Brain, Behavior, & Immunity - Health

ObjectivesActivation of the immune-inflammatory response system (IRS) and a deficiency in the compensatory immunoregulatory system (CIRS), neuronal injuries, and alterations in the glutamate receptor (GlutaR), aquaporin-4 (AQP4), and heat shock protein 60 (HSP60) are involved in delirium. Increased serum levels of neurofilament protein (NFP), glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) are biomarker of neuronal injury and post-surgery cognitive impairments. Polyreactive antibodies (PAbs) contribute to the development of immune-mediated disease. This investigation delineates whether elevated IgA and IgG reactivity against those self-antigens is associated with enhanced IRS responses and delirium severity. MethodsWe measured peak Delirium Rating Scale (DRS) scores on days 2 and 3 following surgery in 59 hip fracture older adults, and IgA/IgG antibody levels against MBP, NFP, GFAP and myelin oligodendrocyte glycoprotein (MOG), GlutaR, N-Methyl-D-Aspartate receptor (NMDAR), APQ4 and HSP60. ResultsThe IgA antibody levels against those self-antigens, especially GFAP, MBP and HSP60, strongly predict peak DRS scores on days 2 and 3 post-surgery. IgA reactivity against NMDAR and baseline DRS scores explained 40.6% of the variance in peak DRS scores, whilst IgA against NMDAR, IgG against MBP and age explained 29.1% of the variance in the IRS/CIRS ratio. There was no correlation between DRS scores and IgG directed against these self-antigens. ConclusionsIncreased IgA levels against neuronal self-antigens, AQP4, and HSP60 are risk factors for delirium. PAb-associated breakdown of immune tolerance, IRS activation and injuries in the neuronal cytoskeleton, oligodendrocytes, astrocytes, glial cells, and myelin sheath are involved in the pathophysiology of delirium.

ObjectiveIraq and Afghanistan war-era (OEF/OIF/OND) Veterans are at elevated risk for physical injuries and psychiatric illnesses, in particular comorbid mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and chronic pain. The gut microbiome has been implicated in modulation of critical processes such as digestion, immune system functioning, and stress responsivity, and may be an important factor in understanding physical and mental health outcomes following deployment and trauma exposure, yet minimal research to date has sought to characterize gut microbiome composition in this population. Methods26 male OEF/OIF/OND Veterans aged 18 to 65 who previously completed a VA Comprehensive TBI Evaluation were enrolled in this study. Participants completed self-report measures of PTSD symptom severity, pain intensity and interference, fatigue, cognitive symptoms, substance use, and sleep quality. Participants submitted fecal samples, and metagenomic sequencing was used to calculate alpha- and beta-diversity and taxonomic microbial composition. Associations between microbiome data and clinical variables was then examined. ResultsAlpha and beta diversity measures were not significantly correlated with clinical outcomes. Fatigue, post-concussive symptoms, executive function symptoms, and cannabis use were associated with differences in gut microbial composition, specifically Verrucomicrobiota. ConclusionThis exploratory study demonstrated that altered gut microbiome composition is associated with psychiatric and cognitive symptoms in OEF/OIF/OND Veterans and highlights a potential new therapeutic target of interest. Future research is needed to examine whether probiotic treatment is effective for reducing symptoms common in this clinical population.

The men and women involved in rescue and recovery operations at the 9/11 World Trade Center (WTC) site have a greater prevalence (23%) of persistent, clinically significant post- traumatic stress disorder (PTSD). Recent structural and functional magnetic resonance imaging (MRI) studies demonstrate significant neural differences between WTC responders with and without PTSD. Here, we used brain age, a novel MRI-based data-driven biomarker optimized to detect accelerated structural aging, and examined the impact of PTSD on this process. Using BrainAgeNeXt, a novel convolutional neural network trained and validated on 11,574 magnetic resonance imaging (MRI) T1- weighted scans, we predicted brain age in WTC responders with PTSD (WTC-PTSD, n = 47) and age/sex matched responders without PTSD (non-PTSD, n = 52). Predicted Age Difference (PAD) was then calculated for each WTC responder by subtracting chronological age from brain age. A positive PAD indicates that the responders brain is aging faster than expected for their chronological age. We found that PAD is significantly greater with WTC-PTSD compared to non-PTSD responders (p < 0.001). Further, we found that WTC exposure duration (months working on site) moderates the association between PTSD and PAD (p=0.0050). Our results suggested that brain age is a valid biomarker to compare aging trajectories in responders with and without PTSD. In particular, PTSD may be a substantial risk factor for accelerated neurodegeneration in this vulnerable and aging population.

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 [&le;]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 [&le;]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.

IntroductionNeuroinflammation is associated with depression and anxiety risk, both of which demonstrate a bilateral relationship with cardiometabolic disorders. Systemic inflammation is also commonly described in patients with cardiometabolic disorders. It is, thus, unclear whether pro-inflammatory cytokines might mediate the relationship between depression, anxiety, and cardiometabolic disorders, particularly in advanced ages. MethodsThe multiethnic [&ge;] 50-year-old study population is a subset of the Health and Aging Brain Study: Health Disparities (HABS-HD). Adjusted logistic and linear regression models were applied to assess associations. Non-linearity was evaluated using restricted cubic splines. Statistical mediation analysis was used to determine the role of inflammation (Tumor Necrosis Factor-alpha (TNF-alpha) and Interleukin-6 (IL-6)). Models were corrected for multiple testing using the False Discovery Rate (FDR)-method. ResultsIn the 2,093 included cases, depression and/or anxiety were significantly associated with 62% higher odds of Cardiovascular Disorder (CVD) (OR=1.62 [95% CI: 1.22-2.15]), 54% of type 2 diabetes (T2DM) (OR=1.54 [95% CI: 1.29-1.85]), 26% of hypertension (OR=26% [95% CI: 1.07-1.48]), and 29% of obesity (OR=1.29 [95% CI: 1.11-1.51]). Only IL-6 showed a significant mediating role in the association of depression and/or anxiety with CVD (10%, p-valueFDR=0.016), T2DM (13%, p-valueFDR<0.001), hypertension (16%, p-valueFDR<0.001), and obesity (23%, p-valueFDR<0.001). ConclusionsDepression and anxiety were significantly associated with higher odds of major cardiometabolic disorders, and IL-6 partly mediated these associations. Clinical studies are needed to replicate the findings and specifically cluster high-risk profiles.

Interest is growing in the potential role of manganese (Mn) in Alzheimers Disease (ADRD). This nested pilot study of a ferroalloy workers cohort was aimed to investigate the effects of long-term occupational Mn exposure on cognitive function through {beta}-amyloid (A{beta}) modification and brain deposition, as well as metabolomic, lipidomic and proteomic profiling. We examined 6 male exposed workers (median age 63, exposure duration 31 yrs), and 5 historical controls (median age 60) who had undergone brain PET scan imaging showing higher A{beta} deposition among the exposed compared to the controls (p < 0.05). The average annual cumulative respirable Mn of the ferroalloy workers was 329.23 {+/-} 516.39 {micro}g/m3 (geometric mean 118.59). Average Mn level in plasma of the exposed subjects (0.704 {+/-} 0.2 ng/mL) was significantly higher than the controls (0.397 {+/-} 0.18). Pathway analyses using LC-MS/MS results revealed impacted metabolomic pathways such as olfactory signaling, mitochondrial fatty acid beta-oxidation, biogenic amine synthesis, SLC-mediated transmembrane transport, and glycerophospholipid and choline metabolism in the Mn exposed group. Single molecule arrays (Simoa) analysis revealed notable modifications of AD-related plasma biomarkers; protein microarray (chip) showed significant changes (p < 0.05) in the levels of some plasma antibodies targeting autoimmune and neuronal associated proteins such as A{beta} (25-35), GFAP, Serotonin, Human NOVA1, and Human Siglec-1/CD169 among the Mn exposed individuals. This data provides evidence on Mn-induced alterations of pathways and biomarkers associated with cognitive neurodegenerative diseases.

BackgroundThe pathophysiology of amnestic Mild Cognitive Impairment (aMCI) is largely unknown, although some papers found signs of immune activation. AimsTo assess the cytokine network in aMCI after excluding patients with major depression (MDD) and to examine the immune profiles of quantitative aMCI (qMCI) and distress symptoms of old age (DSOA) scores. MethodsA cross-sectional study was conducted on 61 Thai aMCI participants and 60 healthy old adults (both without MDD). The Bio-Plex Pro human cytokine 27-plex test kit and LUMINEX 200 were used to assay cytokines/chemokines/growth factors in fasting plasma samples. ResultsaMCI is characterized by significant general immnosuppression, and reductions in T helper 1 (Th)1 and T cell growth profiles, the immune-inflammatory responses system, interleukin (IL)1{beta}, IL6, IL7, IL12p70, IL13, GM-CSF, and MCP-1 as compared with controls. These 7 cytokines/chemokines exhibit neuroprotective effects at physiologic concentrations. In multivariate analyses, three neurotoxic chemokines, CCL11, CCL5, and CXCL8, emerged as significant predictors of aMCI. Logistic regression showed that aMCI was best predicted by combining IL7, IL1{beta}, MCP-1, years of education (all inversely associated) and CCL5 (positively associated). We found that 38.2% of the variance in the qMCI score was explained by IL7, IL1{beta}, MCP-1, IL13, years of education (inversely associated) and CCL5 (positively associated). The DSOA were not associated with any immune data. DiscussionA dysbalance between lowered levels of neuroprotective cytokines and chemokines, and relative increases in neurotoxic chemokines are key factors in aMCI. Future MCI research should always control for the confounding effects of affective symptoms.

BackgroundImpaired endogenous vascular regenerative capacity, reflected by reduced levels of circulating progenitor cells (CPC), has been linked to age-related diseases, especially adverse cardiovascular outcomes. We have previously reported that CPC are associated with cognitive aging, but their impact on cognitive impairment and related brain phenotypes is unclear. Here we report the impact of CPC on cognitive and neuroimaging markers of cognitive impairment. MethodsWe analyzed data from 283 community-dwelling participants (59% female, 39% Black) enrolled in the Brain Stress, Hemodynamics and Risk Prediction (B-SHARP) program. Participants underwent (a) cognitive assessments (including Montreal Cognitive Assessment [MoCA]); (b) brain magnetic resonance imaging (MRI) to derive white matter hyperintensity (WMH) volumes, whole-brain cortical thickness and hippocampal volumes; and (c) flow cytometry for enumerating CPCs as CD45med mononuclear cells expressing CD34 with co-expression with either CD133, chemokine CXC motif receptor 4 (CXCR4), or vascular endothelial growth factor receptor-2 (VEGF2R). Linear regression models were adjusted for demographic and vascular risk factors. ResultsIn fully adjusted models, lower levels of CD34/CD133 CPCs were associated with worse global cognition (MoCA: {beta} = 0.59, p = 0.01), reduced cortical thickness ({beta} = 0.01, p = 0.01), and greater WMH burden ({beta} = -0.15, p = 0.01). Lower levels of CD34 and CD34/CXCR4 CPCs were significantly associated with greater WMH volume burden (CD34: {beta} = -0.27, p < 0.01; CD34/CXCR4: {beta} = -0.14, p = 0.03). Higher CD34/VEGFR2 CPCs were associated with higher MoCA scores ({beta} = 0.37, p < 0.01) and language performance on the Boston Naming Test ({beta} = 0.01, p = 0.03) but not with brain phenotypes. ConclusionsReduced regenerative capacity is associated with worse cognitive performance on global tests and with vascular brain injury, including WMH volume and cortical thinning. If validated in future studies, these findings may highlight regenerative capacity as a promising therapeutic target for mitigating cognitive decline.

BackgroundMajor depressive disorder (MDD) involves disturbances in neuroimmune-metabolic and oxidative stress (NIMETOX) pathways. However, oxidized HDL (OxHDL) and oxidized LDL (OxLDL) have not been examined together. MethodsSerum OxHDL, OxLDL, and a panel of oxidative, antioxidant, and acute phase inflammatory (API) biomarkers were measured in 125 Chinese MDD patients and 40 healthy controls using ELISA and spectrophotometry. ResultsMDD patients showed increased OxHDL, reduced OxLDL, and markedly lowered antioxidant defenses, while classical lipid peroxidation markers remained unchanged. These alterations were independent of metabolic syndrome. The acute phase response was closely linked to reductions in HDL-related antioxidants and OxLDL. A combined biomarker model including the HDL/OxHDL ratio, apolipoprotein (ApoA)1, OxHDL, OxLDL, lipid hydroperoxides, and API index achieved an area under the ROC curve of 0.915 (SE=0.023) and a cross-validated sensitivity of 83.1% with 84.6% specificity. The variance in overall severity of depression, physiosomatic symptoms and recurrence of illness was to a large extent explained by oxidative/antioxidant biomarkers. The top-most important biomarkers were OxHDL/OxLDL (increased) and antioxidant (decreased) levels. ConclusionIncreased OxHDL is a key component of MDD, indicating structural and dysfunctional HDL particles and oxidative damage to its major structural protein (ApoA1). HDL particles rather than LDL particles and other lipids are the most vulnerable sites to be attacked by oxidative stress and inflammatory processes in MDD. These data support the view that increased oxidative damage to HDL particles is a key process in MDD. Preventing HDL particle oxidation is a major new drug target in MDD.

BackgroundMajor depressive disorder (MDD) is characterized by interacting neuro-immune, metabolic, and oxidative stress pathways. Here we examine the interactions between the acute phase (AP) response and serum lipids in Chinese MDD patients. MethodsThis case-control study assessed serum lipids and the AP response in 125 MDD patients and 40 healthy controls (HC), while controlling for metabolic confounders, including metabolic syndrome. ResultsWe found an impaired lipid profile in MDD, characterized by reduced levels of high-density lipoprotein cholesterol (HDL), apolipoprotein (Apo) A1, chloromethyl phenylacetate (CMPA)ase activity, a reverse cholesterol transport (RCT) index, and increased ApoB/ApoA1 index. MDD was characterized by an AP response as conceptualized by lower serum albumin and transferrin and increased monomeric C-reactive protein (mCRP). The AP response was significantly and inversely associated with total cholesterol, HDL, low-density lipoprotein cholesterol, ApoA1, ApoB, lecithin cholesterol acyltransferase, CMPAase activity, and RCT index. After adjusting for the AP response, MDD diagnosis maintained significant independent associations with lower HDL-C, ApoA1, RCT, and higher ApoB/ApoA1 ratio. Multivariate (logistic) regression analyses confirmed that these lipid-inflammatory alterations strongly predict MDD diagnosis and clinical symptom severity. We found that around 81.5% of the MDD patients showed metabolic-inflammatory aberrations with a specificity of 82.1% and an area under the receiver operating characteristic (ROC) curve of 0.873. Lower ApoA1 emerged as a particularly robust protective biomarker, showing significant inverse relationships with affective and chronic fatigue severity scores. ConclusionsThese findings illuminate the complex interplay between a smoldering inflammatory response and lipid metabolism in many patients with MDD.

Hurricane Harvey caused record-breaking, catastrophic flooding across the city of Houston. After floodwaters receded, several health concerns arose, including the potential adverse impact of exposure to mold in flooded homes. We rapidly launched the Houston Hurricane Harvey Health Study to evaluate if microbiome sampling in the wake of a disaster could inform flood-associated environmental exposures and adverse health outcomes. We enrolled a total of 347 subjects at 1-month and 12-months post-Harvey, collecting human (stool, nasal, saliva) and environmental (house swab) samples to profile the bacterial and fungal microbiota. Here we show reported exposure to mold was associated with increased risk of allergic symptoms for up to one year post-disaster, and that butyrate-producing bacteria in the gut were linked to protection from allergic symptoms in mold-exposed individuals. Together, these data provide new insights into how microbiome:environment interactions may influence health in the setting of a flood-related disaster.

IntroductionTherapy-resistant depression is associated with higher levels of systemic inflammation and increased odds of metabolic disorders. It is, therefore, crucial to identify the biomarkers of high-risk individuals and understand the key features of depression-immune-metabolic networks. MethodsThe multiethnic [&ge;] 50-year-old study population is a subset of the Health and Aging Brain Study: Health Disparities (HABS-HD) study. Spearmans rank correlation network analysis was performed between immunological, metabolic, and subscales of the Geriatric Depression Scale (GDS). Significant correlations were then evaluated using a multivariable linear regression analysis, including testing for non-linearity and clinical cutoffs. ResultsTwo clusters were formed: the first included the immune-metabolic biomarkers, and the second included the different subscales of GDS. The two clusters were significantly correlated at six edges. IL-6 and HbA1c were significantly correlated with anhedonic and melancholic features. Abdominal circumference and BMI were significantly correlated with anhedonic features. In the subgroup without current depression, IL-6 and Abdominal circumference maintained a significant edge with anhedonic features. The observed correlations remained statistically significant in the confounder-adjusted regression analysis and followed specific patterns. ConclusionsSymptom clustering showed its superiority over relying on dichotomized depression diagnoses for identifying relevant immunometabolic biomarkers. This study is a first step toward understanding the particularities of immunometabolic depression for better risk stratification and to direct personalized preventive and therapeutic strategies in multiethnic aging populations.

IntroductionChronic emotional stress is a well-recognized risk factor for psychiatric and cardiometabolic disorders. The mediating role of low-grade inflammation in older, ethnically diverse populations has never been studied. MethodsThe multiethnic [&ge;] 50-year-old study population is a subset of the Health and Aging Brain Study: Health Disparities (HABS-HD) study. Adjusted logistic and linear regression were used to assess associations. Statistical mediation analysis with non-parametric bootstrapping was used to determine the intermediate role of Interleukine-6 (IL-6). ResultsThe study included 2,173 participants (50-92 years). Hispanic and Black participants disclosed higher chronic stress levels than White participants. Having a chronic stress total score [&ge;] six points is associated with 53% higher odds of disclosing concomitant cardiovascular disease (CVD) (adj.OR=1.53 [1.1-2.53]), 31% of Type-2 diabetes (T2DM) (adj.OR=1.31[1.06-1.62]), 23% of hypertension (adj.OR=1.23 [1.02-1.49]), and 30% obesity (adj.OR=1.3[1.09-1.55]). These associations were statistically mediated by IL-6 (12% (p-valueFDR=0.012) of the association with CVD, 17% T2DM (p-valueFDR<0.001), 18% hypertension (p-valueFDR<0.001), and 29% obesity (p-valueFDR=0.005)). ConclusionsThe study highlights a further aspect of the pathophysiological mechanisms involved in brain-body communication. While IL-6 partially explains statistical associations between chronic emotional stress and major cardiometabolic disorders, potential causal effects need to be explored in larger longitudinal studies.

BackgroundShort-term exposure to ambient temperature is linked to various health outcomes, raising public health concern in the context of climate change. We aimed to investigate longitudinal associations of temperature exposure with inflammation-related proteins among Swedish young adults. MethodsWe conducted three repeated measurements (2020-2022) by collecting self-sampled volumetric dry blood spots (DBS) from 807 participants from the Swedish BAMSE cohort (mean age 25.9 years). We estimated individual-address level daily temperature using a high-resolution spatiotemporal model. Inflammation-related proteins were measured using the Olinks Explore Inflammation panel. Temperature-related proteins were identified using mixed-effect model adjusting for potential covariates, with potential effect modification by sex, smoking, asthma and air pollution explored. We further linked the temperature-related proteins to lung function, blood pressure and HbA1c. In addition, we built an inflammation-proteomic aging clock using a machine-learning approach and estimated the association between temperature exposure and proteomic age acceleration. Findingswe found that 58 (16%) of the 365 studied inflammation-related proteins were significantly associated with short-term exposure to ambient temperatures (P<0.05 after correcting for multiple comparison). The impact of temperature exposure was modified by sex, smoking, asthma, and concurrent exposure to air pollution. A total of five, three and three temperature-related proteins were found to be associated with lung function, blood pressure, and HbA1c, respectively and validated in the UK Biobank. Peak temperature exposure (both cold and heat) was associated with significantly increased proteomic age acceleration. InterpretationOur findings suggest that ambient temperature exposure may cause adverse health effects through perturbating inflammation-related proteins. SynopsisThis study reports significant effects of ambient temperature exposure on inflammation-related proteins, highlighting potential health impacts from ambient temperature exposure. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/25331135v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@16e3eb3org.highwire.dtl.DTLVardef@d67d61org.highwire.dtl.DTLVardef@1c190a2org.highwire.dtl.DTLVardef@feba21_HPS_FORMAT_FIGEXP M_FIG C_FIG

Most commercial passenger jet aircraft use compressed engine air after cooling as a source for ventilation and cabin pressurization onboard. This "bleed air" design means that engine oil and/or hydraulic fluid can contaminate the ventilation supply air during otherwise normal flights, exposing onboard crewmembers and passengers to the fumes. The oils and hydraulic fluids contain a complex mixture of triaryl phosphates (TAPs) and decomposition products. Although the health and flight safety consequences of inhaling these fumes have been widely documented, measures of onboard inhalation exposure have been lacking. An approach is presented for documenting exposure to engine oil fumes by using high-resolution mass spectrometry (MS) to monitor and quantify post-translational modifications of subjects butyrylcholinesterase (BChE) that are consistent with exposure to the engine oil TAPs. We hypothesized that plasma from exposed individuals would show modifications or adducts on the active site serine (Ser198) of BChE. Plasma BChE from 81 exposed subjects was purified to near homogeneity and concentrated using antibodies immobilized on paramagnetic beads. The purified BChE was eluted at low pH, neutralized, digested with trypsin, and analyzed by liquid chromatography (LC)-MS. In subjects reporting onboard oil fume exposures, the most consistent adduct modifying the Ser198-containing tryptic peptide had a mass value of +154.0031 Da. The normalized peak area (NPA) of the +154Da modification was determined by comparing the relative MS1 intensities of the +154Da-modified Ser198 containing peptide to the total observable peptides containing the active site, including missed cleavages. Notably, adducts from in vitro exposures of bioactivated TAPs to purified BChE conducted in this study (i.e., +80Da, +156Da, +170Da, and +186Da) as well as adducts reported in other earlier in vitro studies (i.e., +65Da, +80Da, +91Da, +107Da, +165Da, +180Da, +181Da, and +277Da) were not detected in exposed subjects. Of the 81 subjects in this study, the average NPA of +154Da-Ser198 resulted from fume event exposures that pre-dated 2013 (N=59); range = 0.46%-17.8%, with [X] =4.84% which was 9.7 times higher than control subjects ([X]= 0.50%) These data are uncorrected for the time lag between the reported exposure and the blood draw. Samples from the remaining 16 subjects with exposures from 2016-2024 showed only the 154Da modification at background levels (0.24%-1.13%;[X] =0.55%), as confirmed in control plasma samples from individuals who had not flown in at least three months. The observed reduction in the 154Da adduct over time in exposed individuals is likely a function of the change in the formulation of the OP blends added to engine oils during the course of the study. Further investigation into other protein biomarkers and adducts correlated with exposure to the current oil additives and hydraulic fluid fumes on aircraft is warranted. The most satisfactory solution would be to eliminate the exposure hazard by implementing bleed-free systems or, at a minimum, to develop less toxic oil formulations, suitable bleed air filters, and modified designs.

BackgroundAdults with type 1 diabetes (T1D) have an increased risk of developing cerebral small vessel disease (cSVD)-related brain changes already in midlife, yet their significance for cognitive functions remains poorly understood. We investigated the associations between cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), and cognitive functions, including processing speed, executive functions, and episodic memory, in individuals without detected neurological symptoms. MethodsAdults with T1D (n=167; age 46.4{+/-}7.7 years) underwent clinical and biochemical evaluations, brain magnetic resonance imaging (MRI), and a comprehensive neuropsychological assessment. CMB number and topography (lobar, deep or infratentorial, or mixed location) were rated. WMHs were quantified with volumetric analysis. ResultsCompared to absence of CMBs, higher burden of CMBs ([&ge;]3) was associated independently of age with worse performance in processing speed (stand. {beta}=0.18-0.23, p<0.05) and executive functions (stand. {beta}=0.18-[-0.25], p<0.05), but not with episodic memory. Mild WMHs had no independent relationships with cognition. Compared to strictly lobar or deep or infratentorial CMBs, mixed location of CMBs was more often negatively related to cognitive performance (stand. {beta}=0.20- 0.32, p<0.05). ConclusionsCMBs were related to a subtle, yet systematic impairment in processing speed and executive functions, whereas no such association was observed for WMHs. The results provide insight into the development of early cSVD-related cognitive changes already in midlife and suggest an increased risk of cognitive decline in T1D.

Ketamine has been investigated as a treatment alternative for PTSD for the last 20 years, yet there have been virtually no reports of biological changes or biomarker characterisation related to treatment. To address this significant gap, this study analysed blood samples from 25 participants with PTSD who took part in an open-label 6-week trial of low dose oral ketamine treatment. Serum and plasma samples were quantified before and after ketamine treatment for brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor A (VEGF-A), serotonin, FK506 binding protein 51 (FKBP51) and a panel of cytokines (interleukin (IL)-1{beta}, IL-2, IL-4, IL-6, IL-12p70, IL-17A and tumour necrosis factor alpha (TNF)). Analysis of BDNF and VEGF-A levels detected a significant positive correlation between the two biomarkers and a small but statistically significant decrease in both measures after ketamine treatment. This novel finding reinforces evidence that ketamines effects may rely on a reciprocal interaction between BDNF and VEGF-A, offering potential insights into a biological mechanism underpinning PTSD symptom reduction. Additionally, the analysis of FKBP51 and serotonin revealed novel relationships between these biomarkers and clinical scales, before and after ketamine treatment. Finally, significant changes or relationships involving the immune cytokines were not detected, possibly because half the participants presented with low-grade inflammation while the other half did not. This study represents the first comprehensive analysis of blood biomarkers before and after ketamine treatment for PTSD and reveals important biological changes and relationships related to this treatment.

BackgroundInflammation and autoimmune responses contribute to the pathophysiology of Long COVID, and its affective and chronic fatigue syndrome (CFS) symptoms, labeled "the physio-affective phenome." ObjectivesTo investigate whether Long COVID and its physio-affective phenome are linked to autoimmunity to the tight junction proteins, zonulin and occludin (ZOOC), and immune reactivity to lipopolysaccharides (LPS), and whether the latter are associated with signs of human herpes virus-6 reactivation (HHV-6), autoimmunity directed against oligodendrocyte and neuronal proteins, including myelin basic protein (MBP). MethodsIgA/IgM/IgG responses to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), HHV-6, ZOOC, and neuronal proteins, C-reactive protein (CRP) and advanced oxidation protein products (AOPP), were measured in 90 Long COVID patients and 90 healthy controls. The physio-affective phenome was conceptualized as a factor extracted from physical and affective symptom domains. ResultsNeural network identified IgA directed to LPS (IgA-LPS), IgG-ZOOC, IgG-LPS, and IgA-ZOOC as the most important variables associated with Long COVID diagnosis with an area under the ROC curve of 0.755. Partial Least Squares analysis showed that 40.9% of the variance in the physio-affective phenome was explained by CRP, IgA-MPB and IgG-MBP. A large part of the variances in both autoimmune responses to MBP (36.3-39.7%) was explained by autoimmunity (IgA and IgG) directed to ZOOC. The latter was strongly associated with indicants of HHV-6 reactivation, which in turn was associated with increased IgM-SARS-CoV-2. ConclusionsAutoimmunity against components of the tight junctions and increased bacterial translocation may be involved in the pathophysiology of Long COVIDs physio-affective phenome.

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.

ObjectiveThis study aims to investigate how neuroinflammation alters gliogenic regulatory pathways and glial cell fate decisions, with a focus on identifying clinically relevant mechanisms that may increase susceptibility to glial-derived brain tumors. By linking inflammatory signaling to early disruptions in gliogenesis, this study seeks to inform future strategies for risk assessment, early detection, and potential therapeutic intervention in inflammation-associated neuro-oncology. BackgroundNeuroinflammation alters gliogenic signaling by disrupting key regulatory pathways such as FGFR3, JAK-STAT, STAT3, and others. This dysregulation affects glial cell differentiation and lineage decisions, contributing to impaired neurodevelopment and increased susceptibility to glial-derived brain tumors, particularly gliomas. Understanding these inflammatory mechanisms is essential for identifying early biomarkers, evaluating long-term tumor risk, and developing strategies to prevent or mitigate neuro-oncological outcomes in individuals with acute or chronic CNS inflammation. MethodsDatabases, including PubMed, MEDLINE, Google Scholar, and both open-access and subscription-based journals, were searched without date restrictions to investigate the brain inflammation induced disruption of gliogenic regulators (FGFR3, JAK-STAT, STAT3, S100, Hey1, HES1, DTX, IL-6, NF-{kappa}B, Neuregulin-1, MAPK/MEK, E2F/TCFL2, NFIX/Ephrins/Netrins) resulting in glial cell fate dysregulations and Its contribution to brain tumor risk. Studies meeting the criteria outlined in the methods section were systematically reviewed to address the research question. This study adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. ResultsNeuroinflammation significantly alters gliogenic regulators, including FGFR3, JAK-STAT, STAT3, S100, IL-6, and NF-{kappa}B, disrupting normal glial maturation, migration, and lineage commitment. This leads to aberrant cell fate decisions, sustained proliferation, and genomic instability, conditions favorable for glioma initiation. Pro-inflammatory pathways, notably IL-6 and NF-{kappa}B, drive oxidative stress and cellular dysfunction, reinforcing the tumor-permissive environment. These insights point to the clinical relevance of inflammation-driven glial dysregulation in brain tumor pathogenesis. ConclusionDisruption of gliogenic regulators by neuroinflammation alters glial fate specification, promotes proliferative stress, and contributes to oncogenic transformation within the CNS. These findings emphasize the need to clinically monitor individuals with significant or recurrent brain inflammation for long-term neuro-oncological risks. Early recognition of these disturbances may guide risk stratification, surveillance, and development of anti-inflammatory or gliogenesis-targeted interventions to prevent glial-origin brain tumors.