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: 10667585
• 负责人: YU-SHIN DING
• 金额: $ 82.48万
• 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/10667585
• 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; Attention; Autopsy; Behavioral Research; Biological; Biological Markers; Black Populations; 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; Human; Hypertension; Image; Impaired cognition; Income; 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; United States National Institutes of Health; Universities; Vascular Diseases; Washington; age difference; age related; aging population; allostatic load; amyloid pathology; black men; cerebrovascular; cohort; ethnic difference; ethnic discrimination; functional decline; health disparity; hippocampal atrophy; innovation; locus ceruleus structure; male; middle age; neuron loss; noradrenaline transporter; norepinephrine system; normal aging; novel strategies; perceived discrimination; perceived stress; pre-clinical; predictive marker; 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.

项目总结 阿尔茨海默病(AD)是老龄化人口和整个社会面临的全球性危机。尽管有研究 这表明黑人患AD的风险可能更大，认知障碍的患病率是黑人的2-3倍 与白人相比，很少有调查健康差异的研究，而黑人一直 在许多著名的美国AD生物标记物研究和临床试验中代表性不足。当前的生物标志物 分类系统(即ATN模型)不能完全解释健康差异，也不能解释 阿尔茨海默病和血管危险因素在黑人中的患病率增加，如糖尿病和 与白人相比，患高血压的人更多。对认知老化的研究传统上集中在如何衰退 在不同的皮质和海马区影响认知。然而，tau病理出现了几十年。 在淀粉样变之前，最先出现在脑干；特别是在蓝斑(LC)，这是 脑部去甲肾上腺素(NE)。我们在人体上使用去甲肾上腺素转运体(NET)进行了长达十年的研究- 选择性放射性示踪剂([11C]MRB)显示了LC对衰老和应激的特殊易感性。我们的 初步数据显示，净值的下降率通常与由于净值损失而导致的老化有关 可获得性和细胞死亡在35岁左右开始的黑人中要快得多，特别是在黑人男性中(例如， 黑人男性与白人男性相比，丘脑和脑干中的2-3%/年比0.14-0.23%/年(p&lt；0.00001)。作为LC 在整合和协调中枢神经系统对不同应激源的适应性反应中发挥核心作用 挑战，我们假设 社会经济劣势和种族歧视的累积风险 可能会导致LC功能的长期变化，继而导致LC神经元丢失，这可以解释不同的 黑人的AD表型临床表现(即较少的tau负担，但较多的LC丢失和血管 损坏)。我们的假设也得到了广泛证据的支持，即LC是AD的早期部位 与其他核团相比，神经退行性变和LC细胞密度与认知功能下降的相关性更强。我们 建议通过证明网络上会有年龄和种族/民族差异来检验这一假设 (用[11C]MRB测量)LC及其目标脑区的中年和晚年的可用性(目标1)， 而净可获得性的下降与压力水平和认知障碍(目标2)以及 净可获得性对认知纵向变化的预测价值(目标3)。有可能会 确定LC功能障碍是否为：i)AD病理增加的潜在标记物 正常衰老；ii)代谢综合征、血管功能障碍和认知发展的关键因素 由于慢性压力而下降；三)与AD和血管危险因素的患病率增加有关 与白人相比，黑人的AD；iv)与日常压力水平和累积压力有关 负担；v)造成AD表达健康差异的关键机制。