Publications
Please find below a list of our recent featured papers. You can click to access our PubMed or Google Scholar pages to find a complete list of journal article publications.
Previous parity differentially influences cognition in later life depending on dementia status
Sex influences cognitive aging and dementia, yet research on the impact of female-specific factors, such as parity and fetal sex, on later-life cognition remains limited and equivocal. Inconsistencies in the literature may reflect varying effects across cognitive domains and dementia status. This study reviewed data from female participants of the University of British Columbia Hospital Clinic for Alzheimer and Related Dementias (UBCH CARD) to examine how parity and son-to-daughter ratio affect performance on medial temporal lobe-dependent (episodic memory) and prefrontal lobe-dependent (executive function) tasks depending on dementia status. Among females with dementia, higher parity was associated with reduced episodic memory but enhanced executive function performance, whereas a greater son-to-daughter ratio was associated with reduced executive function performance. These relationships were not observed in cognitively normal females or those diagnosed with mild cognitive impairment. These results emphasize the importance of integrating sex-specific factors into research and the development of precision therapeutics.
One size does not fit all: how type of menopause and hormone therapy matters for brain health
Background: Menopause is an inflection point in the ageing trajectory. Independent of chronological age, menopause is associated with the biological ageing of several body systems. In this review, we highlight the importance of considering the influence of menopause - its types, symptoms and interventions - on brain health. Supplementing the loss of ovarian hormones with menopausal hormone therapy (MHT) may be key for supporting the healthy brain ageing of females. MHT has been associated with reduced risk of several neurodegenerative diseases; however, its benefits are not always observed on brain health. Aims: This narrative review highlights often overlooked MHT factors that influence its effects to produce positive or negative effects on brain health, cognition and neurodegenerative disease risk. These factors include the many varieties of MHT, including formulation, administration route and dosing schedule, as well as individual characteristics, particularly the presence of vasomotor symptoms and apolipoprotein ε4 (APOE4) genotype. Method: PubMed and Scopus were used to identify articles with relevant search terms. Results: Menopause factors, including age, abruptness and symptoms, influence brain ageing. MHT influences brain health, with transdermal MHT showing more positive effects on brain ageing, but its effectiveness may depend on individual factors such as genotype, reproductive and lifestyle factors. Conclusions: To develop effective and individualised MHT treatments, further research is needed. Preclinical models must consider the type of human menopause and MHT. To achieve the greatest dementia prevention in females, more menopause education and care is needed that extends beyond 60 years of age, or 10 years postmenopause.
Sex-specific metabolic and central effects of GLP-1-estradiol conjugate in middle-aged rats on a standard or western diet
Middle age represents a critical window for metabolic and cognitive health, particularly in the context of rising obesity and diabetes rates. Glucagon-like peptide-1 (GLP-1)-based therapies, which regulate blood glucose and body weight, show sex-specific effects, with estradiol potentiating their metabolic benefits. However, research on GLP-1's cognitive and neuroprotective roles has largely been conducted in males. Here, we investigated the effects of GLP-1 conjugated to estradiol (GE2) on metabolism, cognition, cytokine levels and neurogenesis in the dentate gyrus of middle-aged male and female rats fed a standard (SD) or Western (WD) diet. In both sexes, WD increased body weight and plasma leptin levels, regardless of sex. GE2 treatment led to weight loss, enhanced cued and contextual fear memory, reduced cytokine levels in the hippocampus in SD rats, and increased neurogenesis in the dorsal dentate gyrus (DG), regardless of sex. Sex-specific differences were observed in fat distribution, glucose regulation, central cytokine levels, and neuroplasticity after WD and GE2 treatment. In females only, GE2 reduced visceral (gonadal) fat, reduced cytokines in the dorsal hippocampus, and improved basal blood glucose in response to a WD. In males only, GE2 restored neurogenesis in the DG after WD exposure, and reduced cytokine levels in the amygdala. These findings suggest that although WD increased body weight and GE2 improved associative learning in both sexes, both WD and GE2 had differential affects on metabolic hormones, insulin regulation, cytokine levels and neuroplasticity. Our findings underscore the importance of sex-specific approaches in metabolic and neuroprotective therapeutics in middle age.
Sex-specific influences of APOEε4 genotype on hippocampal neurogenesis and progenitor cells in middle-aged rats
Female sex and Apolipoprotein (APOE) ε4 genotype are top risk factors for late-onset Alzheimer’s disease. This research investigates how these two risk factors might interact to influence biomarkers of brain health at middle age using a rat model. Compared to healthy controls, male rats with hAPOEε4 genotype showed reduced neural stem cell-like cells and new adult-born brain cells and increased microglia (marker of inflammation in the brain) at middle age. In contrast, female rats with hAPOEε4 genotype showed increased new adult-born neurons, but no changes in the other cell types, suggesting a possible compensatory response to the effects of hAPOEε4 at this time point. These results highlight the importance of examining sex-specific pathways in AD, as they may uncover unique protective mechanisms and inform development of tailored treatment strategies.
Association Between Menopause Age and Estradiol-Based Hormone Therapy With Cognitive Performance in Cognitively Normal Women in the CLSA
Background and objectives: Menopause and menopausal hormone therapy (MHT) affect cognition, although existing studies are inconclusive. Age-related declines in executive functions, episodic memory, and prospective memory may be differentially sensitive to menopause age and MHT, due to variations in which brain regions are involved and their estrogen receptor density. Few studies have explored how menopause age and estradiol (E2)-based MHT by administration route affect these domains, a gap that this study addresses. Methods: This was a cross-sectional observational cohort study using baseline data from the Canadian Longitudinal Study of Aging. We separately examined the associations of age at menopause and E2-based MHT with performance in 3 cognitive domains: episodic memory, prospective memory, and executive functions. Linear regression models were used the test the association between cognitive performance and menopause variables. Results: This cohort included 7,251 postmenopausal women (mean age at baseline 60.5 ± 10.2 years, mean age at menopause 50.5 ± 4.2 years), with models adjusted for age, education, and vascular risk. Earlier age at menopause was significantly associated with lower scores across all cognitive domains tested (episodic memory β = 0.050, 95% CI 0.027-0.072, p < 0.001; prospective memory β = 0.047, 95% CI 0.024-0.070, p < 0.001; executive functions β = 0.061, 95% CI 0.039-0.083; p 0.350; 4+ children β = 0.215, 95% CI 0.133-0.296, p < 0.001) and there was a greater effect size among APOE ε4 carriers compared to non-carriers (β = 0.070, 95% CI 0.016-0.123, p
Leveraging research into sex differences and steroid hormones to improve brain health
Sex differences, driven in part by steroid hormones, shape the structure and function of the brain throughout the lifespan and manifest across brain health and disease. The influence of steroid hormones on neuroplasticity, particularly in the adult hippocampus, differs between the sexes, which has important implications for disorders and diseases that compromise hippocampus integrity, such as depression and Alzheimer disease. This Review outlines the intricate relationship between steroid hormones and hippocampal neuroplasticity across the adult lifespan and explores how the unique physiology of male and female individuals can affect health and disease. Despite calls to include sex and gender in research, only 5% of neuroscience studies published in 2019 directly investigated the influence of sex. Drawing on insights from depression, Alzheimer disease and relevant hippocampal plasticity, this Review underscores the importance of considering sex and steroid hormones to achieve a comprehensive understanding of disease susceptibility and mechanisms. Such consideration will enable the discovery of personalized treatments, ultimately leading to improved health outcomes for all. Results: We categorized a total of 8,964 Project and Operating grant abstracts awarded from 2009 to 2020 based on their study of female-specific or a 2S/LGBTQ + populations or their mention of sex or gender. Overall, under 3% of grant abstracts funded by CIHR explicitly mentioned sex and/or gender, as 1.94% of grant abstracts mentioned sex, and 0.66% mentioned gender. As one of the goals of SGBA is to inform on health equity and understudied populations with respect to SGBA, we also found that 5.92% of grant abstracts mentioned female-specific outcomes, and 0.35% of grant abstracts focused on the 2S/LGBTQ + community. Conclusions: Although there was an increased number of funded grants with abstracts that mentioned sex and 2S/LGBTQ + health across time, these increases were less than 2% between 2009 and 2020. The percentage of funded grants with abstracts mentioning female-specific health or gender differences did not change significantly over time. The percentage of funding dollars allocated to grants in which the abstracts mentioned sex or gender also did not change substantially from 2009 to 2020, with grant abstracts mentioning sex or female-specific research increasing by 1.26% and 3.47%, respectively, funding allocated to research mentioning gender decreasing by 0.49% and no change for 2S/LGBTQ +-specific health. Our findings suggest more work needs to be done to ensure the public can evaluate what populations will be examined with the funded research with respect to sex and gender to advance awareness and health equity in research. Keywords: 2S/LGBTQ + health; CIHR; Canada; Female; Gender; Research funding; Sex; Women’s health.
Inflammatory signalling during the perinatal period: Implications for short- and long-term disease risk
During pregnancy and the postpartum, there are dynamic fluctuations in steroid and peptide hormone levels as well as inflammatory signalling. These changes are required for a healthy pregnancy and can persist well beyond the postpartum. Many of the same hormone and inflammatory signalling changes observed during the perinatal period also play a role in symptoms related to autoimmune disorders, psychiatric disorders, and perhaps neurodegenerative disease later in life. In this review, we outline hormonal and immunological shifts linked to pregnancy and the postpartum and discuss the possible role of these shifts in increasing psychiatric, neurodegenerative disease risk and autoimmune symptoms during and following pregnancy. Furthermore, we discuss how key variables such as the number of births (parity) and sex of the fetus can influence inflammatory signalling, and possibly future disease risk, but are not often studied. We conclude by discussing the importance of studying female experiences such as pregnancy and parenting on physiology and disease.
Estrogens dynamically regulate neurogenesis in the dentate gyrus of adult female rats
Estrone and estradiol differentially modulate neuroplasticity and cognition. How they influence the maturation of new neurons in the adult hippocampus, however, is not known. The present study assessed the effects of estrone and estradiol on the maturation timeline of neurogenesis in the dentate gyrus (DG) of ovariectomized (a model of surgical menopause) young adult Sprague–Dawley rats using daily subcutaneous injections of 17β-estradiol, estrone or vehicle. Rats were injected with a DNA synthesis marker, 5-bromo-2-deoxyuridine (BrdU), and were perfused 1, 2, or 3 weeks after BrdU injection and daily hormone treatment. Brains were sectioned and processed for various markers including: sex-determining region Y-box 2 (Sox2), glial fibrillary acidic protein (GFAP), antigen kiel 67 (Ki67), doublecortin (DCX), and neuronal nuclei (NeuN). Immunofluorescent labeling or co-labelling of BrdU with Sox2 (progenitor cells), Sox2/GFAP (neural progenitor cells), Ki67 (cell proliferation), DCX (immature neurons), NeuN (mature neurons) was used to examine the trajectory and maturation of adult-born neurons over time. Estrogens had early (1 week of exposure) effects on different stages of neurogenesis (neural progenitor cells, cell proliferation and early maturation of new cells into neurons) but these effects were less pronounced after prolonged treatment. Estradiol enhanced, whereas estrone reduced cell proliferation after 1 week but not after longer exposure to either estrogen. Both estrogens increased the density of immature neurons (BrdU/DCX-ir) after 1 week of exposure compared to vehicle treatment but this increased density was not sustained over longer durations of treatments to estrogens, suggesting that the enhancing effects of estrogens on neurogenesis were short-lived. Longer duration post-ovariectomy, without treatments with either of the estrogens, was associated with reduced neural progenitor cells in the DG. These results demonstrate that estrogens modulate several aspects of adult hippocampal neurogenesis differently in the short term, but may lose their ability to influence neurogenesis after long-term exposure. These findings have potential implications for treatments involving estrogens after surgical menopause.