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.

项目摘要 阿尔茨海默氏病（AD）是整个人口和社会面临的全球危机。尽管有研究 表明黑人可能面临发展AD的风险更大，认知患病率提高了2-3倍 损害比白人的损害，很少有研究调查健康差异，黑人已经存在 在许多著名的美国AD生物标志物研究和临床试验中的代表性不足。当前的生物标志物 分类系统（即ATN模型）并未充分说明健康分布，也无法解释 AD和血管危险因素的黑人患病率增加了糖尿病和AD的血管风险因素 与白人相比，高血压。关于认知衰老的研究传统上关注的是如何下降 在各种皮质和海马地区，都会影响认知。但是，tau病理学数十年 在淀粉样病理学之前，首先出现在脑干中；特别是在基因座（LC）中， 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）的人类研究长达十年的研究 - 选择性放射性激素（[11C] MRB）表现出LC与衰老和压力的特殊脆弱性。我们的 初步数据表明，净的下降率，通常与净损失有关 从30年代中期开始的黑人，尤其是黑人男性的可用性和细胞死亡速度要快得多（例如 2-3％/年与黑人男性与白人男性的丘脑和脑干中的0.14-0.23％/年（p <0.00001））。作为LC 在对各种压力源的自适应中枢神经系统响应的整合和编排中起着核心作用 挑战，我们假设 累积暴露于社会经济障碍和种族歧视 可能会导致LC功能的长期变化，然后引起LC神经元丧失，这将解释不同的 黑人之间的AD表型临床表现（即，较少的tau burnen，但更多的LC损失和血管 损害）。我们的假设也得到了广泛证据，表明LC是AD的早期地点 与其他核相比，神经变性和LC细胞密度与认知下降更密切相关。我们 提议通过证明网络上会有年龄和种族/种族差异来检验这一假设 LC及其目标大脑区域的中年和后期的可用性（用[11C] MRB测量）（AIM 1）， 而且，改善的净可用性与压力水平和认知受损有关（AIM 2）以及 净可用性对认知纵向变化的预测价值（AIM 3）。有潜力 确定LC的功能障碍是否是：i）在 正常衰老； ii）代谢综合征，血管功能障碍和认知的关键因素 由于慢性压力而下降； iii）与AD和血管风险因素的患病率增加有关 与白人相比，黑人的广告； iv）与每天的压力水平和累积压力相关 伯恩v）有助于AD表达的健康差异的关键机制。