ESTROGEN INFLUENCES ON COGNITIVE AGING IN THE MONKEY

雌激素对猴子认知衰老的影响

• 批准号: 6869958
• 负责人: PETER R RAPP
• 金额: $ 23.07万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869958
• 关键词: Macaca mulatta; aging; behavioral /social science research tag; cognition; drug administration rate /duration; estrogens; female; hormone regulation /control mechanism; hormone therapy; neural plasticity; neuropsychological tests; neuropsychology; ovariectomy; progesterone; psychological aspect of aging

Substantial evidence suggests that ovarian hormones might importantly influence the course of normal cognitive aging. Relevant research in women, however, has yielded mixed results. Studies conducted during the current project period used a controlled, prospective design to define the cognitive effects of surgical menopause and unopposed, cyclic estradiol replacement in an established nonhuman primate model of normal aging. The results demonstrate that this clinically approved regimen potently regulates cognitive function, including a near complete reversal of the most well-characterized signature of age-related decline in monkeys. Our revised proposal builds on this background to address several, inter-related aims. Current evidence suggests that aging modulates the cognitive and neurobiological response to estrogen, and studies to be completed early in the coming funding period will be among the first to test this proposal directly in a nonhuman primate model. A second major initiative is to expand our earlier analysis to compare the effects of multiple, clinically relevant replacement strategies on the cognitive outcome of aging: 1) long-term continuous estrogen alone, 2) long-term continuous estrogen plus concurrent micronized progesterone, 3) long-term continuous estrogen plus cyclic progesterone, delivered for 10 consecutive days of each 28 day cycle, and 4) long-term cyclic estrogen plus cyclic progesterone. Ovariectomy and replacement will be implemented following a brief period of pre-operative testing, and monkeys wilt be evaluated subsequently across a neuropsychological battery with established sensitivity to aging and ovarian hormone status. By this approach the project will yield entirely novel data documenting whether progesterone influences the cognitive response to continuous and cyclic estrogen, and whether these effects are dependent on the specific schedule of progesterone administration. Assessment also will include systematic manipulations of interference and distraction, aimed at illuminating the specific information processing functions that mediate the effects of replacement. As with all studies in the project, the behavioral results ultimately will be evaluated in relation to the neurobiological consequences of ovarian hormone manipulation. This integrated approach is expected to realize substantial progress toward the development of safe and effective strategies for optimizing women's neurobiological health after menopause.

大量证据表明，卵巢激素可能重要地影响正常认知衰老的过程。然而，对女性的相关研究产生了不同的结果。在当前项目期间进行的研究使用受控的前瞻性设计来定义手术更年期和无反对的，环状雌二醇的认知作用，这是在正常衰老的既定非人类灵长类动物模型中。结果表明，该临床批准的方案有效地调节了认知功能，包括几乎完全完全逆转了猴子年龄相关的最佳特征签名。我们的修订建议以这种背景为基础，以解决几个相互关联的目的。当前的 有证据表明，衰老调节对雌激素的认知和神经生物学反应，并且在即将到来的资金期初将完成的研究将是最早直接在非人类灵长类动物模型中测试该提案的研究。第二个主要举措是扩大我们的早期分析，以比较多种，临床上相关的替换策略对衰老的认知结果的影响：1）单独的长期连续雌激素，2）长期连续雌激素，同时发生的微生物孕酮，3）长期连续的雌激素，连续雌激素，每次连续的循环速度，并在28天的28天周期中，以及44天的28天周期，并在44天循环。孕酮。短暂的术前测试后，将实施卵巢切除术和替换，然后对猴子枯萎进行评估 在神经心理电池中，对衰老和卵巢激素状态具有既定敏感性。通过这种方法，该项目将产生完全新颖的数据，记录孕酮是否影响对连续和环状雌激素的认知反应，以及这些作用是否取决于孕激素的特定时间表。评估还将包括系统的干扰和分心操纵，旨在阐明介导替换效果的特定信息处理功能。与项目中的所有研究一样，行为结果最终将根据卵巢激素操纵的神经生物学后果进行评估。这种综合方法是 预计将在更年期后建立安全有效的策略来制定安全有效的策略。