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Background As the number of older people with HIV is expected to grow and experience age-related cognitive declines, concerns mount that such existing cognitive impairments may become exacerbated in already cognitively vulnerable subgroups such as women with HIV. These cognitive impairments can develop into everyday functional impairment in either basic or instrumental activities of daily living. Methods In the Women’s Interagency HIV Study, we examined the association between objective cognitive test performance and the self-rated Lawton and Brody scale of Independent Activities of Daily Living (IADL) in 754 older (50+) women with HIV (WWH; 84% virally suppressed). To handle this longitudinal data, weighted logistic mixed effect models examined associations between cognitive domain performance (predictor) and functional outcomes (IADL item level scores). Results In the total sample, poorer motor performance was associated with impairments in home repairs, housekeeping, and laundry and poorer executive functioning was associated with impairment in planning social activities. Among older virally suppressed-WWH, poorer motor performance was associated with deficits in home repair and poorer executive performance was associated with deficits in planning social activities. Conclusion Since motor and executive performance were related to impairments in certain IADLs, strategies such as cognitive training targeting these domains could improve everyday functioning. Such approaches could improve autonomy as WWH age.

To investigate if accounting for a cup-to-disc ratio (CDR) genetic risk score (GRS) modified the association between large CDR and cognitive function among women. This was a retrospective study using data from the Women's Health Initiative. Patients with glaucoma or ocular hypertension were excluded. Large CDR was defined as ≥ 0.6 in either eye. Cognitive function was measured by the Modified Mini-Mental State Examination (3MSE). We used the combined effects from 13 single nucleotide polymorphisms (SNPs) to formulate the GRS for CDR. We used logistic regression to investigate associations between weighted GRS and large CDR, then a linear regression to assess the association between weighted GRS and 3MSE scores, and between weighted GRS, CDR, and 3MSE scores, adjusted for demographic and clinical characteristics. Final analyses included 1,196 White women with mean age of 69.60 ± 3.62 years and 7.27% with large CDR. Mean GRS in women with and without large CDR was 1.51 ± 0.31 vs. 1.41 ± 0.36, respectively (p = 0.004). The odds of large CDR for a one unit increase in GRS was 2.30 (95% CI: (1.22, 4.36), p = 0.011). Adding the CDR GRS in the model with CDR and 3MSE, women with large CDR still had statistically significantly lower 3MSE scores than those without large CDR, yielding a predicted mean difference in 3MSE scores of 0.84 (p = 0.007). Independent of the CDR GRS, women with large CDR had a lower cognitive function.

INTRODUCTION Disrupted rest‐activity rhythms (RARs) have been linked to poorer cognitive function and Alzheimer's disease (AD) biomarkers. Here we extend this work to midlife women, who commonly experience menopause‐related sleep and cognitive problems. METHODS One hundred ninety‐four postmenopausal participants underwent a neuropsychological evaluation, 72 h of wrist actigraphy generating RAR variables, and a blood draw to measure AD biomarkers: phosphorylated tau (p‐tau181, p‐tau231) and amyloid beta (Aβ40, Aβ42). RESULTS Lower interdaily stability (IS) and relative amplitude (RA) and higher interdaily variability (IV) and least active 5 h (L5) were associated with worse processing speed, independent of sleep. Adjustment for sleep significantly attenuated the associations of RA with memory. Lower RA was associated with higher p‐tau231 level, independent of sleep. Further adjustment for menopause‐related factors modestly accounted for the associations between RAR, cognitive measures, and AD biomarkers. DISCUSSION Weaker RAR, particularly RA, was associated with worse cognitive functions, and higher AD biomarkers levels, possibly linking RAR with AD pathology in women. Highlights Lower rhythm stability and robustness and higher fragmentation were associated with worse processing speed. Lower robustness was associated with higher levels of phosphorylated tau‐231. Menopause factors did not attenuate the association between rest‐activity rhythms and cognitive function.

We determined whether the effect of apolipoprotein E (APOE)-ε4 genotype on Alzheimer's disease (AD) markers differs in men and women across AD stages. Among normal control (NC) participants (N = 702) and participants with mild cognitive impairment (N = 576) and AD (N = 305), we examined the associations of sex and APOE-ε4 carrier status with cortical amyloid-β (Aβ) burden, hippocampal volume ratio (HpVR; hippocampal volume/intracranial volume × 103), brain glucose metabolism, and verbal memory. In NC, APOE-ε4 related to greater Aβ burden and poorer verbal memory across sex but to smaller HpVR and hypometabolism in men only. In mild cognitive impairment, APOE-ε4 related to smaller HpVR, hypometabolism, greater Aβ burden, and poorer verbal memory across sex. In AD, APOE-ε4 related to greater Aβ burden in men only and smaller HpVR across sex and showed no association with hypometabolism or verbal memory. Sex differences in the association between APOE-ε4 and AD markers vary by disease stage.

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 of SE were similar. ED and SE levels were associated with distinct taxonomical signatures and the gut microbiota data improved the prediction of SE levels compared with models based on socio-demographic characteristics alone. Integration of self-reported symptoms, microbial and immune information revealed a possible mediation effect of Bacteroides uniformis between the immune system (through CXCL11) and SE. The study identified links between distinct taxonomical and immunological signatures with perceived stress. The data are congruent with a model where gut microbiome and immune factors, both impacting and reflecting factors such as close social relationships and dietary fiber, may modulate neural plasticity resulting in increased SE during pregnancy. The predictive value of these peripheral markers merit further study.

Introduction: The female advantage in brain metabolic function may confer cognitive resilience against Alzheimer's disease (AD). Methods: A total of 1259 participants (44% women; 52% mild cognitive impairment; 18% AD) aged 55 to 90 from the Alzheimer's Disease Neuroimaging Initiative (ANDI) completed tests of global cognition, verbal memory, and executive function, and neuroimaging assessments of regional glucose metabolism, hippocampal volume (HV), and amyloid beta (Aβ). We examined sex differences in brain metabolism and cognition by AD biomarker quartiles (Aβ, HV). We then examined if metabolism mediates sex differences in cognition. Results: Metabolism was higher in women versus men when pathology was mild‐to‐moderate (quartiles 2 to 3). Women outperformed men on all cognitive outcomes at ≥1 biomarker quartile, reflecting minimal‐to‐moderate pathology; however, these differences were eliminated/attenuated after adjusting for metabolism. The female advantage in verbal memory was also observed at minimal pathology quartiles but was unchanged after metabolism adjustment. Discussion: Women's greater brain metabolism may confer cognitive resilience against early AD.

Women carrying the allele are at greater risk of developing Alzheimer's disease (AD) from ages 65-75 years compared to men. To better understand the elevated risk conferred by carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and carrier status on regional brain volumes in a sample of late midlife postmenopausal women. Participants were enrolled in MsBrain, a cohort study of postmenopausal women (  = 171, mean age = 59.4 years, mean MoCA score = 26.9; race = 83.2% white, carriers = 40). Serum estrone (E1) and estradiol (E2) levels were assessed using liquid chromatography-tandem mass spectrometry. APOE genotype was determined using TaqMan SNP genotyping assays. Plasma AD biomarkers were measured using single molecule array technology. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Multiple linear regression models were conducted to determine whether separate and interactive associations between endogenous estrogen levels, plasma AD biomarkers (Aβ42/Aβ40, Aβ42/p-tau181), and carrier status predict regional brain volume (21 regions per hemisphere, selected ); and, whether significant interactive associations between estrogens and AD biomarkers on brain volume differed by carrier status. There was no main effect of carrier status on regional brain volumes, endogenous estrogen levels, or plasma AD biomarkers. Estrogens did not associate with regional brain volumes, except for positive associations with left caudal middle frontal gyrus and fusiform volumes. The interactive association of estrogens and carrier status on brain volume was not significant for any region. The interactive association of estrogens and plasma AD biomarkers predicted brain volume of several regions. Higher E1 and E2 were more strongly associated with greater regional brain volumes among women with a poorer AD biomarker profile (lower Aβ42/40, lower Aβ42/p-tau181 ratios). In -stratified analyses, these interactions were driven by non- carriers. We demonstrate that the brain volumes of postmenopausal women with poorer AD biomarker profiles benefit most from higher endogenous estrogen levels. These findings are driven by non- carriers, suggesting that carriers may be insensitive to the favorable effects of estrogens on brain volume in the postmenopause.

BACKGROUNDIdentifying a quantitative biomarker of neuropsychiatric dysfunction in people with HIV (PWH) remains a significant challenge in the neuroHIV field. The strongest evidence to date implicates the role of monocytes in central nervous system (CNS) dysfunction in HIV, yet no study has examined monocyte subsets in blood as a correlate and/or predictor of neuropsychiatric function in virally suppressed PWH.METHODSIn 2 independent cohorts of virologically suppressed women with HIV (vsWWH; n = 25 and n = 18), whole blood samples were obtained either in conjunction with neuropsychiatric assessments (neuropsychological [NP] test battery, self-report depression and stress-related symptom questionnaires) or 1 year prior to assessments. Immune cell subsets were assessed by flow cytometry.RESULTSA higher proportion of intermediate monocytes (CD14+CD16+) was associated with lower global NP function when assessing monocytes concurrently and approximately 1 year before (predictive) NP testing. The same pattern was seen for executive function (mental flexibility) and processing speed. Conversely, there were no associations with monocyte subsets and depression or stress-related symptoms. Additionally, we found that a higher proportion of classical monocytes was associated with better cognition.CONCLUSIONAlthough it is widely accepted that lentiviral infection of the CNS targets cells of monocyte-macrophage-microglial lineage and is associated with an increase in intermediate monocytes in the blood and monocyte migration into the brain, the percentage of intermediate monocytes in blood of vsWWH has not been associated with neuropsychiatric outcomes. Our findings provide evidence for a new, easily measured, blood-based cognitive biomarker in vsWWH.FUNDINGR01-MH113512, R01-MH113512-S, P30-AI094189, R01-MH112391, R01-AI127142, R00-DA044838, U01-AI35004, and P30-MH075673.

Approximately 4% to 8% of pregnant individuals meet the criteria for current posttraumatic stress disorder (PTSD), a known risk factor for a multitude of adverse maternal and child health outcomes. However, PTSD is rarely detected or treated in obstetric settings. Moreover, available prenatal PTSD treatments require in-person services that are often inaccessible due to barriers to care. Thus, web-based interventions offer great potential in extending PTSD treatment to high-risk pregnant individuals by providing affordable, accessible care. However, there are currently no web-based interventions designed specifically for the treatment of PTSD symptoms during pregnancy. This study aims to develop and pilot a 6-week, web-based, cognitive behavioral therapy intervention for PTSD, SunnysideFlex, in a sample of 10 pregnant women with current probable PTSD. Consistent with established guidelines for developing and testing novel interventions, the focus of this pilot study was to evaluate the initial feasibility and acceptability of the SunnysideFlex intervention and preintervention to postintervention changes in PTSD and depression symptoms. This approach will allow for early refinement and optimization of the SunnysideFlex intervention to increase the odds of success in a larger-scale clinical trial. The SunnysideFlex intervention adapted an existing web-based platform for postpartum depression, Sunnyside for Moms, to include revised, trauma-focused content. A total of 10 pregnant women in weeks 16 to 28 of their pregnancy who reported lifetime interpersonal trauma exposure (ie, sexual or physical assault) and with current probable PTSD (scores ≥33 per the PTSD checklist for DSM-5) were enrolled in the SunnysideFlex intervention. Assessments took place at baseline and 6 weeks (postintervention). All participants were retained through the postintervention assessment period. Engagement was high; participants on average accessed 90% of their lessons, logged on to the platform at least weekly, and reported a generally positive user experience. Moreover, 80% (8/10) of participants demonstrated clinically meaningful reductions in PTSD symptoms from baseline to postintervention, and 50% (5/10) of participants no longer screened positive for probable PTSD at postintervention. Most (6/10, 60%) of the participants maintained subclinical depression symptoms from baseline to postintervention. Findings from this small pilot study indicate that SunnysideFlex may be a feasible and acceptable mechanism for delivering PTSD intervention to high-risk, trauma-exposed pregnant women who might otherwise not have opportunities for services. Larger-scale trials of the intervention are necessary to better understand the impact of SunnysideFlex on PTSD symptoms during pregnancy and the postpartum period.

The population of the developed world is ageing; consequently there is an increasing prevalence of age-related neuropsychiatric disorders, such as dementia of any cause and Alzheimer's disease (AD), for which few treatments are available. Observational studies suggested that hormone therapy (HT) might protect postmenopausal women against cognitive decline and AD. However, the results of randomised controlled trials in women age 65 years and older were negative. There has been extensive media coverage of these trials and many doctors are asked whether HT improves or worsens brain function in younger women who are prescribed HT for the treatment of menopausal symptoms. The Women's Health Inititiative Memory Study (WHIMS) was a multicentre, randomised, double-blind, placebo-controlled clinical trial in which a subgroup of women who participated in the Women's Health Initiative study were assessed for the effects of HT on dementia and mild cognitive impairment. There were two study arms, one involving 4532 postmenopausal women who received continuous combined oestrogen (conjugated equine oestrogens [CEE] plus medroxyprogesterone acetate) or placebo, and the other involving 2947 hysterectomised women randomised to continuous unopposed CEE or placebo. All participants were age 65 years or older. CEE with or without medroxyprogesterone acetate, given to women age 65 years and older, does not protect against dementia or cognitive decline, but substantially increases the risk of dementia of any cause and cognitive decline. WHIMS answered critically important questions about whether HT can protect against dementia in elderly women who start HT some years after menopause. However, several clinically important questions are unanswered, including questions about the generalisability of WHIMS to groups of women for whom HT is an indication—perimenopausal women and those soon after menopause who have menopausal symptoms—and other methods of treatment delivery and treatment regimens.