Impact of brain estrogens on cognition and brain aging in a non-human primate

脑雌激素对非人类灵长类动物认知和大脑衰老的影响

• 批准号: 10079902
• 负责人: Agnes Lacreuse
• 金额: $ 56.34万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10079902
• 关键词: Accelerometer; Adjuvant Therapy; Adverse effects; Affect; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid deposition; Animal Model; Architecture; Area; Aromatase; Aromatase Inhibition; Aromatase Inhibitors; Behavior; Behavior assessment; Behavioral; Brain; Brain region; Breast Cancer Patient; Breast Cancer Prevention; Callithrix; Callithrix jacchus jacchus; Chronic; Cognition; Cognitive deficits; Development; Electrophysiology (science); Emotional; Estradiol; Estrogens; Female; Gene Expression; Gene Expression Profiling; Genes; Goals; Heart Rate; Hippocampus (Brain); Hormonal; Hot flushes; Human; Hydrocortisone; Hypothalamic structure; Image; Impaired cognition; Impairment; Individual Differences; Knowledge; Letrozole; Long-Term Effects; Longitudinal Studies; Measures; Modeling; Monkeys; Moods; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiologic Thermoregulation; Physiological; Placebos; Polysomnography; Prefrontal Cortex; Primates; Prodrugs; Quality of life; Recording of previous events; Recurrence; Reporting; Severity of illness; Skin Temperature; Sleep; Sleeplessness; Source; Stress; Symptoms; Tauopathies; Testing; Testosterone; abeta deposition; aging brain; behavioral outcome; brain behavior; brain tissue; cancer recurrence; cognitive ability; cognitive function; cognitive performance; computerized; depressive symptoms; design; emotion regulation; enzyme activity; experience; face skin; frontal lobe; genome-wide analysis; heart rate variability; improved; in vivo; interest; locus ceruleus structure; male; malignant breast neoplasm; middle age; neuronal excitability; neuropathology; nonhuman primate; novel; novel therapeutics; prevent; relating to nervous system; response; side effect; sleep pattern; treatment group

SUMMARY Aromatase inhibitors (AIs) are drugs that inhibit estrogen synthesis and that are prescribed to prevent the recurrence of estrogen responsive breast cancers. However, AIs, such as the commonly prescribed Letrozole (LET), are associated with severe side-effects that further burden the quality of life, including insomnia, hot flashes, depressive symptoms and cognitive deficits. The precise mechanisms by which AIs may give rise to these CNS symptoms remain unclear and difficult to study in humans, as control for individual differences in disease severity, treatment history and experienced stress is lacking. Furthermore, AI treatment is recommended for 3 to 5 years, yet little is known about the effects of long-term AI use on the brain and behavior, especially with regards to age-related cognitive decline and Alzheimer's disease (AD) risk. We propose to develop a primate model for AI-induced CNS effects to advance our knowledge in this area and facilitate the design of novel therapeutics. This application uses the marmoset (Callithrix jacchus), a small primate with a brain architecture, sleep patterns, cognitive abilities, emotional responses and thermoregulation patterns that are comparable to those of humans (1) to study the effects of chronic LET use on the brain and behavior and (2) to test whether DHED, a prodrug that delivers E2 selectively to the brain, can effectively and safely prevent LET-associated adverse effects. To achieve these aims, middle-aged male and female marmosets treated with LET, LET + DHED or Vehicle for 3 years will be studied longitudinally for changes in sleep/wake patterns, cognitive performance, emotional regulation, and thermoregulation. The monkeys will be outfitted with an activity monitor for sleep/wake patterns analysis. Cognitive function will be assessed via an automated computerized battery. Thermal imaging will be used to measure changes in facial skin temperature during a thermal challenge. Emotional regulation will be assessed by measuring heart rate variability and facial skin temperature in monkeys viewing emotional and neutral videos. Following these in vivo behavioral assessments, analyses of brain tissues from underlying brain regions (hypothalamus, hippocampus, prefrontal cortex, locus coeruleus) will be carried out to quantify gene expression of selected genes, tauopathies, β-amyloid deposition and neuronal excitability. The results will have important translational applications for AI-treated patients by (1) characterizing the effects of AIs on multiple neural and behavioral outcomes; (2) determining whether long-term estrogen suppression promotes the development of an AD-like phenotype and (3) whether providing the brain with an alternate source of estrogen can counteract the adverse effects of AIs on the brain and behavior.

概括 芳香酶抑制剂（AI）是抑制雌激素合成的药物，用于预防 然而，雌激素反应性乳腺癌的复发，例如常用的来曲唑。 （LET），与严重的副作用相关，进一步影响生活质量，包括失眠、热 人工智能可能引起闪光、抑郁症状和认知缺陷的确切机制。 这些中枢神经系统症状仍然不清楚，也很难在人类中进行研究，以控制个体差异 缺乏疾病严重程度、治疗史和经历过的压力。此外，建议进行人工智能治疗。 3到5年，但人们对长期使用人工智能对大脑和行为的影响知之甚少，尤其是 关于与年龄相关的认知能力下降和阿尔茨海默病（AD）风险，我们建议培育灵长类动物。 人工智能引起的中枢神经系统效应模型，以增进我们在该领域的知识并促进新颖的设计 疗法。 该应用程序使用狨猴（Callithrix jacchus），一种具有大脑结构、睡眠的小型灵长类动物 模式、认知能力、情绪反应和体温调节模式与正常人相当 人类 (1) 研究长期使用 LET 对大脑和行为的影响，以及 (2) 测试 DHED（DHED）是否是一种 选择性地将 E2 递送至大脑的前药，可以有效且安全地预防 LET 相关的不良反应 影响。 为了实现这些目标，中年雄性和雌性狨猴接受 LET、LET + DHED 或 将纵向研究车辆 3 年的睡眠/觉醒模式、认知表现、 猴子将配备用于睡眠/觉醒的活动监视器。 认知功能模式将通过自动计算机热成像进行评估。 将用于测量热挑战期间面部皮肤温度的变化。 通过测量猴子观察情绪和面部皮肤温度的心率变异性和面部皮肤温度来评估 在这些体内行为评估之后，对底层大脑的脑组织进行分析。 将进行区域（下丘脑、海马、前额皮质、蓝斑）的基因量化 选定基因的表达、tau蛋白病、β-淀粉样蛋白沉积和神经兴奋性。 该结果将对接受人工智能治疗的患者产生重要的转化应用：(1) 表征 AI 对多种神经和行为结果的影响；（2）确定是否长期雌激素 抑制会促进 AD 样表型的发展，以及 (3) 是否为大脑提供 雌激素的替代来源可以抵消人工智能对大脑和行为的不利影响。