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老化过程产生重要影响。然而，对女性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项对照的前瞻性设计，在已建立的正常衰老的非人类灵长类动物模型中，确定了手术绝经和非对抗性周期雌二醇替代对认知的影响。结果表明，这种临床批准的方案有效地调节了认知功能，包括几乎完全逆转了猴子最典型的年龄相关性衰退的特征。我们的修订提案建立在这一背景之上，以解决几个相互关联的目标。当前 有证据表明，衰老会调节认知和神经生物学对雌激素的反应，将在即将到来的资助期早期完成的研究将是第一批在非人类灵长类动物模型中直接测试这一假设的研究之一。第二个主要举措是扩展我们早期的分析，以比较多种临床相关的替代策略对衰老认知结果的影响：1)长期持续雌激素单独使用，2)长期持续雌激素+同步微粒化黄体酮，3)长期持续雌激素+环孕酮，每28天周期中连续10天服用，以及4)长期循环雌激素+环孕酮。卵巢切除和置换将在一段简短的术前测试后实施，随后将对猴子进行评估 对衰老和卵巢激素状态具有公认的敏感性的神经心理电池。通过这种方法，该项目将产生全新的数据，记录黄体酮是否影响对持续和循环雌激素的认知反应，以及这些影响是否依赖于黄体酮给药的特定时间表。评估还将包括干扰和分心的系统操作，旨在阐明调解替换效果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作的神经生物学后果进行评估。这种集成的方法是 预期在制定安全有效的战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.