PROJECT SUMMARY/ABSTRACT Vascular contributions to cognitive impairment and dementia (VCID) are now recognized as a key pathogenic factor in dementia, and represent a promising target for intervention. Adverse pregnancy outcomes (APOs), such as preeclampsia, preterm delivery, and fetal growth restriction, are associated with future maternal cardiovascular and cerebrovascular risk. However, the impact of APOs on maternal VCID remains unexamined. Most existing women's cardiovascular and aging cohorts lack rigorously phenotyped, prospectively collected pregnancy data, and the impact of maternal factors that may predispose to both APOs and VCID is not well understood. From 2010-2013, the Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b) study enrolled a diverse cohort of 10,037 healthy women at 8 US academic medical centers, who were followed from early in conception through the delivery of their first child. Several years later, the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be Heart Health Study (nuMoM2b-HHS) brought back 4,475 nuMoM2b women for a second study wave, to characterize subsequent pregnancy outcomes and accumulation of cardiovascular risk factors following pregnancy. A third study wave of in-person visits will begin in early 2022. In this ancillary study, we propose to conduct neurocognitive assessments on all nuMoM2b-HHS participants during this third study wave. We will perform brain magnetic resonance imaging (MRI) on a sub-cohort of 250 women followed at the Columbia University Irving Medical Center study site, including all who experienced APOs in the index pregnancy. The overall goal of the study is to capitalize on this unique obstetric cohort to determine the impact of APOs on long term maternal VCID, through the following specific aims: (1) Investigate the impact of APOs on maternal cognition 10-15 years after delivery by comparing global cognition scores between women who experienced APOs and women who did not; (2) Determine the impact of APOs on MRI biomarkers of maternal VCID, including white matter hyperintensity volume and additional markers of cerebral small vessel disease. We hypothesize that the association of APOs with VCID markers will be partially mediated by development of new hypertension after the index pregnancy. As an exploratory aim, we will use deep pregnancy phenotyping, including maternal characteristics, biomarkers of ischemic placental disease and APOs, to create a VCID prediction model. This will be the first US study to use prospectively collected pregnancy data to investigate the impact of APOs, a sex-specific vascular risk factor, on VCID in women. Understanding the effects of APOs on early markers of VCID could help us identify women early in life who are at higher risk of dementia, and develop preventive strategies to thwart the progression of cognitive decline in this population. In addition, the collection of neurocognitive assessments on the entire nuMoM2b-HHS cohort during this study wave is an important investment, which will provide baseline data for future studies as these women continue to age.

PROJECT NARRATIVE Adverse pregnancy outcomes (APOs), such as preeclampsia, preterm delivery, and fetal growth restriction, are associated with future maternal cerebrovascular risk; however, the impact of APOs on vascular contributions to cognitive impairment and dementia (VCID) in women remains unexamined, and the effects of factors that may predispose to both APOs and VCID are not well understood. The overall goal of this ancillary study is to determine the impact of APOs on long term maternal VCID, by performing neurocognitive assessments and brain imaging on a large, diverse, well-phenotyped prospective cohort of US women followed since early in their first pregnancies 10-15 years ago. Understanding the effects of APOs on early markers of VCID could help us identify women early in life who are at higher risk of dementia, and develop preventive strategies to thwart the progression of cognitive decline in this population.