Peripheral Inflammatory Markers Research Articles

The peripheral blood inflammatory markers in Ménière's disease patients with and without migraine

Objective: To investigate the peripheral blood inflammatory markers including white blood cell count (WBC), monocytes, neutrophils, lymphocytes, platelets, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), high-density lipoprotein(HDL-C), low-density lipoprotein and fibrinogen (FIB) in Ménière's disease (MD) patients with and without migraine, and to explore the relationship between the inflammatory response with MD and migraine. Methods: The general physical condition, clinical manifestations, pure-tone audiometry, and peripheral blood inflammatory markers of 92 unilateral MD patients who were hospitalized in Peking University People's Hospital for surgical treatment from January 2017 to January 2021 were continuously collected. Meanwhile, 50 healthy controls matched with age and sex were included, and their general physical conditions and peripheral blood inflammatory markers were also collected. This study consisted of two parts. First, the differences in epidemical characteristics and peripheral blood inflammatory markers between MD patients and healthy controls were compared by univariate analysis. Second, all 92 MD patients were divided into two subgroups according to whether they were accompanied by migraine. The clinical characteristics and peripheral blood inflammatory markers of MD patients with and without migraine were compared by univariate analysis. Thereafter, binary Logistic regression was used to analyze the related factors of whether MD patients were accompanied with migraine. Results: Compared with the healthy control group, the peripheral blood WBC, neutrophils and FIB of MD patients were significantly increased (all P<0.05). Compared with MD patients without migraine, MD patients with migraine had higher female prevalence, longer disease history, lower low-frequency hearing threshold, higher frequency of vertigo attacks and higher HDL-C levels (all P<0.05), meanwhile, female, frequency of vestibular attacks and HDL-C were independent related factors of whether MD patients were accompanied with migraine. Conclusion: The occurrence of MD and migraine may be related to the inflammatory response. The level of anti-inflammatory factors in the blood of MD patients with migraine are higher, suggesting that the inflammatory response status of MD patients with and without migraine is different.

Associations of white blood cell and platelet counts with specific depressive symptom dimensions in patients with bipolar disorder: Analysis of data from the FACE-BD cohort

Evidences suggest that inflammation is increased in a subgroup of patients with depression. Moreover, increased peripheral inflammatory markers (cells and proteins) are associated with some, but not all depressive symptoms. On the other hand, similar studies on bipolar disorders mainly focused on blood cytokines. Here, we analysed data from a large (N = 3440), well-characterized cohort of individuals with bipolar disorder using Kendall partial rank correlation, multivariate linear regression, and network analyses to determine whether peripheral blood cell counts are associated with depression severity, its symptoms, and dimensions. Based on the self-reported 16-Item Quick Inventory of Depressive Symptomatology questionnaire scores, we preselected symptom dimensions based on literature and data-driven principal component analysis. We found that the counts of all blood cell types were only marginally associated with depression severity. Conversely, white blood cell count was significantly associated with the sickness dimension and its four components (anhedonia, slowing down, fatigue, and appetite loss). Platelet count was associated with the insomnia/restlessness dimension and its components (initial, middle, late insomnia and restlessness). Principal component analyses corroborated these results. Platelet count was also associated with suicidal ideation. In analyses stratified by sex, the white blood cell count-sickness dimension association remained significant only in men, and the platelet count-insomnia/restlessness dimension association only in women. Without implying causation, these results suggest that peripheral blood cell counts might be associated with different depressive symptoms in individuals with bipolar disorder, and that white blood cells might be implicated in sickness symptoms and platelets in insomnia/agitation and suicidal ideation.

Single-balloon Enteroscopy for Evaluation of Small Bowel Crohn Disease Strictures: Peripheral Blood Lymphocytes As a Risk Factor for Strictures.

Few reports have focused on single-balloon enteroscopy (SBE) for evaluation of small bowel Crohn disease (CD) strictures. The aim of this study was to analyze the relationships between peripheral blood inflammatory markers and small bowel CD strictures observed by SBE. CD patients who underwent SBE between January 2016 and December 2020 were enrolled. The clinical characteristics and peripheral blood inflammatory markers were collected and analyzed to screen for predictive factors significantly associated with small bowel CD strictures. A total of 221 CD patients underwent SBE. The lymphocyte (LC) counts in peripheral blood were significantly lower in the active group (n=178) than in the inactive group (n=43) according to the simple endoscopic score for CD (SES-CD), P =0.011, and was correlated with the SES-CD ( r =-0.134, P =0.047). The LC levels were significantly lower in the stricture group (n=116) than in the nonstricture group (n=105) based on whether small bowel strictures developed, P =0.000, and LC was a risk factor for strictures in the multivariate analysis [hazard ratio (HR), 2.332; 95% CI, 1.102-4.937; P =0.027]. In the subgroup analysis, LC levels notably decreased after stricture aggravation ( P =0.000). Forty-seven patients who underwent small bowel resection underwent SBE at 6 to 12 months after surgery. The LC level was significantly lower in the postoperative patients with strictures ( P =0.025), and LC (HR, 4.444; 95% CI, 1.265-15.617; P =0.020) was a risk of postoperative strictures by univariate analysis, but the age at diagnosis (HR, 6.462; 95% CI, 1.272-22.560; P =0.022) was an independent risk factor by multivariate analysis. Peripheral blood LC levels were correlated with SES-CD and gradually decreased as the intestinal stricture increased in small bowel CD patients. The LC level was also significantly lower in the postoperative CD patients with strictures. The level of LC was a risk factor for small bowel strictures. These results suggest that peripheral blood LC could be a novel marker of small bowel CD strictures to guide CD diagnosis and therapy.

Role of Peripheral Inflammatory Markers in Patients with Acute Headache Attack to Differentiate between Migraine and Non-Migraine Headache.

Although the potential relationship between headaches, particularly migraine, and peripheral inflammatory markers (PIMs) has been investigated, it is unclear whether PIMs are involved in the pathogenesis of migraine or can differentiate it from non-migraine headaches (nMHs). Using 10 years of data from the Smart Clinical Data Warehouse, patients who visited the neurology outpatient department (OPD) within 30 days after visiting the emergency room (ER) for headaches were divided into migraine and nMH groups, the PIMs were compared including the neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte (PLR) ratios, and neutrophil-to-monocyte ratio (NMR). Of the 32,761 patients who visited the ER for headaches, 4005 patients visited the neurology OPD within 30 days. There were significant increases in the NLR, MLR, and NMR, but a lower PLR in the migraine and nMH groups than the controls. The NMR was significantly higher in the migraine than the nMH group. A receiver operating characteristic curve analysis showed that the ability of the NLR and NMR to differentiate between migraine and nMHs was poor, whereas it was fair between the migraine groups and controls. The elevated PIMs, particularly the NLR and NMR, during headache attacks in migraineurs suggest that inflammation plays a role in migraine and PIMs may be useful for supporting a migraine diagnosis.

Trajectories of peripheral inflammatory markers in women with different stress exposure during pregnancy in association to postpartum depression vs resilience

Trajectories of peripheral inflammatory markers in women with different stress exposure during pregnancy in association to postpartum depression vs resilience

Preoperative peripheral blood inflammatory markers especially the fibrinogen-to-lymphocyte ratio and novel FLR-N score predict the prognosis of patients with early-stage resectable extrahepatic cholangiocarcinoma.

Systemic inflammation is important in the development of extrahepatic cholangiocarcinoma (ECC). The aim of this study was to compare the prognostic power of preoperative peripheral blood inflammatory markers and the novel FLR-N score in patients with resectable ECC. A total of 140 patients with resectable ECC and 140 healthy controls (HCs) were recruited for the study. The Mann-Whitney U test was used to evaluate the differences in inflammatory markers between groups. Kaplan-Meier and Cox regression analyses were used to evaluate the prognostic power of preoperative fibrinogen, albumin, prealbumin, bilirubin, neutrophils, lymphocytes, monocytes, platelets, fibrinogen-to-lymphocyte ratio (FLR), fibrinogen-to-albumin ratio (FAR), fibrinogen-to-prealbumin ratio (FPR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), FLR-neutrophil (FLR-N) score, and CA19-9 in patients with resectable ECC. Nomogram was developed based on the results of multivariate Cox analyses. Patients with resectable ECC had significantly higher levels of neutrophils, monocytes, fibrinogen, FLR, FAR, FPR, NLR, PLR, and MLR and lower levels of lymphocytes, albumin, and prealbumin than HCs (all P < 0.01). Albumin, prealbumin, and FPR had a good ability to distinguish between ECC patients with total bilirubin < 34 µmol/L and HCs (AUCs of 0.820, 0.827, and 0.836, respectively). Kaplan-Meier analysis showed that high neutrophil, fibrinogen, FLR, FAR, PLR, MLR, and FLR-N score values were associated with poor survival in patients with resectable ECC. Multivariate analyses indicated that neutrophils (P = 0.022), FLR (P = 0.040), FLR-N score (P < 0.0001), and positive lymph node metastasis (P = 0.016) were independent factors for overall survival (OS). Nomogram were developed to predict OS for patients with ECC. The prognostic roles of inflammatory markers in patients with resectable ECC were different. The preoperative neutrophil count, FLR and FLR-N score could serve as noninvasive markers for predicting the prognosis of resectable ECC.

Association between air pollution and CSF sTREM2 in cognitively normal older adults: The CABLE study.

Ambient air pollution aggravates the process of Alzheimer's disease (AD) pathology. Currently, the exact inflammatory mechanisms underlying these links from clinical research remain largely unclear. This study included 1,131 cognitively intact individuals from the Chinese Alzheimer's Biomarker and LifestylE database with data provided on cerebrospinal fluid (CSF) AD biomarkers (amyloid beta-peptide 42 [Aβ42], total tau [t-tau], and phosphorylated tau [p-tau]), neuroinflammatory (CSF sTREM2), and systemic inflammatory markers (high sensitivity C-reactive protein and peripheral immune cells). The 2-year averaged levels of ambient fine particulate matter with diameter <2.5μm (PM2.5 ), nitrogen dioxide (NO2 ), and ozone (O3 ) were estimated at each participant's residence. Multiple-adjusted models were approached to detect associations of air pollution with inflammatory markers and AD-related proteins. Ambient 2-year averaged exposure of PM2.5 was associated with changes of neuroinflammatory markers, that is, CSF sTREM2 (β=-0.116, p=0.0002). Similar results were found for O3 exposure among the elderly (β=-0.111, p=0.0280) or urban population (β=-0.090, p=0.0144). No significant evidence supported NO2 related to CSF sTREM2. For potentially causal associations with accumulated AD pathologies, the total effects of PM2.5 on CSF amyloid-related protein (CSF Aβ42 and p-tau/Aβ42) were partly mediated by CSF sTREM2, with proportions of 14.22% and 47.15%, respectively. Additional analyses found inverse associations between peripheral inflammatory markers with PM2.5 and NO2 , but a positive correlation with O3 . These findings demonstrated a strong link between PM2.5 exposure and microglial dysfunction. Furthermore, CSF sTREM2 as a key mediator modulated the influences of PM2.5 exposure on AD amyloid pathologies.

Serum Inflammatory Markers and Their Associations with the Integrity of the Cingulum Bundle in Schizophrenia, from Prodromal Stages to Chronic Psychosis.

Peripheral cytokines may affect the brain through chronic activation of microglia and, as a result, can potentially lead to decreased integrity of white matter of cingulum bundle (CB). Therefore, the aim of the study was to analyze the relationships between peripheral inflammatory markers and the integrity of the CB in various states: from healthy controls, through prodromal states and first-episode psychosis, to long-term schizophrenia. The integrity of the CB was measured using diffusion tensor imaging. We analyzed six parameters: CRP, IL-6, IL-8, IL-10, TNF-α, and IFN-γ. We found that levels of IL-6 and IFN-γ differed significantly between groups. Initial analysis showed some correlations between the inflammatory markers and CB integrity, in particular a correlation with IL-6 that was present in several groups. However, none of the analyzed parameters were associated with the integrity of the CB after correction for multiple comparisons. Conclusions: Our results supported our hypothesis that there are increased levels of inflammatory markers in psychotic disorders, but did not allow to confirm our hypothesis that there is a link between increased peripheral inflammatory markers and decreased integrity of the CB. However, we found some interesting trend levels that need to be verified in larger studies.

Research on the Correlation of Peripheral Blood Inflammatory Markers with PCT, CRP, and PCIS in Infants with Community-Acquired Pneumonia.

Aims This study aimsto investigate the relationship between peripheral blood neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), and procalcitonin (PCT), C-reactive protein (CRP), and pediatric critical illness score (PCIS) in infants with community-acquired pneumonia (CAP). Methods 100 infants with bacterial CAP admitted to our hospital between January 2021 and December 2021 were selected as the infected group, and another 100 healthy infants who underwent health check-ups at the same time were selected as the control group, and the NLR, PLR, and SII of peripheral blood of infants in both groups and the serum PCT, CRP, and PCIS scores of infants in the infected group were tested. The correlation between NLR, PLR, SII, and PCT, CRP, and PCIS was analyzed by Spearman's analysis. Results The peripheral blood levels of NLR, PLR, and SII were higher in the infected group than in the control infants (P < 0.05). The ROC results showed that the AUCs of peripheral blood NLR, PLR, and SII for the diagnosis of infants with CAP were 0.934, 0.737, and 0.882, respectively. The ROC results showed that the AUCs of peripheral blood NLR, PLR, and SII for assessing the extent of disease in infants with CAP were 0.815, 0.710, and 0.813, respectively, with best cut-off values of 2.05, 98.57, and 823.41; the joint predicted AUC was 0.862. Conclusions NLR, PLR, and SII were significantly elevated in the peripheral blood of infants with CAP, positively correlated with PCT and CRP, and negatively correlated with PSIC scores, and NLR and SII also have some guiding value in early diagnosis and assessment of the extent of the disease in infants and toddlers with CAP.

Systemic Inflammation Is Implicated in De Novo Seizures Following Meningioma Resection

Abstract AIMS To investigate the association between perioperative peripheral blood inflammatory markers and seizures in patients who have undergone meningioma resection. METHOD A single neurosurgery tertiary centre blood bank database was screened to extract pre-operative and post-operative white cell count (WCC), neutrophils, lymphocytes, monocytes, platelets and neutrophil-lymphocyte ratio (NLR) and derived NLR (dNLR). All patients who underwent resection of meningioma from 2012 to 2020 were eligible. Patients were excluded if they had an inflammatory condition, peri-operative infection, medical illness or operative complication. RESULTS 30 patients suffered pre-operative seizures only, 16 experienced de novo post-operative seizures within 1 year and 42 patients did not experience seizures throughout their treatment timeline. In those who had never had a seizure, there was a significant increase in WCC post-operatively (15.2 vs. 10.6 × 109/L (95% CI 2.1-8.2), p=0.02). Patients who suffered de novo seizures had a significantly higher post-operative day 1 to 4 WCC than those with no seizures (21.1 vs. 14.8 × 109/L (2.1-12.6), p=0.48). However, this difference of WCC was poorly predictive of de novo seizures at one year (AUC 0.61). There was no difference in pre-operative inflammatory markers between pre-operative seizure patients, de novo seizure or never seizure patients. CONCLUSION There is a significantly higher post-operative systemic inflammatory response in patients who suffered de novoseizures after meningioma resection. Peripheral blood markers have the potential to predict seizures in patients with meningioma.

A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder

BackgroundMajor depressive disorder (MDD) is a leading cause of disability worldwide. The current treatments are ineffective in approximately one-third of patients, resulting in a large economic burden and reduced quality of life for a significant proportion of the global population. There is considerable evidence that increased inflammation may distinguish a sub-type of MDD, and there are no validated diagnostic tools or treatments for neuroinflammation in MDD patients. The current study aims to explore the potential role of low-dose naltrexone (LDN), a drug with purported anti-inflammatory properties in the central nervous system, as an adjunctive treatment in patients with MDD.Methods/designThis double-blind placebo-controlled hybrid parallel arm study enables the exploration of peripheral and central inflammatory markers with LDN as an approach to investigate inflammation as a pathophysiological contributor to MDD. Eligible participants with MDD (n = 48) will be stratified into the high and low inflammatory groups according to the levels of high-sensitivity C-reactive protein (hs-CRP) and then randomized to receive LDN or placebo for an initial 12 weeks, followed by a further 12 weeks during which all participants will receive LDN. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) administered at baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, and 24 weeks, to assess the effectiveness of the anti-depressant response. The secondary outcomes include the use of MRI techniques including quantitative magnetization transfer (qMT), echo-planar spectroscopic imaging (EPSI), and diffusion-weighted imaging (DWI) to help to elucidate the neurobiological mechanism of LDN, and the inflammatory mechanisms in action in MDD. Electroencephalography, blood samples, cognitive tasks, and additional questionnaires will also be used to determine if there is a specific profile of symptoms in individuals with inflammatory MDD. Healthy participants (n = 24) will be recruited for baseline outcome measures only, to enable comparison with patients with MDD.DiscussionThis trial contributes to the literature on inflammation in MDD, including the understanding of the pathophysiology and efficacy of anti-inflammatory treatments. The investigation of inflammatory mechanisms in MDD is an important first step in the development of biomarkers to classify patient sub-groups, increase the accuracy of diagnosis, and tailor the approach to patients in clinical practice. This study may provide evidence of the benefit of LDN for the groups in whom conventional anti-depressants are ineffective and lead the way for translation into clinical practice.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12622000881730. Registered on 21 June 2022

Elevation of C-reactive protein in adolescent bipolar disorder vs. anxiety disorders

Bipolar disorder (BD) largely begins in adolescence, but diagnosis lags for years, causing significant morbidity and mortality, and demonstrating the need for better diagnostic tools. Suggesting an association between BD and immune activity, elevated levels of peripheral inflammatory markers, including C-reactive protein (CRP), have been found in adults with BD. As similar data are extremely limited in adolescents, this study examined CRP levels in adolescents with BD (n = 37) compared to those with anxiety disorders (ADs, n = 157) and healthy controls with no psychiatric diagnoses (HCs, n = 2760). CRP blood levels for patients aged 12–17 years were retrieved from a nationwide repository of deidentified clinical data. After excluding patients with inflammatory conditions, differences in CRP were examined using multivariate and weighted regressions (covariates: demographics and BMI). Mean CRP levels were significantly elevated in adolescents with BD relative to those with ADs and HCs. Mean CRP levels were lower in the ADs cohort versus HCs. Although CRP levels were significantly higher in males and younger patients, the significant between-cohort differences in CRP remained after controlling for multiple confounders. To our knowledge, our study is the first to compare CRP levels between adolescent BD, ADs, and HCs, comprising a novel and essential contribution. Our results suggest the presence of a unique immune process in adolescents with BD and indicate that CRP may represent a biomarker with a crucial role in the diagnostic assessment of adolescent BD.

Transdiagnostic inflammatory subgroups among psychiatric disorders and their relevance to role functioning: a nested case-control study of the ALSPAC cohort

Individuals with psychotic disorders and depressive disorder exhibit altered concentrations of peripheral inflammatory markers. It has been suggested that clinical trials of anti-inflammatory therapies for psychiatric disorders should stratify patients by their inflammatory profile. Hence, we investigated whether different subgroups of individuals exist across psychiatric disorders, based on their inflammatory biomarker signatures. We measured the plasma concentrations of 17 inflammatory markers and receptors in 380 participants with psychotic disorder, depressive disorder or generalised anxiety disorder and 399 controls without psychiatric symptoms from the ALSPAC cohort at age 24. We employed a semi-supervised clustering algorithm, which discriminates multiple clusters of psychiatric disorder cases from controls. The best fit was for a two-cluster model of participants with psychiatric disorders (Adjusted Rand Index (ARI) = 0.52 ± 0.01) based on the inflammatory markers. Permutation analysis indicated the stability of the clustering solution performed better than chance (ARI = 0.43 ± 0.11; p < 0.001), and the clusters explained the inflammatory marker data better than a Gaussian distribution (p = 0.021). Cluster 2 exhibited marked increases in sTNFR1/2, suPAR, sCD93 and sIL-2RA, compared to cluster 1. Participants in the cluster exhibiting higher inflammation were less likely to be in employment, education or training, indicating poorer role functioning. This study found evidence for a novel pattern of inflammatory markers specific to psychiatric disorders and strongly associated with a transdiagnostic measure of illness severity. sTNFR1/2, suPAR, sCD93 and sIL-2RA could be used to stratify clinical trials of anti-inflammatory therapies for psychiatric disorders.

REACTIVE TRHOMBOCYTOSIS IN CHILDREN

Thrombocytosis is a condition which the platelet count exceeds 450,000/mm3. Thrombocytosis was classified as: mild (450,000-700,000/mm3), moderate (700,000-900,000/mm3), severe (900,000-1,000,000/mm3) and extreme (1,000,000/mm3). Functionally, thrombocytosis is divided into primary (essential) and secondary (reactive). The novelty of this study due to examining reactive thrombocytosis in children. The purpose of this study was to look at reactive thrombocytosis in children. Essential thrombocytosis is a myeloproliferative disorder due to monoclonal or polyclonal abnormalities of hematopoietic cells or biologic abnormalities of thrombopoietin (Tpo) in the primary regulation of megakaryopoiesis. Meanwhile, reactive thrombocytosis occurs temporarily due to stimulation of megakaryopoiesis with haematological or non-haematological abnormalities. Reactive thrombocytosis is an increase in thrombopoiesis due to reactive process due to infection, chronic inflammation, malignancy, and splenectomy surgery. Bacterial or viral infections are the most common cause (about 37-78%) at any age during childhood. Reactive thrombocytosis are asymptomatic and is usually found incidentally. Based on the guidelines the British Society for Haematology recommends three initial investigations: (1) Peripheral blood smear, (2) Inflammatory markers, and (3) Iron status. Management of reactive thrombocytosis by threated the main diseases, then platelet count returns to normal after the underlying disease is resolved. The overall prognosis depends on the underlying causative condition, approximately 8% of patients with acute infection examined have mild, transient thrombocytosis and show no infectious complications. However, these patients had an increased acute-phase response, prolonged length of stay, more bacteraemia and increased mortality although it only affected a minority of patients. This distinction between essential and reactive thrombocytosis is important because it implies evaluation, prognosis and treatment.Keywords: Reactive Thrombocytosis; Secondary Thrombocytosis; Transient.

Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis.

Background and ObjectivesIn a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results.MethodsParticipants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 × 106 cells/kg) IV every 4 weeks and IL-2 (2 × 105 IU/m2) injections 3 times/wk or matching placebo in a 24-week randomized controlled trial (RCT). Six participants proceeded into a 24-week dose-escalation open-label extension (OLE). Two additional participants entered directly into the OLE. The OLE included dose escalation of Treg infusions to 2 × 106 cells/kg and 3 × 106 cells/kg at 4-week intervals.ResultsThe Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive function was higher in the active group of the RCT. A meaningful evaluation of progression rates in the RCT between the placebo and active groups was not possible due to the limited number of enrolled participants aggravated by the COVID-19 pandemic. In the 24-week OLE, the Treg/IL-2 treatments were also safe and well tolerated in 8 participants who completed the escalating doses. Treg suppressive function and numbers were increased compared with baseline. Six of 8 participants changed by an average of −2.7 points per the ALS Functional Rating Scale–Revised, whereas the other 2 changed by an average of −10.5 points. Elevated levels of 2 markers of peripheral inflammation (IL-17C and IL-17F) and 2 markers of oxidative stress (oxidized low-density lipoprotein receptor 1 and oxidized LDL) were present in the 2 rapidly progressing participants but not in the slower progressing group.DiscussionTreg/IL-2 treatments were safe and well tolerated in the RCT and OLE with higher Treg suppressive function. During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623).Classification of EvidenceThis study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.

Brain microglia activation and peripheral adaptive immunity in Parkinson’s disease: a multimodal PET study

BackgroundAbnormal activation of immune system is an important pathogenesis of Parkinson’s disease, but the relationship between peripheral inflammation, central microglia activation and dopaminergic degeneration remains unclear.ObjectivesTo evaluate the brain regional microglia activation and its relationship with clinical severity, dopaminergic presynaptic function, and peripheral inflammatory biomarkers related to adaptive immunity.MethodsIn this case–control study, we recruited 23 healthy participants and 24 participants with early-stage Parkinson’s disease. 18F-PBR06 PET/MR for microglia activation, 18F-FP-DTBZ for dopaminergic denervation, total account of T cells and subpopulations of T helper (Th1/Th2/Th17) cells, and the levels of serum inflammatory cytokines were assessed. Sanger sequencing was used to exclude the mix-affinity binders of 18F-PBR06-PET.ResultsCompared to healthy controls, patients with Parkinson’s disease had an increased 18F-PBR06-PET standardized uptake value ratio (SUVR) in the putamen, particularly in the ipsilateral side of the motor onset. 18F-PBR06-PET SUVR was positively associated with 18F-FP-DTBZ-PET SUVR in the brainstem and not associated with disease severity measured by Hoehn and Yahr stage, MDS-UPDRS III scores. Patients with Parkinson’s disease had elevated frequencies of Th1 cells and serum levels of IL10 and IL17A as compared to healthy controls. No significant association between peripheral inflammation markers and microglia activation in the brain of PD was observed.ConclusionParkinson’s disease is associated with early putaminal microglial activation and peripheral phenotypic Th1 bias. Peripheral adaptive immunity might be involved in microglia activation in the process of neurodegeneration in PD indirectly, which may be a potential biomarker for the early detection and the target for immunomodulating therapy.

Peripheral inflammatory markers during an acute bacterial infection in older patients with and without cognitive dysfunction: A case control study

Dementia is a known risk factor for acute bacterial infections which may also play a significant role in promoting or accelerating cognitive impairment. Pneumonia and urinary tract infections are the main cause of hospitalisation of dementia patients and infections are a major precipitant of delirium. It is well established that peripheral immune signals induce a neuroinflammatory response largely mediated by microglial cells which is amplified with advanced age, neurodegenerative disorders and genetic characteristics. Reversely, the innate immune response to acute bacterial infection is tightly regulated by the brain. It remains unclear whether dysfunctional neural circuits affected by dementia and/or delirium could alter systemic innate immune responses at the periphery. The current study aims to determine if dementia and/or delirium are associated with an altered systemic inflammatory response to an acute bacterial infection. We recruited 46 hospitalised older patients with acute bacterial infections. From these, 29 participants had cognitive dysfunction (6 with delirium, 12 with dementia and 11 with delirium superimposed on dementia) and 17 had normal cognition. We also included a control group of 11 patients with dementia but with no current infection matched for age and educational status. Baseline characteristics were tested between groups using Kruskal-Wallis test and pairwise comparisons were subsequently assessed with Bonferroni correction for multiple comparisons for continuous variables. Chi square test was used to assess differences between groups in categorical data and correlations between peripheral inflammatory parameters were assessed with Spearman's test. The 4 groups with infection and the control group with no infection had similar characteristics except for cognitive function and functionality which was higher for the group of infected cognitively healthy participants. Levels of C-reactive protein were similar between the infected groups and higher than the non-infected dementia group. Infected patients with cognitive dysfunction (delirium and/or dementia) had higher serum levels of IL-6, TNF-alpha and IL-1beta. These participants had reduced expression of miR-145 in circulating exosomes which correlated negatively with miR-155 levels (r = −0.411, p = 0.027). Expression of CR1 in circulating CD14+ monocytes was higher in infected participants with cognitive dysfunction and, in this group, PICALM correlated both with TNF-alpha and IL-6. In contrast to what was observed in participants with normal cognition, expression of CR1 did not correlate with DAP12 in infected participants with cognitive dysfunction. Taken together, our findings suggest that cognitive dysfunction is associated with an exaggerated proinflammatory response during acute bacterial infection with deregulation of several molecular signalling pathways in circulating exosomes and in monocytes.

Fatigue in Multiple Sclerosis Is Associated with Reduced Expression of Interleukin-10 and Worse Prospective Disease Activity.

In multiple sclerosis (MS), fatigue is a frequent symptom that negatively affects quality of life. The pathogenesis of fatigue is multifactorial and inflammation may play a specific role. To explore the association between fatigue, central inflammation and disease course in MS in 106 relapsing-remitting (RR)-MS patients, clinical characteristics, including fatigue and mood, were explored at the time of diagnosis. NEDA (no evidence of disease activity)-3 status after one-year follow up was calculated. Cerebrospinal fluid (CSF) levels of a set of proinflammatory and anti-inflammatory molecules and peripheral blood markers of inflammation were also analyzed. MRI structural measures were explored in 35 patients. A significant negative correlation was found at diagnosis between fatigue measured with the Modified Fatigue Impact Scale (MFIS) and the CSF levels of interleukin (IL)-10. Conversely, no significant associations were found with peripheral markers of inflammation. Higher MFIS scores were associated with reduced probability to reach NEDA-3 status after 1-year follow up. Finally, T2 lesion load showed a positive correlation with MFIS scores and a negative correlation with CSF IL-10 levels at diagnosis. CSF inflammation, and particularly the reduced expression of the anti-inflammatory molecule IL-10, may exacerbate fatigue. Fatigue in MS may reflect subclinical CSF inflammation, predisposing to greater disease activity.

Peripheral inflammation levels associated with degree of advanced brain aging in schizophrenia.

Brain structural abnormalities have been demonstrated in schizophrenia (SZ); these resemble those seen in typical aging, but are seen at younger ages. Furthermore, SZ is associated with accelerated global brain aging, as measured by brain structure-based brain predicted age difference (Brain-PAD). High heterogeneity exists in the degree of brain abnormalities in SZ, and individual differences may be related to levels of peripheral inflammation and may relate to cognitive deficits and negative symptoms. The goal of our study was to investigate the relationship between brain aging, peripheral inflammation, and symptoms of SZ. We hypothesized older brain-PAD in SZ vs. healthy comparison (HC) participants, as well as positive relationships of brain-PAD with peripheral inflammation markers and symptoms in SZ. We analyzed data from two cross-sectional studies in SZ (n = 26; M/F: 21/5) and HC (n = 28; 20/8) (22–64 years). Brain-PAD was calculated using a previously validated Gaussian process regression model applied to raw T1-weighted MRI data. Plasma levels of inflammatory biomarkers (CRP, Eotaxin, Fractalkine, IP10, IL6, IL10, ICAM1, IFNγ, MCP1, MIP1β, SAA, TNFα, VEGF, VCAM1) and cognitive and negative symptoms were assessed. We observed a higher brain-PAD in SZ vs. HC, and advanced brain age relative to chronological age was related to higher peripheral levels of TNFα in the overall group and in the SZ group; other inflammatory markers were not related to brain-PAD. Within the SZ group, we observed no association between cognitive or negative symptoms and brain-PAD. These results support our hypothesis of advanced brain aging in SZ. Furthermore, our findings on the relationship of the pro-inflammatory cytokine TNFα with higher brain-PAD of SZ are relevant to explain heterogeneity of brain ages in SZ, but we did not find strong evidence for cognitive or negative symptom relationships with brain-PAD.

Association of low 25-OH-vitamin D levels and peripheral inflammatory markers in patients with autism spectrum disorder: Vitamin D and inflammation in Autism

Inflammatory mechanisms and Vitamin D are reported to play important roles in the pathophysiology of Autism Spectrum Disorders (ASD). There are ample evidences that vitamin D has an anti-inflammatory effect. In this study, we aimed, for the first time, to investigate the 25-OH-vitamin D with inflammation markers in ASD patients. The study included 154 patients with ASD and 98 healthy subjects. 25-OH-Vitamin D levels and simple peripheral inflammatory markers such as Neutrophil-Lymphocyte ratio (NLR), C-reactive protein (CRP) and, sedimentation were measured in all subjects. K-SADS-PL-DSM 5 were administered to all subjects to evaluate the psychiatric diagnosis. Childhood Autism Rating Scale was used to asses severity of autism. In the patient group, high CRP rate, leukocyte, neutrophil and NLR were significantly high compared to the healthy control group. 25-OH-Vitamin D levels were found to be statistically significantly lower in the ASD group. While a significant negative correlation was found between 25-OH-Vitamin D and CRP, NLR, neutrophil counts in ASD patients, a positive correlation was found between lymphocyte counts. Especially in male ASD patients, the relationship between 25-OH-Vitamin D and inflammation markers was more pronounced. Our findings support the association of vitamin D and inflammation in ASD.