This is a application to implement blood based screening for postpartum depression (PPD) using a novel epigenetic biomarker we have developed, enabling the longitudinal evaluation of PPD specific neuroimaging phenotypes in the postpartum period in individuals at risk and in matched controls. The project will take advantage of the talents of a leader in the field of women's mental health and PPD, a highly experienced DNA methylation and biomarker researcher, and an accomplished neuroimager. Through a recent cross species translational experiment investigating hippocampal epigenetic responses to estrogen and epigenomic profiling in a prospective sample of women at risk for PPD, we identified a set of epigenetic marks functionally related to modulating synaptic plasticity and capable of predicting PPD with >85% accuracy. Our results indicated that risk to PPD is mediated by an increased sensitivity to estrogen. The availability of peripheral biomarkers opens novel opportunities to perform imaging epigenetics in the PPD population. While there is some consistency across MDD and PPD specific neuroimaging phenotypes, it is unclear if these findings represent disease etiology or the state of depression and requires longitudinal study in spontaneous and previous mood disorder diagnosed cases to elucidate. The central hypothesis is that PPD risk may arise due to an altered sensitivity of the epigenetic reprogramming machinery in response to gonadal hormones and that peripherally measured epigenetic variation at these loci will be associated with longitudinally progressive depression associated neuroimaging phenotypes including resting state functional connectivity alterations of corticolimbic pathways, emotional processing, working memory, and hippocampal subregion specific activity changes in the postpartum period.
In Aim 1, we will use standard third trimester blood draws to perform PPD prediction and generate a sample of women at risk for PPD from the general population and from women with a previous history of mood disorder.
In Aim 2, we will perform a series of fMRI tests to assess resting state functional connectivity, emotional response, working memory, and hippocampal subregion specific alterations at both a pre-depression time point of two weeks at six weeks during major depressive episodes. A within groups comparison will identify trait associated endophenotypes that will be integrated with epigenetic, serum hormone, and psychological data in Aim 3. The analyses performed will identify novel brain endophenotypes susceptible to hormone and epigenetic interaction that will aid in our understanding of the molecular pathology of PPD and hold the potential to act as novel and modifiable therapeutic targets.

Public Health Relevance

Postpartum depression (PPD) affects up to 18% of women in the general population and represents a serious health risk not only to the affected mother but also to the offspring, with potential deleterious outcomes including low cognitive performance, abuse, and infanticide. This study proposes to collect a prospective sample of women and assess for PPD risk using a novel epigenetic biomarker model, followed by longitudinal neuroimaging based identification of pre- depression endophenotypes in both a high risk population and in spontaneous cases from the general population. The study will stand as a proof of principle for pregnancy screening for PPD, translating into direct clinical benefit, and potentially identifying novel brain regions and endophenotypes susceptible to hormone and epigenetic interaction that will aid in our understanding of the molecular pathology of PPD and hold the potential to act as novel and modifiable therapeutic targets.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01MH104262-01
Application #
8753547
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Meinecke, Douglas L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
None
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218