Background:Preclinical and postmortem human studies demonstrate significant opioid-related alterations in the neuroimmune system. However, studies investigating the neuroimmune system in living people with opioid use disorder (OUD) are lacking, thereby motivating this pilot study. Methods:Individuals with OUD (n = 6; DSM-5 criteria) were admitted inpatient and stabilized on an individualized buprenorphine dose for 5 to 10 days before a 120-min Positron Emission Tomography (PET) [11C]PBR28 scan. Using multilinear analysis-1 (MA-1; t* = 30), total volume of distribution (V T; 'TSPO availability') was estimated in 10 brain regions of interest (ROIs) incorporating the metabolite-corrected arterial input function. Demographically-matched non-OUD comparators (n = 18) underwent identical PET imaging procedures. Group differences in regional [11C]PBR28 V T were evaluated using linear mixed effects models. Partial correlations, controlling for rs6971 genotype, investigated relationships between regional [11C]PBR28 V T and subjective, behavioral, and biomarker data. Results:OUD participants exhibited higher brain TSPO availability by 20% across ROIs, on average (range: 12-22%) relative to non-OUD comparators (Group Effect; p = 0.036) whereas plasma cytokine/chemokine levels did not differ (ps > 0.05). Greater opioid craving correlated with higher TSPO availability in the parietal (r=0.82, p = 0.048) and prefrontal cortices (r=0.80, p = 0.059). Longer treatment duration correlated with lower TSPO availability in the prefrontal cortex (r = -0.93, p = 0.024). Conclusions:Results are the first exploratory evidence that living participants with OUD, stabilized on buprenorphine inpatient, exhibit elevated TSPO availability, an in vivo neuroimmune marker. TSPO availability was positively correlated with opioid craving and negatively correlated with treatment duration. While preliminary, our findings suggest that the neuroimmune system may be a therapeutic target in OUD.
Introduction Monocyte chemoattractant protein-1 (MCP-1; also known as CCL2) is a chemokine implicated in neuroinflammatory pathways that may contribute to cognitive decline in Alzheimer’s disease (AD). Elevated MCP-1 is associated with glial activation, blood-brain barrier dysfunction, and immune-cell recruitment. This study assessed the longitudinal association between peripheral MCP-1 and cognitive decline in biomarker-confirmed participants across the AD continuum and explored whether psychological stress was associated with longitudinal MCP-1 changes. Methods This pilot longitudinal study included 21 amyloid-/p-tau-positive participants across the AD continuum, including six with mild cognitive impairment and 15 with AD. Participants underwent baseline and a single 1-year follow-up assessment. Global cognition was assessed using the Alzheimer’s Disease Assessment Scale cognitive subscale Japanese version, and serum MCP-1 concentrations were measured using enzyme-linked immunosorbent assay. Stress response, depression, anxiety, apathy, and neuropsychiatric symptoms were assessed using validated behavioral and psychological scales. Stepwise multiple regression and partial correlation analyses were performed. Results Annual changes in peripheral MCP-1 were significantly associated with cognitive decline (β = 0.54, P = 0.005). Psychological stress, measured by the Stress Response Scale-18, was positively correlated with MCP-1 changes (r = 0.75, P = 0.003). These findings suggest that longitudinal serum MCP-1 changes may be associated with cognitive decline in the AD continuum and that psychological stress may be related to MCP-1 dynamics. Discussion MCP-1 may contribute to AD-related neuroinflammatory activity. The association between psychological stress and MCP-1 changes should be interpreted as exploratory and requires validation in larger longitudinal cohorts.
Background Delirium in mechanically ventilated intensive care unit (ICU) patients is linked to inflammatory dysregulation, but whether the pulmonary microbiome contributes to delirium risk remains unclear. Methods We performed a secondary analysis of 132 mechanically ventilated adults from the MicroNAV cohort. Baseline bronchoalveolar lavage (BAL) samples collected within 12 h of intubation were profiled by 16S rRNA gene sequencing; total bacterial burden was quantified by droplet digital PCR (ddPCR; n = 125), and BAL cytokines were measured using a multiplex assay (n = 70). Concordant genus-level signals identified by four differential-abundance methods were aggregated into ecological scores and tested using logistic regression adjusted for age and Glasgow Coma Scale at intubation. Absolute abundance was estimated by multiplying relative abundance by ddPCR-derived bacterial burden. Results Delirium was recorded in 45 patients (34.1%). Total bacterial DNA concentration was lower in patients with delirium (median 7,419 vs 98,326 copies/μL, P = 0.001). A putative short-chain fatty acid (SCFA)-producing commensal score (Phocaeicola, Selenomonas, and Fretibacterium) was inversely associated with delirium in compositional analysis (OR 0.83, 95% CI 0.75–0.92, P < 0.001) and after ddPCR-anchored absolute quantification (OR 0.84, 95% CI 0.75–0.94, P = 0.002). This depletion extended to oral-core commensals (absolute OR 0.80, P < 0.001) and a pre-specified oral anaerobe score (absolute OR 0.82, P = 0.002). Opportunistic colonizers were enriched compositionally but not in absolute abundance (OR 1.10, P = 0.187). Commensal scores were positively associated with BAL IL-1β and TNF-α, whereas opportunistic-colonizer scores showed inverse associations. Conclusions Early pulmonary depletion of oral-derived commensals, particularly putative SCFA producers, was associated with ICU delirium. Prospective studies with standardized delirium assessment and functional metabolite measurements are needed.
Major depressive disorder (MDD) has been associated with both immune dysregulation and autonomic nervous system (ANS) dysfunction, and growing evidence suggests that bidirectional interactions between these systems may contribute to depression pathophysiology. However, the existing evidence has not yet been comprehensively synthesized, limiting understanding of the ANS–immune axis in MDD.This scoping review aimed to map the literature investigating interactions between the ANS and immune system in MDD, identify methods assessing this relationship, and explore implications for stratification.Following PRISMA-ScR and Joanna Briggs Institute guidelines, a systematic search of 12 databases and trial registers was conducted through January 2026. Eligible studies included human studies examining both ANS functioning and immune markers in MDD. Data were synthesized across three ANS domains: catecholaminergic signaling, cardiac autonomic measures, and vagus nerve functioning.Twenty-five studies published between 1989 and 2025 were included. Studies on catecholamine–immune interactions reported both positive associations and null findings between catecholamines and inflammatory markers, while in vitro studies showed both suppressive and enhancing immune effects. Several studies investigating heart rate variability (HRV) have reported inverse associations between inflammatory markers and vagally mediated HRV indices, although many of these studies lacked covariate adjustment. Studies investigating vagal function and vagus nerve stimulation reported immunomodulatory effects, but these varied according to stimulation modality, duration, and participant stratification.Current evidence suggests that altered ANS functioning may be associated with immune dysregulation in MDD, but findings remain heterogeneous. Larger longitudinal studies with standardized methods are needed to clarify these ANS–immune interactions.
Background:Cross-sectional and standard approaches to examining proinflammatory activity and sleep disturbances separately hinder understanding of their additive, long-term impacts on major depressive disorder (MDD). The current study used latent profile analysis (LPA) to identify multimodal neuroimmune profiles and to investigate whether subtypes predicted 9-year MDD severity in a community-dwelling adult sample. Method:Community adults (N = 306) completed psychiatric interviews to measure MDD symptoms at baseline and 9-year follow-up. The Pittsburgh Sleep Quality Index and eight-day actigraphy captured subjective and objective sleep disturbances, respectively. Nine log-transformed inflammatory markers-including C-reactive protein, E-selectin, intercellular adhesion molecule-1, fibrinogen, interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α-were assayed. An LPA with an interpretable 13-variable core set was conducted, with model selection based on various metrics, including split-sample Adjusted Rand Index (ARI) stability. Results:The two-profile solution provided the best fit (ARI = 0.948). Profile 1 (n = 212) was marked by adequate sleep and low inflammation; Profile 2 (n = 94) by insufficient sleep and high inflammation. Profile 2 membership was a strong predictor of greater 9-year MDD severity (Cohen's d = 0.244, p = .039) after controlling for baseline demographics and MDD severity. This effect remained practically significant in the completely adjusted model (d = 0.208). LPA had superior performance than variable-centered approaches on parsimony-based model fit. Conclusions:A neuroimmune profile characterized by proinflammatory activity and insufficient, fragmented sleep functioned as a distal risk factor of MDD symptoms. A person-centered, multimodal risk stratification approach may enhance targeted prevention of long-term MDD.
Arginine vasopressin (AVP) is a pleiotropic neuroendocrine hormone with diverse physiological functions that have important implications for immune regulation. Although AVP has been reported to exert both immunostimulating and immunosuppressive effects, its actions on immune function are highly context-dependent and arise largely from its established roles in stress physiology, vascular regulation, osmoregulation, and thermoregulation. AVP influences immune activity indirectly through modulation of the hypothalamic-pituitary-adrenal (HPA) axis, blood flow, vascular and lymphatic permeability, fluid balance, and fever responses - all of which shape immune cell trafficking, activation, and inflammatory signaling. In addition, the expression of AVP and its receptors on immunocompetent cells - including T cells, dendritic cells, macrophages, neutrophils, and microglia - supports a role for direct, cell-specific AVP signaling, although the functional consequences of these interactions remain incompletely defined. AVP signaling affects both innate and adaptive immune responses by altering immune cell proliferation, migration, differentiation, and cytokine production in a manner that depends on receptor subtype, cellular content, and physiological state. These immunomodulatory properties are particularly relevant in conditions characterized by neuroendocrine dysregulation, including chronic stress, acquired brain injury, and autoimmune disease, where AVP contributes to cerebral edema, blood-brain barrier disruption, dysregulated HPA axis feedback, and secondary immune activation. This review synthesizes current evidence describing how AVP shapes immune function through integrated neuroendocrine, vascular, and cellular mechanisms, highlights key gaps in mechanistic understanding, and discusses the therapeutic potential - and limitations - of targeting AVP signaling in inflammatory and neuroimmune disease.
Purpose We aimed to identify protein patterns in peripheral blood mononuclear cells (PBMCs) associated with autism spectrum disorder (ASD) diagnosis and clinical heterogeneity and to explore their relevance to biological processes implicated in ASD. Methods PBMC proteomic profiles were examined in a Thai cross-sectional cohort of 191 children with ASD and 106 typically developing (TD) controls. Mass spectrometry (LC-MS/MS) was performed to identify differentially expressed proteins (DEPs). Exploratory classification performance was assessed by ROC analysis across clinical subgroups. Associations between DEPs and behavioral and cognitive symptoms were evaluated using mixOmics multivariate integration. DEPs were further assessed for overlap with ASD-associated genes and previously reported ASD blood and brain proteomic datasets, and functionally annotated using protein–protein interaction and enrichment analyses. Results Thirty-nine annotated proteins were differentially expressed between children with ASD and TD controls, while a subset was associated with heterogeneity within ASD. Several DEPs were encoded by known ASD-associated genes and overlapped with proteins previously reported in ASD blood and brain studies. Functional analyses identified enrichment of cytoskeletal and chromatin-associated pathways, including an actin-centered protein interaction network. Multivariate integration analyses revealed associations between these proteins and behavioral, social, emotional, sensory, and cognitive phenotypes, while subgroup analyses indicated subtle molecular heterogeneity within ASD. Conclusion PBMC proteomic profiles identified molecular signatures associated with ASD diagnosis and clinical heterogeneity in this discovery cohort. Exploratory network analyses highlighted cytoskeletal- and chromatin-associated proteins, supporting further evaluation of peripheral proteomics as a tool for investigating ASD biology and biologically informed stratification.
Obesity has been associated with cognitive impairment, yet the contribution of obesity-related genetic liability to cognition across the lifespan remains unclear. Here, we investigated associations between body mass index (BMI), obesity polygenic risk score (PRS), and cognitive performance in 796 individuals from the FOR2107 Marburg-Münster Affective Disorders Cohort Study (MACS). Cognitive function was assessed using a neuropsychological test battery covering working memory, episodic memory, attention, processing speed, executive function, and crystallized intelligence. Multivariate analyses of covariance revealed significant age-dependent associations of both BMI (ηp2(BMI*age) = 0.038, F (10,771) = 3.06, p = 0.001) and obesity PRS (ηp2(PRS*age) = 0.028, F (10,763) = 2.20, p = 0.016) with cognitive performance, indicating that these associations differed across lifespan. No significant sex moderation or overall multivariate associations of BMI or PRS with cognition were observed. Both interactions remained significant after adjustment for education, perceived stress, and childhood trauma. In a sensitivity analysis, the PRS*age interaction remained significant after additional adjustment for BMI. Follow-up linear regression analyses revealed that increasing age was associated with a more negative relationship of BMI with episodic memory (B = -0.087, SE = 0.029, p = 0.003) and a more positive relationship with crystallized intelligence (B = 0.089, SE = 0.032, p = 0.005). Similarly, increasing age was associated with a more negative relationship of obesity PRS with episodic memory (B = -0.083, SE = 0.031, p = 0.008) and a more positive relationship with working memory (B = 0.073, SE = 0.034, p = 0.032). Ultimately, our findings suggest that age is a key moderator of the associations between BMI, PRS, and cognition. The persistence of the PRS*age interaction after adjustment for BMI indicates that obesity-related genetic liability may influence cognition through mechanisms beyond current body weight.
Sepsis survivors often experience long-term cognitive and mental health impairment. We lack a clear understanding of the biological mechanisms driving impairment after sepsis and the factors that make a brain vulnerable to dysfunction after sepsis. We hypothesize that amyloid pathology, which is neuroinflammatory and accumulates with age even in cognitively normal people, is a latent risk factor for post-sepsis decline driven in part by neuroinflammation and microglial dysfunction. We induced sepsis via polymicrobial abdominal infection (cecal ligation and puncture; CLP) in young adult 5xFAD mice to model early amyloid pathology. 5xFAD CLP mice demonstrated generalized conditioned fear response and impaired cognition in the puzzle box task. Brain transcriptomics revealed persistent upregulation of neuroinflammatory pathways after resolution of the infection, with a distinct increase in 5xFAD CLP survivor mice. Complement gene expression and C3aR protein were heightened in 5xFAD mice, while C3 increased after infection. Microglial synaptic phagocytosis, a potential mechanism driving brain dysfunction after sepsis, was increased in 5xFAD CLP survivor mice 3 weeks after infection. While there was a small C3aRhigh microglial population in 5xFAD brains, the change in synaptic phagocytosis occurred in microglia with basal levels of C3aR expression. Overall, our findings suggest that early amyloid pathology synergistically heightens the behavioral change, neuroinflammation, and microglial synaptic phagocytosis caused by sepsis.
Objective To characterise symptom onset, progression, and persistence in paediatric N-methyl-D-aspartate receptor antibody encephalitis (NMDARE) using the Paediatric Autoimmune encephalitis Severity Scale (PASS), and to describe real-world symptomatic pharmacological management. Methods We performed a retrospective study of children (<18 years) with confirmed NMDARE admitted to two tertiary centres (2012-2024). Disease severity was assessed using the modified Rankin Scale (mRS) and PASS at nadir, discharge, one year, and last follow-up. Symptomatic treatments and their timings, clinician-rated benefits and adverse events were recorded, with adverse event:benefit ratios calculated. Results Thirty-five patients were included (median age 8 years [IQR 4–13]; 71% female). Median peak severity was mRS 5 and PASS 22/30. Seizures and psychiatric manifestations were the most frequent presenting symptoms, whereas movement disorders, motor deficits, and autonomic dysfunction typically appeared later. Younger children (<12 years) presented with a more florid neurological picture, whereas older patients more often presented with psychiatric features; both groups progressed to similar multisystem severity at nadir. At one year, 68% achieved mRS 0–1 (median PASS 3/30), increasing to 87% at last follow-up (median 5 years). PASS identified persistent impairments in activities of daily living (26%), speech/communication (17%), and sleep (14%) at last follow-up. Symptom-directed treatments showed high perceived benefit across drug classes; second-generation antipsychotics were generally well tolerated, except risperidone, which showed higher adverse event rates. Interpretation Persistent neurocognitive and functional deficits are common following NMDARE, captured better by PASS than mRS. Symptom-directed treatments showed overall favourable tolerability, with second-generation antipsychotics except risperidone demonstrating good safety.
Traumatic brain injury (TBI) alters neuroimmune physiology resulting in an imbalance between pro- and anti-inflammatory cascades. Whereas acute inflammation serves as an adaptive defense mechanism of the innate immune system to promote healing and restore homeostasis after injury, unresolved pro-inflammatory cascades have been shown to contribute to long-term sequelae of TBI. An important, yet understudied, neuroimmune signaling pathway affected by TBI is the kynurenine pathway (KP). Kynurenine is a product of tryptophan metabolism by indoleamine 2,3 dioxygenase in the central nervous system, a metabolite downstream of kynurenine, e.g., quinolinic acid and kynurenic acid, as products of kynurenine 3 monooxygenase and kynurenine aminotransferase, respectively. TBI patients exhibit disrupted levels of KP metabolites, including kynurenine and quinolinic acid, in plasma, cerebrospinal fluid, and brain. Alterations in KP metabolite levels have been reported in both Major Depressive Disorder and pain-related conditions, including headaches, fibromyalgia, and neuropathic pain, thereby suggesting a role of the KP in progression of prevalent pathological TBI sequalae, that include depression and chronic pain. This narrative review outlines the KP, evaluates its alterations following TBI in relation to sequelae such as chronic pain and depression, and discusses potential KP directed therapeutic targets within the TBI framework.
Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine implicated in systemic inflammatory and renal stress biology. It remains unclear whether GDF-15 reflects diagnosis-specific biology or transdiagnostic physiological burden at acute psychiatric admission. In this cross-sectional study, 190 acutely admitted in-patients with schizophrenia spectrum disorders (SSD, n = 126) or mood disorders (MD, n = 64) underwent blood sampling within 12 h of emergency presentation. Serum GDF-15, interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and soluble urokinase plasminogen activator receptor (suPAR) were assayed, alongside creatinine, urea, and estimated glomerular filtration rate (eGFR). Group comparisons were conducted using independent-samples t-tests or Mann-Whitney U tests for continuous variables and χ2 or Fisher's exact tests for categorical variables. Following Bonferroni correction across 31 comparisons (p < 1.6 × 10-3), antidepressant burden and previous hospitalizations were the only significant between-group differences. GDF-15 showed a non-significant trend towards higher values in MD than SSD patients. In the primary complete-case multivariable model, diagnostic category was not independently associated with ln (GDF-15) after adjustment for age, urea, ln (IL-6), and ln (suPAR) (MD vs SSD: B = -0.012, β = -0.010, p = 0.900). Instead, ln (GDF-15) was associated with older age (B = 0.013, p = 3.0 × 10-4), higher urea (B = 0.010, p = 0.027), higher ln (IL-6) (B = 0.167, p = 2.4 × 10-4), and higher ln (suPAR) (B = 0.297, p = 0.001), explaining 40.2% of variance. Sensitivity analyses adjusting for smoking, cardiovascular disease, thyroid disorder, sex, and alternative diagnostic classification did not materially alter the absence of a diagnostic-group effect. In conclusion, GDF-15 variation was better explained by transdiagnostic renal-immune a stress phenotype than by categorical diagnosis, supporting its evaluation as a marker of systemic physiological burden rather than a diagnosis-specific biomarker.
Background: Perinatal depression (PND) occurs during a period marked by profound endocrine, metabolic, and immune adaptation. Although alterations in immune–metabolic regulation have been reported in PND, how such changes manifest across distinct biological compartments remains unclear. The oral mucosal ecosystem represents an immunologically active interface with direct connections to systemic circulation, yet its functional characteristics in PND have been insufficiently explored. In this study, we examined whether PND is characterized by differences in oral microbial functional profiles alongside systemic immune–metabolic features. Methods: We performed an integrated multi-omics analysis combining salivary shotgun metagenomics and untargeted serum metabolomics in 31 women with PND and 32 healthy controls. Oral microbial taxonomic composition and inferred functional profiles were analyzed together with circulating metabolites related to endocrine and immune processes. Cross-omics analyses were used to evaluate overall concordance as well as pathway- and feature-level associations between microbial functional signals and host metabolic features. Findings: The oral microbiome of women with PND showed largely preserved community structure and diversity, while differences were observed at the level of inferred functional pathways, including enrichment of lipopolysaccharide biosynthesis and virulence-associated functional categories. Concurrently, the serum metabolome exhibited differences in steroid-related metabolites, bile acid profiles, and lipid mediator–associated features involved in immune modulation, including putatively annotated resolvin D5. Global concordance between oral microbial functional profiles and systemic metabolomic patterns was limited; however, reproducible associations were observed at the pathway and feature levels, such as an inverse association between the relative abundance of the genus Abiotrophia and the bile acid taurochenodeoxycholate-7-sulfate. Interpretation: Together, these findings describe concurrent differences in oral microbial functional signatures and systemic immune–metabolic features in women with PND, occurring in the context of minimal changes in microbial community composition. The limited global concordance and selective pathway-level correspondence across omic layers are consistent with asynchronous patterns of biological variation during the perinatal period. These observations support the potential relevance of the oral–systemic axis as a non-invasive perspective for characterizing biological heterogeneity associated with perinatal depression.
Cytokines and chemokines are key mediators of immune-brain communication and play important roles in central nervous system development, homeostasis, and aging. While individual cytokines and chemokines have been implicated in neurodevelopmental and age-related processes, a systematic characterization of their expression in the brain across the lifespan is lacking. Here, we performed a multiplex analysis of cytokine and chemokine levels in whole-brain homogenates from C57BL/6 mice spanning early postnatal life to advanced aging (postnatal day 3 to 24 months). Using a multiplex immunoassay, we quantified 21 chemokines and 9 cytokines and identified distinct age-associated expression patterns. Several chemokines exhibited elevated levels during early postnatal development, whereas others were selectively increased in the aged brain. Notably, a subset of chemokines displayed biphasic expression, with higher levels during both early life and aging. Cytokine analysis revealed increased levels of IL-1β and IL-2 during early postnatal development, while aging was associated with elevated TNF-α, IL-2, and IL-4. Together, these data provide a descriptive resource of cytokine and chemokine expression in the mouse brain across the lifespan, highlighting life stage-specific immune signatures that may differentially influence immune cell trafficking, neuron-glia interactions, and brain function during neural development and aging.
Background:Previous studies suggest that specific depressive symptoms such as low energy, fatigue, sleep and appetite disturbances are associated with systemic low-grade inflammation. In this study, we investigated associations between an inflammatory symptom profile of depression and proteomic markers spanning inflammatory and metabolic pathways. Methods:We analyzed 158 proteins related to inflammation and metabolism using proximity extension assay in blood samples from 165 patients with Major Depressive Disorder (MDD). Severity of inflammatory depressive symptoms was assessed using a composite score summarizing Patient Health Questionnaire-9 (PHQ-9) items related to fatigue and sleep/appetite disturbances. We used partial least squares (PLS), PLS discriminant analysis (PLS-DA) and linear regression models to identify proteins related to inflammatory depressive symptom severity. Results:Out of the 158 proteins, 14 were selected by either PLS or PLS-DA. After false discovery rate correction, proteins identified by PLS or PLS-DA that remained significantly associated with more severe inflammatory depressive symptoms included several immunometabolic biomarkers, namelyinterleukin-6 (IL-6), hepatocyte growth factor, oncostatin M, thrombospondin-4, low affinity immunoglobulin gamma Fc region receptor II-a and intercellular adhesion molecule 1. With the exception of IL-6, none of these markers showed significant associations with the remaining PHQ-9 items that were not classified as inflammatory depressive symptoms. Conclusions:These findings support the growing body of evidence linking inflammatory and metabolic protein alterations to specific depressive symptoms.
Background: Post-COVID-19 Syndrome (PCS) encompasses a range of persistent symptoms, including cognitive and autonomic disturbances, potentially linked to microvascular or neuroinflammatory mechanisms. Retinal imaging provides a non-invasive window into the central nervous system and vascular integrity. This study aimed to assess retinal structural and microvascular alterations in PCS patients and explore their relationship with symptom severity. Methods: In this monocentric, cross-sectional, exploratory study, we performed Optical Coherence Tomography (OCT) and OCT Angiography (OCTA) in patients with PCS and a group of COVID-19 recovered individuals. Multiple circulating biomarkers reflecting endothelial dysfunction and chronic inflammation were measured. Associations with validated symptom scores (PCS Score, C19-YRS, PHQ-9, GAD-7) were evaluated. Results: After adjusting for age and gender, no significant differences were observed in OCTA-derived vessel density (VD) or foveolar avascular zone (FAZ) between PCS patients and COVID-19-recovered controls. However, PCS patients exhibited significant thinning of the peripapillary retinal nerve fibre layer (pRNFL), ganglion cell inner plexiform layer (GCIP), and total macular volume (TMV). Lower values of these structural parameters were consistently observed in patients with higher symptom severity. Vascular parameters (VD and FAZ) were not related to clinical scores. Higher MCP-1 levels, a chemokine associated with chronic inflammation, were linked to lower inner nuclear layer and GCIP thickness. Conclusion: Structural retinal alterations in PCS were associated with symptom burden and may reflect underlying neuroinflammatory or neurodegenerative processes. OCT parameters could serve as potential non-invasive biomarkers, warranting further investigation in longitudinal, multicenter studies.
Background:Autoimmune encephalitis (AIE) comprises a diverse group of neurological disorders characterized by autoantibodies targeting specific antigens of the central nervous system (CNS). While the pathophysiological effects of these autoantibodies have been extensively studied, the principles and immunological triggers underlying their generation remain less well understood. Viral infections and antiviral vaccinations have been reported as potential immunological triggers. However, a systematic overview of their specific associations and frequencies across AIE subtypes is lacking. Methods:Here, we performed a systematic literature review in PubMed to identify published cases of AIE linked to viral infections or antiviral vaccinations, and to test whether herpes simplex virus (HSV)-associated anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E) represents a disproportionately strong association. We quantified the frequencies of viral infection- or vaccine-related AIE across ten common antibody-defined subtypes, and characterized their epidemiological and clinical features, complemented by data from 23 population-based viral encephalitis cohorts. Results:We identified 556 cases, of which 488 were infection-associated and 68 followed vaccination. The most frequent combination was HSV infection in association with NMDAR-E, which outnumbered all other reported virus-AIE associations combined and was almost exclusively attributable to preceding HSV encephalitis (HSE). Other recurrent associations included Japanese encephalitis virus, Epstein-Barr virus (EBV), and SARS-CoV-2 infections, although EBV- and SARS-CoV-2-associated cases were less clearly suggestive of causal post-infectious autoimmunity. Across 23 population-based viral encephalitis cohorts from five continents, HSV was the leading causative pathogen. Despite this high background frequency, HSV was significantly overrepresented among viral CNS infection-associated NMDAR-E cases in our dataset compared with the reference cohorts (P < 0.0001), indicating a disproportionate association. Most reported HSE-associated NMDAR-E cases originated from Europe and occurred in young children (median age 6 years), with a balanced sex distribution and a median interval between infection and NMDAR-E onset of 30 days. Conclusion:Collectively, these findings provide the most comprehensive overview of viral infection- and antiviral vaccination-associated AIE to date and support a pathogen-specific link between HSE and secondary NMDAR-E as the most dominant virus-AIE association in the published literature. They underscore the need to elucidate the underlying immunological mechanisms and to develop biomarkers predictive of secondary NMDAR-E.
Allostatic load (AL), defined as nervous system wear and tear in response to repeated or prolonged stress, has been hypothesized to underlie risk for the onset and/or maintenance of chronic pain. However, minimal research has directly examined the measurement and interpretation of AL in relation to chronic pain in clinical populations. Recent work in a community sample of adults suggests relations between chronic pain and “allostatic load phenotypes” (e.g. parasympathetic dysregulation and metabolic dysregulation), where the metabolic dysregulation phenotype showed to predict greater pain interference and a higher number of pain sites compared to low allostatic load phenotype. Given the dearth of understanding on how AL manifests in youth with chronic pain, the current study aimed to investigate AL phenotypes in youth with chronic pain and their associations with clinical outcomes. Allostatic load measures, including salivary cortisol, dehydroepiandrosterone (DHEA), and C-reactive protein, as well as waist–hip ratio, body-mass index, and blood pressure, were collected during previously scheduled new patient evaluations at a tertiary pain clinic. Results indicate biomarkers related to cardiovascular and cortisol phenotypes show good fit with the data. Further, youth with high cardiovascular risk and low cortisol risk evidenced greater pain catastrophizing, and those with high Cortisol risk evidenced greater exposure to childhood adversity. Future research should continue to examine the manifestation of these phenotypes in larger and broader chronic pain populations in youth and capture how these phenotypes may respond to intervention.
Cognitive impairment is a common and debilitating complication of multiple sclerosis (MS), but non-pharmacological strategies such as diet for its management have not yet been fully explored. The aim of this review is to synthesize the evidence on the relationship between diet and cognitive outcomes in people with MS. Clinical interventional and observational studies evaluating the association between the diet and cognitive outcomes in MS were considered. The diets most frequently evaluated were Mediterranean (n = 3), modified Paleolithic/Wahls (n = 3), Swank (n = 1), ketogenic (n = 2), and time-restricted eating (n = 1). Other included studies investigated the broader association between overall dietary quality, healthy-eating patterns, and cognitive outcomes in MS patients. Trials of the Mediterranean diet have generally shown no significant cognitive improvements, although a recent study on a low-calorie Mediterranean diet, as well as observational studies, has reported increased processing speed, manual dexterity, and fewer cognitive complaints. The Wahls/Paleolithic interventions showed improvements in processing speed and mental cognition that were comparable to the Swank diet. Limited evidence from small studies suggested potential benefits of ketogenic and time-restricted diets, while findings were inconsistent for general healthy or high-fiber diets. Dietary interventions may hold promise as adjunctive strategies for cognitive health in MS; however, inconsistencies in study designs, cognitive measures, and intervention duration, combined with limited high-quality evidence, undermine strong recommendations, which warrant further evaluations.
Introduction:Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a debilitating condition characterized by severe fatigue and post-exertional malaise (PEM). Reported neuropsychophysiological abnormalities suggest ME/CFS is multifactorial, but current knowledge remains fragmented. This study protocol outlines a multimodal investigation designed to (1) compare neuropsychophysiological mechanisms between ME/CFS patients and healthy participants, (2) test an integrative model of ME/CFS, (3) identify neuropsychophysiological subgroups within the patient population, and (4) identify predictors of symptom response during rehabilitation. Methods and analysis:This study will enroll 115 ME/CFS patients and 55 healthy participants. Groups will be comparable in age, sex, and education level, with a larger patient sample enabling subgroup and longitudinal analyses. A cross-sectional assessment at baseline will be carried out in both groups. Patients will then be evaluated longitudinally throughout a standardized cognitive-behavioral therapy rehabilitation program delivered as routine care. Baseline measures include systemic inflammation and general health biomarkers, measures of autonomic and central nervous system function, neuroinflammation (magnetic resonance spectroscopy, [18F]DPA714 PET in a subsample), serum short-chain fatty acid levels, gut microbiota composition and function, and neuroendocrine and self-reported responses to psychosocial stress. Fatigue severity (physical and cognitive) and PEM will be assessed through validated questionnaires, ecological momentary assessment, and laboratory tasks. These will be re-evaluated during therapy, and all non-neuroimaging measures will be repeated after the rehabilitation program. Statistical analyses will comprise multivariate analysis of variance, general linear models, classification algorithms, structural equation models, least absolute shrinkage selection operator principal component regression (LASSO-PCR), cluster analysis and latent class growth analysis (LCGA).
