Psychoneuroendocrinology

The menopausal transition represents a major neuroendocrine shift marked by declining estradiol and progesterone, rising follicle-stimulating hormone, and increased vulnerability to cognitive and affective symptoms. Despite extensive evidence of hormone-related neural changes, few biomarkers directly index hormone-sensitive neuronal adaptations in vivo. Neuron-enriched extracellular vesicles (nEVs) isolated from blood provide a minimally invasive window into central nervous system (CNS) biology by carrying microRNAs (miRNAs) linked to neuronal regulatory processes. This pilot study tested whether L1 cell adhesion molecule (L1CAM)-positive nEV miRNA profiles differ between early (STRAW stage - 2; n = 22) and late (STRAW stage - 1; n = 24) perimenopause. A pooled discovery screen of 179 miRNAs identified 10 candidates with substantial fold-change differences between groups; these were then quantified at the individual level using qPCR. Linear mixed-effects models showed a significant main effect of STRAW stage, with late perimenopause associated with higher {Delta}Cq values (lower overall expression) across the miRNA panel. The miRNA x STRAW stage interaction was not significant, indicating a coordinated shift across the measured miRNAs rather than miRNA-specific regulation. No evidence of an association between nEV miRNA expression and current estradiol levels or menopausal symptom severity was observed. Bioinformatic analysis of predicted mRNA targets identified significant enrichment of the gonadotropin-releasing hormone (GnRH) receptor pathway, along with related growth factor, immune, and intracellular signaling pathways, with preferential expression in brain-relevant tissues. These findings are consistent with stage-related differences in hormone-sensitive neuronal regulatory processes across the transition.

ImportanceBlood-based biomarkers hold promise for psychiatric diagnosis and prognosis, yet clinical translation is constrained by poor reproducibility. Psychiatric biomarker studies are typically small, and demographic, behavioral, and temporal covariates often go undetected or cannot be adequately modeled. This may lead to residual confounding and unstable associations. ObservationsLeveraging UK Biobank data (N=~500,000), we systematically quantified how technical, demographic, behavioral, and temporal covariates influence 29 blood biomarkers commonly measured in research studies in psychiatry. Variance analyses showed substantial differences across biomarkers. Technical factors explained 1-6% and demographic factors explained 5-15% of the variance, with pronounced age-by-sex interactions for lipids and sex hormones. Behavioral covariates, particularly body mass index (BMI) and smoking, strongly influenced inflammatory markers. Temporal factors introduced systematic confounding. Chronotype was associated with blood collection time, multiple biomarkers exhibited marked diurnal rhythms (including testosterone, triglycerides, and immune markers), and inflammatory markers showed seasonal peaks in winter. In association analysis of biomarkers with major depression, bipolar disorder and schizophrenia, covariate adjustments attenuated or eliminated a substantial proportion of the biomarker-disorder associations, with BMI emerging as the dominant confounder. These findings demonstrate that such confounding structures exist and can be characterized in large cohorts, though specific biomarker-disorder relationships require validation in clinical samples. Conclusions and RelevancePoor reproducibility of biomarkers may not only stem from insufficient biological signal but also from inconsistent handling of confounders. We propose a systematic framework distinguishing technical factors (to be removed), demographic factors (addressed through adjustment or stratification), temporal factors (ideally controlled at design stages), and behavioral factors (requiring explicit causal reasoning). Associations robust to multiple adjustment strategies should be prioritized for clinical biomarker development. Standardized collection protocols, comprehensive covariate measurement, and transparent reporting across models are essential to improve reproducibility and identify biomarkers that reflect genuine illness-related pathophysiology.

Background: Early adolescence is a common period of onset for depressive symptoms. In part, this may reflect a developmental manifestation of individual's genetic propensities as they undergo physiological and hormonal changes and interact with new environments. Many commonly proposed mechanisms assume direct effects of an individual's own genes on emerging variation in their depressive symptomatology. However, estimates of genetic influence based on analyses in unrelated individuals capture not only direct genetic effects but also genetic effects from parents and other biologically related family members. Aim: In data from the Norwegian Mother, Father and Child Cohort (MoBa), we used linear mixed models to distinguish developmentally-stable and adolescence-specific direct and parental indirect genetic effects. We examined effects of polygenic scores for major depressive disorder (MDD), ADHD, anxiety disorders, and educational attainment (EA) on depressive symptoms, which were assessed by maternal reports at ages 8 and 14. Results: Children's own MDD polygenic scores showed adolescence-specific effects on depressive symptoms ( b_PGS*wave=0.041, [95% CI: 0.017, 0.065]). Developmentally-stable direct effects from children's polygenic scores for MDD (b=0.016, [0.006, 0.039]), ADHD (b=0.024, [0.008, 0.041]) and EA (b=-0.02, [ -0.038, -0.002]) were also evident. The only evidence of indirect genetic effects was a stable effect of maternal EA polygenic scores (b=0.04, [0.024, 0.054]). Conclusion: Direct genetic effects linked to genetic liability to MDD accounted for emerging variation in depressive symptoms in adolescence. These results imply that specific etiological mechanisms related to MDD may become particularly relevant for depressive symptoms during early adolescence compared to at earlier ages.

Emotions often occur within social interactions where affective cues are accessible or inferable by others. This raises questions regarding how and to which degree social context modulates subjective, physiological and behavioural affective responses, as well as their coherence, questions which remain points of tension in emotion research. To investigate this, we measured subjective affective ratings, autonomic sympathetic and parasympathetic activity, and facial behaviour while participants completed an emotion-induction task. In the social-context condition (but not control), participants believed that their video feed was accessible to a potential future interaction partner. Results show that even such "minimal social context" selectively and differentially modulated affective response modalities, characterised by both intensification of autonomic responses and dampening of overt facial and subjective affect. Multivariate dimensionality analysis further identified a cross-modal affective dimension Interestingly, social context reduced participants coupling with this shared affective response structure, indicating weaker cross-modal coherence. These findings suggest that emotional responding relies on a flexible, rather than rigid, configuration of affective features, likely recruited to meet the socioemotional demands of a given context. This has important implications for understanding the structure and function of emotion, as well as typical and atypical socioemotional responding.

Affective biases are important neuropsychological mechanisms by which emotions modulate cognition, behaviour and the subjective experience of mood. Previous studies have shown that the rapid-acting antidepressant, ketamine, and serotonergic psychedelic, psilocybin, modulate affective biases in a translational rat model. Both treatments differ from conventional, delayed onset antidepressants in being able to attenuate negatively biased memories and facilitate re-learning with a more positive affective valence. Psilocybin, but not ketamine, also positively biased new experiences, an effect similar to conventional antidepressants. This study used the different affective bias test protocols, in adult male rats, to investigate the effects of acute treatment with the serotonergic psychedelics N,N-DMT, LSD and 5-MeO-DMT, and MDMA. These drugs have different pharmacology in relation to their effects on serotonin receptor subtypes and we hypothesised this may influence their modulation of affective biases. When comparing the ability to attenuate a negatively biased memory, only MDMA had specific effects although for all drugs tested, retrieval of the FG7142-induced negative affective bias was more variable and less robust statistically. LSD attenuated the negative bias at higher doses but had non-specific effects on memory retrieval. At 24hrs post treatment only N,N-DMT had a sustained effect and none of the treatments facilitated re-learning with a more positive affective valence. However, like psilocybin and conventional antidepressants, N,N-DMT positively biased new experiences. These findings suggest there are divergent affective bias modulating effects associated with different psychedelics which may be relevant to their antidepressant effects.

Chronotype reflects individual circadian preference for timing of sleep, wakefulness, and peak performance and has been linked to variability in prefrontal cognitive function across the day. Whether chronotype independently relates to dual-task gait cost (DTC) and whether this relationship differs by cognitive task domain is unclear. Sixty-nine healthy young adults (37 female; mean age 21.3 years) completed the Morningness-Eveningness Questionnaire (MEQ). Spatiotemporal gait parameters were recorded with three-dimensional motion capture during single-task walking and three dual-task conditions: backward word spelling (5LWB; phonological), serial subtraction by seven (SS7; arithmetic), and reverse month recitation (RMR; sequential). DTC was calculated for eight gait parameters. Condition differences were assessed with nonparametric tests and post-hoc comparisons. Multiple linear regression, adjusting for age, sex, BMI, and baseline gait velocity, tested the independent association between MEQ score and mean velocity DTC; exploratory Spearman correlations examined other parameters. SS7 produced the largest mean velocity DTC (-12.76%), significantly greater than 5LWB (-7.95%; p = 0.002) and RMR (-9.57%; p = 0.021). MEQ score independently predicted mean velocity DTC in 5LWB ({beta} = -0.51, p < 0.001, R{superscript 2} = 0.269) and RMR ({beta} = -0.55, p = 0.004, R{superscript 2} = 0.222), indicating greater morningness associated with better gait-speed preservation under cognitive load; the SS7 association was not significant ({beta} = -0.33, p = 0.071). Exploratory correlations showed MEQ-DTC associations across 7/8 parameters in 5LWB, 4/8 in RMR, and 3/8 in SS7. Chronotype is independently associated with dual-task gait cost in a task-domain-specific manner, with stronger effects for phonological and sequential tasks than for arithmetic processing. The SS7 condition yielded the largest interference but weakest chronotype modulation, suggesting arithmetic dual-task disruption may be less sensitive to circadian arousal. Fixed testing time and cross-sectional design warrant within-subject, multi-timepoint studies to confirm chronotype effects separate from time-of-day confounds.

Importance: Adverse neighborhood conditions can lead to poorer health outcomes, potentially through accelerated biological aging. However, whether these relationships are explained by individual- or neighborhood-level factors remains unclear. Objective: To examine the association between neighborhood deprivation, measured by the Area Deprivation Index (ADI), and epigenetic age acceleration and assess whether individual- and neighborhood-level characteristics mediate or modify these associations. Design: Cross-sectional study using data from a Yale Stress Center study between 2008 and 2012. Data analysis was conducted from July 2025 to January 2026. Setting: Community-based sample from the greater New Haven, CT area. Participants: A total of 370 healthy adults aged 18 to 50 years without major psychiatric, medical, or cognitive disorders who provided blood samples for DNA methylation analysis. Main Outcomes and Measures: Epigenetic age acceleration measured from DNA methylation using four second-generation epigenetic clocks, with associations assessed among aging, neighborhood deprivation, and individual- and neighborhood-level factors. Results: Data were analyzed from 370 participants (212 women [57.3%], 158 men [42.7%]; mean [SEM] age, 29.3 [0.46] years). Greater neighborhood deprivation was associated with greater lifetime adversity ({beta}=0.112, p<.001) and lower educational attainment ({beta}=-0.019, p=.012), and accelerated epigenetic aging as measured by GrimAge ({beta}=0.037, p<.001), PCGrimAge ({beta}=0.019, p<.001), and PCPhenoAge ({beta}=0.041, p<.001), but not PhenoAge (p=.23). In multivariable models accounting for individual factors, neighborhood deprivation remained associated with these three clocks. Lifetime adversity partially mediated the association between ADI and accelerated GrimAge (20.3% of total effect) and PCGrimAge (23.3%). Race moderated the direct association between ADI and epigenetic aging, with stronger associations between neighborhood deprivation and accelerated GrimAge ({beta}=0.061, p=.004) and PCPhenoAge ({beta}=0.057, p=.02) observed among Black participants compared to White. Conclusions: Greater neighborhood deprivation was associated with accelerated epigenetic aging across multiple second-generation clocks, with lifetime adversity partially mediating these associations. Stronger effects were observed among Black participants. These findings suggest that neighborhood environments and cumulative stress may contribute to biological aging and racial disparities in aging trajectories.

Background: Alzheimer's disease (AD) exhibits marked sex differences. While sex hormone levels across the lifespan likely contribute to this, little remains known about their causal impact and their relation to sex-biased genetic risk for AD. We therefore sought to identify potential shared genetic architectures, as well as causal genes and relationships, between sex hormone-related traits and AD risk. Methods: Large-scale AD sex-stratified genome-wide association study (GWAS) results were available from case-control, proxy-based, and population-based cohorts, including the Alzheimer's Disease Genetics Consortium, Alzheimer's Disease Sequencing Project, UK Biobank, and FinnGen. Sex hormone-related trait GWAS were available for age at menarche, menopause, and voice breaking, as well as testosterone, sex hormone-binding globulin (SHBG), progesterone, follicle stimulating hormone, luteinizing hormone, and estradiol levels. Cross-trait conjunctional analyses were conducted to identify pleiotropic overlap between sex-hormone traits and AD, followed by prioritization of candidate causal sex-biased AD genes through quantitative trait locus genetic colocalization analyses. The potential regulatory impact of sex hormones on these genes was assessed through transcription factor motif analyses. Finally, sex-stratified mendelian randomization analyses were used to infer causal effects of sex hormones on AD risk. Results: Genome-wide pleiotropy analyses demonstrated enrichment of AD with testosterone, SHBG, and age-at-menarche traits in women. We identified 12 high-confidence pleiotropic loci, 9 of which showed stronger AD effect sizes in women (3 in men) and 8 that were novel. Genes at these loci were often causally implicated in brain tissues and enriched for promoter-associated androgen receptor transcription factor binding motifs. Mendelian randomization indicated higher bioavailable testosterone in women (OR:0.88; 95%-CI:0.82-0.96) and higher SHBG levels in men (OR:0.86; 95%-CI:0.77-0.96) were associated with lower AD risk. Conclusions: Our findings reveal sex-specific shared genetic architectures between AD and sex hormone-related traits and nominate related genes that may drive sex-biases in AD risk. Several of the implicated female-biased genes are relevant to phosphatidylinositol and lipid metabolism, including Fatty Acid Desaturase 2 (FADS2). While we observed no causal effect of estradiol-related traits on AD risk, the protective effects of bioavailable testosterone in women and SHBG in men provide targets for sex-informed AD risk stratification and prevention strategies.

Alzheimers disease (AD) neuropathological changes can be detected with blood-based biomarkers during the long preclinical phase that precedes clinical diagnosis. Tau phosphorylated at threonine 217 (p-tau217) has been found to closely correlate with brain A{beta} burden. A recent large-scale cross-sectional study showed elevated p-tau217 concentrations in older individuals (Aarsland et al., 2025). This increase was higher in those with AD dementia and mild cognitive impairment (MCI), and lower in those with intact cognition and higher educational attainment. Thus, intact cognition and higher education may be associated with lower levels of AD neuropathological changes. Here we tested this hypothesis using longitudinal data from the population-based Betula study (n=1005; 1531 samples). The results revealed increases with increasing age over 10 years in p-tau217, where individuals with accelerated episodic-memory decline had the strongest increase. There were no differences in p-tau217 trajectories between individuals with lower or higher education or with well-maintained or age-typical decline in episodic memory. The lack of association with education was further replicated in the independent BioFINDER-2 cohort. These findings underscore the value of plasma p-tau217 for detecting early pathological changes in population-based settings but provide no support that individuals with well-maintained episodic memory or high educational attainment are spared from neuropathological changes.

ObjectiveTo examine whether menopausal women who initiate systemic menopausal hormone therapy (MHT) around menopause (45-60 years old) have a different risk of developing dementia than those not taking MHT. DesignSystematic review and meta-analysis of randomised controlled trials and longitudinal observational studies. Risk of bias was assessed using ROB-2 and ROBINS I-V2. Data sourcesMEDLINE, Web of Science, EMBASE, and Cochrane Library to 27 March 2026. Eligibility criteria for selecting studiesStudies which measured dementia or cognitive decline in women who initiated systemic MHT between ages 45-60 or within 5 years of menopause, compared with placebo or no MHT. Authors contacted for additional details if needed. Main outcome measuresDementia, Alzheimers disease (AD), cognitive decline. Results10 studies totalling 213,678 participants (189,525 in studies with the primary population). There was no significant increased risk in women with a uterus for all cause dementia (pooled hazard ratio (HR): 1.12; 95% CI 0.91-1.31, N=78,613, I2 = 96.9%), but increased AD risk (HR: 1.14; 95% CI 1.02, 1.29, N=134,865, I2 = 35.6%). Results were similar in sensitivity analyses including women with or without a uterus. Results for cognitive decline were variable. ConclusionsMHT initiated around the age of menopause should not be prescribed for cognition or dementia prevention. It is not protective against dementia and may increase risk slightly. The magnitude of risk was similar in AD and dementia, but the latter with larger confidence intervals. Studies which followed up individuals rather than on health records lost people to follow up. This may account for difference in cognitive decline outcomes between studies, as people with cognitive impairment and dementia are more likely not to attend. MHT prescribing should balance benefits against risks, including evidence of a small increased dementia risk. There are few high-quality studies, so further research would inform recommendations. Systematic review registration Prospero CRD420251010663 What is already known on this topic?O_LIMenopausal hormone therapy (MHT) is effective for alleviating vasomotor symptoms. Contemporary guidelines recommend treatment should be initiated for such symptoms under age 60 and or within 10 years of menopause onset. C_LIO_LIA large randomised trial on the topic found increased risk of dementia in women initiating MHT after the age of 65. C_LIO_LIIt is unknown whether initiating MHT around the age of menopause impacts the risk of dementia or cognitive decline. C_LI What this study addsO_LIThere was no evidence that taking MHT around the time of menopause decreases the risk of dementia or cognitive impairment. C_LIO_LIThey should not be prescribed for these indications. C_LIO_LIWe were able to find more studies which examine this question by contacting authors for additional data. C_LIO_LIInitiating MHT in women with a uterus around the age of menopause increased the risk of Alzheimers disease slightly, by over 10%, and there is a similar but not significant effect in the fewer studies of all cause dementia. Women with or without a uterus show similar results. C_LIO_LIWe found no significant difference shown in cognitive decline, possibly due to loss to follow up. This may be because most studies of cognitive decline follow up C_LI

BackgroundX chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to equalise gene expression between 46, XX females and 46, XY males. Though XCI is expected to result in a random pattern of mosaicism across tissues, some females display a significantly unbalanced ratio in immune cells, termed XCI-skew, in which [&ge;]75% of cells have the same X inactivated. XCI-skew is associated with adverse health outcomes and its prevalence increases with age - particularly after midlife - yet the specific risk factors have yet to be identified. The menopausal transition, which is driven by profound shifts in sex hormone levels, has significant impact on chronic disease risk yet the molecular and cellular effects are incompletely understood. We hypothesised that the menopausal transition may impact XCI-skew. MethodsUsing XCI data measured in blood-derived DNA from 1,395 females from the TwinsUK population cohort, along with questionnaires, genetic data, and sex hormone measures, we carried out a cross-sectional study to assess the impact of the menopausal transition and sex hormones on XCI-skew. ResultsWe demonstrate that early menopause (<45yrs) is associated with increased risk of XCI-skew. In subset analyses across those who had a surgically induced or natural menopause, we find the association restricted to those who underwent a surgical menopause. We next identify a low polygenic score (PGS) for testosterone levels is significantly associated with XCI-skew, which we replicate in an independent dataset (n=149), while a PGS for age at natural menopause is not associated. Finally, using longitudinal measures across two time points spanning [~]18 years we show XCI-skew is a stable cellular phenotype that typically increases over time. DiscussionThese data represent the first environmental and genetic risk factors of XCI-skew, both of which implicate endogenous sex hormone levels, particularly testosterone. We propose XCI-skew may have clinical relevance in postmenopausal females.

BackgroundThe severity of positive psychotic symptoms largely defines emerging psychosis syndromes. However, depressive and negative symptoms are strongly psychologically and biologically interlinked. A transdiagnostic exploration of symptom severity across early illness syndromes could enhance the understanding of shared common factors and future trajectories of mental illness. We aimed to identify subgroups based on the severity of positive, negative, and depressive symptoms and assess relationships with: 1) premorbid functioning, 2) longitudinal illness course, 3) genetic risk, and 4) brain volume differences. MethodsWe analysed 749 participants from a multisite, naturalistic, longitudinal (18 months) cohort study of: clinical high risk for psychosis (n=147), recent onset psychosis (n=161), and healthy controls (n=286), and recent onset depression (n=155). Participants were stratified into subgroups based on severity of baseline positive, negative, and depression symptoms. Baseline and longitudinal differences between groups for clinical, functioning, and polygenic risk scores (schizophrenia, depression, cross-disorder) were assessed with ANOVAs and linear mixed models. Voxel-based morphometry was used to examine whole-brain grey matter volume differences. Discovery findings were replicated in a held-out sample (n=610). ResultsParticipants were stratified into no (n=241), mild (n=50), moderate (n=182), and severe symptom (n=254) subgroups. The mean (SD) age was 25.3 (6.0) and 344 (47.3%) were male. Symptom severity was associated with poorer premorbid functioning and illness trajectory, greater genetic risk, and lower brain volume. Findings were not confounded by the original study groups or symptoms and were largely replicated. Conclusions and relevanceTransdiagnostic symptom severity is linked to shared aetiologies, prognoses, and biological markers across diagnoses and illness stages. Such commonalities could guide therapeutic selection and future research aiming to detect unique contributions to specific psychopathologies.

Earlier menopause is a risk factor for several age-related diseases, including dementia. The biological pathways linking menopause timing to later-life brain aging are not understood. Leveraging large-scale plasma proteomics in postmenopausal women from the UK Biobank (N=15,012), earlier menopause was associated with upregulation of pro-inflammatory and extracellular matrix degradation pathways, plus accelerated aging across proteomic clocks of organ and cellular aging, including brain and oligodendrocyte aging. Elevated GDF15, a canonical aging marker, was the top protein correlate of earlier menopause. We observed robust replication of menopause timing proteomic shifts in the Women's Health Initiative Long Life Study (N=1,210). In UKB, proteins associated with earlier menopause, including GDF15, exhibited concordant associations with incident dementia risk and brain atrophy, cerebral small vessel disease burden, and white matter microstructural integrity. Collectively, our findings identify proteomic signatures linking ovarian aging to brain aging, providing a framework to inform interventions to reduce dementia risk.

There is a dearth of information on how different cocktails sweetened with different sugars impact brain activity. Glucose enters the brain faster and in greater concentration than fructose and directly affects neuronal activity of melanin-concentrating hormone (MCH) neurons. MCH signaling promotes both glucose drinking and alcohol intake by integrating central and sensory inputs, but it is currently unknown how MCH neuronal activity relates to sweetened cocktail drinking. This study sought to investigate the relationship between MCH activity and sugar-sweetened alcoholic cocktail drinking. We also sought to compare MCH neuronal responses to the sugar solutions without alcohol as well as their response to sensory stimuli. In female and male rats, we used fiber photometry to monitor MCH neurons in response to sensory stimuli and during drinking of 10% glucose, 10% fructose, and glucose or fructose cocktails with 1.25% or 10% alcohol. We found that MCH activity rises in response to a variety of sensory stimuli and peaks before the start of drinking for all cocktails, before returning to baseline near the start of drinking. The cocktail type impacted the dynamics of MCH activity, where increased alcohol concentration resulted in earlier MCH activity for fructose but not glucose cocktails. Finally, we found that peak MCH activity during drinking is correlated with approach behavior for all sugar and cocktail types. These findings suggest that glucose and alcohol may interact to directly influence MCH activity. Further, MCH neurons may regulate cocktail drinking in response to sugar type and alcohol concentration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/719280v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@b992c3org.highwire.dtl.DTLVardef@1526895org.highwire.dtl.DTLVardef@1504c6dorg.highwire.dtl.DTLVardef@c990fc_HPS_FORMAT_FIGEXP M_FIG C_FIG New and noteworthyFiber photometry was used to monitor lateral hypothalamic melanin-concentrating hormone (MCH) neurons in male and female rats during sensory stimuli and drinking of glucose, fructose, or glucose- or fructose-sweetened alcoholic cocktails. Subsecond-scale changes in MCH activity occurred after stimuli. Peak MCH activity during drinking was correlated with approach behavior. Alcohol concentration only impacted MCH activity with fructose cocktails. We discuss the implications of MCH dynamics towards brain function, associative learning, and alcohol use disorder.

Aging is a major risk factor for joint disease, yet the impact of physiological aging on the synovium remains poorly defined. Here we generate a single-cell atlas of murine ankle synovium across age and identify the sublining stromal-myeloid niche as a major site of age-associated remodeling. Aging shifted fibroblast states toward oxidative stress and matrix-remodeling programs, accompanied by sublining collagen accumulation, reduced cellularity, and loss of THY1+ sublining fibroblasts. In parallel, resident synovial macrophages exhibited altered inflammatory and phagocytic responses together with a preferential decline in TIM4+VSIG4- sublining macrophages, without overt local myeloid expansion despite systemic inflammaging. Macrophage depletion experiments further supported a link between sublining macrophages and extracellular matrix homeostasis. Together, these findings provide a reference framework for synovial aging and uncover niche-specific stromal and macrophage alterations associated with aging.

Objective: Childhood poverty is a high-risk context that involves diverse adversities, making it difficult to understand how poverty confers later psychopathology risk and why some children remain resilient despite growing up in poverty. To address this heterogeneity, we quantified adversity-linked vulnerability as adversity-psychopathology coupling and tested whether childhood poverty amplifies this coupling and whether multilevel inhibitory-control profiles stratify vulnerability and resilience within poverty-exposed youth. Methods: We analyzed 10,112 youth (48.4% female; mean age = 9.92 years) from the Adolescent Brain Cognitive Development Study, linking baseline cumulative early-life adversity (ELA) to later behavioral problems across 4 waves. In the stop-signal task fMRI subsample of 7,401 youth, semi-supervised clustering of inhibitory-control activation identified neurofunctional subtypes within poverty-exposed youth. We also tested temperamental inhibitory control as an additional moderator. Results: Childhood poverty amplified the association between cumulative ELA and behavioral problems at baseline ({Delta}{beta} = 0.088; P < .001) and across follow-up waves. Two neurofunctional subtypes were identified within poverty-exposed youth: subtype-1 showed greater vulnerability than higher-income peers ({Delta}{beta} = 0.149; P < .001), whereas subtype-2 showed attenuated vulnerability and did not differ from higher-income peers ({Delta}{beta} = 0.049; P = .135); this pattern persisted longitudinally. Among poverty-exposed youth in subtype-2 with high temperamental inhibitory control, the association between cumulative ELA and later behavioral problems was no longer significant. Conclusions: Childhood poverty strengthened the translation of adversity burden into later behavioral problems, but inhibitory-control profiles differentiated higher- and lower-risk pathways within poverty, highlighting inhibitory control as a candidate target for prevention.

Objective. Menopause is a significant physiological transition with implications for health outcomes (e.g., cardiometabolic), yet gaps remain in understanding the menopause transition, including how menopause timing and type influence health outcomes. Large-scale cohort studies in midlife (age~40-60) females, including the All of Us Research Program (AoURP), provide opportunities to study menopause across diverse populations and data modalities. We characterized menopause-related data in AoURP, focusing on age distributions and concordance between EHR diagnosis codes and self-reported survey responses. Methods. We analyzed menopause-related survey, EHR diagnostic code, and genomic data among ~396,000 participants in AoURP with female sex. We summarized menopause data across modalities, overlap between survey, EHR, and genomic data, and age distributions overall and across sociodemographic characteristics. Results. Among ~396,000 females, surveys captured ~193,000 menopause observations, nearly seven times more than structured EHR diagnoses (~28,000), suggesting under- ascertainement in EHR data. Nearly all females (~99%) with an EHR menopause diagnosis also reported menopause in the survey. Approximately 22,000 participants had intersected EHR, survey, and genomic menopause-related data. Survey-based age patterns matched expectations, with participants <40 years predominantly reporting pre-menopausal status and those >60 years predominantly reporting post-menopausal status. A small subset (N{approx}1,700; 4%) (age>70 years) reported no menopause, suggesting response or recall bias. EHR menopause codes were concentrated after age>45 years, with a notable spike at age 65. Modest differences in survey-based menopause age distributions were observed by sociodemographic characteristics (e.g., race, ancestry). Conclusions. These findings inform sampling strategies, power calculations, phenotype definition, and study design for menopause research using AoURP.

Chronic inflammation is a common feature of aging and is observed across various age-related neurodegenerative diseases, including Alzheimers disease (AD). It has, however, been challenging to develop measurements of brain structure directly linked to peripheral measures of neuroinflammation. This cross-sectional study examined whether plasma levels of markers related to inflammation are associated with diffusion magnetic resonance imaging (dMRI) measures of white matter microstructure: mean diffusivity (MD) and Neurite Orientation Dispersion and Density Imaging (NODDI) free water fraction (FWF) and orientation dispersion index (ODI). Participants included 457 dementia-free individuals (mean age=63.82, SD=7.63). Blood plasma markers related to inflammation included two measures of systemic inflammation, (1) high-sensitivity C-reactive protein (CRP), and (2) a composite of pro-inflammatory cytokines (IL-1, IL-1{beta}, IL-2, IL-6, IL-8, TNF-, TNF-{beta}), as well as (3) glial fibrillary acidic protein (GFAP), a measure of astrocytic activation. Higher cytokine composite levels were associated with higher values of all three measures (FWF, ODI, MD) in cerebral white matter, and with higher ODI in the cerebellar peduncles. Higher CRP levels were associated with higher ODI in cerebral and cerebellar white matter. Associations with GFAP were not significant after adjusting for multiple comparisons. Results were consistent after accounting for plasma biomarkers of AD pathology (p-tau181/A{beta}42). Thus, higher levels of peripheral pro-inflammatory markers are associated with white matter microstructure (higher FWF, ODI, and MD), supporting the view that these dMRI-based metrics are sensitive to inflammatory processes. Additionally, the sensitivity of dMRI-based measures to inflammation may differ by inflammatory marker types.

Individuals with autism spectrum disorder (ASD) often exhibit atypical auditory processing, yet it remains unclear whether and how the integration of simple acoustic features and contextual information is impacted in ASD. One real-world example of this integration is the auditory looming bias, the prioritized processing and perception of approaching auditory stimuli. We designed a paradigm that presents intensity-rising (looming) and intensity-falling (receding) auditory stimuli to 3-4-year-old children with ASD (n = 21), children with sensory processing concerns who do not have ASD (SPC; n = 16) and children with typical development (TD; n = 30). We recorded neural responses using electroencephalography (EEG) and found evidence of looming bias in the SPC and TD groups, as indexed by greater P1 peak amplitude during the looming than receding stimuli (TD: t(64) = 6.87, p < .001; SPC: t(64) = 4.07, p < .001). But this finding was not present in the ASD group (p = .194). Additionally, the ASD group showed reduced differentiation between looming and receding stimuli, as indicated by significantly lower Rise-Fall Difference Score (RFDS) in comparison to the TD group (Z = -3.00, padj = .008). These findings suggested altered context-dependent modulation of sensory input in ASD.

BackgroundScalable, low-burden behavioral interventions are needed to address rising subclinical mental health symptoms. However, few randomized controlled trials have evaluated ultra-brief, remotely delivered, meditation using multimodal outcome assessment under real-world conditions. MethodsWe conducted a fully remote randomized controlled trial (ClinicalTrials.gov: NCT06014281) evaluating a focused-attention meditation intervention delivered via brief instructor training and independent daily practice. A total of 299 meditation-naive adults were randomized to immediate intervention or waitlist control in a delayed-intervention design. Participants practiced [&ge;]10 minutes daily for 8 weeks within a 16-week study. Outcomes included validated self-report measures, web-based cognitive tasks, and wearable-derived physiological metrics. ResultsAcross randomized and within-participant replication phases, the intervention was associated with significant reductions in anxiety and mind wandering, with effects remaining stable during 8-week follow-up. Improvements were greatest among participants with higher baseline symptom burden. Sleep disturbance improved selectively among individuals with poorer baseline sleep. Secondary outcomes, including rumination, perceived stress, social connectedness, and quality of life, also improved. Cognitive performance showed modest improvements primarily among lower-performing participants. Resting heart rate exhibited nominal reductions. ConclusionsAn ultra-brief, fully remote meditation intervention requiring 10 minutes per day was associated with sustained improvements in psychological functioning and smaller, baseline-dependent effects on cognition in a non-clinical population. These findings support digital delivery of low-dose meditation as a scalable preventive mental health strategy.