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.

Public Health Relevance

Depression and memory problems are common complaints among menopausal women;however, this is not a universal experience. A sizable subset of women appears to be uniquely sensitive to the brain effects associated with the loss of estradiol that occurs with menopause. Animal studies suggest that early life stress could render women vulnerable to the mood and cognitive changes triggered by dwindling estradiol production. One mechanism by which early life events may contribute many years later to these suboptimal adjustments to menopause is through stress-induced increases in systemic inflammation. Utilizing previously collected, as well as data to be collected from the Penn Ovarian Aging Study (POAS) cohort of 245 women, we will conduct the first study to determine whether early life adversity as defined by self-report of physical, emotional or sexual abuse, emotional or physical neglect, or evidence of household dysfunction (violence against mother, parental divorce/separation, parental incarceration, parental mental illness or substance abuse), is associated with an increase in pro-inflammatory cytokines and increased risk of first episode of major depressive disorder during the menopause transition. Likewise, we will explore whether early life stress and inflammation contribute interactively and/or individually to the decline in verbal memory and measures of executive function across the menopause transition. The significance of these lines of investigation is considerable as the negative health effects of inflammation are potentially modifiable, if not reversible, if initiated during critical windows ofthe lifespan through targeted pharmacotherapies, stress-reduction, diet, and exercise.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZAG1)
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Wagster, Molly V
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University of Pennsylvania
Schools of Medicine
United States
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Epperson, C Neill; Sammel, Mary D; Bale, Tracy L et al. (2017) Adverse Childhood Experiences and Risk for First-Episode Major Depression During the Menopause Transition. J Clin Psychiatry 78:e298-e307
Morrison, Kathleen E; Epperson, C Neill; Sammel, Mary D et al. (2017) Preadolescent Adversity Programs a Disrupted Maternal Stress Reactivity in Humans and Mice. Biol Psychiatry 81:693-701
Bale, Tracy L; Epperson, C Neill (2017) Sex as a Biological Variable: Who, What, When, Why, and How. Neuropsychopharmacology 42:386-396
Bale, Tracy L; Epperson, C Neill (2015) Sex differences and stress across the lifespan. Nat Neurosci 18:1413-20
Santoro, Nanette; Epperson, C Neill; Mathews, Sarah B (2015) Menopausal Symptoms and Their Management. Endocrinol Metab Clin North Am 44:497-515
Epperson, C Neill; Shanmugan, Sheila; Kim, Deborah R et al. (2015) New onset executive function difficulties at menopause: a possible role for lisdexamfetamine. Psychopharmacology (Berl) 232:3091-100
Altemus, Margaret; Sarvaiya, Nilofar; Neill Epperson, C (2014) Sex differences in anxiety and depression clinical perspectives. Front Neuroendocrinol 35:320-30