否因性别而异。 我们以美国国立卫生研究院资助的多巴哥加勒比地区持续20多年的PAA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名年龄在65岁以上、已有中年的人 测量范围：骨质疏松症、其他肥胖症、人口统计学、病史和生育史、循环 代谢的生物标记物(HOMA-IR、血脂等)、亚临床血管测量和血液生物库。我们 将重复这些措施，并新增加详细的神经心理测试，血浆ADRD水平 生物标记物和脂肪因子。我们在中年(使用我们现有的生物库)和在 建议进行新的考试。 这项研究提供了一个前所未有的机会来研究中年骨质疏松症和相关疾病的影响。 使用成本效益研究设计和现有的美国国立卫生研究院研究肌动蛋白对少数民族人群脑健康的影响 投资。我们期望确定肌瘤病与特定肌瘤病相关的程度。 肌细胞因子模式对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 可能导致针对亚组的新的针对肌肉脂肪的干预措施，以降低PAA的ADRD风险。