Winners! The Women’s Brain Health Young Investigator Award

The Women's Health Research Cluster is passionate about supporting the professional development of young investigators. That is why we decided to select 7 winners for the Young Investigator Award despite changes to our conference date. Please join us in congratulating the following winners of the 2020 Young Investigators Award.

	Claudia Barth, PhD. Summary of Research Sex Hormones and Women's Brain Aging: Evidence for an “Optimal Lifetime Sex Hormone Exposure” Hypothesis Exposure to sex hormones such as estrogen may influence women's risk of Alzheimer's disease (AD), and recent findings indicate protective effects of parity on brain aging. Here, we investigated the link between endogenous and exogenous estrogen exposure, genetic risk for AD and brain aging in middle to older-aged women UK Biobank women, beyond the effects of parity.We calculated brain age relative to chronological age in 16,854 women with a mean age of 54.70 years ± 7.29 (standard deviation). Brain age was estimated based on 1118 T1-weighted 3-Tesla magnetic resonance imaging measures. Index of cumulative estrogen exposure (ICEE) was estimated including age at menarche and menopause, time since menopause, body mass index, and duration of hormone replacement therapy (HRT) use. Exogenous sex hormone exposure was estimated by usage, onset, and duration of HRT. Genetic risk for AD was approximated by apolipoprotein e4 genotype. Multiple regression analyses revealed that, when corrected for effects of parity, higher ICEE and HRT usage were each linked to more apparent brain aging. For HRT user, earlier onset of treatment, particularly before menopause, was associated with less apparent brain aging, but only in women with a genetic risk for AD. The results provide evidence for an “optimal lifetime sex-hormone exposure” hypothesis, indicating that favorable levels of sex-hormone exposure during reproductive and peri-menopausal years confer protective effects on women's brain aging trajectories. In addition, genetic factors may influence the impact of exogenous sex hormone use on brain-aging trajectories later in life.
	Cindy Barha, PhD. Summary of Research Walking For Brain Health: The Effects of Biological Sex And Parity On Exercise Efficacy Aerobic exercise (AE) is a promising strategy for the promotion of brain health. Despite its overall therapeutic potential, substantial variation exists in AE efficacy. Given the faster progression of Alzheimer’s disease in women compared to men, and known sex differences in brain architecture, analysis of sex differences in the relationship between AE and cognition, including underlying mechanisms, is warranted. To address this, we conducted secondary analyses of data from two studies: 1) PROMoTE – a randomized controlled trial of 6-month, thrice-weekly AE in older adults with mild vascular dementia, and 2) Health ABC – a 10-year cohort study of 2873 older adults with retrospective AE measured through self-reported walking. Analysis of covariance and latent growth curve modeling were utilized with appropriate covariates. We found that AE was significantly associated with greater executive functioning in females, but not males. Mechanistically, in the PROMoTE study, AE increased levels of brain-derived neurotrophic factor in females only. In Health ABC, maintenance of AE over time was related to larger dorsal lateral prefrontal cortical volume in females only. We hypothesize that this may be related to long-lasting effects of parity on neuroplastic processes in females, possibly altering the way the female brain responds to AE later in life. In support of this, I will present preliminary findings indicating that in older females the strength of the association between AE and cognition is modified by multiparity. This new knowledge of biological moderators of AE may foster development of personalized, tailored exercise recommendations to promote healthy brain aging.
	Catriona Hippman, PhD. Summary of Research Pharmacogenetic testing for CYP2D6 and CYP2C19: Can it offer guidance for pregnant women taking SSRIs? Depression during pregnancy affects 10-15% of women, and 5% of women take antidepressants during pregnancy. Clinical practice guidelines from the Clinical Pharmacogenetics Implementation Consortium provide recommendations for selective serotonin reuptake inhibitor (SSRI) drug choice and dose based on CYP2D6 and CYP2C19 genotype; guidelines are, however, based on evidence from non-pregnant cohorts. The aim of this study was to test the hypothesis that women with deleterious variants in these pharmacogenes taking SSRIs prenatally, would have more depression symptoms than women whose pharmacogenetic variants have been associated with normal SSRI metabolism. Methods: Comprehensive CYP2D6 and CYP2C19 genotyping utilized a range of methods, including gene copy number analysis, and was performed as secondary analyses on two longitudinal cohorts of pregnant women (N=83) taking SSRIs. The Kruskal-Wallis Test compared mean depression scores across four predicted metabolizer groups: poor (n=5), intermediate (n=10), normal (n=53), and ultrarapid (n=15). Results: There were no significant differences between mean depression scores across the four metabolizer groups (H(3)=.73, p=.87).Conclusion: Findings from this first, exploratory study of CYP2D6 and CYP2C19 pharmacogenetic variations in relation to depression symptoms and citalopram, escitalopram, and sertraline use in pregnancy do not support the clinical use of pharmacogenetic testing for antidepressant use during pregnancy, although these findings should be confirmed in larger cohorts. There is an urgent need for further research to clarify the utility of pharmacogenetic testing for pregnant women, as companies offering direct-to-consumer genetic testing continue to become more prominent and active in their marketing efforts.
	Travis Hodges, PhD. Summary of Research Sex-specific behaviours in a fear-based cognitive bias task and neural correlates from adolescence to adulthood in rats Negative cognitive bias is an increased perception of neutral situations or objects as negative, and is a cognitive symptom of depression. However, the underlying neural mechanisms of cognitive bias have seldom been investigated. Here, adolescent, young adult, and middle-aged adult male and female Sprague-Dawley rats underwent a fear-based cognitive bias task. Rats were trained for 16 days to distinguish between two contexts: a context paired with foot-shock and a context paired with no foot-shock. Two days after initial training (day 18), rats were tested for cognitive bias in response to an ambiguous context and coded for positive (low freezing) or negative (high freezing) cognitive bias. Adolescent rats displayed a positive bias, whereas young adult rats displayed a negative bias in response to the ambiguous context, regardless of sex. Curiously, in middle-aged adults, females displayed a more positive bias (less freezing) in response to the ambiguous context whereas middle-aged males displayed a negative cognitive bias. Sex differences in activation of the basolateral amygdala and the hippocampus (Fos-ir) in response to the ambiguous context in middle-aged rats were seen with negative correlations in males and positive correlations in females. Sex- and age-specific correlations between freezing behaviour and immature neurons in the hippocampus were also examined. Our data suggest a more optimistic cognitive bias in females than in males that emerges in older adulthood. A more optimistic cognitive bias is seen adolescence, regardless of sex, which may be driven by experience or hormone environment.
	Melissa Woodward, PhD. Summary of Research Medial Temporal Lobe Cortical Changes In Response To Exercise Interventions In Women With Early Psychosis: A Randomized Controlled Trial Exercise has been shown to induce changes in hippocampal volume in individuals with psychosis, but its ability to impact cortical regions remains equivocal. Psychosis patients are observed to have neuroanatomical deficits in the prefrontal-limbic network, associated with greater positive symptom severity and cognitive impairment. Despite the fact that women have greater potential to benefit from exercise interventions due to greater exercise-induced upregulation of brain growth factors, women with psychosis have been under-represented in exercise intervention studies. We hypothesized that women with early psychosis who complete an aerobic exercise intervention would demonstrate significant increases in prefrontal-limbic cortical regions and these neuroplastic changes would be associated with reduced symptom severity. Methods: In a cohort of 51 women with early psychosis from Hong Kong, we investigated the effects of a twelve-week exercise intervention (yoga, aerobic or waitlist group) on cortical grey matter. Clinical assessments and structural MRI were completed at the beginning and end of the intervention. Results:Increases in cortical volume and thickness were observed in the medial temporal cortical regions, primarily in the entorhinal and fusiform temporal gyrus for participants who completed the aerobic intervention. For the aerobic group only, increases in the entorhinal and fusiform temporal gyri were associated with decreasing psychosis symptom severity, particularly for the general psychopathology subscale. Conclusions: Neuroplastic increases in cortical grey matter were observed in women with early psychosis and these exercise-induced changes were associated with improvements in psychosis symptom severity. Psychosis patients may benefit from aerobic exercise interventions as a safe, adjunct treatment.
	Caitlin Taylor, PhD. Summary of Research Progesterone Shapes Medial Temporal Lobe Volume Across a Human Menstrual Cycle  The rhythmic production of sex steroid hormones is a feature of the mammalian endocrine system. In rodents and nonhuman primates, sex hormones are powerful regulators of hippocampal subfield morphology. However, it remains unknown whether intrinsic fluctuations in sex hormones alter hippocampal morphology in the human brain. In a series of dense-sampling studies, we used high-resolution imaging of the medial temporal lobe (MTL) to determine whether endogenous fluctuations (Study 1, n = 30 days) and exogenous manipulation (Study 2, n = 30 days) of sex hormones alter MTL volume over time. Across the menstrual cycle, intrinsic fluctuations in progesterone were associated with volumetric changes in CA2/3, entorhinal, perirhinal, and parahippocampal cortex. Chronic progesterone suppression abolished these cycle-dependent effects and led to pronounced volumetric changes in entorhinal cortex and CA2/3 relative to freely cycling conditions. No associations with estradiol were observed. These results establish progesterone’s ability to rapidly and dynamically shape MTL morphology across the human menstrual cycle. Data from a parallel dense-sampling study in a male (n = 30 days) demonstrate that intrasubject variability in MTL subregion volume does not differ between the sexes. Overall variability was highly similar for both time-series. Further, cross-sectional data from a population cohort (n = 1113) indicate that inter-subject variability in hippocampal volume is greater for males. Together, these findings reveal progesterone’s role in shaping MTL volume in females across the menstrual cycle, and that this variability is on par with, or less than, the intrinsic variability observed in males. Funding: This work was supported by the Harvey L. Karp Discovery Award (CMT), the Brain and Behavior Research Foundation (EGJ), the California Nanosystems Institute (EGJ), the Hellman Family Fund (EGJ) and the Rutherford B. Fett Fund (STG).
	Ann-Marie de Lange, PhD. Summary of Research Population-based Neuroimaging Reveals Traces of Childbirth in the Maternal Brain Pregnancy is one of the most dynamic periods in a woman’s life, involving a remarkable potential for brain plasticity. During pregnancy and postpartum, fundamental neurobiological processes are instigated to support maternal adaptation and ensure protection of the offspring. Structural brain alterations have been found in both animals and humans, but little is known about the long-term effects of pregnancy on women’s brain aging trajectories. Using neuroimaging and machine-learning based brain age prediction, we investigated history of previous childbirths and structural brain aging in 12,021 women from the UK Biobank cohort (age range 40 - 70 years). To parse the effects of common genetic variation, we performed a genome-wide association study (GWAS) on the phenotype number of births in 271,312 healthy UK Biobank women (excluding our imaging subsample). The results showed less evident brain aging in parous women compared to nulliparous women, and within parous women, a higher number of childbirths was associated with less evident brain aging. This relationship could not be fully explained by common genetic variation measured by polygenic risk scores, or by confound variables including ethnic background, education, BMI, age at menarche and menopause, age at first birth, and number of incomplete pregnancies. Although prospective longitudinal studies are required in order to conclude, the findings indicate that I) pregnancy-related neurobiological changes may persist beyond the postpartum period and confer a protective effect on brain aging, and II) such effects may be more prominent following multiple childbirths. This research was conducted using the UK Biobank under Application 27412, and received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (802998), the Research Council of Norway (286838, 273345, 249795, 276082, 223273), the South-East Norway Regional Health Authority (2015073, 2019107), and the Medical Research Council (MR/K006673/1).

All registrants of the 2021 Women's Brain Health Conference will have another opportunity to win a Young Investigator Award, regardless of whether they applied to the 2020 competition. Details surrounding the competition will be released at the end of 2020.