Brain Effects of Lifetime Racial/Ethnic Discrimination on the LC-NE Function and the Risk for Alzheimer's Disease

终生种族/民族歧视对 LC-NE 功能和阿尔茨海默病风险的大脑影响

• 批准号: 10214313
• 负责人: YU-SHIN DING
• 金额: $ 84.71万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-05 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10214313
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Arousal; Autopsy; Behavioral Research; Biological; Biological Markers; Black race; Blood Vessels; Body mass index; Brain; Brain Stem; Brain region; Cell Death; Cell Density; Cell Nucleus; Cells; Cerebrospinal Fluid; Chronic; Chronic stress; Classification; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive aging; Communities; Data; Dementia; Deposition; Development; Diabetes Mellitus; Diagnosis; Disadvantaged; Discrimination; Disease; Education; Elderly; Exposure to; Fright; Functional disorder; High Prevalence; Hippocampus (Brain); Human; Hypertension; Image; Impaired cognition; Income; Lead; Measures; Metabolic syndrome; Modeling; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Norepinephrine; Participant; Pathology; Play; Positron-Emission Tomography; Predictive Value; Predictive Value of Tests; Prevalence; Publishing; Race; Regulation; Reporting; Research; Risk; Risk Marker; Role; Scanning; Severities; Site; Social Environment; Societies; Source; Stress; Substance abuse problem; Symptoms; System; Testing; Thalamic structure; Therapeutic Intervention; Time; United States National Institutes of Health; Universities; Vascular Diseases; Washington; age difference; age related; aging population; allostatic load; amyloid pathology; base; black men; cerebrovascular; clinical phenotype; cohort; ethnic difference; ethnic discrimination; experience; functional decline; health disparity; hippocampal atrophy; innovation; locus ceruleus structure; male; middle age; neuron loss; noradrenaline transporter; norepinephrine system; normal aging; novel strategies; pre-clinical; predictive marker; racial and ethnic; racial difference; racial discrimination; racial disparity; radiotracer; response; reuptake; sex; social; socioeconomic disadvantage; stressor; tau Proteins; vascular risk factor; β-amyloid burden

PROJECT SUMMARY Alzheimer’s disease (AD) is a global crisis facing the aging population and society as a whole. Despite studies suggesting that blacks may be at greater risk of developing AD, with 2-3 times higher prevalence rate of cognitive impairment than whites, there have been few studies investigating health disparities, and blacks have been underrepresented in many prominent U.S. AD biomarker studies and clinical trials. The current biomarker classification system (i.e., the ATN model) does not fully account for health disparities and can’t explain the increased prevalence among blacks of both AD and vascular risk factors for AD such as diabetes and hypertension when compared to whites. Research on cognitive aging has traditionally focused on how decline in various cortical and hippocampal regions influences cognition. However, tau pathology emerges decades before amyloid pathology, appearing first in the brainstem; particularly in the locus coeruleus (LC), the source of brain’s norepinephrine (NE). Our decade-long studies in humans using a norepinephrine transporter (NET)- selective radiotracer ([11C]MRB) have demonstrated a special vulnerability of LC to aging and stress. Our preliminary data reveals that the decline rate of NET, normally associated with aging due to loss in NET availability and cell death, is much faster among blacks starting in the mid-30s, particularly in black males (e.g., 2-3%/yr vs. 0.14-0.23%/yr in thalamus and brainstem for black males vs. white males (p<0.00001)). As the LC plays a central role in the integration and orchestration of the adaptive CNS response to various stressors or challenges, we hypothesize that cumulative exposure to socioeconomic disadvantage and racial discrimination may cause long-lasting changes in LC function followed by LC neuronal loss, which would explain the different AD phenotypical clinical presentation among blacks (i.e., less tau burden but more LC loss and vascular damage). Our hypothesis is also supported by the broad evidence that the LC is an early site of AD neurodegeneration and LC cell density is more strongly associated with cognitive decline than other nuclei. We propose to test this hypothesis by demonstrating that there will be age and race/ethnic differences on NET availability (measured with [11C]MRB) across midlife and late-life in the LC and its target brain regions (Aim 1), and that decreased NET availability is associated with stress levels and impaired cognition (Aim 2), as well as the predictive value of NET availability on longitudinal change in cognition (Aim 3). There is the potential to determine if dysfunction of the LC is: i) a potential marker for the increased AD pathology that is observed in normal aging; ii) a key contributor to the development of metabolic syndrome, vascular dysfunction, and cognitive decline, as result of chronic stress; iii) associated with increased prevalence of both AD and vascular risk factors for AD in blacks when compared to whites; iv) associated with everyday stress levels and cumulative stress burden; v) a key mechanism that contributes to the health disparities in AD expression.

项目概要 阿尔茨海默病（AD）是人口老龄化和整个社会面临的全球性危机。尽管研究 表明黑人患 AD 的风险可能更高，认知障碍患病率高出 2-3 倍 健康差异比白人差，很少有研究调查健康差异，而且黑人一直在 在许多著名的美国 AD 生物标志物研究和临床试验中代表性不足。目前的生物标志物 分类系统（即 ATN 模型）没有充分考虑健康差异，也无法解释 黑人中 AD 和 AD 血管危险因素（如糖尿病和糖尿病）的患病率增加 与白人相比，高血压。认知衰老的研究传统上集中于认知衰退是如何发生的 各个皮质和海马区域的神经元会影响认知。然而，tau蛋白病理学几十年来才出现 在淀粉样蛋白病理发生之前，首先出现在脑干；特别是在蓝斑 (LC) 中，它是 大脑的去甲肾上腺素（NE）。我们使用去甲肾上腺素转运蛋白 (NET) 对人类进行了长达十年的研究 - 选择性放射性示踪剂（[11C]MRB）已证明 LC 对老化和压力特别脆弱。我们的 初步数据显示，NET 的下降率通常与由于 NET 损失而导致的衰老有关 从 30 多岁开始的黑人，尤其是黑人男性（例如， 黑人男性与白人男性的丘脑和脑干分别为 2-3%/年和 0.14-0.23%/年 (p<0.00001))。作为LC 在整合和协调中枢神经系统对各种压力源的适应性反应中发挥着核心作用 挑战，我们假设 社会经济劣势和种族歧视的累积暴露 可能会导致 LC 功能的长期变化，然后导致 LC 神经元损失，这可以解释不同的情况 黑人中的 AD 表型临床表现（即 tau 负载较少，但 LC 丢失和血管性 损害）。我们的假设也得到了广泛证据的支持，表明 LC 是 AD 的早期部位 与其他细胞核相比，神经退行性变和 LC 细胞密度与认知能力下降的相关性更强。我们 建议通过证明 NET 上存在年龄和种族/民族差异来检验这一假设 LC及其目标大脑区域在中年和晚年的可用性（用[11C]MRB测量）（目标1）， 网络可用性下降与压力水平和认知受损有关（目标 2），以及 NET 可用性对认知纵向变化的预测价值（目标 3）。有潜力 确定 LC 功能障碍是否是： i) 中观察到的 AD 病理增加的潜在标志 正常老化； ii) 代谢综合征、血管功能障碍和认知障碍发生的关键因素 由于长期压力而衰退； iii) 与 AD 和血管危险因素患病率增加相关 与白人相比，黑人的AD； iv) 与日常压力水平和累积压力相关 负担; v) 导致 AD 表达健康差异的关键机制。