Cerebrospinal Fluid Tumor Necrosis Factor-alpha Research Articles

Changes in neuroinflammatory biomarkers correlate with disease severity and neuroimaging alterations in patients with COVID-19 neurological complications

COVID-19 induces acute and persistent neurological symptoms in mild and severe cases. Proposed concomitant mechanisms include direct viral infection and strain, coagulopathy, hypoxia, and neuroinflammation. However, underlying molecular alterations associated with multiple neurological outcomes in both mild and severe cases are majorly unexplored. To illuminate possible mechanisms leading to COVID-19 neurological disease, we retrospectively investigated in detail a cohort of 35 COVID-19 mild and severe hospitalized patients presenting neurological alterations subject to clinically indicated cerebrospinal fluid (CSF) sampling. Clinical and neurological investigation, brain imaging, viral sequencing, and cerebrospinal CSF analyses were carried out. We found that COVID-19 patients presented heterogeneous neurological symptoms dissociated from lung burden. Nasal swab viral sequencing revealed a dominant strain at the time of the study, and we could not detect traces of SARS-CoV-2's spike protein in patients' CSF by multiple reaction monitoring analysis. Patients presented ubiquitous systemic hyper-inflammation and broad alterations in CSF proteomics related to inflammation, innate immunity, and hemostasis, irrespective of COVID-19 severity or neuroimaging alterations. Elevated CSF interleukin-6 (IL6) correlated with disease severity (sex-, age-, and comorbidity-adjusted mean Severe 24.5 pg/ml, 95% confidence interval (CI) 9.62–62.23 vs. Mild 3.91 pg/mL CI 1.5–10.3 patients, p = 0.019). CSF tumor necrosis factor-alpha (TNFα) and IL6 levels were higher in patients presenting pronounced neuroimaging alterations compared to those who did not (sex-, age-, and comorbidity-adjusted mean TNFα Pronounced 3.4, CI 2.4–4.4 vs. Non-Pronounced 2.0, CI 1.4–2.5, p = 0.022; IL6 Pronounced 33.11, CI 8.89–123.31 vs Non-Pronounced 6.22, CI 2.9–13.34, p = 0.046). Collectively, our findings put neuroinflammation as a possible driver of COVID-19 acute neurological disease in mild and severe cases.

Cerebrospinal fluid tumor necrosis factor-alpha (TNF-α) levels in children with cerebral malaria.

This prospective cross-sectional study evaluated the diagnostic and prognostic role of cerebrospinal fluid (CSF) tumor necrosis factor-alpha (TNF-α) in children with cerebral malaria (CM) and its role in the differentiation of CM from non-cerebral severe malaria. CSF TNF-α was measured using a human TNF-α enzyme-linked immunosorbent assay kit of 39 cases of CM and 19 cases of non-cerebral severe malaria. CSF TNF-α levels were significantly higher in CM (p < 0.001). Based on the receiver operating characteristics curve, a cutoff value of CSF TNF-α was 5.7 pg/ml for diagnosis of CM with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 87.2%, 94.7%, 97.1% and 78.3% respectively. The cutoff value of CSF TNF-α was 13.7 pg/ml for predicting adverse outcomes in CM with sensitivity, specificity, PPV and NPV of 100%, 96.8%, 88.9% and 100%, respectively. However, the cutoff value of CSF TNF-α was 4.96 pg/ml for predicting adverse outcomes in non-cerebral severe malaria with a sensitivity, specificity, PPV and NPV of 100%, 94.1%, 88.9% and 100% respectively. So, CSF TNF-α is an excellent biomarker and can be used as a diagnostic and prognostic tool. More studies are needed to establish CSF TNF-α as a predictor of neurological sequelae.

The reduction of CSF tumor necrosis factor alpha levels in schizophrenia: no correlations with psychopathology and coincident metabolic characteristics.

AimThe aim of this study was to assess whether tumor necrosis factor alpha (TNF-α) levels are correlated with the behavioral syndrome of schizophrenia and/or metabolic abnormalities.MethodsSixty patients with first-onset schizophrenia were recruited. The concentrations of TNF-α in the cerebrospinal fluid (CSF) were determined in 22 schizophrenia patients and ten patients with nonsuppurative appendicitis using a radioimmunoassay. Physiological characteristics such as fasting blood glucose, fasting insulin, triglycerides, corrected QT interval, waist circumference, and body mass index were measured prior to CSF collection. Subjects were screened for insulin resistance using the homeostasis model assessment. The extent of positive and negative behavioral symptoms was scored using the Positive and Negative Syndrome Scale.ResultsThe CSF TNF-α levels in schizophrenic patients were significantly lower than those in the control group. The age of disease onset was positively correlated with the CSF TNF-α level using Pearson correlation analysis (r=0.37, P<0.05). There were no significant differences in CSF TNF-α levels in terms of age, duration of schizophrenia, or systolic and diastolic blood pressure. Furthermore, the CSF TNF-α levels were not significantly correlated with fasting blood glucose, fasting insulin, insulin resistance index, triglycerides, corrected QT interval, waist circumference, or body mass index. No significant correlation was found between CSF TNF-α levels and the Positive and Negative Syndrome Scale total scores or other factors scores. There were also no significant differences in CSF TNF-α levels between patients with schizophrenia types I and II.ConclusionCSF TNF-α levels are decreased in schizophrenia, although this reduction does not correlate with the psychopathology or coincident metabolic characteristics of this disease.

Experimental study of cerebrospinal fluid tumor necrosis factor-alpha release in penicillin- and cephalosporin-resistant pneumococcal meningitis treated with different antibiotic schedules.

To measure the inflammatory response in terms of tumor necrosis factor-alpha (TNF-α) levels in cerebrospinal fluid (CSF), using bacteriolytic versus nonbacteriolytic antibiotic therapy and adjunctive treatment with dexamethasone in an experimental rabbit model of pneumococcal meningitis. In a rabbit model of pneumococcal meningitis, we tested CSF TNF-α levels in several samples from rabbits infected with the HUB 2349 strain and treated with ceftriaxone 100mg/kg/d, ceftriaxone plus vancomycin 30mg/kg/d, or daptomycin at 15mg/kg or 25mg/kg. Daptomycin schedules were compared with the same doses in combination with dexamethasone at 0.125mg/kg every 12hours over a 26-hour period. The ceftriaxone group had the highest levels of TNF-α. TNF-α levels were significantly higher after ceftriaxone administration than in both daptomycin groups. The high-dose daptomycin group presented the lowest inflammatory levels in CSF samples. Adjunctive treatment with dexamethasone in this group modulated the inflammatory response, bringing down CSF TNF-α levels. CSF TNF-α levels were significantly lower in rabbits treated with daptomycin than in rabbits treated with ceftriaxone. Daptomycin avoided the inflammatory peak after administration observed in ceftriaxone-treated rabbits. The use of daptomycin plus dexamethasone achieved a significantly larger reduction in CSF TNF-α levels.

Prolonged intrathecal release of soluble Fas following severe traumatic brain injury in humans

The mechanisms underlying cell death following traumatic brain injury (TBI) are not fully understood. Apoptosis is believed to be one mechanism contributing to a marked and prolonged neuronal cell loss following TBI. Recent data suggest a role for Fas (APO-1, CD95), a type I transmembrane receptor glycoprotein of the nerve growth factor/tumor necrosis factor superfamily, and its ligand (Fas ligand, FasL) in apoptotic events in the central nervous system. A truncated form of the Fas receptor, soluble Fas (sFas) may indicate activation of the Fas/FasL system and act as a negative feedback mechanism, thereby inhibiting Fas mediated apoptosis. Soluble Fas was measured in cerebrospinal fluid (CSF) and serum of 10 patients with severe TBI (GCS≤8) for up to 15 days post-trauma. No sFas was detected in CSF samples from patients without neurological pathologies. Conversely, after TBI 118 out of 120 CSF samples showed elevated sFas concentrations ranging from 56 to 4327 mU/ml. Paired serum samples showed above normal (8.5 U/ml) sFas concentrations in 5 of 10 patients. Serum levels of sFas were always higher than CSF levels. However, there was no correlation between concentrations measured in CSF and in serum ( r 2=0.078, p=0.02), suggesting that the concentrations in the two compartments are independently regulated. Also, no correlation was found between sFas in CSF and blood brain barrier (BBB) dysfunction as assessed by the albumin CSF/serum quotient ( Q A), and concentrations of the cytotoxic cytokine tumor necrosis factor-alpha in CSF, respectively. Furthermore, there was no correlation with two markers of immune activation (soluble interleukin-2 receptor and neopterin) in CSF. Maximal CSF levels of sFas correlated significantly ( r 2=0.8191, p<0.001) with the early peaks of neuron-specific enolase in CSF (a marker for neuronal cell destruction), indicating that activation of the Fas mediated pathway of apoptosis may be in part the direct result of the initial trauma. However, the prolonged elevation of sFas in CSF may be caused by the ongoing inflammatory response to trauma and delayed apoptotic cell death.

7-Nitroindazole, but Not Aminoguanidine, Attenuates the Acute Inflammatory Responses and Brain Injury during the Early Phase of Escherichia coli Meningitis in the Newborn Piglet

We evaluated the anti-inflammatory and neuroprotective effects of the selective neuronal nitric oxide synthase inhibitor 7-nitroindazole and aminoguanidine, which predominantly inhibits inducible nitric oxide synthase, during the early phase of experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 10⁸ colony-forming units of Escherichia coli in 100 µl of saline. 7-Nitroindazole significantly attenuated the meningitis-induced acute inflammatory responses such as increased intracranial pressure, decreased cerebrospinal fluid (CSF) glucose concentration, and CSF leukocytosis at 2 h. However, meningitis-induced CSF leukocytosis at 4 h and increased CSF lactate and tumor necrosis factor alpha levels were not significantly attenuated. Reduced cerebral cortical cell membrane Na⁺,K⁺-ATPase activity and increased lipid peroxidation products, indicative of meningitis-induced brain cell membrane dysfunction, were also significantly improved with 7-nitroindazole treatment. In contrast, although aminoguanidine significantly attenuated the increase in the CSF tumor necrosis factor alpha level, it failed to attenuate the acute inflammation and the ensuing brain injury in bacterial meningitis. In summary, 7-nitroindazole, but not aminoguanidine, significantly attenuated the acute inflammatory responses and brain injury during the early phase of neonatal bacterial meningitis.

Cerebrospinal fluid cytokine levels and dexamethasone therapy in bacterial meningitis.

cerebrospinal fluid (CSF) levels of interleukin (IL)-1 beta and tumor necrosis factor (TNF) alpha were measured to assess the effect and application of dexamethasone (Dex) therapy for bacterial meningitis. associations between clinical findings and CSF parameters were first investigated, and prognosis was compared between 25 patients with Dex and 12 without Dex therapy. patients with the presence of disturbed consciousness showed higher CSF levels of TNF alpha (mean: 3015 pg/ml) or protein (mean: 215 mg/dl) than those without it (both, P < 0.O5). Simultaneous increase of TNF alpha (> 1000 pg/ml) and protein (> 100 g/dl) was observed in 80%, of patients with profoundly disturbed consciousness. Patients with Dex therapy presented higher TNF alpha/protein levels at diagnosis than those without Dex therapy (P < 0.05). Despite worse conditions at diagnosis, only one of 14 Dex-treated patients whose initial CSF TNF alpha levels exceeded 1000 pg/ml developed deafness. On the other hand, two of four patients without Dex therapy who had the same TNF alpha level suffered from psychomotor retardation. The differences in the frequency of sequelae between those with and without Dex therapy were significant in patients showing high TNF alpha level (P < O.05), but not in those showing high CSF levels of IL-1 beta or protein. The logistic regression analysis indicated that high CSF protein level (P < O.0001), or no Dex therapy (P=0.0001) was the independent risk factor for sequelae. although the study number was small, our observations suggested that CSF TNF alpha/protein levels reflected the neurologic severity, and implied that early Dex therapy might be beneficial for patients with prominently high TNF alpha levels.

Tumor necrosis factor-alpha (TNF alpha) in cerebrospinal fluid from patients with meningitis of different etiologies: high levels of TNF alpha indicate bacterial meningitis.

The levels of tumor necrosis factor (TNF)-alpha in cerebrospinal fluid (CSF) were analyzed in 139 patients with meningitis and in 20 control subjects. Elevated concentrations were observed in 42 (82%) of 51 patients with purulent bacterial meningitis (18/24 Haemophilus influenzae, 13/14 Streptococcus pneumoniae, 7/7 Neisseria meningitidis, and 4/6 with other purulent bacterial etiology). In contrast, elevated levels were found in only 5 of 78 individuals with nonbacterial meningitis (2/8 with herpes simplex type 2, 3/3 with varicella-zoster virus). Thus, the positive and negative predictive values were 0.89 for indicating a purulent bacterial meningitis. Raised CSF TNF alpha levels were observed in 7 of 8 patients with purulent bacterial meningitis in whom the routinely used parameters did not unequivocally indicate the diagnosis. Moderately increased levels were seen in 5 of 6 patients with Mycobacterium tuberculosis meningitis and in 1 of 4 cases of Borrelia burgdorferi. Thus, the present study indicates that concentrations of TNF alpha in CSF usually can discriminate between purulent bacterial and nonbacterial meningitis. These findings may contribute diagnostic guidance with routinely used CSF parameters.