Cytokines In Cerebrospinal Fluid Research Articles

Specimen type validation and establishment of normal cytokine reference intervals in cerebrospinal fluid

Cerebrospinal fluid (CSF) is a critical body fluid to examine in attempts to discover potential biomarkers for neuroinflammatory and other disorders of the central nervous system (CNS). Serum and/or plasma cytokine levels have been associated with a variety of inflammatory conditions, and some have been shown to be actionable therapeutic targets. Less is known, however, about cytokine levels in CSF. Serum and plasma cytokine testing is widely available in clinical and research laboratories, but cytokine testing in CSF is extremely limited and if performed, accompanied by a disclaimer that it is an unvalidated specimen type. In this study, we validate CSF as a suitable specimen type and determine normal reference intervals for multiple cytokines as well as a soluble cytokine receptor. CSF was validated as a specimen type for testing using a laboratory developed multiplexed cytokine assay previously validated to measure 13 cytokines/markers in serum and plasma. Performance parameters including specimen dilution, specimen interference, linearity and precision were examined. Reference intervals were established using 197 normal and control CSF specimens by non-parametric quantile-based methods. CSF cytokine analysis demonstrated within and between run precision of <10% and < 20% CV, respectively and linearity of ±15% for all analytes throughout the analytical measurement range of the assay. Reference intervals for the 13 cytokines/markers were established from 197 normal and control CSF specimens (78 Male; mean 44.8 y ± 21.7 SD, 119 Female; mean 42.8 y ± 20.3 SD). Cytokine concentrations in CSF from normal donors and controls were less than the lower limit of quantitation of our assay for 6 of the 13 measured cytokines/markers. The chemokine IL8 demonstrated the highest concentration of all analytes measured. CSF demonstrated acceptable performance as a specimen type in our multiplexed cytokine assay. By validating CSF as a specimen type and establishing normal reference intervals for cytokine concentrations in CSF, their potential as biomarkers for infectious, autoimmune and other inflammatory CNS disorders can be more appropriately investigated.

The role of cytokines and chemokines in the maintenance of chronic pain-a pilot study.

The immune system is believed to be important in the initiation and maintenance of chronic pain. The aim was to investigate whether patients with chronic painful polyneuropathy (PP) differ in cytokine profiles of serum and/or cerebrospinal fluid (CSF) compared with pain-free controls. Thirty-nine patients (16 women and 23 men, mean age, 69.2 ± 12.7 years, range 41-92 years) with PP (mean duration 43 ± 48.3 months) were phenotyped with quantitative sensory testing and electroneurography, and serum and CSF samples were analyzed by 40-multiplexed, bead-based cytokine immunoassays. Results were compared with 36 age- and gender-matched patients with normal pressure hydrocephalus and absence of abnormal CSF findings. Compared with controls, patients with PP had lower concentrations of several proinflammatory and anti-inflammatory chemokines and cytokines in CSF, and others showed the same tendency, among these were tumor necrosis factor-α (14.1 ± 10.0 vs 23.9 ± 16.4 pg/mL, P < 0.005), interleukin (IL)-2 (0.6 ± 0.4 vs 1.2 ± 0.6 pg/mL, P < 0.0001), IL-6 (4.7 ± 6.8 vs 7.3 ± 9 pg/mL, P = 0.001), and IL-10 (7.5 ± 6.8 vs 16.8 ± 19.2 pg/mL, P < 0.01), whereas no differences were observed in serum. Results suggest that (1) inflammatory mediators play a minor role in the maintenance of chronic pain in contrast to initiation of acute pain, (2) chemokines/cytokines are downregulated in chronic pain, or (3) chemokines/cytokines have a protective role for nerve regeneration that is disturbed in patients with chronic pain.

Evidence for cytokine dysregulation in schizophrenia spectrum disorders: A comparison of cerebrospinal fluid and blood samples

Abnormalities in immune function have been described in schizophrenia but few studies have investigated cytokines in cerebrospinal fluid (CSF) and their correlation with blood levels. In this cross-sectional study, cytokines were measured in CSF and plasma of 30 subjects with schizophrenia spectrum disorder (SSD) diagnosis and 23 healthy volunteers (HV). Results showed that CSF TNFα was increased in SSD subjects compared to HV and there were no correlations between CSF and plasma cytokine levels. The present findings provide evidence of dysregulation of TNFα in CSF of schizophrenia. These results identify elevated CSF TNFα levels as a potential biomarker in schizophrenia.

Second-line immunotherapy in new onset refractory status epilepticus.

Several pieces of evidence suggest immune dysregulation could trigger the onset and modulate sequelae of new onset refractory status epilepticus (NORSE), including its subtype with prior fever known as febrile infection-related epilepsy syndrome (FIRES). Consensus-driven recommendations have been established to guide the initiation of first- and second-line immunotherapies in these patients. Here, we review the literature to date on second-line immunotherapy for NORSE/FIRES, presenting results from 28 case reports and series describing the use of anakinra, tocilizumab, or intrathecal dexamethasone in 75 patients with NORSE. Among them, 52 patients were managed with anakinra, 21 with tocilizumab, and eight with intrathecal dexamethasone. Most had elevated serum or cerebrospinal fluid cytokine levels at treatment initiation. Treatments were predominantly initiated during the acute phase of the disease (92%) and resulted, within the first 2 weeks, in seizure control for up to 73% of patients with anakinra, 70% with tocilizumab, and 50% with intrathecal dexamethasone. Cytokine levels decreased after treatment for most patients. Anakinra and intrathecal dexamethasone were mainly initiated in children with FIRES, whereas tocilizumab was more frequently prescribed for adults, with or without a prior febrile infection. There was no clear correlation between the response to treatment and the time to initiate the treatment. Most patients experienced long-term disability and drug-resistant post-NORSE epilepsy. Initiation of second-line immunotherapies during status epilepticus (SE) had no clear effect on the emergence of post-NORSE epilepsy or long-term functional outcomes. In a small number of cases, the initiation of anakinra or tocilizumab several years after SE onset resulted in a reduction of seizure frequency for 67% of patients. These data highlight the potential utility of anakinra, tocilizumab, and intrathecal dexamethasone in patients with NORSE. There continues to be interest in the utilization of early cytokine measurements to guide treatment selection and response. Prospective studies are necessary to understand the role of early immunomodulation and its associations with epilepsy and functional outcomes.

Simian varicella virus infection and reactivation in rhesus macaques trigger cytokine and Aβ40/42 alterations in serum and cerebrospinal fluid.

Simian varicella virus (SVV) produces peripheral inflammatory responses during varicella (primary infection) and zoster (reactivation) in rhesus macaques (RM). However, it is unclear if peripheral measures are accurate proxies for central nervous system (CNS) responses. Thus, we analyzed cytokine and Aβ42/Aβ40 changes in paired serum and cerebrospinal fluid (CSF) during the course of infection. During varicella and zoster, every RM had variable changes in serum and CSF cytokine and Aβ42/Aβ40 levels compared to pre-inoculation levels. Overall, peripheral infection appears to affect CNS cytokine and Aβ42/Aβ40 levels independent of serum responses, suggesting that peripheral disease may contribute to CNS disease.

Association of postoperative delirium with serum and cerebrospinal fluid proteomic profiles: a prospective cohort study in older hip fracture patients.

Postoperative delirium (POD) is a common neuropsychiatric complication in geriatric inpatients after hip fracture surgery and its occurrence is associated with poor outcomes. The purpose of this study was to investigate the relationship between preoperative biomarkers in serum and cerebrospinal fluid (CSF) and the development of POD in older hip fracture patients, exploring the possibility of integrating objective methods into future predictive models of delirium. Sixty hip fracture patients were recruited. Blood and CSF samples were collected at the time of spinal anesthesia when none of the subjects had delirium. Patients were assessed daily using the 4AT scale, and based on these results, they were divided into POD and non-POD groups. The Olink® platform was used to analyze 45 cytokines. Twenty-one patients (35%) developed POD. In the subsample of 30 patients on whom proteomic analyses were performed, a proteomic profile was associated with the incidence of POD. Chemokine (C-X-C motif) ligand 9 (CXCL9) had the strongest correlation between serum and CSF samples in patients with POD (rho = 0.663; p < 0.05). Although several cytokines in serum and CSF were associated with POD after hip fracture surgery in older adults, there was a significant association with lower preoperative levels of CXCL9 in CSF and serum. Despite the small sample size, this study provides preliminary evidence of the potential role of molecular biomarkers in POD, which may provide a basis for the development of new delirium predictive models.

COVID-19-associated serum and cerebrospinal fluid cytokines in post- versus para-infectious SARS-CoV-2-related Guillain-Barré syndrome.

Guillain-Barré syndrome associated with Coronavirus-2-related severe acute respiratory syndrome (COV-GBS) occurs as para- or post-infectious forms, depending on the timing of disease onset. In these two forms, we aimed to compare the cerebrospinal fluid (CSF) and serum proinflammatory cytokine profiles to evaluate differences that could possibly have co-pathogenic relevance. We studied a retrospective cohort of 26 patients with either post-COV-GBS (n = 15), with disease onset occurring > 7days after SARS-CoV-2 infection, or para-COV-GBS (n = 11), with disease onset 7days or less. TNF-α, IL-6, and IL-8 were measured in the serum with SimplePlex™ Ella™ immunoassay. In addition to the para-/post-COV-GBS patients, serum levels of these cytokines were determined in those with non-COVID-associated-GBS (NC-GBS; n = 43), paucisymptomatic SARS-CoV-2 infection without GBS (COVID, n = 20), and in healthy volunteers (HV; n = 12). CSF cytokine levels were measured in patients with para-/post-COV-GBS, in those with NC-GBS (n = 29), or with Alzheimer's disease (AD; n = 24). Serum/CSF cytokine levels did not differ in para- vs post-COV-GBS. We found that SARS-CoV-2 infection raises the serum levels of TNF-α, IL-6, and IL-8, as well as an increase of IL-6 (in serum and CSF) and IL-8 (in CSF) in either NC-GBS or COV-GBS than controls. CSF and serum cytokine levels resulted independent one with another. The change of cytokines linked to SARS-CoV-2 in COV-GBS appears to be driven by viral infection, although it has unique characteristics in GBS as such and does not account for cases with para- or post-infectious onset.

Blood-brain barrier damage associates with glia-related cytokines in the cerebrospinal fluid of patients with Multiple Sclerosis

BackgroundThe presence of Blood-Brain Barrier (BBB) dysfunction is defined by albumin quotient (QALB) and characterize a group of Multiple Sclerosis (MS) patients at clinical onset. We evaluated the concentration in cerebrospinal fluid (CSF) of 87 cytokines, to better characterize the CSF inflammatory pattern in presence of BBB damage. Materials and MethodIn an exploratory cohort, CSF cytokines were evaluated by means of Multiplex technology (Bio-Plex Pro-Human Cytokine, GF and Diabetes 27-Plex Panel, Bio-Plex Pro-Human Chemokines 40-Plex Panel, Bio-Plex Pro-Human Inflammation Assays 37-Plex Panel) in a cohort of Other Not Inflammatory Neurological Disorders (ONIND) and in cohort of patients with MS, stratified according to BBB damage into QALB+ and QALB− MS patients. In the validation cohort, we evaluated the relevant molecules in a cohort of MS patients, stratified again into QALB+ and QALB−, including also Neurofilament Light (NfL) and Chitinase 3-like 1 (CHI3L1) CSF concentration. ResultsWhile MIP-1α, CXCL-13, and CCL-22 CSF concentrations were higher in both MS groups compared to ONIND, in QALB+ MS CSF concentrations of CXCL-9 (17.85 ± 4.69 pg/mL), CXCL-10 (476.5 ± 324.3 pg/mL), and IL-16 (96.08 ± 86.17 pg/mL) were higher than in QALB− MS (8.98 ± 5368 pg/mL, p < 0.005, 281.0 ± 180.9 pg/mL, p < 0.05, and 47.35 ± 36.87 pg/mL, p < 0.005, respectively) and ONIND (8.98 ± 5368 pg/mlL, p < 0.005, 281.0 ± 180.9 pg/mL, p < 0.005, and 47.35 ± 36.87 pg/mL, p < 0.001, respectively). A strong correlation was observed between CXCL-9 and CXCL-10 in all MS groups (all r>0.75, all p < 0.001). In the validation cohort again CXCL-10 CSF concentration were higher in QALB+ MS than in QALB− MS (94.25 ± 64.75 vs 153.8 ± 99.52, p < 0.05), while no difference was observed in serum. CSF NfL (1642 ± 1963 vs 3231 ± 3492 pg/mL, p < 0.05) and CHI3L1 (183.9 ± 86.62 vs 262 ± 137.5 ng/mL, p < 0.05) were increased in QALB+ MS. ConclusionsBBB damage in MS is linked to a specific CSF cytokines pattern (CXCL-9, CXCL-10, IL-16), that are also involved in astrocyte-microglia interaction. To what extent their continuous production in the CNS may mark a more severe disease course merits to be investigated.

Effect of Zuogui Jiangtang Jieyu Formula on intestinal flora and short-chain fatty acid metabolism in rats with diabetes mellitus complicated with depression

This study aimed to investigate the regulatory effects of Zuogui Jiangtang Jieyu Formula(ZJJ) on the intestinal flora, short chain fatty acids(SCFAs), and neuroinflammation in rats with diabetes mellitus complicated depression(DD). The DD model was established in rats and model rats were randomly divided into a model group, a positive drug(metformin + fluoxetine) group, a ZJJ low-dose group, and a ZJJ high-dose group, with eight rats in each group. Another eight rats were assigned to the blank group. Subsequently, depressive-like behavior test was conducted on the rats, and cerebrospinal fluid samples were collected to measure pro-inflammatory cytokines [interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α)]. Blood serum samples were collected to measure proteins related to the hypothalamic-pituitary-adrenal axis(HPA axis), including corticotropin-releasing hormone(CRH), adrenocorticotropic hormone(ACTH), and cortisol(CORT), as well as glucose metabolism. Gut contents were collected from each group for 16S rRNA sequencing analysis of intestinal flora and SCFAs sequencing. The results indicated that ZJJ not only improved glucose metabolism in DD rats(P&lt;0.01) but also alleviated depressive-like behavior(P&lt;0.05) and HPA axis hyperactivity(P&lt;0.05 or P&lt;0.01). Besides, it also improved the neuroinflammatory response in the brain, as evidenced by a significant reduction in pro-inflammatory cytokines in cerebrospinal fluid(P&lt;0.05 or P&lt;0.01). Additionally, ZJJ improved the intestinal flora, causing the intestinal flora in DD rats to resemble that of the blank group, characterized by an increased Firmicutes abundance. ZJJ significantly increased the levels of SCFAs(acetic acid, butyric acid, valeric acid, and isovaleric acid)(P&lt;0.01). Therefore, it is deduced that ZJJ can effectively ameliorate intestinal flora dysbiosis, regulate SCFAs, and thereby improve both glucose metabolism disturbances and depressive-like behavior in DD.

Levels of cytokines in the cerebrospinal fluid of patients with psychotic disorders compared to individually matched healthy controls

BackgroundIncreased peripheral cytokine levels have been observed in patients with psychotic disorders; however, large high-quality studies with individually matched healthy controls have been lacking regarding cytokines in cerebrospinal fluid (CSF) of individuals with psychotic disorders. MethodsPatients diagnosed with a non-organic, non-affective psychotic disorder (ICD-10: F20/22–29) within a year prior to inclusion and individually age- and sex-matched healthy controls were included by identical in- and exclusion criteria’s except for the psychiatric diagnoses. All participants were aged 18–50 years and individuals with neurological or immunological disorders were excluded. CSF cytokines were analyzed with MesoScale V-PLEX neuroinflammation panel. Co-primary outcomes were CSF interleukin-6 (IL-6) and IL-8. ResultsWe included 104 patients and 104 healthy controls, matching on age, sex and BMI. No significant differences were found for the primary outcomes IL-6 (relative mean difference (MD): 0.97, 95 %CI: 0.84–1.11, p = 0.637) or IL-8 (MD: 1.01, 95 %CI: 0.93–1.09, p = 0.895). Secondary analyses found patients to have higher IL-4 (MD: 1.30, 95 %CI: 1.04–1.61, p = 0.018), a trend towards higher IFN-γ (MD: 1.26, 95 %CI: 0.99–1.59, p = 0.056), and lower IL-16 (MD: 0.83, 95 %CI: 0.74–0.94, p = 0.004) than healthy controls, though not significant after correction for multiple testing. IL-8 and IL-16 were found positively associated with CSF white blood cells and CSF/serum albumin ratio. The study was limited by 77.9 % of the patients being on antipsychotic treatment at time of intervention, and that levels of nine of the 26 cytokines were below lower limit of detection (LLOD) in >50 % of samples; however, for the primary outcomes IL-6 and IL-8 more than 99.5 % of the samples were above LLOD and for IL-8 all samples exceeded the lower limit of quantification (LLOQ). ConclusionsWe found no evidence of increased IL-6 and IL-8 in patients with recent-onset psychotic disorders in contrary to previous findings in meta-analyses of CSF cytokines. Secondary analyses found indication of higher IL-4, decreased IL-16, and borderline increased IFN-γ in patients, neither of which have previously been reported on in CSF analyses of individuals with psychotic disorders.

Cerebrospinal fluid cytokine profile in autoimmune encephalitis related to covid-19 vaccination

Encephalitis is an inflammatory disease of the central nervous system most usually caused by a viral infection. Autoimmune encephalitis is also common. The mechanism of action of various vaccines aim to elicit immune response. Major neurological complications indicative of vaccination-related autoimmune encephalitis and acute encephalitis after the first dose of mRNA COVID-19 vaccines have been reported. We present a 59-year-old female patient with subtle initiation of cognitive and behavioral deterioration two months after the second dose of SARSCoV-2 vaccine. Diagnostic work-up was suggestive of encephalitis. The findings fulfilled the criteria for possible autoimmune encephalitis related to prior vaccination with detected cytokine elevation.

Combined cerebrospinal fluid metabolomic and cytokine profiling in tuberculosis meningitis reveals robust and prolonged changes in immunometabolic networks

Much of the high mortality in tuberculosis meningitis (TBM) is attributable to excessive inflammation, making it imperative to identify targets for host-directed therapies that reduce pathologic inflammation and mortality. In this study, we investigate how cytokines and metabolites in the cerebral spinal fluid (CSF) associate with TBM at diagnosis and during TBM treatment. At diagnosis, TBM patients (n = 17) demonstrate significant increases of cytokines and chemokines that promote inflammation and cell migration including IL-17A, IL-2, TNFα, IFNγ, and IL-1β versus asymptomatic controls without known central nervous system pathology (n = 20). Inflammatory immune signaling had a strong positive correlation with immunomodulatory metabolites including kynurenine, lactic acid, and carnitine and strong negative correlations with tryptophan and itaconate. Inflammatory immunometabolic networks were only partially reversed with two months of effective TBM treatment and remained significantly different compared to CSF from controls. Together, these data highlight a critical role for host metabolism in regulating the inflammatory response to TBM and indicate the timeline for restoration of immune homeostasis in the CSF is prolonged.

Predictive analysis between cytokine profile and Aβ42, p‐Tau, and p‐Tau/Aβ42 levels in the cerebrospinal fluid of older adults with and without cognitive impairment

AbstractBackgroundThe immune system activation observed in Alzheimer’s disease (AD) pathology contributes to its pathogenesis. It is proposed that ongoing interactions between β‐amyloid plaques, Tau protein, and neuroinflammatory mediators such as cytokines contribute to the maintenance of the inflammatory state in the brain. The aim was to evaluate whether cytokine profiles can predict variations in Aβ42, pTau, and pTau/Aβ42 cerebrospinal fluid (CSF) levels in older adults with and without objective cognitive impairment.MethodsEighty older adults were recruited, with a clinical diagnosis of AD dementia (36), with Mild Cognitive Impairment (MCI) (24), and without objective cognitive impairment (20). CSF levels of Aβ42, pTau, and 27 cytokines were assessed by the Luminex xMAP technique. Significant associations between Aβ42, p‐Tau, and p‐Tau/Aβ42 CSF levels and cytokines were explored in multiple linear regression analyses adjusted for age, education, and APOE ε4 carrier status.ResultsWe found that Granulocyte and Macrophage colony‐stimulating factors (GM‐CSF) (β = ‐.375; p = .010) and IL‐6 (β = ‐.370; p = .014) had a negative significant association with Aβ42, while IL‐8 (β = .452; p = .002) and IL‐4 (β = .488; p = .001) had positive significant association and higher magnitude of effect on Aβ42. For pTau, age (β = .240; p = .029), IL‐2 (β = .314; p = .012) and ε4 allele (β = 0.349; p = .002) had a positive significant association. The variable with the greatest magnitude of the effect was the presence of the ε4 allele. For the p‐Tau/Aβ42 ratio, G‐CSF (β = .423; p = .003) and GM‐CSF (β = .317; p = .019) had a significant positive association, while for IL‐8 (β = ‐.554; p = .001) and IL‐12 (β = ‐.334; p = .019) the association was significantly negative. IL‐8 had the greatest magnitude of effect on p‐Tau/Aβ42 ratio values.ConclusionThe higher levels of IL‐4 and the IL‐8 associated to a higher Aβ42 suggest their role at the beginning of the disease. On the other hand, the lower level of IL‐8 associated with a higher p‐Tau/Aβ42 suggests its inactivation as the disease progresses. Conversely, the higher levels of GM‐CSF associated with higher p‐Tau/Aβ42 suggests a more robust recruitment of the immune cell system at later stages.Reference: Aksnes, M., et al., (2021). Associations of cerebrospinal fluid amyloidogenic nanoplaques with cytokines in Alzheimer’s disease. Translational Neurodegeneration.

The Haptoglobin Response after Aneurysmal Subarachnoid Haemorrhage

Haptoglobin is the body’s first line of defence against the toxicity of extracellular haemoglobin released following a subarachnoid haemorrhage (SAH). We investigated the haptoglobin response after SAH in cerebrospinal fluid (CSF) and serum. Paired CSF and serum samples from 19 controls and 92 SAH patients were assayed as follows: ultra-performance liquid chromatography for CSF haemoglobin and haptoglobin, immunoassay for serum haptoglobin and multiplexed CSF cytokines, and colorimetry for albumin. There was marked CSF haptoglobin deficiency: 99% of extracellular haemoglobin was unbound. The quotients for both CSF/serum albumin (qAlb) and haptoglobin (qHp) were used to compute the CSF haptoglobin index (qHp/qAlb). CSF from SAH patients had a significantly lower haptoglobin index compared to controls, especially in Haptoglobin-1 allele carriers. Serum haptoglobin levels increased after SAH and were correlated with CSF cytokine levels. Haptoglobin variables were not associated with long-term clinical outcomes post-SAH. We conclude that: (1) intrathecal haptoglobin consumption occurs after SAH, more so in haptoglobin-1 allele carriers; (2) serum haptoglobin is upregulated after SAH, in keeping with the liver acute phase response to central inflammation; (3) haptoglobin in the CSF is so low that any variation is too small for this to affect long-term outcomes, emphasising the potential for therapeutic haptoglobin supplementation.

Cerebrospinal Fluid IL-6 Plus IL-10 As Effective Diagnostic Biomarkers for Secondary Central Nervous System Lymphoma

Background : Secondary central nervous system lymphoma (SCNSL) characterized by the involvement of the CNS at initial diagnosis of systemic lymphoma or in the setting of relapse. Accurate diagnosis and therapeutic response of SCNSL are particular challenges, which need to be improved. We aimed to evaluate the diagnostic and the post-therapeutic prognostic value of cerebrospinal fluid (CSF) cytokine in patients with SCNSL. Methods: In this retrospective study involving 234 NHL patients and 53 other CNS patients, the NHL patients was divided into two sub-groups based on with and without CNS involvement: SCNSL (n=57) and non-SCNSL (n=177). The CSF cytokine profiles (interleukin (IL)-2, -4, -6, and -10, tumor necrosis factor-α, interferon-γ, and IL-17A) of these patients were measured by cytometric bead assay and evaluated the ability of CSF cytokine levels as diagnostic, therapeutic and prognostic biomarkers for SCNSL. Results: CSF IL-6 and IL-10 levels were significantly higher in SCNSL patients than non-SCNSL and other CNS patients. CSF levels of IL-6 and IL-10 were significantly higher in patients with an stage at Ⅲ and Ⅳ, CSF WBC counts&amp;gt;5/µL, CSF protein ≥0.45g/L.Using a CSF IL-6 cut-off value of 10.13 pg/ml yielded a diagnostic sensitivity and specificity was 62.34% and 87.57%, respectively (AUC, 0.7798; 95% CI, 0.7083 to 0.8514); For a CSF IL-10 cutoff value of 7.82, the sensitivity was 76.23%, and the specificity was 98.31% (AUC, 0.8164; 95% CI, 0.7466 to 0.8862). Combined CSF IL-6 and IL-10 significantly improved the diagnostic effect of SCNSL (AUC, 0.8959; 95% CI, 0.8371 to 0.9547). The levels of IL-6 and IL-10 in cerebrospinal fluid of SCNSL patients who responded to intrathecal chemotherapy were significantly decreased during follow-up, while the levels of these two cytokines showed fluctuating changes in patients with progressive SCNSL. Moreover, poor Progression free survival (PFS) for patients with SCNSL was associated with the increased CSF IL-10 level at diagnosis with CNS involvement (P=0.035), but not with the increased CSF IL-6 level. Conclusion: Our study confirmed CSF level of IL-6 and IL-10 were potentially effective diagnostic biomarkers for SCNSL, and poor progression free survival (PFS) for patients with SCNSL was associated with the increased CSF IL-10 level.

Inflammatory changes in the plasma and cerebrospinal fluid of patients with persistent pain and postpartum depression after elective Cesarean delivery: an exploratory prospective cohort study.

Severe acute pain after Cesarean delivery increases the risk of developing persistent pain (~20% incidence) and postpartum depression (PPD) (~15% incidence). Both conditions contribute to maternal morbidity and mortality, yet early risk stratification remains challenging. Neuroinflammation has emerged as a key mechanism of persistent pain and depression in nonobstetric populations. Nevertheless, most studies focus on plasma cytokines, and the relationship between plasma and cerebrospinal fluid (CSF) cytokine levels is unclear. Our primary aim was to compare inflammatory marker levels between patients who developed the composite outcome of persistent pain and/or PPD vs those who did not. We recruited term patients with singleton pregnancies undergoing elective Cesarean delivery under neuraxial anesthesia into an exploratory prospective cohort study. We collected baseline demographic, obstetric, and Edinburgh Postnatal Depression Scale information, and performed quantitative sensory tests. Plasma was collected preoperatively and 48hr postoperatively. In the operating room, 10mL of CSF was collected, followed by a standardized anesthetic. Intra- and postoperative management were according to standard practice. We obtained Edinburgh Postnatal Depression Scale and pain scores at six weeks and three months after delivery. The primary outcome was persistent pain and/or PPD at three months. We analyzed the difference in inflammatory marker levels between the groups (primary aim) using two-sided Mann-Whitney tests. Eighty participants were enrolled, and 63 patients completed the study; 23 (37%) experienced the primary outcome at three months. Preoperative plasma transforming growth factor beta 1 (TGF-β1) concentration was higher in patients who developed the primary outcome compared with those who did not (median [interquartile range (IQR)], 2,879 [2,241-5,494] vs 2,292 [1,676-2,960]pg·mL-1; P = 0.04), while CSF IL-1β concentration was higher in patients who developed the primary outcome than in those who did not (median [IQR], 0.36 [0.29-0.39] vs 0.30 [0.25-0.35]pg·mL-1; P = 0.03). We observed differential levels of plasma and CSF inflammatory biomarkers in patients who developed persistent pain and PPD compared with those who did not. We showed the feasibility of collecting plasma and CSF samples at Cesarean delivery, which may prove useful for future risk-stratification. ClinicalTrials.gov (NCT04271072); registered 17 February 2020.

COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications.

To investigate evidence of residual viral infection, intrathecal immune activation, central nervous system (CNS) injury, and humoral responses in cerebrospinal fluid (CSF) and plasma in patients recovering from coronavirus disease 2019 (COVID-19), with or without neurocognitive post-COVID condition (PCC). Thirty-one participants (25 with neurocognitive PCC) underwent clinical examination, lumbar puncture, and venipuncture ≥3 months after COVID-19 symptom onset. Healthy volunteers were included. CSF and plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and spike antigen (N-Ag, S-Ag), and CSF biomarkers of immune activation and neuronal injury were analyzed. SARS-CoV-2 N-Ag or S-Ag were undetectable in all samples and no participant had pleocytosis. We detected no significant differences in CSF and plasma cytokine concentrations, albumin ratio, IgG index, neopterin, β2M, or in CSF biomarkers of neuronal injury and astrocytic damage. Furthermore, principal component analysis (PCA1) analysis did not indicate any significant differences between the study groups in the marker sets cytokines, neuronal markers, or anti-cytokine autoantibodies. We found no evidence of ongoing viral replication, immune activation, or CNS injury in plasma or CSF in patients with neurocognitive PCC compared with COVID-19 controls or healthy volunteers, suggesting that neurocognitive PCC is a consequence of events suffered during acute COVID-19 rather than persistent viral CNS infection or residual CNS inflammation.

Blood-brain barrier permeability is associated with different neuroinflammatory profiles in Alzheimer's disease.

Inflammation is an important player in Alzheimer's disease (AD), whose effects can be influenced by the blood-brain barrier (BBB). Here, we investigated the relationship between BBB permeability, indicated by cerebrospinal fluid (CSF)/plasma albumin quotient (Qalb), and CSF indexes of neuroinflammation in a cohort of biologically defined AD patients. Fifty-nine consecutive patients with mild cognitive impairment (MCI) or early AD (Mini-Mental State Examination [MMSE] >22) underwent CSF analysis for inflammatory cytokines (interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, Il-10, IL-12, IL-13, IL-17, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], granulocyte-monocyte colony-stimulating factor [GM-CSF], granulocyte colony-stimulating factor [G-CSF]). Using backward stepwise linear regression analysis, we explored the potential influence of each cytokine CSF level on Qalb considering age, sex, and apolipoprotein E (APOE) as covariates. Higher levels of IL-4 (β = 0.356, 0.005) and IL-8 (β = 0.249, 0.05) were associated with higher Qalb values, while macrophage inflammatory protein-1α (MIP-1β) (β = -0.274; p = 0.032) and TNF-α (β = -0.248; p = 0.031) showed a significant negative association with BBB permeability. Age was also positively associated with Qalb (β = 0.283; p = 0.016). Despite the overall integrity of the BBB, its permeability could either influence or be influenced by central neuroinflammation, reflected by CSF cytokine levels. This is in line with previous studies that showed that patients with a more intact barrier are those with more prominent neurodegeneration. Our findings suggest that different neuroinflammatory profiles can be associated with different levels of BBB permeability in AD.

Cytokine Dynamics in Autism: Analysis of BMAC Therapy Outcomes.

Autism spectrum disorder (ASD) has recently been linked to neuroinflammation and an aberrant immune response within the central nervous system. The intricate relationship between immune response and ASD remains elusive, with a gap in understanding the connection between specific immune mechanisms and neural manifestations in autism. In this study, we employed a comprehensive statistical approach, fusing both overarching and granular methods to examine the concentration of 16 cytokines in the cerebrospinal fluid (CSF) across each autologous bone marrow aspirate concentrate (BMAC) intrathecal administration in 63 male and 17 female autism patients. Following a six-month period post the third administration, patients were stratified into three categories based on clinical improvement: Group 1- no/mild (28 subjects), Group 2-moderate (16 subjects), and Group 3-major improvement (15 subjects). Our integrated analysis revealed pronounced disparities in CSF cytokine patterns and clinical outcomes in autism subjects pre- and post-BMAC transplantation. Crucially, our results suggest that these cytokine profiles hold promise as predictive markers, pinpointing ASD individuals who might not exhibit notable clinical amelioration post-BMAC therapy.

Serum cytokine and chemokine profiles of patients with confirmed bacterial and viral meningitis

Abstract Introduction: Cerebrospinal fluid (CSF) cytokines and chemokines have been reported by several studies as useful markers to discriminate bacterial and viral meningitis (BM and VM). This study aimed to investigate if serum cytokine and chemokine profiles could also differentiate BM from VM, thus circumventing the need for an invasive lumbar puncture. Methods: Serum cytokines and chemokines were measured in 153 samples from patients with BM (n=58), VM (n=69), and controls (C, n=26) using multiplex assays. Cytokine and chemokine concentrations were compared among groups, correlation analyses were performed, and BM and VM cases classification based on cytokine and chemokine patterns was tested using a Machine Learning algorithm. Results: IL-8, IL-1β, IL-6, IL-10, TNF-α, MCP-1, and ENA-78 showed a pronounced increase in the BM group compared to C (P&lt;0.01). Comparison of cytokines and chemokines in BM vs. VM showed significantly higher levels of MCP-1, IL-8, IL-1β, IL-6 and IL-10 (P&lt;0.01). Serum cytokine and chemokine concentrations were highly correlated in BM, being strongest for: MCP-1/IL-8, MCP-1/IL-1β, and IL-8/IL-1β (r=0.83; r=0.72; r=0.78, respectively). In VM, cytokine and chemokine correlations were weaker. The best predictors in the cytokine and chemokine pattern identified with a Random Forest algorithm for classifying BM vs VM were IL-8 and IL-10, and IL-6, but the specificity and sensitivity were low (85% and 69%, respectively). Conclusion: Our results suggest significant changes in serum IL-6, IL-8, IL-10, and IL-1β in BM, but these mediators may have limited value in differentiating BM from VM.