Pauline M. Maki

BackgroundIdentifying risk factors for Alzheimer disease in women is important as women compose two-thirds of individuals with Alzheimer disease. Previous work links vasomotor symptoms, the cardinal menopausal symptom, with poor memory performance and alterations in brain structure, function, and connectivity. These associations are evident when vasomotor symptoms are monitored objectively with ambulatory skin conductance monitors.ObjectiveThis study aimed to determine whether vasomotor symptoms are associated with Alzheimer disease biomarkers.Study DesignBetween 2017 and 2020, the MsBrain study enrolled 274 community-dwelling women aged 45 to 67 years who had a uterus and at least 1 ovary and were late perimenopausal or postmenopausal status. The key exclusion criteria included neurologic disorder, surgical menopause, and recent use of hormonal or nonhormonal vasomotor …

Objective:While modern antiretroviral therapy (ART) is highly effective and safe, depressive symptoms have been associated with certain ART drugs. We examined the association between common ART regimens and depressive symptoms in women with HIV (WWH) with a focus on somatic vs. nonsomatic symptoms.Design:Analysis of longitudinal data from the Women's Interagency HIV Study.Methods:Participants were classified into three groups based on the frequency of positive depression screening (CES-D≥ 16): chronic depression (≥ 50% of visits since study enrollment), infrequent depression (< 50% of visits), and never depressed (no visits). Novel Bayesian machine learning methods building upon a subset-tree kernel approach were developed to estimate the combined effects of ART regimens on depressive symptoms in each group after covariate adjustment.Results:The analysis included 1538 WWH …

Background: Pregnancy alters many physiological systems, including the maternal gut microbiota. Diet is a key regulator of this system and can alter the host immune system to promote inflammation. Multiple perinatal disorders have been associated with inflammation, maternal metabolic alterations, and gut microbial dysbiosis, including gestational diabetes mellitus, preeclampsia, preterm birth, and mood disorders. However, the effects of high inflammatory diets on the gut microbiota during pregnancy have yet to be fully explored. Objective: To use a systems-based approach to characterize associations among dietary inflammatory potential, a measure of diet quality, and the gut microbiome during pregnancy. Methods: Forty-nine pregnant persons were recruited prior to 16 weeks of gestation. Participants completed a food frequency questionnaire (FFQ) and provided fecal samples. Dietary inflammatory potential was assessed using the Dietary Inflammatory Index (DII) from FFQ data. Fecal samples were analyzed using 16S rRNA amplicon sequencing. Differential taxon abundance with respect to DII score were identified, and microbial metabolic potential was predicted using PICRUSt2. Results: Inflammatory diets were associated with decreased vitamin and mineral intake and dysbiotic gut microbiota structure and predicted metabolism. Gut microbial compositional differences revealed a decrease in short chain fatty acid producers such as Faecalibacterium, and an increase in predicted vitamin B12 synthesis, methylglyoxal detoxification, galactose metabolism and multi drug efflux systems in pregnant individuals with increased DII scores …

Those with mild cognitive impairment (MCI), a precursor to dementia, have a gut microbiome distinct from healthy individuals, but this has only been shown in healthy individuals, not in those exhibiting several risk factors for dementia. Using amplicon 16S rRNA gene sequencing in a case-control study of 60 older (ages 55–76), obese, predominately female, African American adults, those with MCI (cases) had different gut microbiota profiles than controls. While microbial community diversity was similar between cases and controls, the abundances of specific microbial taxa weren’t, such as Parabacteroides distasonis (lower in cases) and Dialister invisus (higher in cases). These differences disappeared after adjusting for markers of oxidative stress and systemic inflammation. Cognitive scores were positively correlated with levels of Akkermansia muciniphila, a bacterium associated with reduced inflammation. Our study shows that gut microbial composition may be associated with inflammation, oxidative stress, and MCI in those at high risk for dementia.

ObjectiveWomen with HIV(WWH) are more likely to discontinue/change antiretroviral therapy(ART) due to side effects including neuropsychiatric symptoms. Efavirenz and integrase strand transfer inhibitors(INSTIs) are particularly concerning. We focused on these ART agents and neuropsychiatric symptoms in previously developed subgroups of WWH that differed on key sociodemographic factors as well as longitudinal behavioral and clinical profiles. WWH from the Women’s Interagency HIV Study were included if they had ART data available, completed the Perceived Stress Scale-10 and PTSD Checklist-Civilian. Questionnaires were completed biannually beginning in 2008 through 2016. To examine ART-symptom associations, constrained continuation ratio model via penalized maximum likelihood were fit within 5 subgroups of WWH. Data from 1882 WWH contributed a total of 4598 observations. 353 women …

BackgroundPrenatal depression affects ∼12% of pregnant women in the United States and is associated with an increased risk of adverse birth outcomes and maternal mortality. Adherence to a healthy dietary pattern may reduce and/or protect against depressive symptoms.ObjectivesTo investigate the relationship between adherence to a Mediterranean diet and depressive symptoms among pregnant women in the United States.MethodsWe used data from the National Health and Nutrition Examination Survey (2005–2018, N = 540) and included pregnant women aged 18–44 y with a positive urine pregnancy test. The Mediterranean diet score (aMED) was calculated from 1 24-h recall; aMED typically ranges from 0–9, but in these analyses, it ranged from 0–8 because alcohol was not included. The aMED score was dichotomized as high (>3) compared with low (≤3). The Patient Health Questionnaire-9 (PHQ-9 …

Women have a greater risk of developing Alzheimer's disease (AD) compared to men. This biological sex difference is primarily due to the greater longevity of women compared to men, but other factors also contribute to this difference, including a greater risk of AD among those with the apolipoprotein epsilon 4 (APOE4) genetic risk factor. Sex steroid hormones have myriad effects on the central nervous system, and other bodily systems that play an important role in brain health, including immune, metabolic and cardiovascular systems. Knowledge of the brain changes that occur in menopause is limited by the lack of large-scale longitudinal neuroimaging studies of women transitioning through the menopause, though such studies are currently underway. Initial evidence from cross-sectional studies and small longitudinal studies suggest that both brain structure and function may undergo changes, and that AD …

Background During the menopause transition, levels of estradiol (E2) ecline. Although these changes are likely key determinants of cognition and brain structure during the menopause transition, how they are related to brain volume in women at elevated risk of Alzheimer’s disease (AD) is not known. We predict associations of endogenous E1 and E2 levels to regional brain volumes will depend on APOE4 carrier status, such that the associations between lower levels of E1 and E2 and lower regional brain volumes will be more positive among APOE4 carriers. Methods Participants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 191, mean age 59.4 +/‐ 3.4 years, 45 APOE4 carriers, 84.3% white). Serum E1 and E2 were assessed using liquid chromatography‐tandem mass spectrometry. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE …

An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes are key to unleashing Aβ effects in pathological tau phosphorylation. In a large study (n= 1,016) across three cohorts, we tested whether astrocyte reactivity modulates the association of Aβ with plasma tau phosphorylation in CU people. We found that Aβ pathology was associated with increased plasma phosphorylated tau levels only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau-PET analysis revealed that tau tangles accumulated as a function of Aβ burden only in CU Ast+ individuals with a topographic distribution compatible with early AD …

BackgroundNeuroactive steroids (NAS) surge early in pregnancy and may be a biomarker for perinatal depression. Their role in perinatal-emergent depression versus persistent depression in early pregnancy is unknown. We compared first trimester (T1) NAS levels in low-income persons of color with T1-emergent depression, persistent depression perinatally with a history of depression, those euthymic with a history of depression, and never depressed participants.MethodsParticipants (n= 40, 53% Black) provided blood samples for NAS assays and completed a self-reported mental health history and diagnostic depression measure (CAD-MDD) before 16 weeks gestation (range 5-15 wk). Linear regression models assessed the association between history of depression and current T1 depression status with T1 levels of 4 NAS: allopregnanolone (ALLO), isoallopregnanolone (ISO), pregnanolone (PA), and …

An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast+ individuals. Our findings suggest astrocyte reactivity …

African American adults have a higher prevalence of Alzheimer’s dementia (AD) than non-Hispanic Whites. The impact of a Mediterranean Diet (Med Diet) and intentional weight loss (IWL) on the gut microbiome may alter AD risk. A post hoc analysis of the Building Research in Diet and Cognition (BRIDGE) trial was performed to determine whether participation in an 8-month Med Diet lifestyle intervention with (n = 35) or without IWL (n = 31) was associated with changes in gut microbiota structure, abundance, and function and whether these changes were related to changes in cognitive performance. The results showed that family and genus alpha diversity increased significantly in both groups combined (p = 0.0075 and p = 0.024, respectively). However, there were no other significant microbially related within- or between-group changes over time. Also, an increase in Med Diet adherence was significantly associated with a decrease in alpha diversity at the phylum level only (p = 0.049). Increasing alpha diversity was associated with decreasing cognitive performance, but this association was attenuated after controlling for Med Diet adherence. In sum, an 8-month Med Diet lifestyle intervention with or without IWL did not appreciably alter the gut microbiome.

Background APOE4 genotype is a stronger risk factor for Alzheimer’s disease (AD) in women than men, and its influence on memory and AD biomarkers differs by disease stage. Among cognitively normal older APOE4 carriers, APOE4 status influences memory similarly in males and females but adversely influences hippocampal volume in males. The effect of APOE4 status on regional brain volumes earlier in life, and in relation to memory, are less well understood. We examined whether associations between verbal memory performance and regional brain volumes differed by APOE4 status in cognitively normal midlife women. We hypothesized that APOE4 carriers would show weaker associations between memory performance and brain volumes than non‐carriers, particularly in the temporal lobe. Method Participants were enrolled in MsBrain, a cohort study of midlife women. Verbal memory was assessed …

Background and ObjectivesThe menopause transition is increasingly recognized as a time of importance for women's brain health. A growing body of work indicates that the classic menopausal symptom, vasomotor symptom (VMS), may be associated with poorer cardiovascular health. Other work links VMS to poorer cognition. We investigate whether VMS, when rigorously assessed using physiologic measures, are associated with greater white matter hyperintensity volume (WMHV) among midlife women. We consider a range of potential explanatory factors in these associations and explore whether VMS are associated with the spatial distribution of WMHV.MethodsWomen aged 45–67 years and free of hormone therapy underwent 24 hours of physiologic VMS monitoring (sternal skin conductance), actigraphy assessment of sleep, physical measures, phlebotomy, and 3 Tesla neuroimaging. Associations between …

Mental health conditions are the leading cause of pregnancy-related death in Illinois (40%) and across the United States (21%).(1, 2) There is increasing recognition in primary care that major depressive disorder (MDD) often co-occurs with other mental health conditions. Funding bodies, such as the Agency for Healthcare Research and Quality (3) and the Health Resources and Service Administration,(4) have spotlights on improving screening and access to care for depression and substance use disorders (SUDs). However, the needs of individuals with multiple mental health conditions still often go unrecognized and unaddressed in perinatal health settings.The US Preventive Services Task Force recommends that all adults be screened for depression, alcohol use, and drug use, and will be recommending screening for anxiety.(5, 6) The American College of Obstetrics and Gynecology recommends screening for …

ObjectiveSexual and physical abuse are highly prevalent among women living with HIV (WLWH) and are risk factors for the development of mental health and substance use disorders (MHDs, SUDs), and cognitive and medical comorbidities. We examined empirically derived patterns of trauma, MHD, and SUD, and associations with later cognitive and health outcomes.MethodsA total of 1027 WLWH (average age= 48.6 years) in the Women’s Interagency HIV Study completed the World Mental Health Composite International Diagnostic Interview from 2010 to 2013 to identify MHDs, SUDs, and age at onset of sexual and physical abuse. Then, cognitive impairment, cardiovascular/metabolic conditions, and HIV disease outcomes were assessed for up to 8.8 years. Latent class analysis identified patterns of co-occurring trauma, MHDs, and/or SUDs. Generalized estimating equations determined associations between …

ObjectiveTo assess the rates and feasibility of assessing comorbid mental health disorders and referral rates in low-income urban and rural perinatal patients.MethodsIn two urban and one rural clinic serving primarily low-income perinatal patients of color, a computerized adaptive diagnostic tool CAT-MH® was implemented to assess major depressive disorder (MDD), general anxiety disorder (GAD), suicidality (SS), substance use disorder (SUD), and post-traumatic stress disorder (PTSD) at the first obstetric visit and/or 8 weeks postpartum.ResultsOf a total of 717 screens, 10.7% (n = 77 unique patients) were positive for one or more disorders (6.1% one, 2.5% two, 2.1% three or more). MDD was the most common disorder (9.6%) and was most commonly comorbid with GAD (33% of MDD cases), SUD (23%), or PTSD (23%). For patients with a positive screen, referral to treatment was 35.1% overall, with higher …

Background A significant percentage of Aβ‐positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, cognitive decline.Experimental literature suggest that reactive astrocytes are necessary to unleashing Aβ effects in pathological tau phosphorylation.Here we aimed to investigate whether astrocyte reactivity is key to determining the association of Aβ burden with early tau phosphorylation in preclinical Alzheimer’s disease (AD). Method We assessed 1,016 CU individuals from two research and one population‐based cohort (TRIAD, Pittsburgh and MYHAT) with Aβ (plasma or PET), plasma p‐tau and GFAP measures. Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aβ‐ individuals.Lowess method and linear regressions accounting for age and sex were used to …

Perinatal depression (PND) is one of the most common medical complications during pregnancy and postpartum period, affecting 10–20% of pregnant individuals. Black and Latina women have higher rates of PND, yet they are less likely to be diagnosed and receive treatment. Machine learning (ML) models based on Electronic Medical Records (EMRs) have been effective in predicting postpartum depression in middle-class White women but have rarely included sufficient proportions of racial and ethnic minorities, which contributed to biases in ML models for minority women. Our goal is to determine whether ML models could serve to predict depression in early pregnancy in racial/ethnic minority women by leveraging EMR data. We extracted EMRs from a hospital in a large urban city that mostly served low-income Black and Hispanic women (N= 5,875) in the US Depressive symptom severity was assessed from …

Higher stress during pregnancy associates with negative outcomes and elevated inflammation. The gut microbiota, reflecting environment and social interactions, alongside host immune responses have the potential to better understand perceived stress and identify when stress is excessive in pregnancy. Two U.S. cohorts of 84 pregnant individuals, composed of urban women of color and suburban white women, completed the Perceived Stress Scale-10 (PSS-10) and provided fecal and blood samples at two time points. Confirmatory Factor Analysis assessed the robustness of a two-factor PSS-10 model (Emotional Distress/ED and Self-Efficacy/SE). Gut microbiota composition was measured by 16 S rRNA amplicon sequencing and the immune system activity was assessed with a panel of 21 T-cell related cytokines and chemokines. ED levels were higher in the suburban compared to the urban cohort, but levels …