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

扭转童年逆境对抑郁症的影响

• 批准号: 8797776
• 负责人: C. Neill NEILL EPPERSON
• 金额: $ 32万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8797776
• 关键词: Address; Adult; Adverse effects; Affect; Age; Aging; Alcohol consumption; Animals; Behavior; Biological Assay; Body mass index; Brain; Brain region; C-reactive protein; Childhood; Cognition; Cognitive; Cognitive aging; Cohort Studies; Data; Data Quality; Dementia; Development; Digit structure; Education; Endocrine system; Estradiol; Event; Functional disorder; Funding; Future; Health; Hippocampus (Brain); Hormones; Household; Hypogonadism; Immune system; Impaired cognition; Imprisonment; Incidence; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Investigation; Life; Life Stress; Life Style; Link; Longevity; Major Depressive Disorder; Measures; Mediating; Memory; Menopause; Mental Depression; Mental disorders; Mood Disorders; Moods; Mothers; Neuraxis; Ovarian; Ovarian hormone; Patient Self-Report; Performance; Peripheral; Pharmacotherapy; Postmenopause; Prefrontal Cortex; Premenopause; Production; Psychosocial Stress; Publishing; Questionnaires; Recording of previous events; Regulation; Relapse; Relative (related person); Reporting; Research; Research Activity; Research Personnel; Risk; Sampling; Serum; Sex Characteristics; Sexual abuse; Sleep; Smoking Status; Social support; Socioeconomic Status; Staging; Stress; Stress and Coping; Substance abuse problem; TNF gene; Testing; Time; Violence; Waxes; Woman; Women' s Health; base; biobehavior; cognitive change; cohort; cytokine; diet and exercise; divorce/separation; emotional abuse; emotional neglect; executive function; experience; inflammatory marker; nonhuman primate; physical abuse; physical neglect; processing speed; public health relevance; reproductive hormone; resilience; response; senescence

 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.

 描述（由申请人提供）：众所周知，童年逆境是成人情感障碍最有效的预测因素之一，尤其是在女性中。同样，压力与认知老化不良有关，尽管此类事件发生的发育阶段的重要性尚不清楚。直接或通过中枢神经系统目标对免疫和内分泌系统进行压力调节，是童年逆境影响认知和情绪的一种可能机制。为了回应这份 RFA，我们建议利用长达 14 年的宾夕法尼亚大学卵巢衰老研究（POAS，PI：E. Freeman）期间收集的数据来解决有关早期生活逆境对重度抑郁症（MDD）风险和次优认知老化影响的可逆性的关键问题，特别关注更年期过渡，在此期间生殖激素的变化揭示了抑郁症和认知问题的脆弱性。 许多女性。利用 POAS 队列的数据，我们最近报告称，有两次或两次以上不良童年经历 (ACE) 史的女性在绝经过渡期间新发 MDD 的风险增加了 2 倍。同样，我们首次证实更年期对即时和延迟言语记忆产生与年龄无关的影响，并且最近获得了初步证据表明 ACE 可能在某些认知领域产生额外的不利影响。虽然这些发现表明童年逆境与抑郁症和更年期认知能力下降的风险之间存在着有趣且重要的相互作用，但如果不进一步利用这一队列来确定介导、加剧和/或改善童年逆境对情绪和认知的负面影响的因素，那么对于女性健康以及情感障碍和痴呆症的潜在性别差异研究来说，这将是一个失去的机会。此外，在女性生命的一个重要过渡时期，卵巢激素存在明显的波动，因此很少有机会像这样丰富地探索这些因素。这次 RFA 的时机恰到好处，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症发作时间、认知能力下降斜率和卵巢衰老轨迹的影响程度； 2）对一生的逆境进行全面评估，以确定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）收集更强有力的认知测量，特别是那些与执行功能和影响调节相关的测量，因为这些是更年期妇女普遍关心的问题，而前额叶皮层和海马脑区是应激激素和神经炎症的主要目标，最后4）检验炎症至少部分介导童年逆境与MDD出现和认知能力下降之间关系的假设 雌二醇产量下降的背景。该研究合作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，为未来针对在 2 年 R01 资助过程中确定的可逆生物行为因素的研究的发展提供信息。