Reversing Impact of Childhood Adversity on MDD & Cognitive Decline in Menopause

 描述（由申请人提供）：众所周知，童年逆境是成人情感障碍的最有效预测因素之一，特别是在女性中。同样，压力也与认知老化有关，尽管发生这种事件的发育阶段的重要性并不清楚。免疫和内分泌系统的压力调节，直接或通过其中枢神经系统的目标，是一个可能的机制，童年逆境影响认知和情绪。针对该RFA，我们建议利用在长达14年的Penn卵巢老化研究（POAS，PI：E）中收集的数据。Freeman），以解决有关早期生活逆境对重度抑郁症（MDD）和次优认知衰老风险影响的可逆性的关键问题，特别关注绝经过渡期，在此期间，生殖激素变化揭示了许多女性对抑郁症和认知投诉的脆弱性。使用POAS队列的数据，我们最近报道了在有两次或两次以上不良童年经历（ACE）史的女性中，绝经过渡期新发MDD的风险增加2倍。同样，我们发表了第一个证实，更年期对即时和延迟的言语回忆产生了年龄无关的影响，最近获得的初步证据表明，ACE可能会在某些认知领域产生额外的不良影响。虽然这些研究结果表明，童年逆境和抑郁症和认知能力下降的风险与更年期之间的一个有趣的和重要的相互作用，这将是一个失去的机会，妇女的健康，并在情感障碍和痴呆症的潜在性别差异研究，不利用这个队列进一步确定因素，调解，加剧和/或改善童年逆境对情绪和认知的负面影响。此外，很少有机会像这样丰富，以探讨这些因素的存在下，在一个重要的过渡时期，在妇女的生活卵巢激素波动的特点。这项RFA是完美的时机，因为资金将使我们能够1）利用POAS队列的现有生物行为数据来确定童年逆境对抑郁发作时间的影响程度，认知下降的斜率和卵巢衰老的轨迹; 2）对终身逆境进行全面评估，以确定特定的“集群”逆境和/或“双重打击”有必要观察早期生活压力的影响; 3）收集更可靠的认知测量，特别是与执行功能和情感调节相关的测量，因为这些是绝经期妇女的常见问题，并且前额叶皮层和海马脑区域是应激激素和神经炎症的主要靶点，最后4）测试炎症介导的假设，至少在一定程度上，在雌二醇产量下降的背景下，儿童期逆境与MDD和认知能力下降之间的关系。该研究者合作小组的广泛专业知识和POAS队列数据的质量将确保成功完成拟议的分析/研究活动，以告知未来针对在2年R 01资助期间确定的可逆生物行为因素的研究的发展。

 DESCRIPTION (provided by applicant): It is well established that childhood adversity is one of the most potent predictors of adult affective disorders, particularly among women. Similarly, stress has been linked with poor cognitive aging, although the importance of the developmental stage at which such events occur is not as clear. Stress modulation of both immune and endocrine systems, directly or through their central nervous system targets, is one possible mechanism by which childhood adversity impacts both cognition and mood. In response to this RFA, we propose to utilize data collected during the 14-year long Penn Ovarian Aging Study (POAS, PI: E. Freeman) to address critical questions regarding the reversibility of early life adversity impact on risk for major depressive disorder (MDD) and sub-optimal cognitive aging, with a particular focus on the menopause transition during which reproductive hormone changes unmask vulnerability to depression and cognitive complaints in many women. Using data from the POAS cohort, we recently reported a 2-fold increased risk of new onset MDD during the menopause transition among women with a history of two or more adverse childhood experiences (ACEs). Likewise, we published the first confirmation that menopause exerts an age-independent effect on immediate and delayed verbal recall and have recently obtained preliminary evidence that ACEs may contribute an additional adverse effect in some cognitive domains. While these findings suggest an intriguing and important interaction between childhood adversity and risk for depression and cognitive decline with menopause, it would be a lost opportunity for women's health, and potentially sex difference research in affective disorders and dementia, to not utilize this cohort further to identify factors that mediate, exacerbate and/or ameliorate the negative impact of childhood adversity on mood and cognition. Moreover, there are few opportunities as rich as this to explore these factors in the presence of well-characterized ovarian hormone fluctuations over an important transition period in women's lives. This RFA is perfectly timed as funding would enable us to 1) utilize the existing biobehavioral data from the POAS cohort to determine the extent of the impact of childhood adversity on timing of depression onset, slope of the decline in cognition and trajectory of ovarian senescence; 2) conduct comprehensive assessments of life-long adversity to address whether specific "clusters" of adversity and/or a "double-hit" is necessary to observe the impact of early life stress; 3) collect more robust measures of cognition, particularly those related to executive functions and affect regulation as these are common concerns among menopausal women, and prefrontal cortex and hippocampal brain regions are a primary target of stress hormones and neuro-inflammation, and finally to 4) test the hypothesis that inflammation mediates, at least in part, the relationship between childhood adversity and the emergence of MDD and cognitive decline in the context of declining estradiol production. The extensive expertise of this collaborative group of investigators and the quality of data from the POAS cohort will insure successful completion of the proposed analyses/research activities to inform development of future studies targeting the reversible biobehavioral factors identified during the course of this 2-year R01 funding.