ESTROGEN INFLUENCES ON COGNITIVE AGING IN THE MONKEY

大量证据表明，卵巢激素可能会对正常认知衰老过程产生重要影响。然而，对妇女的相关研究产生了好坏参半的结果。在当前项目期间进行的研究使用了一种对照的前瞻性设计，以确定在已建立的正常衰老的非人灵长类动物模型中手术绝经和无对抗的周期性雌二醇替代的认知影响。结果表明，这种临床批准的方案有效地调节认知功能，包括几乎完全逆转猴子中年龄相关性衰退的最充分表征的特征。我们的订正提案是在这一背景下提出的，以处理几个相互关联的目标。电流 有证据表明，衰老调节了对雌激素的认知和神经生物学反应，在即将到来的资助期内完成的研究将是第一批直接在非人类灵长类动物模型中测试这一提议的研究。第二个主要举措是扩展我们早期的分析，比较多种临床相关的替代策略对衰老认知结果的影响：1）长期连续的雌激素单独给药，2）长期连续的雌激素加同时的微粒化孕酮，3）长期连续的雌激素加环孕酮，在每个28天周期中连续给药10天，（4）长期周期性雌激素+周期性孕激素。在短暂的术前测试后，将实施卵巢切除术和置换术，随后将对猴进行评价 通过对衰老和卵巢激素状态的敏感性建立的神经心理学电池。通过这种方法，该项目将产生全新的数据，记录孕激素是否影响对连续和周期性雌激素的认知反应，以及这些影响是否取决于孕激素给药的具体时间表。评估还将包括干扰和分心的系统操作，旨在阐明介导替代效应的特定信息处理功能。与该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 预计将在开发安全有效的策略以优化绝经后妇女的神经生物学健康方面取得实质性进展。

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.