Central Inflammation Research Articles

Mechanisms of inflammation after ischemic stroke in brain-peripheral crosstalk.

Stroke is a devastating disease with high morbidity, disability, and mortality, among which ischemic stroke is more common. However, there is still a lack of effective methods to improve the prognosis and reduce the incidence of its complications. At present, there is evidence that peripheral organs are involved in the inflammatory response after stroke. Moreover, the interaction between central and peripheral inflammation includes the activation of resident and peripheral immune cells, as well as the activation of inflammation-related signaling pathways, which all play an important role in the pathophysiology of stroke. In this review, we discuss the mechanisms of inflammatory response after ischemic stroke, as well as the interactions through circulatory pathways between peripheral organs (such as the gut, heart, lung and spleen) and the brain to mediate and regulate inflammation after ischemic stroke. We also propose the potential role of meningeal lymphatic vessels (MLVs)-cervical lymph nodes (CLNs) as a brain-peripheral crosstalk lymphatic pathway in ischemic stroke. In addition, we also summarize the mechanisms of anti-inflammatory drugs in the treatment of ischemic stroke.

Tailored exercise programmes for fibromyalgia: a clinical practical guide.

To evaluate the role of exercise in the management of fibromyalgia syndrome (FM) by addressing its complex pathogenesis involving central sensitisation, autonomic dysfunction, inflammation, and neurological irregularities, and examining how exercise impacts symptom exacerbation caused by external stressors and comorbid conditions. This review synthesises evidence from current literature focusing on the benefits of structured and personalised exercise programmes in FM management. It discusses the importance of specifying exercise type, intensity, frequency, duration, and progression tailored to individual patient needs and clinical objectives. Regular physical activity effectively mitigates core aetiopathogenetic mechanisms of FM and improves associated conditions such as stress and obesity. It also provides benefits for preventing other chronic diseases, enhancing well-being, and promoting healthy ageing. Structured and personalised exercise programmes that start with a low-demand protocol and gradually increase exercise volume are most beneficial, by improving patient compliance and reducing the risk of adverse effects. Effective management of FM requires a patient-centred approach integrating both pharmacological and non-pharmacological treatments, with exercise playing a pivotal role. Personalised exercise prescriptions that consider FM patients' specific needs and limitations are crucial for optimising treatment outcomes and enhancing quality of life.

Chronic Astrocytic TNFα Production in the Preoptic-Basal Forebrain Causes Aging-like Sleep-Wake Disturbances in Young Mice.

Sleep disruption is a frequent problem of advancing age, often accompanied by low-grade chronic central and peripheral inflammation. We examined whether chronic neuroinflammation in the preoptic and basal forebrain area (POA-BF), a critical sleep-wake regulatory structure, contributes to this disruption. We developed a targeted viral vector designed to overexpress tumor necrosis factor-alpha (TNFα), specifically in astrocytes (AAV5-GFAP-TNFα-mCherry), and injected it into the POA of young mice to induce heightened neuroinflammation within the POA-BF. Compared to the control (treated with AAV5-GFAP-mCherry), mice with astrocytic TNFα overproduction within the POA-BF exhibited signs of increased microglia activation, indicating a heightened local inflammatory milieu. These mice also exhibited aging-like changes in sleep-wake organization and physical performance, including (a) impaired sleep-wake functions characterized by disruptions in sleep and waking during light and dark phases, respectively, and a reduced ability to compensate for sleep loss; (b) dysfunctional VLPO sleep-active neurons, indicated by fewer neurons expressing c-fos after suvorexant-induced sleep; and (c) compromised physical performance as demonstrated by a decline in grip strength. These findings suggest that inflammation-induced dysfunction of sleep- and wake-regulatory mechanisms within the POA-BF may be a critical component of sleep-wake disturbances in aging.

Contribution of youth sport participation to physical activity levels and cardiovascular disease risk factors in 5-year-old to 14-year-old children: a study protocol for systematic review and meta-analysis

IntroductionCardiovascular disease (CVD) accounts for 18 million deaths per year, disproportionately burdens under-represented racial and ethnic groups, and has economic costs greater than any other health condition. Participation in youth...

HIV-derived Proteins induce Hypertension, Sympatho-activation, and neuroinflammation via T cell-dependent mechanisms

Combination antiretroviral therapy (cART) has markedly increased life expectancy in people living with HIV (PLWH) and induced a switch in the cause of death from opportunistic diseases to cardiovascular disease (CVD). CVD is currently the leading cause of death in PLWH and hypertension, the primary risk factor for CVD, presents in more than 65% of them. However, the mechanisms whereby hypertension develops in PLWH remain unknown. In PLWH on cART, T lymphocytes (T cells) remain a viral reservoir for HIV and continue to secrete viral proteins. Viral proteins remain in circulation and are expressed in the central nervous system. Herein, we tested the hypothesis that expression of HIV-derived proteins increases blood pressure (BP), induces sympatho-activation and inflammation of the central nervous system. We utilized the Tg26 mouse model which expresses 7/9 viral proteins. Quantitative PCR analysis of viral protein expression showed that Tat, gp120, Nef, Vif, and Vpr are primarily expressed in spleen, lung, and brain tissues in Tg26 mice. Morphometric analysis revealed slight but significant increases and decreases in lean mass and fat weights respectively in Tg26. Flow cytometry analysis showed no reduction in CD4+ T cells in Tg26 mice indicating that this mouse model does not progress to AIDS and reproduce the conditions of virally suppressed PLWH. Blood pressure (BP) measurement via telemetry revealed a hypertensive phenotype in male and female Tg26 mice. Hypertension was associated with a larger drop in BP in response to ganglionic blockade but no alterations in heart rate responses to muscarinic and β-adrenergic receptor blockade in Tg26 mice, indicating that viral proteins expression increases neurogenic control of BP but did not alter cardiac autonomic control. β-adrenergic receptor blockade did not reduce BP in Tg26 mice. Tg26 mice also display increased aortic vasoconstriction to phenylephrine. To test the contribution of T cells in BP regulation and sympatho-activation, mice were subjected to a CTLA-4 inhibitor, abatacept, which inhibits T cell activation. Abatacept treatment significantly reduced BP, sympatho-activation, and phenylephrine constriction in Tg26 mice with no effects on wild-type mice. To determine whether the increase in sympatho-activation involves central inflammation, inflammatory cytokines and T cell markers levels were measured in the brain. Levels of pro-inflammatory cytokines including IL-1α, TNFα, IL-6, and CCL2 were increased in the brain of Tg26 mice as well as levels of the T-cell marker GATA3. Altogether, our data shows that the expression of HIV-derived proteins increases BP, sympatho-activation, and vascular adrenergic contractility via T cell-dependent mechanisms likely through central mechanisms involving neuro-inflammation. R01HL147639-01A1, R01HL15526501 and 19EIA34760167 (E.J.B). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Which aspects of education are health protective? a life course examination of early education and adulthood cardiometabolic health in the 30-year study of early child care and Youth Development (SECCYD)

BackgroundPast research describes robust associations between education and health, yet findings have generally been limited to the examination of education as the number of years of education or educational attainment. Little is known about the specific features or processes underpinning education that are health protective. The objective of the current study was to address this gap by examining specific aspects of early education pertaining to student characteristics and experiences, as well as features of the classroom environment, in predicting cardiometabolic health in adulthood.MethodsSubjects were 1364 participants in the NICHD Study of Early Child Care and Youth Development (SECCYD, 1991–2009) and recent SECCYD 30-year follow-up, the Study of Health in Early and Adult Life (SHINE, 2018–2022). Models examined individual education indicators (student social skills, student-teacher relationship quality, and classroom emotional and instructional quality in the period of elementary school and student academic performance between ages 54 months and 15 years) in relation to a composite of cardiometabolic risk in adulthood (ages 26–31), reflecting central adiposity, blood pressure, insulin resistance, inflammation, and dyslipidemia. Models were adjusted for key explanatory factors including socio-demographics, infant characteristics, parental socioeconomic status (SES), and child health status. Follow-up analyses were performed to test potential mediators of early education effects on adult health, including adult SES (educational attainment, household income) and health behaviors (diet quality, activity level, sleep duration, smoking).ResultsIn adjusted models, results showed greater student social skills, indexed by a mean of annual teacher ratings between kindergarten and 6th grade, predicted lower cardiometabolic risk in adulthood (β=-0.009, p <.05). In follow-up analyses, results showed the protective effect of student social skills on cardiometabolic risk may be mediated by adult income (β=-0.0014, p <.05) and diet quality (β=-0.0031, p <.05). Effects of the other early education indicators were non-significant (ps > 0.05).ConclusionsFindings point to the potential significance of early student social competence as a link to long-term health, possibly via the acquisition of resources needed for the maintenance of health, as well as through engagement in health behaviors supporting healthy eating. However, more research is needed to replicate these findings and to elaborate on the role of early student social competence and the pathways explaining its effects on cardiometabolic health in adulthood.

Mediterranean diet protects against a neuroinflammatory cortical transcriptome: Associations with brain volumetrics, peripheral inflammation, social isolation, and anxiety in nonhuman primates (Macaca fascicularis)

Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets; however, the underlying biology is poorly understood. We assessed the effects of Western versus Mediterranean-like diets on RNAseq-generated transcriptional profiles in lateral temporal cortex and their relationships with longitudinal changes in neuroanatomy, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques (Macaca fascicularis). Diet resulted in differential expression of seven transcripts (FDR < 0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., “lunatic fringe” (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways. KATNB1 encodes a subcomponent of katanin, important in maintaining microtubule homeostasis. BTN2A1 is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects. CDK14, LFNG, MRC2, and SLCA32 are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with peripheral monocyte transcript levels, neuroanatomical changes determined by MRI, and with social isolation and anxiety. These results provide important insights into the potential mechanistic processes linking diet, peripheral and central inflammation, and behavior. Collectively, our results provide evidence that, relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and socioemotional behavior. Ultimately, such protective effects may confer resilience to the development of neuropathology and associated disease.

COVID‐19 and cognitive impairment: From evidence to SARS‐CoV‐2 mechanism

AbstractCaused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), coronavirus disease 2019 (COVID‐19) primarily manifests as respiratory dysfunction. However, emerging evidence suggests SARS‐CoV‐2 can invade the brain, leading to cognitive impairment (CI). It may spread to other brain regions through transsynaptic neurons, including the olfactory, optic, and vagus nerves. Moreover, it may invade the central nervous system through blood transmission or the lymphatic system. This review summarizes the neuroimaging evidence from clinical and imaging studies of COVID‐19‐associated CIs, including magnetic resonance imaging and 18F‐fluorodeoxyglucose positron emission tomography‐computed tomography. The mechanisms underlying COVID‐19‐associated CIs are currently being actively investigated. They include nonimmune effects, such as viral proteins, tissue hypoxia, hypercoagulability, and pathological changes in neuronal cells, and immune effects, such as microglia and astrocyte activation, peripheral immune cell infiltration, blood‐brain barrier impairment, cytokine network dysregulation, and intestinal microbiota. Inflammation is the central feature. Both central and systemic inflammation may cause acute and persistent neurological changes, and existing evidence indicates that inflammation underlies the elevated risk of Alzheimer's disease. Finally, potential therapeutic options for COVID‐19‐associated CIs are discussed. In‐depth research into the pathological mechanisms is still needed to help develop new therapies.

Are central and systemic inflammation associated with fatigue in cerebral small vessel disease?

Fatigue is a common symptom in cerebral small vessel disease (SVD), but its pathogenesis is poorly understood. It has been suggested that inflammation may play a role. We determined whether central (neuro) inflammation and peripheral inflammation were associated with fatigue in SVD. Notably, 36 patients with moderate-to-severe SVD underwent neuropsychometric testing, combined positron emission tomography and magnetic resonance imaging (PET-MRI) scan, and blood draw for the analysis of inflammatory blood biomarkers. Microglial signal was taken as a proxy for neuroinflammation, assessed with radioligand 11C-PK11195. Of these, 30 subjects had full PET datasets for analysis. We assessed global 11C-PK11195 binding and hotspots of 11C-PK11195 binding in the normal-appearing white matter, lesioned tissue, and combined total white matter. Peripheral inflammation was assessed with serum C-reactive protein (CRP) and using the Olink cardiovascular III proteomic panel comprising 92 biomarkers of cardiovascular inflammation and endothelial activation. Fatigue was assessed using the fatigue severity scale (FSS), the visual analog fatigue scale, and a subscale of the Geriatric Depression Scale. Mean (SD) age was 68.7 (11.2) years, and 63.9% were male. Of these, 55.6% showed fatigue on the FSS. Fatigued participants had higher disability scores (p = 0.02), higher total GDS scores (p = 0.02), and more commonly reported a history of depression (p = 0.04). 11C-PK11195 ligand binding in the white matter was not associated with any measure of fatigue. Serum CRP was significantly associated with average fatigue score on FSS (ρ = 0.48, p = 0.004); this association persisted when controlling for age, sex, disability score, and depression (β = 0.49, 95% CI (0.17, 2.26), p = 0.03). Blood biomarkers from the Olink panel showed no association with fatigue. In symptomatic SVD patients, neuroinflammation, assessed with microglial marker 11C-PK11195, was not associated with fatigue. We found some evidence for a role of systematic inflammation, evidenced by an association between fatigue severity and raised CRP, but further studies are required to understand this relationship and inform whether it could be therapeutically modified to reduce fatigue severity. Data for this study are available from the corresponding author upon reasonable request.

Intestinal MAdCAM-1 imaging as biomarker for prognostic in murine models of multiple sclerosis

IntroductionMultiple sclerosis (MS) is an autoimmune disease of the central nervous system. Recent evidence suggests that lymphocyte trafficking in the intestines could play a key role in its etiology. Nevertheless, it is not clear how intestinal tissue is involved in the disease onset nor its evolution. In the present study, we aimed to evaluate intestinal inflammation dynamic throughout the disease course and its potential impact on disease progression. MethodsWe used tissue immunophenotyping (immunohistofluorescence and flow cytometry) and a recently described molecular magnetic resonance imaging (MRI) method targeting mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to assess intestinal inflammation in vivo in two distinct animal models of MS (Experimental Autoimmune Encephalomyelitis − EAE) at several time points of disease progression. ResultsWe report a positive correlation between disease severity and MAdCAM-1 MRI signal in two EAE models. Moreover, high MAdCAM-1 MRI signal during the asymptomatic phase is associated with a delayed disease onset in progressive EAE and to a lower risk of conversion to a secondary-progressive form in relapsing-remitting EAE. During disease evolution, in line with a bi-directional immune communication between the gut and the central nervous system, we observed a decrease in T-CD4+ and B lymphocytes in the ileum concomitantly with their increase in the spinal cord. ConclusionAltogether, these data unveil a crosstalk between intestinal and central inflammation in EAE and support the use of molecular MRI of intestinal MAdCAM-1 as a new biomarker for prognostic in MS patients.

Supplementation of yam bean (Pachyrhizus erosus L.) fiber ameliorates dyslipidemia, liver pathology and hypersecretion of metabolic hormones in mice fed a highfat diet

Introduction: Yam bean (Pachyrhizus erosus L.) offers numerous health benefits. However, the effects of its dietary fiber (yam bean fiber, YBF) on dyslipidemia, liver disease, and the overproduction of metabolic hormones, specifically glucagon-like peptide-1 (GLP1) and fibroblast growth factor 21 (FGF21), resulting from a high-fat diet (HFD) remain underexplored. Thus, our present investigation sought to address this gap. Methods: Adult male mice (n = 24) were randomly assigned into four different groups such as normal diet (ND) as a control group, HFD, and HFD supplemented with either 2.5% or 10% YBF. After a 12-week dietary regimen, plasma lipid profiles, liver histology and biochemistry, and the levels of FGF21 and GLP-1 were assessed. Results: YBF supplementation, especially at 10% dose, effectively lowered total serum cholesterol, triglyceride (TG), and low-density lipoprotein (LDL) compared with those fed HFD (P &lt; 0.05). YBF also reduced liver weight and mitigated the elevation of malondialdehyde (MDA) and the depletion of catalase (CAT) activity induced by HFD in liver tissues (P &lt; 0.05). Furthermore, 10% YBF supplementation effectively countered liver pathology, including central vein enlargement, hepatic steatosis, inflammation, abnormal sinusoids, and hepatocyte degeneration caused by HFD (P &lt; 0.05). YBF at 10% also attenuated the HFDinduced hypersecretion of FGF21 and GLP-1 hormones. Conclusion: Our findings indicate that YBF supplementation could counteract the adverse effects of HFD, particularly in terms of dyslipidemia, liver disease, and metabolic hormone imbalances. Incorporating YBF into diets may thus offer protective benefits against HFDinduced metabolic diseases and associated health issues.

Effect of electroacupuncture on behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome.

To observe the effect of electroacupuncture (EA) on the changes of behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome (CFS), so as to explore its possible mechanisms in the treatment of CFS. Twenty-seven SD rats were randomly divided into control, model and electroacupuncture (EA) groups (n=9 rats in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (10 Hz) at "Shenting" (GV24) penetrating "Baihui" (GV20), "Dazhui" (GV14) for 15 min, twice a day for 14 days. The general conditions, Morris water maze test, open field test, the exhausted running platform were conducted for determining the rats' locomotor and learning-memory activities. H.E. staining was used to observe the morphological structure of neurons in hippocampal CA1 region. The contents of interleukin (IL)-10, IL-17 and transforming growth factor (TGF) β1 in hippocampus and serum of rats were detected by ELISA, and the positive expressions of IL-10, IL-17 and TGF-β1 in hippocampal CA1 region were detected by immunofluorescence staining. Compared with the control group, the score of general condition was increased (P<0.05), the escape latency was prolonged (P<0.05), the number of crossing the original platform was decreased (P<0.05), the numbers of crossing the grid and entering the central area were increased (P<0.05), and the exhaustive treadmill time was shortened (P<0.05) in the model group. The contents of IL-10 in the hippocampus and serum were decreased (P<0.05), while IL-17 and TGF-β1 contents were increased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was decreased (P<0.05), while the intensity of IL-17 and TGF-β1 were increased (P<0.05). After treatment, compared with the model group, the score of general condition was decreased (P<0.05), the escape latency was shortened (P<0.05), the number of crossing the original platform was increased (P<0.05), the numbers of crossing the grid and entering the central area were decreased (P<0.05), and the exhaustive treadmill time was prolonged (P<0.05) in the EA group. The contents of IL-10 in the hippocampus and serum were increased (P<0.05), while IL-17 and TGF-β1 levels were decreased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was increased (P<0.05), while the intensity of IL-17 and TGF-β1 were decreased (P<0.05). H.E. staining showed that in the model group, the number of neurons in the hippocampus decreased, with disordered arrangement and loose structure, and a small numbers of neuronal nuclei were missing. The degree of tissue damage of the EA group was milder than that of the model group. EA can alleviate fatigue and spatial learning and memory impairment in CFS rats, which may be related to the regulation of peripheral and central inflammation.

Evaluation of canine adipose-derived mesenchymal stem cells for neurological functional recovery in a rat model of traumatic brain injury

BackgroundTraumatic brain injury (TBI) is a common condition in veterinary medicine that is difficult to manage.Veterinary regenerative therapy based on adipose mesenchymal stem cells seem to be an effective strategy for the treatment of traumatic brain injury. In this study, we evaluated therapeutic efficacy of canine Adipose-derived mesenchymal stem cells (AD-MSCs)in a rat TBI model, in terms of improved nerve function and anti-neuroinflammation.ResultsCanine AD-MSCs promoted neural functional recovery, reduced neuronal apoptosis, and inhibited the activation of microglia and astrocytes in TBI rats. According to the results in vivo, we further investigated the regulatory mechanism of AD-MSCs on activated microglia by co-culture in vitro. Finally, we found that canine AD-MSCs promoted their polarization to the M2 phenotype, and inhibited their polarization to the M1 phenotype. What’s more, AD-MSCs could reduce the migration, proliferation and Inflammatory cytokines of activated microglia, which is able to inhibit inflammation in the central system.ConclusionsCollectively, the present study demonstrates that transplantation of canine AD-MSCs can promote functional recovery in TBI rats via inhibition of neuronal apoptosis, glial cell activation and central system inflammation, thus providing a theoretical basis for canine AD-MSCs therapy for TBI in veterinary clinic.

A multiscale inflammatory map: linking individual stress to societal dysfunction.

As populations worldwide show increasing levels of stress, understanding emerging links among stress, inflammation, cognition, and behavior is vital to human and planetary health. We hypothesize that inflammation is a multiscale driver connecting stressors that affect individuals to large-scale societal dysfunction and, ultimately, to planetary-scale environmental impacts. We propose a 'central inflammation map' hypothesis to explain how the brain regulates inflammation and how inflammation impairs cognition, emotion, and action. According to our hypothesis, these interdependent inflammatory and neural processes, and the inter-individual transmission of environmental, infectious, and behavioral stressors - amplified via high-throughput digital global communications - can culminate in a multiscale, runaway, feed-forward process that could detrimentally affect human decision-making and behavior at scale, ultimately impairing the ability to address these same stressors. This perspective could provide non-intuitive explanations for behaviors and relationships among cells, organisms, and communities of organisms, potentially including population-level responses to stressors as diverse as global climate change, conflicts, and the COVID-19 pandemic. To illustrate our hypothesis and elucidate its mechanistic underpinnings, we present a mathematical model applicable to the individual and societal levels to test the links among stress, inflammation, control, and healing, including the implications of transmission, intervention (e.g., via lifestyle modification or medication), and resilience. Future research is needed to validate the model's assumptions, expand the factors/variables employed, and validate it against empirical benchmarks. Our model illustrates the need for multilayered, multiscale stress mitigation interventions, including lifestyle measures, precision therapeutics, and human ecosystem design. Our analysis shows the need for a coordinated, interdisciplinary, international research effort to understand the multiscale nature of stress. Doing so would inform the creation of interventions that improve individuals' lives and communities' resilience to stress and mitigate its adverse effects on the world.

Matrix metalloproteinase 9 (MMP-9) activity, hippocampal extracellular free water, and cognitive deficits are associated with each other in early phase psychosis.

Increasing evidence points toward the role of the extracellular matrix, specifically matrix metalloproteinase 9 (MMP-9), in the pathophysiology of psychosis. MMP-9 is a critical regulator of the crosstalk between peripheral and central inflammation, extracellular matrix remodeling, hippocampal development, synaptic pruning, and neuroplasticity. Here, we aim to characterize the relationship between plasma MMP-9 activity, hippocampal microstructure, and cognition in healthy individuals and individuals with early phase psychosis. We collected clinical, blood, and structural and diffusion-weighted magnetic resonance imaging data from 39 individuals with early phase psychosis and 44 age and sex-matched healthy individuals. We measured MMP-9 plasma activity, hippocampal extracellular free water (FW) levels, and hippocampal volumes. We used regression analyses to compare MMP-9 activity, hippocampal FW, and volumes between groups. We then examined associations between MMP-9 activity, FW levels, hippocampal volumes, and cognitive performance assessed with the MATRICS battery. All analyses were controlled for age, sex, body mass index, cigarette smoking, and years of education. Individuals with early phase psychosis demonstrated higher MMP-9 activity (p < 0.0002), higher left (p < 0.05) and right (p < 0.05) hippocampal FW levels, and lower left (p < 0.05) and right (p < 0.05) hippocampal volume than healthy individuals. MMP-9 activity correlated positively with hippocampal FW levels (all participants and individuals with early phase psychosis) and negatively with hippocampal volumes (all participants and healthy individuals). Higher MMP-9 activity and higher hippocampal FW levels were associated with slower processing speed and worse working memory performance in all participants. Our findings show an association between MMP-9 activity and hippocampal microstructural alterations in psychosis and an association between MMP-9 activity and cognitive performance. Further, more extensive longitudinal studies should examine the therapeutic potential of MMP-9 modulators in psychosis.

Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets.

The involvement of central and peripheral inflammation in the pathogenesis and prognosis of major depressive disorder (MDD) has been demonstrated. The increase of pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-18, and TNF-α) in individuals with depression may elicit neuroinflammatory processes and peripheral inflammation, mechanisms that, in turn, can contribute to gut microbiota dysbiosis. Together, neuroinflammation and gut dysbiosis induce alterations in tryptophan metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related mechanisms, and glutamate-mediated excitotoxicity. This review aims to highlight the inflammatory mechanisms (neuroinflammation, peripheral inflammation, and gut dysbiosis) involved in the pathophysiology of MDD and to explore novel anti-inflammatory therapeutic approaches for this psychiatric disturbance. Several lines of evidence have indicated that in addition to antidepressants, physical exercise, probiotics, and nutraceuticals (agmatine, ascorbic acid, and vitamin D) possess anti-inflammatory effects that may contribute to their antidepressant properties. Further studies are necessary to explore the therapeutic benefits of these alternative therapies for MDD.

Prebiotics modulate the microbiota–gut–brain axis and ameliorate anxiety and depression-like behavior in HFD-fed mice

Previous research has demonstrated that Prebiotics can influence the composition of the gut microbiota, consequently impacting mood regulation. This study aimed to assess the effects of Prebiotics, specifically Fructooligosaccharides (FOS) and Galactooligosaccharides (GOS) on neuroinflammation, depression, and anxiety-like behavior in a mouse model fed a high-fat diet (HFD). Initially, mice were divided into two groups: a control group on a standard diet (n = 15) and a group on an HFD for 18 weeks (n = 45). By the 13th week, the HFD group was further divided into experimental groups: Control (n = 15), HFD (n = 15), HFD receiving Prebiotics (n = 15), and HFD receiving Fluoxetine (n = 15). From the 13th week onward, the HFD + Prebiotics group received both the high-fat diet and a combination of FOS and GOS, while the HFD + Fluoxetine group received Fluoxetine in their drinking water. In the 18th week, all mice underwent tests to evaluate behavior, including the Tail Suspension Test (TST), Forced Swimming Test (FST), Sucrose Preference Test (SPT), and the Plus Maze Test (PMT), after which they were euthanized. Mice on the HFD exhibited increased body weight, abdominal size, blood glucose, triglyceride levels, cholesterol, insulin, HOMA index, and higher serum IL-1β. These obese mice also displayed an increased number of microglia and astrocytes, activation of the TLR4 pathway, and elevated levels of neuroinflammatory markers like TNF-α, IL-1β, and COX-2. Moreover, obese mice showed increased activation of the IDO pathway and decreased levels of NMDA receptors. Additionally, markers of neurogenesis and synaptic plasticity, such as PSD, SAP 102, CREB-p, and BDNF, were lower. Treatment with FOS and GOS reversed symptoms of depression and anxiety in mice subjected to HD. This improvement in behavior resulted from a reduction in dysbiosis with an increase in acetate-producing bacteria (B. acidifaciens and B. dorei) and intestinal permeability, leading to a decrease in chronic peripheral and central inflammation. Furthermore, the modulation of the gut-brain axis by FOS and GOS promoted elevated acetate and GPR43 levels in the brain and a reduction in the levels of pro-inflammatory cytokines, positively impacting signaling pathways of neuronal proliferation and survival in the hippocampus and prefrontal cortex.

Low-contrast visual acuity test is associated with central inflammation and predicts disability development in newly diagnosed multiple sclerosis patients.

The visual system is a prominent site of damage in MS since the earliest phases of the disease. Altered low-contrast visual acuity (LCVA) test has been associated with visual impairment and retinal degeneration, predicting medium- and long-term disability. However, it is unclear whether LCVA may also represent a reliable measure of neuroinflammation and a predictor of disease evolution in the very early stages of MS. We explored in a group of 76 consecutive newly diagnosed relapsing-remitting MS (RR-MS) patients without visual impairment or altered visual evoked potentials, the association between LCVA scores at 2.5% and 1.25% and clinical characteristics, including prospective disability evaluated after 1- and 2 years of follow-up. Associations between LCVA and the CSF levels of IL-10 at diagnosis were also analyzed. A negative correlation was found between LCVA at 2.5% and Expanded Disability Status Scale (EDSS) evaluated at first (Spearman's Rho = -0.349, p = 0.005, n = 62) and second year (Spearman's Rho = -0.418, p < 0.001, n = 62) of follow-up, and negative correlations were found with Multiple Sclerosis Severity Score (MSSS) at first (Spearman's Rho = -0.359, p = 0.004, n = 62) and second year (Spearman's Rho = -0.472, p < 0.001, n = 62). All the data were confirmed by a mixed effect model, considering other clinical variables. A positive correlation was found between the CSF concentrations of IL-10 and LCVA at 2.5% (Spearman's Rho = 0.272, p = 0.020, n = 76), and 1.25% (Spearman's Rho, = 0.276, p = 0.018, n = 76), also evidenced in a linear regression. In MS patients at diagnosis, altered LCVA may be associated with CSF inflammation and represent a useful parameter to identify patients with worse disease course.

Neural Correlates of Obesity and Inflammation in Children and Adolescents with Congenital Adrenal Hyperplasia

Introduction: Patients with classical congenital adrenal hyperplasia (CAH) exhibit an increased prevalence of obesity from childhood including central adiposity and inflammation. There is also an emerging affected brain phenotype in CAH, with decreased cortico-limbic gray matter volumes and white matter abnormalities. We aimed to study the relationship between brain structure, obesity, and inflammation in children and adolescents with CAH compared to controls. Methods: 27 CAH (12.6 ± 3.4 y, 16 females) and 35 control (13.0 ± 2.8 y, 20 females) participants had MRI of gray matter regions of interest (prefrontal cortex [PFC], amygdala, hippocampus) and white matter microstructure (fornix, stria terminalis [ST]). Anthropometric measures and lab analytes were obtained. Relaimpo analyses (relative importance for linear regression; percent variance) identified which brain structures were most different between groups. Subsequent regressions further quantified the magnitude and direction of these relationships. Correlations analyzed relationships between brain structure, obesity, and inflammation in the context of CAH status. Results: PFC (13.3% variance) and its superior frontal (SF) subregion (14%) were most different between CAH and controls for gray matter; ST (16%) for white matter. Patients with CAH had lower caudal middle frontal (β = −0.56 [−0.96, −0.15]) and superior frontal (β = −0.58 [−0.92, −0.25]) subregion volumes, increased orientation dispersion index in the fornix (β = 0.56 [0.01, 1.10]) and ST (β = 0.85 [0.34, 1.36]), and decreased fractional anisotropy in the fornix (β = −0.91 [−1.42, −0.42]) and ST (β = −0.83 [−1.34, −0.33]) (all p’s r = −0.41), visceral adipose tissue (r = −0.25), and waist-to-height ratio (r = −0.27, all p’s r = 0.31) and TNF-α (r = 0.29, all p’s Conclusions: Relationships among key brain structures, body composition, and inflammatory markers in pediatric patients with CAH could be largely driven by having CAH, with implications for obesity and neuroinflammation in this high-risk population.

Perivascular Space Burden and Cerebrospinal Fluid Biomarkers in US Veterans With Blast-Related Mild Traumatic Brain Injury.

Blast-related mild traumatic brain injury (mTBI) is recognized as the "signature injury" of the Iraq and Afghanistan wars. Sleep disruption, mTBI, and neuroinflammation have been individually linked to cerebral perivascular space (PVS) dilatation. Dilated PVSs are putative markers of impaired cerebrospinal fluid (CSF) and interstitial fluid exchange, which plays an important role in removing cerebral waste. The aim of this cross-sectional, retrospective study was to define associations between biomarkers of inflammation and MRI-visible PVS (MV-PVS) burden in Veterans after blast-related mTBI (blast-mTBI) and controls. The CSF and plasma inflammatory biomarker concentrations were compared between blast-mTBI and control groups and correlated with MV-PVS volume and number per white matter cm3. Multiple regression analyses were performed with inflammatory biomarkers as predictors and MV-PVS burden as the outcome. Correction for multiple comparisons was performed using the Banjamini-Hochberg method with a false discovery rate of 0.05. There were no group-wise differences in MV-PVS burden between Veterans with blast-mTBI and controls. Greater MV-PVS burden was significantly associated with higher concentrations of several proinflammatory biomarkers from CSF (i.e., eotaxin, MCP-1, IL-6, IL-8) and plasma (i.e., MCP-4, IL-13) in the blast-mTBI group only. After controlling for sleep time and symptoms of post-traumatic stress disorder, temporal MV-PVS burden remained significantly associated with higher CSF markers of inflammation in the blast-mTBI group only. These data support an association between central, rather than peripheral, neuroinflammation and MV-PVS burden in Veterans with blast-mTBI independent of sleep. Future studies should continue to explore the role of blast-mTBI related central inflammation in MV-PVS development, as well as investigate the impact of subclinical exposures on MV-PVS burden.