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

 描述(由申请人提供)：众所周知，童年的逆境是成人情感障碍最有效的预测因素之一，特别是在女性中。同样，压力也与认知能力低下的衰老有关，尽管这类事件发生的发育阶段的重要性还不清楚。免疫和内分泌系统的应激调节，直接或通过其中枢神经系统靶标，是童年逆境影响认知和情绪的一种可能机制。作为对这种RFA的回应，我们建议利用在长达14年的宾夕法尼亚卵巢老化研究(POAS，PI：E.Freeman)中收集的数据来解决关于早期生活逆境对严重抑郁障碍(MDD)风险的可逆性影响和次优认知衰老的关键问题，特别关注更年期过渡期间生殖激素的变化揭示了许多女性对抑郁和认知疾病的易感性。使用POAS队列的数据，我们最近报道，在有两次或两次以上不良童年经历(ACE)的妇女中，在绝经过渡期间新发MDD的风险增加了2倍。同样，我们发表了首次证实绝经对即时和延迟言语回忆产生年龄无关的影响，并最近获得初步证据表明，ACE可能在某些认知领域造成额外的不利影响。虽然这些发现表明童年逆境与抑郁风险和更年期认知衰退之间存在有趣而重要的相互作用，但如果不进一步利用这一队列来确定调节、加剧和/或改善童年逆境对情绪和认知的负面影响的因素，对妇女的健康以及对情感障碍和痴呆症的潜在性别差异研究来说，将是一个错失的机会。此外，在女性生命中一个重要的过渡期，在卵巢激素波动特征良好的情况下，很少有机会像这样丰富地探索这些因素。这项RFA恰逢其时，因为资金将使我们能够：1)利用POAS队列中现有的生物行为数据，确定童年逆境对抑郁症发病时间、认知下降斜率和卵巢衰老轨迹的影响程度；2)对终身逆境进行全面评估，以解决是否需要特定的逆境“集群”和/或“双重打击”来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绪调节有关的测量，因为这些是更年期女性普遍关心的问题，而前额叶皮质和海马脑区是应激激素和神经炎症的主要靶点，最后，验证以下假设：炎症至少在一定程度上中介了童年逆境与MDD和认知能力下降之间的关系，在雌二醇产生下降的背景下。这一合作研究小组的广泛专业知识和POAS队列的数据质量将确保成功完成拟议的分析/研究活动，以便为未来针对在这项为期2年的R01资助期间确定的可逆生物行为因素的研究的发展提供信息。

 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.