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

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是人口老龄化和整个社会面临的全球性危机。尽管研究 这表明黑人可能处于更大的发展AD的风险中，认知障碍的患病率高2-3倍， 虽然黑人的健康状况比白人差，但很少有研究调查健康差异，黑人一直受到歧视。 在许多著名的美国AD生物标志物研究和临床试验中，目前的生物标志物 分类系统（即，ATN模型）不能完全解释健康差异，也不能解释 在黑人中AD和AD的血管危险因素（如糖尿病）的患病率增加， 与白人相比，认知老化的研究传统上集中在如何衰退 影响认知能力。然而，几十年来， 在淀粉样蛋白病理学之前，首先出现在脑干中;特别是在蓝斑（LC）中， 脑去甲肾上腺素（NE）。我们在人体中进行了长达十年的研究，使用去甲肾上腺素转运蛋白（NET）- 选择性放射性示踪剂（[11 C]MRB）已证明LC对衰老和应激的特殊脆弱性。我们 初步数据显示，净收入的下降率，通常与净收入损失造成的老龄化有关， 可用性和细胞死亡，在30多岁中期开始的黑人中快得多，特别是在黑人男性中（例如， 黑人男性与白色男性的丘脑和脑干中分别为2-3%/年与0.14-0.23%/年（p<0.00001））。作为LC 在对各种应激源的适应性CNS反应的整合和协调中起核心作用，或 挑战，我们假设， 社会经济不利地位和种族歧视的累积风险 可能导致LC功能的长期变化，随后是LC神经元的丢失，这可以解释不同的 黑人中的AD表型临床表现（即，tau负担较少，但LC损失和血管损失较多 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 神经变性和LC细胞密度与认知下降的相关性比其他核更强。我们 我建议通过证明NET存在年龄和种族/民族差异来验证这一假设 LC及其靶脑区域在中年和晚年的可用性（用[11 C]MRB测量）（目标1）， NET可用性降低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（目的3）。有可能 确定LC的功能障碍是否是：i）在LC中观察到的AD病理学增加的潜在标志物， 正常衰老; ii）代谢综合征、血管功能障碍和认知功能障碍的发展的关键因素 下降，由于慢性压力; iii）与AD和血管危险因素的患病率增加相关 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表达中的健康差异的关键机制。

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.