Brain, Behavior, & Immunity - Health

BackgroundObservational studies have linked high adherence to the "Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay" (MIND) diet to improved cognitive functions in older adults. The underlying peripheral and central mechanisms of this association remain poorly understood, although multiple nutrients in the MIND diet are known for their anti-inflammatory effects. Therefore, we explored the cross-sectional relation between MIND diet adherence (Dutch version), systemic inflammation, neuroinflammation, and cognitive functioning in older adults. In addition, we examined the role of intestinal barrier permeability in MIND diet associations with (neuro)inflammation. MethodsWe included 88 older adults (60-75 year) at risk of cognitive decline. MIND-NL diet adherence was assessed using a food frequency questionnaire. Systemic inflammation (C-reactive protein levels, white blood cell-counts and neutrophil-to-lymphocyte ratio) and intestinal barrier permeability (lipopolysaccharide-binding protein, zonulin, and lipopolysaccharide) markers were measured in blood. Neuroinflammation-associated metabolites (myo-inositol, choline and creatine) were measured in the dorsolateral prefrontal cortex with proton magnetic resonance spectroscopy (1H-MRS). Cognitive functioning was assessed with a neuropsychological test battery. ResultsLinear models showed that both MIND diet adherence and systemic inflammation did not predict neuroinflammation or cognition independently. However, MIND diet adherence significantly moderated the relation between systemic inflammation and neuroinflammation ({beta}=-0.11, p=0.04) as well as between systemic inflammation and cognition ({beta}=0.044, p=0.02). Specifically, in individuals with lower MIND diet adherence (identified as scores [≤]7), systemic inflammation was positively related to neuroinflammation, and negatively to cognition. Similarly, MIND diet adherence significantly moderated the relation between intestinal barrier permeability and neuroinflammation ({beta}=-0.17, p=0.05). Finally, within participants with lower MIND adherence (median split at [≤]8.75), systemic inflammation mediated the relation between the intestinal barrier permeability and neuroinflammation ({beta}=0.427 [0.072; 0.891], p=0.04). ConclusionOur findings suggest that higher MIND diet adherence might protect against the detrimental effect of systemic inflammation on neuroinflammation and cognitive functioning. Moreover, we demonstrated that greater adherence to the MIND diet may specifically protect against the systemic inflammation-mediated relationship between intestinal barrier permeability and neuroinflammation. These findings should be confirmed in randomised controlled trials.

Major depressive disorder (MDD) involves dysregulated neuroimmune, metabolic, and oxidative stress (NIMETOX) pathways. Recently, it was shown that NIMETOX pathways should be evaluated in MDD patients stratified for metabolic syndrome (MetS). The current study aims to characterize the metabolic hormone and adipokine profiles of Chinese MDD patients stratified for MetS and to delineate their associations with overall severity of depression (OSOD), suicidal ideation (SI), recurrence of illness (ROI), and physiosomatic symptoms. We enrolled 125 MDD inpatients and 40 healthy controls and measured fasting serum insulin, glucose, glucagon, Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon-Like Peptide-1 (GLP-1), leptin, secretin, Plasminogen Activator Inhibitor-1 (PAI-1), resistin, ghrelin, and adiponectin, as well as the acute-phase inflammatory (API) response using albumin, transferrin (Tf), and monomeric CRP (mCRP). The results revealed a distinct metabolic hormone and adipokine signature in MDD with significantly lower insulin, glucagon, and PAI-1 levels, alongside an elevated API index (after adjusting for age, MetS, and body mass index). A composite GAP index (ghrelin, adiponectin, PAI-1) correlated negatively with OSOD, SI, ROI, physiosomatic symptoms, and adverse childhood experiences (ACEs). Integrative modeling combining the GAP index, API index, and ACEs achieved an area under the receiver operating characteristic (ROC) curve of 0.864 with an accuracy of 80% for discriminating MDD from controls. In conclusion, the findings delineated that many inpatients with severe MDD suffer from suppressed anabolic hormones and lower adipokine levels coupled with a mild, chronic inflammatory response. The deviations in this "hormonal-immune-metabolic" axis are components of the NIMETOX pathways in MDD and are not associated with MetS.

ImportanceTraumatic brain injury (TBI) increases the risk of developing psychiatric symptoms such as post-traumatic stress disorder (PTSD), depression and anxiety, however biological risk and resiliency factors that explain the significant heterogeneity in outcomes are limited. Although 5-10% of the population carries natural autoantibodies to the NMDA receptor (anti-NMDAR1) it is unknown if carrying anti-NMDAR1 autoantibodies modifies risk for psychiatric outcomes after TBI. ObjectiveSince TBI facilitates infiltration of circulating natural anti-NMDAR1 autoantibodies into the brain, we tested the hypothesis that natural anti-NMDAR1 autoantibody levels in plasma may modify risk for development of psychiatric symptoms after TBI. Design, Settings and ParticipantsData were analyzed from 1025 Marine Resiliency Study-II participants, a longitudinal study that included plasma collection and assessments for TBI, PTSD (Clinician Administered PTSD Scale-IV), depression (Beck Depression Inventory-2) and anxiety symptoms (Beck Anxiety Inventory) before and after a combat deployment to Afghanistan (2010-2013). Plasma anti-NMDAR1 autoantibody levels were quantified using a luciferase-based immunnoassay. Outcomes were post-deployment symptoms and the predictor was a continuous or dichotomous measure of anti-NMDAR1 autoantibody level. Covariates included pre-deployment symptoms, deployment history and experiences. ResultsTBI (606 with TBI, 419 without TBI) was associated with significantly greater depression, PTSD and anxiety symptoms post-deployment. In individuals with no TBI history, anti-NMDAR1 autoantibody levels were not associated with symptoms. In individuals that endorsed a TBI however, higher pre-deployment plasma levels of natural anti-NMDAR1 autoantibodies were significantly associated with lower predicted post-deployment depression and PTSD symptoms, but not anxiety. In the TBI group, high autoantibody group membership lowered predicted post-deployment CAPS-IV and BDI-2 scores by 22 and 25% respectively (Cohens d=0.25-0.32). After deployment, prevalence of moderate-severe depression was significantly lower in participants with high anti-NMDAR1 autoantibodies (.8% [2/256 participants]) compared with participants with low anti-NMDAR1 autoantibodies (3.5% [27/763 participants]), as was prevalence of taking psychotropic medications. Conclusions and RelevanceNatural anti-NMDAR1 autoantibodies may be a "resilience" factor for TBI-associated increases in depression and PTSD symptoms, supporting the hypothesis that natural anti-NMDAR1 autoantibodies could have neuroprotective effects. Mechanistic studies are warranted to understand if plasma natural anti-NMDAR1 autoantibodies reach the CNS to suppress glutamate excitotoxicity associated with TBI.

BackgroundPatients with myocardial infarction (MI) often exhibit neuropsychiatric symptoms, but the underlying pathophysiological mechanisms remain elusive. This study examines the roles of the tryptophan catabolite (TRYCAT) pathway, systemic inflammation, and adverse metabolic remodeling in this comorbidity, both before and after percutaneous coronary intervention (PCI). MethodsWe assessed depression, anxiety, and chronic-fatigue syndrome (CFS)-like rating scales, blood levels of TRYCATs, inflammatory markers, and human fatty acid binding protein (h-FABP)4 in MI patients both before and after PCI and in healthy controls. ResultsMI patients exhibited significantly higher neuropsychiatric symptoms, a pro-inflammatory shift, TRYCAT pathway changes, and increased h-FABP4. The TRYCAT profile exhibited a bias towards neurotoxicity, characterized by elevated levels of 3-hydroxykynurenine and quinolinic acid and decreased kynurenic acid. Binary logistic regression revealed that a model using TRYCATs, immune data (e.g., neutrophil/lymphocyte ratio), and h-FABP4 distinguished post-MI patients from healthy controls with 92% cross-validated accuracy. A large part of the variance (around 60%) in the neuropsychiatric scores was explained by immune-metabolic data, higher neurotoxic and lower neuroprotective TRYCATs. PCI significantly improved neuropsychiatric symptoms, TRYCAT pathway-associated neuroprotection, the immune-inflammatory response, and h-FABP4. ConclusionMI is linked to increased TRYCAT-associated neurotoxicity and adverse inflammatory-metabolic remodeling in association with heightened depression, anxiety, and CFS-like symptoms. The reduction in immune activation, the normalization of neurotoxic TRYCAT synthesis, and reversal of adverse metabolic-inflammatory signaling following PCI may explain the observed improvement in neuropsychiatric symptoms following coronary revascularization.

BackgroundSmoking is a major preventable risk factor for all-cause mortality and disability worldwide. It leads to age-related diseases, but the effects and reversibility of smoking behaviors on different epigenetic clocks are not fully explored. ObjectiveTo characterize the association of epigenetic age acceleration in whole blood with active and secondhand smoking (SHS), smoking intensity, and time since cessation among U.S. adults. MethodsThis is a cross-sectional study in adults from the NHANES 1999-2002 survey cycles, a population-based survey representative of the U.S. adult civilian non-institutionalized population. We analyzed 2,320 adults aged [≥]50 years, including non-Hispanic White, non-Hispanic Black, Mexican American, and other populations. Those without available self-reported smoking status data were excluded. Smoking exposure was analyzed in terms of self-reported smoking status (current, former, never), intensity (packs in the last month), years since smoking cessation, and SHS (serum cotinine levels: 0.05-10 ng/ml). Epigenetic age was estimated using 12 DNA methylation age biomarkers. Survey-weighted linear models were used to estimate the association of smoking exposure with epigenetic age acceleration while adjusting for confounders and multiple comparisons. ResultsWe analyzed 1,043 never, 903 former, and 374 current smokers (mean age: 65.1{+/-}9.3 years, female: 49.1%). GrimAge2 was 9.1 years (95% CI: 8.0, 10.2) and 2.8 years (95% CI: 2.3, 3.3) higher in current and former smokers, respectively, than in never smokers. Smokers showed an increased pace of aging, with current smokers aging 0.15 (95% CI: 0.13, 0.17) and former smokers 0.04 (95% CI: 0.03, 0.05) additional years per chronological year, and shorter methylation-predicted telomere length (current: -132{+/-}19 bp; former: -30{+/-}15 bp). Each cigarette pack smoked in the past month was associated with increases of 0.1 years in GrimAge2 and PhenoAge, and 0.01 aged months/year in aging pace. Among former smokers, each year since smoking cessation was associated with a deceleration of -0.14 (GrimAge2) and -0.06 (PhenoAge) years, and -0.03 aged months/year in aging pace. Cotinine analyses supported dose-dependent associations of epigenetic aging with smoking and suggested a 0.8-year increase in GrimAge2 with SHS exposure. ConclusionsSmoking was associated in a dose-dependent manner with accelerated epigenetic aging in former and current smokers. However, epigenetic age acceleration declines with time since smoking cessation among former smokers.

BackgroundAdverse life events and psychosocial stressors contribute to a range of neuropsychiatric disorders. However, the role of inflammatory dynamics around stress exposure remains unclear. Using TriNetX, a large international electronic health records database, we examined how systemic inflammatory activity and its temporal dynamics relate to subsequent risk of mental illness and somatic symptoms. MethodsWe compared 36,772 individuals with records of adverse life events and leukocytosis in the surrounding period with matched individuals with normal leukocyte counts, and performed an analogous comparison for socioeconomic and psychosocial stressors in cohorts of 87,936 individuals with leukocytosis and matched controls. To contrast dynamic with static inflammatory responses, we compared cohorts exhibiting leukocyte count changes with those maintaining persistently normal or persistently elevated leukocyte counts around stressor exposure. Outcomes, including new mental health and somatic symptom presentations, were evaluated within two years of the stressor. ResultsFollowing acute stressors, leukocytosis (compared with normal leukocyte counts) was associated with lower rates of subsequent anxiety disorders, cognitive symptoms and several somatic symptom diagnoses, with similar reductions in anxiety observed after chronic stressors. A dynamic inflammatory response was associated with the most favourable outcomes, with lower rates of anxiety, depression, functional neurological disorder, cognitive and sleep difficulties, fatigue, and multiple pain-related and other somatic symptoms than persistently low or high inflammation. ConclusionOur findings suggest that a well-regulated inflammatory response to stressors is associated with a reduced risk of diverse mental health and somatic outcomes, and that a transient immune activation may support recovery rather than confer risk.

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common and life-threatening complication of chimeric antigen receptor (CAR) T-cell therapy, with early detection being critical for timely intervention and improved outcomes. Cytokines such as interleukin-6 (IL-6) are key mediators of the inflammatory cascade underlying ICANS pathogenesis, but prospective clinical evidence for their predictive value is limited. Here we quantify IL-6 levels in a prospective cohort of 40 CAR-T patients (270 serum samples), using a simple in-house microfluidic bead immunoassay. IL-6 levels measured by our assay were significantly associated with ICANS onset. Specifically, each [~]3.4-fold increase in IL-6 levels was linked to a 74% increase in the odds of developing ICANS the following day, independent of other clinical variables. Overall, we show the prognostic value of IL-6 for next-day ICANS, demonstrate the potential of frequent cytokine measurement to guide CAR-T patient management, and develop a simple experimental method to perform such monitoring.

BackgroundPost-viral diseases, including post-COVID-19 syndrome (PCS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cause substantial long-term morbidity. Persistent cardiovascular (CV) risk after acute infection highlights the need for accessible tools to quantify microvascular health. MethodsAll Eyes on PCS is a prospective, observational study investigating the retinal microcirculation using retinal vessel analysis (RVA). We compared RVA parameters in 102 PCS patients with 204 age- and sex-matched healthy controls (HC, matched from n = 303). Secondary matched analyses included never infected controls (NI, n = 96), recovered individuals (n = 102), PCS patients, and ME/CFS patients (n = 62). Laboratory variables, circulating markers of endothelial dysfunction (ED) and inflammation were compared between cohorts and their associations with RVA parameters were examined. ResultsCompared with HC, PCS patients showed reduced venular flicker-induced dilation (3.7 {+/-} 2.2% vs. 4.5 {+/-} 2.7%, p = 0.005), narrow retinal arterioles (CRAE, 178.3 {+/-} 15.5 {micro}m vs. 183.3 {+/-} 15.9 {micro}m, p = 0.009), and lower arteriolar-to-venular ratio (0.83 {+/-} 0.06 vs. 0.86 {+/-} 0.07, p = 0.004). Findings persisted after adjustment for CV factors and remained evident in an extended secondary matched analysis across NI, recovered, and PCS patients. ME/CFS patients showed the most pronounced alterations. PCS severity correlated with lower AVR (r = -0.21, p = 0.037) and reduced arteriolar FID (r = -0.21, p = 0.039), particularly for neurocognitive symptoms. IL-6, ICAM-1 and VCAM-1 were elevated in PCS and ME/CFS and lower AVR correlated with inflammatory and iron-related markers (all adjusted p < 0.01). A combined model discriminated ME/CFS patients with good accuracy (AUC = 0.80). ConclusionsPCS is associated with persistent ED, most pronounced in ME/CFS patients and linked to symptom severity and ongoing inflammation. RVA may provide a noninvasive, readout of ED in post-viral syndromes. Trial RegistrationThe All Eyes on PCS Study has previously been registered at ClinicalTrials.gov (NCT05635552). Novelty and SignificanceO_ST_ABSWhat is known?C_ST_ABS- PCS and ME/CFS are associated with persistent endothelial dysfunction and increased long-term cardiovascular risk. - Neurocognitive symptoms in post-viral syndromes have been linked to impaired neurovascular coupling. - Retinal vessel analysis provides a validated, non-invasive readout of systemic and cerebral microvascular health. What new information does this article contribute?- PCS is characterized by persistent functional and structural retinal microvascular dysfunction - Retinal endothelial dysfunction scales continuously with post-viral disease severity and is most pronounced in patients fulfilling ME/CFS criteria. - Retinal microvascular alterations are linked to inflammatory-endothelial activation and iron dysregulation, identifying a biologically coherent vascular phenotype. This study provides the first comprehensive human in vivo assessment of retinal microvascular structure and function across the full post-COVID-19 spectrum, from never infected controls to recovered individuals, PCS patients, and those fulfilling ME/CFS criteria. Using retinal vessel analysis as a surrogate of neurovascular and endothelial function, we demonstrate that endothelial dysfunction persists in patients with ongoing post-viral symptomatology. Retinal venular flicker-induced dilation, arteriolar caliber, and autoregulatory capacity decline progressively with increasing clinical severity, indicating a dose-response relationship between microvascular injury and post-infectious disease burden. Importantly, these vascular alterations are linked to sustained inflammatory and endothelial activation and to disturbances in iron homeostasis, indicating an inflammatory-endothelial axis rather than isolated cardiovascular risk. By integrating microvascular phenotyping with symptom profiles and circulating biomarkers, this work identifies retinal endothelial dysfunction as a mechanistically informative and clinically accessible marker of post-viral disease severity. These findings advance understanding of post-infectious vascular pathology and provide a translational framework for biological stratification and risk assessment in PCS and ME/CFS.

BackgroundLoneliness is an emerging public health concern linked to adverse mental and physical outcomes. It may play a key role in cognitive aging, yet its population-level association with subjective cognitive decline (SCD) across demographic groups is not well characterized. We evaluated how the frequency of loneliness relates to SCD in U.S. adults and whether associations differ by sex, age and race/ethnicity. MethodsWe performed a cross-sectional analysis of adults aged [&ge;]16 years using nationally representative 2016-2023 Behavioral Risk Factor Surveillance System data (BFRSS). Loneliness was categorized as never, rarely, sometimes, usually or always. The primary outcome was self-reported SCD in the past year. Survey-weighted logistic regression models adjusted for sociodemographic factors, health insurance, metropolitan status and survey year were used to estimate adjusted marginal probabilities of SCD across loneliness categories. Interaction terms and stratified margins evaluated effect modification by sex, age group (16-44, 45-64 and [&ge;]65 years) and race/ethnicity (non-Hispanic White, non-Hispanic Black and Hispanic). ResultsAmong 85,969 adults who reported loneliness, 13,879 (16.2%) experienced subjective cognitive decline (SCD), with a mean age of 65.7 {+/-} 10.6 years. Loneliness showed a strong dose-response relationship with SCD. Predicted probabilities of SCD increased from 9.9 % (95 % CI, 9.3-10.5 %) among respondents who never felt lonely to 15.0 % (14.1-15.9 %) for rarely, 24.9 % (23.6-26.1 %) for sometimes, 38.4 % (34.4-42.5 %) for usually and 45.7 % (41.0-50.4 %) for always lonely adults (p < 0.001). Women who were always lonely had an adjusted probability of SCD that was 10.7 percentage points higher than men; sex differences were negligible at lower loneliness levels. Age differences were minimal across most loneliness categories; however, among adults who were always lonely, those aged >64 years had significantly lower predicted cognitive function compared with adults aged 18-64 years (p < 0.001). Racial and ethnic differences were modest; the only significant contrast was a 1.7 percentage-point lower probability of SCD for non-Hispanic Black adults compared with Whites among those who never felt lonely. Other subgroup differences were not statistically significant. ConclusionsLoneliness is independently and strongly associated with higher likelihood of subjective cognitive decline among U.S. adults, and this relationship is most pronounced for chronic loneliness. While sex and age modified the effect of loneliness, racial/ethnic disparities were minimal. These findings identify loneliness as a modifiable social determinant of cognitive health, supporting the need for broad social connection initiatives and targeted efforts for women and mid-life adults with chronic loneliness.

BackgroundEarly detection of individuals at risk for clinical deterioration in first-episode psychosis (FEP) remains a vital challenge in psychiatric care. Emerging evidence indicates that immune dysregulation might play a crucial role in the pathophysiology and progression of psychotic disorders. AimsThis study examined the predictive potential of a plasma cytokine and chemokine panel in anticipating clinical stage transition of FEP patients. MethodUsing multiplex immunoassays, plasma samples from a cohort of 35 FEP patients were screened for the quantification of 21 analytes. Participants were clinically assessed at baseline and follow-up and classified according to a validated staging model. Data was used to predict clinical stability over a 12-month follow-up period. ResultsIL-17A was found to be significantly increased in transitioning patients (p = 0.045), with a medium standardized effect size and wide confidence interval (Hedges g = - 0.687, 95% CI [-1.379, 0.004]). A logistic regression model was determined, which revealed that higher baseline levels of IL-17A were significantly linked to progression to a more advanced clinical stage, while higher baseline levels of MIP-3 and IFN-{gamma} were associated with clinical stability. This combined cytokine model exhibited strong predictive capacity (AUC = 0.853), indicating its potential as a biomarker panel for early risk assessment. ConclusionsThese findings highlight the importance of neuroimmune mechanisms in the development of psychotic disorders and advocate for the inclusion of immunological markers within staging-based models of care. Incorporating cytokine profiling into clinical practice could improve personalised treatment strategies and lead to better long-term outcomes for individuals with FEP.

BackgroundBrain perivascular spaces (PVS) are emerging MRI markers of microvascular function and waste metabolite clearance. While PVS enlargement has been linked to aging and vascular risk, it remains unclear whether PVS morphology reflects shared familial microvascular characteristics and how these are shaped by individual vascular, physiological, and neuropsychiatric factors. In this study, we investigated whether PVS morphometry captures these familial characteristics, further modulated by individual determinants. MethodsWe analyzed 1,183 participants from the Stratifying Depression and Resilience Longitudinally (STRADL) family-based cohort, including 324 individuals with first-degree relatives. Automated MRI segmentation quantified PVS volume, count, density, and median length in the centrum semiovale and basal ganglia. Linear mixed-effects models assessed associations with age, hypertension, hair cortisol, depressive symptom scores, and hand grip strength while accounting for familial clustering. ResultsIn 1050 individuals (59.5% female; mean age 59.3 {+/-}10.1 years) PVS burden increased with age (PVSvolume%ROI {beta}=0.18, 95%CI[0.11, 0.26], p<0.0001), current depressive symptoms across both regions (PVS density: CSO, {beta}=0.092, [0.023, 0.16], p=0.009; BG, {beta}=0.11, [0.043, 0.18], p=0.002), and with higher hair cortisol (PVS count {beta}=0.08, [0.003, 0.15], p=0.041) and weaker grip strength (PVSvolume%ROI {beta}=-0.09, [-0.16, -0.02], p=0.013), in the centrum semiovale. Familial clustering was significant for PVS volume ({beta}=0.22, [0.096, 0.52], p=0.013) and median length ({beta}=0.28, [0.16, 0.49], p=0.0003), independent of other factors. ConclusionsPVS morphology reflects neuropsychiatric and shared familial microvascular architecture, with both inherited and individual factors contributing to PVS burden and morphometry, and supporting the use of PVS morphometry as a neuroimaging marker of cerebral microvascular health.

IntroductionThe ischaemic penumbra is the principal therapeutic target in acute ischaemic stroke (AIS). Although perfusion imaging enables identification of salvageable tissue, its availability is limited and iodinated contrast exposure carries risk. Validated blood-based biomarkers could serve as scalable surrogates for imaging-defined penumbra. ObjectiveWe conducted a systematic review and meta-analysis to assess the association between blood-based biomarkers reported in the literature and the ischaemic penumbra. MethodsWe searched Ovid MEDLINE, Embase (Ovid), PsycINFO (Ovid), and Web of Science until December 3, 2025, for studies involving human subjects with AIS aged over 18 years or animal subjects that reported the presence of infarct and ischaemic penumbra. The primary outcome was the difference in mean biomarker levels in subjects with and without ischaemic penumbrae as defined by the study authors. We used the QUADAS-2 tool to assess risk of bias. We calculated each biomarkers pooled standardized mean difference (SMD) and 95% CI where possible. Protein-protein interaction network (PPI) and pathway analyses were conducted in Cytoscape and the enrichR R package (PROSPERO: CRD42023453175). ResultsWe identified 11 studies (1765 human subjects and 8 nonhuman primates) that assessed 53 candidate blood-based biomarkers. Two studies had a low risk of bias, while nine had a risk of bias. A meta-analysis was conducted for seven biomarkers in humans from four studies. Of these, three biomarkers demonstrated significant association with penumbrae in humans: mid-regional pro-adrenomedullin (MR-proADM; SMD 0.80 [95% CI 0.49 to 1.10]), interleukin-10 (IL-10; SMD 1.94 [0.85 to 3.03]), and neuron-specific enolase (NSE; SMD -0.71 [-1.40 to -0.01]). However, substantial statistical heterogeneity was observed for several pooled biomarkers (I{superscript 2} >90%), limiting confidence in effect size precision. Amongst biomarkers where meta-analysis was not possible, 37 biomarkers showed significant association with presence of a penumbra. Oxygen radical absorbance capacity after perchloric acid treatment (ORACPCA; SMD 0.31 [0.01 to 0.60]) showed significant association with penumbra presence; 34 genes (e.g., STK26 r = 0.58, p = 0.003; MGA r = 0.58, p = 0.004; IL1B r = -0.59, p = 0.003; NUP98 r = -0.71, p < 0.001), circOGDH (r = 0.962, p = 0.002), and NT-proBNP (r = 0.199, p < 0.001) were significantly correlated with penumbra volume. PPI analysis identified IL-1{beta} as the most highly connected node (10 interactions), followed by IL-10 and HDAC1/HCAR2. Cdc42 was reported to be significantly associated with penumbrae in nonhuman primates, but there were insufficient data to calculate SMD. Pathway enrichment revealed positive associations with angiogenesis and IL-12 signalling, and negative associations with leukocyte migration, chemokine signalling, and platelet activation. ConclusionsCurrently reported biomarkers of ischaemic penumbra are not ready for clinical implementation. Although implicated pathways converge on inflammatory regulation, haemostasis, and cerebral perfusion, rigorous prospective validation is required before integration into prehospital or emergency triage workflows.

The co-occurrence of per- and polyfluoroalkyl substances (PFAS) and volatile organic compounds (VOCs) in industrial environments poses complex toxicological risks that standard additive models fail to capture. This study elucidates a novel "metabolic blockade" mechanism wherein PFAS competitively inhibits the renal excretion of VOC metabolites, thereby amplifying neurotoxic burdens. Utilizing a Double Machine Learning (DML) framework on data from National Health and Nutrition Examination Survey (2005-2020), we analyzed a final intersectional cohort of 1,975 participants. We identified a robust inhibition of VOC metabolite clearance by serum PFAS. Specifically, PFNA significantly suppressed the excretion of the benzene metabolite URXPMA (Causal {beta}TMLE = -0.219, p < 0.001), with efficacy dependent on perfluorinated chain length. Molecular docking simulations revealed the biophysical basis of this antagonism: long-chain PFNA exhibited superior binding affinity to the Organic Anion Transporter 1 (OAT1) ({Delta}G = -6.333 kcal/mol) compared to native VOC metabolites ({Delta}G = -4.957 kcal/mol), confirming high-affinity competitive inhibition at the renal interface. In a neurocognitive sub-cohort (N = 1,200), this interference translated into functional synergism; high-PFNA exposure magnified VOC-associated cognitive impairment by 1.5-fold and significantly exacerbated the negative association between VOC burden and processing speed ({beta}int = -0.263, p = 0.004). These findings define PFAS as a "metabolic amplifier" of co-contaminant toxicity, necessitating a paradigm shift toward mixture-based hazardous material regulations that account for transporter-level interactions.

BackgroundMajor depressive disorder (MDD) is a neuro-immune-metabolic-oxidative (NIMETOX) disorder. Nevertheless, the effects of alterations in immune responsiveness, oxidative stress, antioxidant defenses, gut-derived short-chain fatty acids (SCFAs), metabolic hormones and adipokines on metabolomic modules and the MDD phenome have remained elusive. MethodsSerum samples from 125 MDD inpatients and 40 healthy controls were analyzed using high-resolution metabolomics assays (liquid chromatography, mass spectrometry) in conjunction with assays of 68 additional NIMETOX markers. A machine learning pipeline was implemented to delineate the associations between MDD, clinical phenome features, metabolomic modules, and 68 NIMETOX biomarkers. ResultsThe metabolomics and NIMETOX biomarkers distinguished MDD from controls with a cross-validated accuracy of >95%. Core biomarkers of MDD encompass (in order of decreasing importance) diacylglycerol lipotoxicity, phospholipid remodeling, fatty acid signaling, mitochondrial-redox dysfunction, diminished antioxidant defenses (including decreased paraoxonase 1 activity, Apolipoprotein A1, reverse cholesterol transport, ether lipids), inflammatory response, increased epidermal growth factor, disbalances in gut-derived SCFAs, increased oxidized high-density lipoprotein cholesterol, and changes in metabolic hormones. A large part of the variance in overall severity of illness (76.3%), physiosomatic symptoms (61.9%), current suicidal ideation (40.6%), and recurrence of illness (28.8%) was explained by those pathways. Lipotoxicity, phospholipid remodeling, fatty acid storage, and clinical phenome features converge onto a singular latent construct--the metabolic phenome of MDD. The various NIMETOX pathways mediate the impact of adverse childhood experiences on metabolomics and MDD. ConclusionsMDD is a NIMETOX disorder in which metabolomic signals represent a final common pathway underlying symptom severity, recurrence of illness, and suicidality.

BackgroundMajor depressive disorder (MDD) is a neuro-immune, oxidative, and nitrosative stress (NIMETOX) disorder, in which peripheral immune-redox pathways intersect with metabolic networks leading to neurotoxicity within the limbic-prefrontal affective circuits. Comprehensive metabolomics analysis in well-phenotyped patients is vital to elucidate their metabolic profile. ObjectivesTo identify metabolic abnormalities that differentiate inpatients with severe MDD from healthy controls through high-resolution, untargeted metabolomics. MethodsSerum samples from 125 MDD inpatients and 40 healthy controls were analyzed utilizing liquid chromatography and mass spectrometry. A meticulously regulated multistage machine learning pipeline with leakage-prevention protocols was employed to analyze differences between MDD and controls and to predict phenome scores. ResultsFeature selection showed that 16 metabolites and 6 functional modules reliably distinguished MDD. The functional profile of the metabolites indicates a convergence of lipotoxicity, phospholipid remodeling, disruptions in fatty acid metabolism, mitochondrial redox imbalance, ether-lipid metabolism, and antioxidant depletion. This MDD metabotype was not affected by metabolic syndrome. A substantial portion of the variance in overall depression severity (72.5%), physiosomatic symptoms (55.8%) and suicidal ideation (23.6%) was accounted for by increased lipitoxicity, phospholipid remodeling, and fatty acid storage/signaling. The recurrence of illness (27.7%) was associated with a self-reinforcing-lipid-redox-inflammatory module that maintains cellular stress. DiscussionThe MDD metabotype represents a cohesive metabolic network that is associated with the NIMETOX pathogenesis of MDD. Metabolomics provides a comprehensive foundation for subtyping and precision psychiatry. Lipoxygenase-15, lipotoxicity, phospholipase A2, and lipid-redox intersections are important drug targets to treat MDD.

Post-stroke depression (PSD) represents one of the most prevalent psychiatric complications after stroke, affecting up to one-third of survivors, and it can substantially influence both the extent of functional impairments and the recovery trajectory. A reciprocal relationship between depressive symptoms and cognitive dysfunction in this population has been commonly demonstrated, underscoring the need to clarify their intercorrelation and shared neuroanatomical underpinnings. To address this a combined cognitive dysfunction linked to PSD and imaging study, a total of 125 unilateral stroke patients were classified into two groups based on the presence of depressive symptoms using a BDI cutoff score of 14. Using principal component analysis (PCA) on 16 cognitive test variables from 64 patients with PSD and 61 without PSD, four principal components of cognitive function were extracted. Among these, the attention factor showed a significant group difference, with the PSD group exhibiting greater attentional impairments than the non-PSD group. Voxel-based lesion-symptom mapping (VLSM) further revealed that attentional performance was significantly associated with lesions in the left insula across groups. Importantly, the lesion clusters were more extensive in patients with PSD, suggesting a more pronounced role of insular damage in depressive symptomatology following stroke. Taken together, these findings highlight the pivotal contribution of the insula to both attentional processing and the pathophysiology of PSD, suggesting that the insula mediates attentional networks closely linked to depressive symptoms in stroke survivors.

BackgroundAntenatal depressive symptoms (ADS) are common and underdiagnosed, particularly in low- and middle-income countries, and are associated with adverse maternal and offspring outcomes. Current screening relies on subjective symptom reporting, limiting early identification and prevention. Epigenetic modifications, particularly DNA methylation, offer a promising avenue for objective, early biomarkers of depression risk during pregnancy. MethodsIn this nested case-control design within the STRiDE (Stratification of Risk of Diabetes in Early Pregnancy study) prospective cohort, 189 pregnant women with no depressive symptoms in early pregnancy (<16 weeks of gestation. PHQ-9 [&le;]4) were followed longitudinally. 89 ADS individuals were identified by the emergence of depressive symptoms at 24-28 weeks of gestation (PHQ-9 [&ge;]5), while 100 women remained symptom-free (Controls). Genome-wide DNA methylation profiling of early-pregnancy peripheral blood was performed using the Illumina EPIC 850K array. Epigenome-wide association analyses were combined with machine-learning approaches to identify predictive CpG panels. Model robustness was assessed using bootstrap validation, and a methylation risk score (MRS) was constructed. Functional enrichment analyses were conducted to explore biological pathways. ResultsEpigenome-wide analysis identified 2,447 differentially methylated positions associated with subsequent ADS. A robust panel of 10 CpGs in early pregnancy predicted later ADS with excellent performance (testing AUC=0.99. bootstrap-validated AUC=0.91), independent of maternal risk factors. The MRS markedly outperformed traditional clinical predictors (AUC=0.94) and further improved prediction when combined with maternal characteristics (AUC=0.95). ADS-associated methylation changes were enriched in neurodevelopmental, synaptic, immune, and metabolic signaling pathways. Limited concordance with placental methylation suggested maternal-specific epigenetic regulation. ConclusionsEarly-pregnancy DNA methylation signatures can predict antenatal depressive symptoms before clinical onset. This blood-based 10-CpG biomarker panel offers a biologically informed and objective tool for early risk stratification, with the potential to enable preventive interventions and enhance perinatal mental health care, particularly in resource-constrained settings.

Aging is the strongest known risk factor for Alzheimers disease (AD), and elevated plasma amyloid-{beta} (A{beta}) levels in healthy adults are associated with increased AD risk. Aging is also associated with autonomic imbalance, characterized by increased sympathetic and decreased parasympathetic activity. In our previous randomized clinical trial, we found that four weeks of daily slow-paced breathing designed to enhance parasympathetic activity reduced plasma A{beta}42 and A{beta}40 levels in younger and older adults and showed a trend toward increasing A{beta}42/A{beta}40 ratio only in older adults. The primary goal of the current study was to extend these findings in 62 adults aged 50 to 70 years using randomized assignment to 10 weeks of slow-paced breathing or a random-paced breathing control with three assessment time points. Secondary objectives included examining the effects of slow-paced breathing on brain structure (i.e., perivascular space and hippocampal volumes) and cognitive performance. Consistent with prior findings, the slow-paced breathing group showed greater decreases in plasma A{beta}42 than the control group. However, group differences were not significant for A{beta}40 or A{beta}42/A{beta}40 ratios, and no significant effects were observed for the secondary outcomes. The non-significant findings may be due to changes we made to both intervention and control condition methods relative to our previous trial. Further research is needed to explore the underlying mechanisms and potential effects of slow-paced breathing on A{beta} accumulation in the brain. HighlightsO_LIParticipants were randomly assigned to slow-placed breathing or a breathing control C_LIO_LIIndividualized protocols determined breathing paces C_LIO_LITen weeks of daily slow-paced breathing practice reduced plasma A{beta}42 levels C_LI

BackgroundMajor depressive disorder (MDD) severely impairs individual health and creates heavy societal burdens. Diagnostic and therapeutic research remains hindered by MDDs marked heterogeneity and the absence of valid biomarkers. As a neuro-immune, metabolic, and oxidative stress (NIMETOX) disorder, MDD exhibits metabolomic signatures as a final common pathway in the Chinese population. ObjectivesTo identify lipidomic profile differences between MDD patients and healthy controls and examine associations between lipidomic alterations and clinical phenotypes. MethodsWe recruited 125 MDD patients and 40 healthy controls, and measured serum lipidomic profiles using liquid chromatography-mass spectrometry. A rigorously controlled multistage machine learning pipeline with leakage-prevention measures was utilized to examine disparities between MDD and control groups and to predict phenome features. ResultsWe identified 43 differentially abundant lipids between the MDD and control groups. Subsequent factor analysis clustered the 43 lipids into 3 functional modules, namely the increased ceramide/GM3/LNAPE (CERLNAPE) module, the decreased mitochondrial fatty acid oxidation/acetyl-flux (CARSM) module, and the reduced lysophospholipid/ether-lysolipid (LYSOPE) module. The three lipidomic modules correlated with six previously reported metabolomic functional domains, establishing an integrated metabolomics-lipidomics architecture in MDD. A substantial portion of the variance in the overall severity of depression (74.0%), physiosomatic symptoms (58.5%), suicidal ideation (11.1%), and recurrence of illness (36.6%) was associated with the integrated metabolomics-lipidomics architecture. ConclusionThe MDD lipotype indicates a unified metabolic network linked to the NIMETOX pathophysiology of MDD. Lipidomics provides a robust foundation for subtyping and precision psychiatry. Ceramide, acetyl carnitine, lipotoxicity, and plasmalogens are potential drug targets to treat MDD.

BackgroundInhaled combusted cannabis and co-use of combusted cannabis and nicotine electronic cigarettes (nECIGs) are on the rise, yet their long-term cardiovascular risk is unclear due to the high prevalence of confounders in observational human studies. Using primary plasma and monocytes and a novel ex vivo mechanistic model of two early steps in atherogenesis, this study examined whether chronic combusted cannabis use is associated with atherogenic changes, as estimated by 1) monocyte transendothelial migration (MTEM), and 2) monocyte-derived foam cell formation (MDFCF), and whether nECIG co-use further amplifies this risk. MethodsA cross-sectional parallel group comparison study was conducted in healthy adults (21-30 years) who chronically 1) used combusted cannabis, 2) co-used both combusted cannabis and nECIGs, and 3) were non-using controls. Using our ex vivo atherogenesis assay, primary outcomes of MTEM, MDFCF, and median fluorescence intensity (MFI) of the lipid-staining fluorochrome BODIPY were determined using primary plasma and autologous primary monocytes from participants. Using flow cytometry and the fluorochrome CELLROX, cellular oxidative stress (COS) in monocytes was determined. ResultsOf the 134 participants, 59 used cannabis, 26 co-used cannabis/nECIG, and 49 were non-using controls. The groups had similar age, sex, and race. Median MTEM was 1.13 fold greater in people who used cannabis compared to non-users 27.8% (IQR 26.1:29.2%) vs 24.5%, (IQR 22.9:27.4%), p<0.0001, and tended to be greater in people who co-used cannabis/nECIG by 1.22-fold 34.1%, (IQR 29.9:38.3%, p=0.17). Median MDFCF and MFI were also increased in people who used cannabis compared to non-users (MDFCF 36.3%, IQR 31.8:35.8%, vs 26.6%, IQR 23.8:25.8%, 1.36-fold and MFI 1163.8, IQR 1042.8:1155.0, vs 940.2 IQR 849.9:1101.4, 1.24-fold) and were further increased in people who co-used cannabis/nECIG (MDFCF 48.7%, IQR 37.3:52.4%, 1.34-fold, MFI 1433.7, IQR 1263.8:1686.4, 1.23-fold; all comparisons p<0.008). Foam cell formation, but not transendothelial migration, was strongly positively correlated with COS. All primary outcomes increased with greater frequency of cannabis and/or nECIG use. ConclusionsIn healthy young adults, exclusive cannabis use is associated with increased atherogenic properties of monocytes and plasma, and this atherogenic effect is further amplified by co-use of nECIGs.