Changes in serum TNF-α, IL-18, and IL-6 concentrations in patients with chronic schizophrenia at admission and at discharge

ObjectiveSchizophrenia is correlated with aberrant cytokine concentrations. The goal of our study was to detect the serum concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-18, and IL-6 concentrations in patients with chronic schizophrenia in the acute relapse state at admission and at discharge and to analyze the correlations between the three cytokine concentrations with psychosis symptoms.MethodsEnzyme-linked immunosorbent assay (ELISA) was used to analyze serum concentrations of TNF-α, IL-18, and IL-6 in 68 patients with chronic schizophrenia at admission and at discharge and in 80 controls. The Positive and Negative Syndrome Scale (PANSS) was used to analyze psychosis symptoms of the patients.ResultsSerum concentrations of TNF-α, IL-18, and IL-6 in patients at admission were significantly elevated compared to those in controls. After treatment, IL-6 concentrations in patients at discharge were significantly reduced compared to those in patients at admission, and IL-6 concentrations showed no significant difference between patients at discharge and controls. In contrast, TNF-α and IL-18 concentrations showed no significant difference between patients at discharge and patients at admission, and TNF-α and IL-18 concentrations in patients at discharge were still significantly elevated compared to those in controls. IL-6 concentrations in patients at admission showed a positive correlation with negative scores, and IL-6 concentrations in patients at discharge showed positive correlations with positive, negative, and total scores. Reduction in IL-6 concentrations showed positive correlations with reduction in positive, negative, and total scores in patients at discharge.ConclusionSerum concentrations of TNF-α, IL-18, and IL-6 were significantly elevated in patients with chronic schizophrenia in the acute relapse state. After treatment, IL-6 concentrations in patients at discharge were significantly reduced compared to these in patients at admission.     

Psychoticism in patients with panic disorder with or without comorbid agoraphobia

Objective: A few case-reports have previously described transient psychotic-like symptoms in non-psychotic patients with panic disorder (PD). We aimed to systematically explore whether PD patients without any current or past psychosis can be differentiated according to the severity of ‘psychoticism’ as a dimension, comprising clinical features such as psychotic-like experiences, increased social alienation, hostility and suspiciousness.

Methods: Sample included 35 (female?=?26) medication-free, non-psychotic patients consecutively referred from our Department’s Outpatient Clinic for acute symptoms of DSM-5 PD with (PDA; N?=?29) or without concurrent agoraphobia. Psychometric measures included the Symptom Checklist–90–Revised (SCL-90-R), Agoraphobic Cognitions Questionnaire (ACQ), Body Sensations Questionnaire (BSQ), and panic attacks during last 21 days PA-21d.

Results: Multiple regression analysis (forward stepwise) revealed that, among all SCL-90-R subscales, the psychoticism-subscale was most significantly associated with panic-related beliefs included in the ACQ, while significant associations emerged between the paranoid ideation-subscale and the ACQ and BSQ measures. Moreover, significant correlations emerged between the SCL-90-R psychoticism-subscale and all three measures of PD symptoms (ACQ, BSQ, PA-21d) and between the SCL-90-R paranoid ideation-subscale and both the ACQ and BSQ.

Conclusions: This significant association between levels of psychoticism and severity of panic symptoms may reflect a more severe subtype of PD.     

The use of a symptom "self-report" inventory to evaluate the acceptability and efficacy of a walking program for patients suffering with chronic fatigue syndrome

OBJECTIVES: The purpose of this research was to evaluate the effectiveness of the modality of walking as a management strategy for patients suffering with chronic fatigue syndrome (CFS). METHODS: Six males and fourteen females with medically diagnosed CFS (CDC, 1994), completed a 12-week walking program. Prior to starting the program subjects underwent an incremental walking exercise test to predetermine their walking intensity. The SCL-90-R symptom "self-report" questionnaire was administered prior to, and at the completion of, the walking program. RESULTS: At the completion of the 12 weeks of walking, changes in four of the nine SCL-90-R dimensions were significant (somatisation, paranoid ideation, phobic anxiety, and psychoticism). Also significant were the changes in the combination indices, the Global Indices of Distress (GID) and the Positive Symptom Total (PST). CONCLUSION: This group of CFS subjects, by way of "self-report", indicated the possibility of an exercise-induced decrease in psychological stress. The walking intervention may have evoked positive changes in their well-being and, furthermore, provided no evidence of any exacerbation in their symptoms.     

Changed signals of blood adenosine and cytokines are associated with parameters of sleep and/or cognition in the patients with chronic insomnia disorder

ObjectivesThis study aimed to investigate whether plasma levels of adenosine, adenosine deaminase (ADA), and certain cytokines change in patients with chronic insomnia disorder (CID), and if so, whether these alterations are associated with poor sleep quality and cognitive dysfunction.MethodsFifty-five CID patients were selected for the study, along with fifty-five healthy controls (HC) matched to the patients according to their basic data. All subjects completed sleep, emotion, and cognition assessments, with some CID patients also completing an overnight polysomnography. The plasma level of adenosine was measured using liquid chromatography–tandem mass spectrometry, while ADA level was quantified using a quantitative sandwich enzyme-linked immunosorbent assay. Levels of cytokines, including IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α, and IFN-γ, were measured using Luminex liquid chip technology.ResultsCID patients had a lower adenosine level, and higher levels of ADA and some of the cytokines (IL-1β, IL-2, IL-6, IL-10 and TNF-α) compared with controls. In the CID group, plasma concentrations of adenosine were negatively correlated with Pittsburgh Sleep Quality Index scores, while concentrations of IL-1β, IL-6 and TNF-α were positively correlated with these scores. Concentrations of IL-1β and TNF-α were negatively correlated with scores on the Chinese-Beijing Version of the Montreal Cognitive Assessment. Moreover, levels of IL-1β, TNF-α, IL-6, and IL-2 were positively correlated with memory test errors by CID patients after controlling for confounding factors.ConclusionsThe reduced adenosine and elevated cytokine levels of CID patients were associated with the severity of insomnia and/or cognitive dysfunction.     

Serum TNF-α and neurodegeneration in isolated REM sleep behavior disorder

ObjectiveTo investigate serum inflammatory cytokine profiles in patients with isolated REM sleep behavior disorder (iRBD) and to explore whether these markers are associated with phenoconversion risk to α-synucleinopathies.MethodsIn this prospective cohort study, we analyzed serum samples from patients with polysomnography-confirmed iRBD (n = 30) and healthy controls (n = 12). We measured the following cytokines: interleukin (IL)-1β, IL-2, IL-6, IL-10, and tumor necrosis factor-α (TNF-α). All patients underwent motor and non-motor evaluations and dopamine transporter imaging at baseline for predicting the phenoconversion risk. We followed the patients quarterly over up to 6 years to identify disease conversion. We also assessed longitudinal changes in cytokine levels from baseline at the 2- and 4-year follow-up visits.ResultsThe baseline cytokine levels did not differ between the patients and controls. However, the TNF-α levels were significantly increased in a subgroup of the patients with multiple markers (≥3) for phenoconversion risk compared to those without (p = 0.008) and controls (p = 0.003). At longitudinal analyses, patients with TNF-α levels above the median showed a higher incidence of phenoconversion than those with lower TNF-α levels (47% vs. 7%; p = 0.008), and this significant association persisted after adjusting for covariates (p = 0.026). The cytokine levels over 4 years of follow-up period did not change significantly.ConclusionsOur data suggest a possible link between serum TNF-α and phenoconversion risk in iRBD. Further studies are warranted to confirm the role of peripheral TNF-α in the pathogenesis of neurodegeneration in this disorder.     

Cytokine gene polymorphisms in obstructive sleep apnoea/hypopnoea syndrome

ObjectiveThe pro-inflammatory cytokines, TNF-α, IL-6, and IL-8 are elevated in obstructive sleep apnoea/hypopnoea syndrome (OSAHS). Cytokine gene interactions are complex and haplotype analysis may be more informative. We hypothesized that the effects of TNF-α in OSAHS might be due to linkage disequilibrium of the TNF-α (−308A) single nucleotide polymorphism (SNP) with other polymorphisms within the TNF-α gene, and that predisposition to elevated IL-6 and IL-8 levels in OSAHS might be attributable to pro-inflammatory IL-6 and IL-8 gene promoter polymorphisms.Method173 subjects were classified as having definite OSAHS or not on the basis of apnoea–hypopnoea frequency, sex, age, and symptoms. Population controls comprised 192 random UK blood donors. Genotyping was undertaken for the TNF- α promoter polymorphisms (−1031, −863, −857, −238), two lymphotoxin-α polymorphisms (intron 1 and Thr60Asn), the pro-inflammatory IL-6 gene promoter polymorphism (−174), and IL-8 gene promoter polymorphisms (−251; −781).ResultsThere was no significant difference between groups re: genotype/allelic frequency in the genes investigated. Association between disease status and the TNF-α alleles independently (TNF-103, TNF-803, TNF-857, TNF-238) with five haplotypes of TNF-α was not significant (p > 0.05). There was no difference in allelic or genotypic frequencies between obese and non-obese subjects with OSAHS. The TNF- α (−863A) allele alone, was significantly associated with obesity (OR 2.4; CI95% 1.1–5; p = 0.025).ConclusionOnly the TNF- α (308A) SNP appears to be significantly associated with OSAHS. The impact of cytokine gene polymorphisms on phenotypic expression of inflammation in OSAHS is likely to be complex.     

Blood levels of interleukin-1 beta,interleukin-6 and tumor necrosis factor-alpha and cognitive functions in patients with obsessive compulsive disorder

BackgroundCognitive dysfunction and immune system disorders are two actual issues for the patients with Obsessive Compulsive Disorder (OCD). The cognitive dysfunctions have been considered to substantial part of clinical phenomenon of OCD but exploration of various etiopathogenesis of cognitive dysfunction is needed. Immune dysfuncion has been implicated to be important part of pathopysiology of OCD and different lines of evidence suggests immune abnormalities in OCD. But whether these immune changes are traits of disease or secondary to clinical burden of the disease such as cognitive dysfunctions has not been determined. Data regarding relation between the cognitive dysfunctions and immune system disorders in OCD is unsatisfied. In this study we aimed to investigate the relation of blood levels of interleukin 1-beta (IL-1ß), interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) with various neurocognitive functions in patients with OCD in comparison with its autogenous/reactive subtypes and healthy controls. Further exploration of the effects of various clinical variables on cognitive functioning in patients with OCD and additional investigation of whether the cognitive dysfunction associated with this disorder differs from or overlap with that in other anxiety disorders are needed.MethodsForty-two patient with OCD and 45 age, sex and educational level matched healthy control were enrolled in the study. The diagnosis of OCD was made with Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Yale- Brown Obsessive-Compulsive Scale, Beck Anxiety and Depression Inventory Scales were administered. Neuropsychological test battery including Wisconsin Card Sorting Test (WCST), Trail Making Test A and B (TMT-A, TMT-B) were used for evaluation of the patients and healthy control. The plasma of interleukin-1beta (IL-1ß), interleukin-6 (IL-6), Tumor Necrosis Factor-Alpha (TNF-α) of both groups were measured with ELISA kits.ResultsBlood levels of IL-1ß, IL-6 and TNF-α were significantly higher in patients with OCD than the healthy control. There was significant difference in IL-1ß, IL-6 but not in TNF-α between autogenous/reactive subtypes and healthy controls. TNF-α is positively correlated with TMT-A, TMT-B and Stroop Test Part 5, negatively correlated with immediate memory, verbal learning, interference effect, immediate recall, delayed recall and recognition in RAVLT. IL-1ß was positively correlated with TMT-A score. IL-6 was positively correlated with scores of TMT-A, TMT-B. IL-6 was negatively correlated with immediate memory, verbal learning, interference effect, immediate recall and delayed recall in RAVLT, positively correlated with number of perseverative error and negatively correlated with the number of categories completed in WCST.ConclusionThis is the first study that investigates the relation of IL- 1ß, IL-6 and TNF-α levels with cognitive functions in OCD. There may be a contribution to pathogenesis of OCD and subtypes then new choices for treatment might be developed. Moreover, uncovering the effect of cytokine blood levels on cognitive function of OCD, new data concerning etiopathogenesis and further treatment choices can be gained.     

Psychiatric symptoms in ankylosing spondylitis: their relationship with disease activity,functional capacity,pain and fatigue

ObjectivesThe aim of this study is to evaluate psychiatric symptoms in patients with ankylosing spondylitis (AS) and to investigate the relationship of the disease activity, functional capacity, pain, and fatigue with psychiatric symptoms.MethodsEighty AS patients and 80 healthy controls were included in the study. Spinal pain by visual analog scale (pain VAS-rest), disease activity by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), functional capacity by Bath Ankylosing Spondylitis Functional Index (BASFI), and fatigue by Multidimensional Assessment of Fatigue (MAF) were assessed in patients. Psychiatric symptoms were measured using the Symptom Checklist-90-R (SCL-90 R), Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Pittsburgh Sleep Quality Index (PSQI) and Rosenberg Self-Esteem Scale (RSES).ResultsSCL-90-R total and all subscale scores (except interpersonal sensitivity and psychoticism) and BDI scores were significantly higher in the AS group compared to control group. PSQI total and all subscale scores were significantly higher in the AS group. State anxiety scale score was significantly higher and RSES score was significantly lower in the AS group. Psychiatric symptoms (except Rosenberg Self-Esteem score) were significantly correlated with BASDAI, BASFI, pain VAS rest, and MAF scores.ConclusionPsychiatric symptoms are often seen in patients with AS. Disease activity, functional capacity, pain and fatigue were correlated with psychiatric symptoms but self-esteem was not. Therefore, psychiatric symptoms should be taken into consideration in the management of AS.     

The role of tumour necrosis factor alpha and soluble tumour necrosis factor alpha receptors in the symptomatology of schizophrenia

Background Immunological mechanisms may be responsible for the development and maintenance of schizophrenia symptoms. Aim The aim of this study is to measure tumour necrosis factor-alpha (TNF-α), soluble tumour necrosis factor-alpha receptor I (sTNF-αRI), and soluble tumour necrosis factor-alpha receptor II (sTNF-αRII) levels in patients with schizophrenia and healthy individuals, and to determine their relationship with the symptoms of schizophrenia. Methods Serum TNF-α, sTNF-αRI and sTNF-αRII levels were measured. The Positive and Negative Syndrome Scale (PANSS) was administered for patients with schizophrenia (n?=?35), and the results were compared with healthy controls (n?=?30). Hierarchical regression analyses were undertaken to predict the levels of TNF-α, sTNF-αRI and sTNF-αRII. Results No significant difference was observed in TNF-α levels, but sTNF-αRI and sTNF-αRII levels were lower in patients with schizophrenia. Serum sTNF-αRI and sTNF-αRII levels were found to be negatively correlated with the negative subscale score of the PANSS, and sTNF-αRI levels were also negatively correlated with the total score of the PANSS. Smoking, gender, body mass index were not correlated with TNF-α and sTNF-α receptor levels. Conclusions These results suggest that there may be a change in anti-inflammatory response in patients with schizophrenia due to sTNF-αRI and sTNF-αRII levels. The study also supports low levels of TNF activity in schizophrenia patients with negative symptoms.     

Identification of actin network proteins,talin-1 and filamin-A,in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/chronic fatigue syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30–50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90–94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.     

Severe Versus Moderate Criteria for the New Pediatric Case Definition for ME/CFS

The new diagnostic criteria for pediatric ME/CFS are structurally based on the Canadian Clinical Adult case definition, and have more required specific symptoms than the (Fukuda et al. Ann Intern Med 121:953–959, 1994) adult case definition. Physicians specializing in pediatric ME/CFS referred thirty-three pediatric patients with ME/CFS and 21 youth without the illness. Those who met ME/CFS criteria were separated into Severe and Moderate categories. Significant differences were found for symptoms within each of the six major categories: fatigue, post-exertional malaise, sleep, pain, neurocognitive difficulties, and autonomic/neuroendocrine/immune manifestations. In general, the results showed participants who met the Severe ME/CFS criteria reported the highest scores, the Moderate ME/CFS group show scores that were a little lower, and the control group evidenced the lowest scores. Findings indicate that the Pediatric Case Definition for ME/CFS can distinguish between those with this illness and controls, and between those with Severe versus Moderate manifestations of the illness.     

Inflammatory cytokines,complement factor H and anhedonia in drug-naïve major depressive disorder

ObjectiveAnhedonia is a core symptom of major depressive disorder (MDD) and often associated with poor prognosis. The main objective of the present study was to explore the relationship between complement factor H (CFH), inflammatory cytokines and anhedonia in drug-naïve MDD patients.MethodsA total of 215 participants (61 MDD patients with anhedonia, 78 MDD patients without anhedonia, and 76 control subjects) were included. Severity of depression and levels of anhedonia were evaluated by Hamilton Rating Scale for Depression-17 (HAMD-17) and SHAPS (Snaith-Hamilton Pleasure Scale). Plasma levels of CFH, interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α) were measured.ResultsThe plasma levels of CFH, IL-10 and TNF-α were higher in drug-naïve MDD patients than control subjects. Compared to MDD patients without anhedonia, patients with anhedonia showed higher levels of CFH and IL-6. The stepwise regression analysis revealed that IL-10, TNF-α, as well as IL-10 × TNF-α were associated with depressive symptoms measured by HAMD-17 in drug-naïve MDD patients, while only CFH levels were identified as a mediator factor for the severity of anhedonia in the patients.ConclusionMDD patients with anhedonia showed different inflammatory characteristics compared to patients without anhedonia. Our results provide novel evidence suggesting that increased plasma CFH levels may be a potential biomarker of anhedonia of subtyping MDD.     

Blood levels of histamine,IL-1β, and TNF-α in patients with mild to moderate alzheimer disease

In this study, we have evaluated the levels of blood histamine, serum interleukin-1 beta (IL-1β), and plasma tumor necrosis factor-alpha (TNF-α) in 20 patients with mild to moderate Alzheimer disease (AD; 13 early onset and 7 late-onset AD subjects) and in 20 agematched control subjects (C). AD patients showed higher concentrations of histamine (AD=452.9±237.9 pmol/mL; C=275.3±151.5 pmol/mL;p<0.05) and IL-1β (AD=211.2±31.1 pg/mL; C=183.4±24.4 pg/mL;p<0.01), and lower values of TNF-α (AD=3.59±2.02 pg/mL; C=9.47±2.64 pg/mL;p<0.001) than elderly controls. Increased levels of histamine and decreased levels of TNF-α were observed in both early onset AD (EOAD) and late-onset AD (LOAD) patients, but only EOAD subjects had elevated serum IL-1β values compared with age-matched controls. Age negatively correlated with histamine (r=?0.57;p<0.05) and positively with IL-1β levels (r=0.48;p<0.05) in healthy subjects, but not in AD, whereas a positive correlation between TNF-α scores and age was only found in AD patients (r=0.46;p<0.05). Furthermore, histamine and TNF-α values correlated negatively in AD (r=?0.50,p<0.05). In addition, cognitive impairment increased in patients with lower TNF-α and higher histamine and IL-1β levels, as indicated by the correlations between mental performance scores and histamine (r=?0.37, ns), IL-1β (r=?0.33, ns) and TNF-α levels (r=0.42,p<0.05). Finally, histamine concentrations decreased as depression scores increased in AD (r=?0.63,p<0.01). These data suggest a dysfunction in cytokine and histamine regulation in AD, probably indicating changes associated with inflammatory processes.     

Interaction of BDNF with cytokines in chronic schizophrenia

Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment.     

Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome

ObjectivesStressors and emotional distress responses impact chronic fatigue syndrome (CFS) symptoms, including fatigue. Having better stress management skills might mitigate fatigue by decreasing emotional distress. Because CFS patients comprise a heterogeneous population, we hypothesized that the role of stress management skills in decreasing fatigue may be most pronounced in the subgroup manifesting the greatest neuroimmune dysfunction.MethodsIn total, 117 individuals with CFS provided blood and saliva samples, and self-report measures of emotional distress, perceived stress management skills (PSMS), and fatigue. Plasma interleukin-1-beta (IL-1β, IL-2, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α), and diurnal salivary cortisol were analyzed. We examined relations among PSMS, emotional distress, and fatigue in CFS patients who did and did not evidence neuroimmune abnormalities.ResultsHaving greater PSMS related to less fatigue (p = .019) and emotional distress (p < .001), greater diurnal cortisol slope (p = .023) and lower IL-2 levels (p = .043). PSMS and emotional distress related to fatigue levels most strongly in CFS patients in the top tercile of IL-6, and emotional distress mediated the relationship between PSMS and fatigue most strongly in patients with the greatest circulating levels of IL-6 and a greater inflammatory (IL-6):anti-inflammatory (IL-10) cytokine ratio.DiscussionCFS patients having greater PSMS show less emotional distress and fatigue, and the influence of stress management skills on distress and fatigue appear greatest among patients who have elevated IL-6 levels. These findings support the need for research examining the impact of stress management interventions in subgroups of CFS patients showing neuroimmune dysfunction.     

A formal analysis of cytokine networks in Chronic Fatigue Syndrome

Chronic Fatigue Syndrome (CFS) is a complex illness affecting 4 million Americans for which no characteristic lesion has been identified. Instead of searching for a deficiency in any single marker, we propose that CFS is associated with a profound imbalance in the regulation of immune function forcing a departure from standard pre-programmed responses. To identify these imbalances we apply network analysis to the co-expression of 16 cytokines in CFS subjects and healthy controls. Concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12, 13, 15, 17 and 23, IFN-γ, lymphotoxin-α (LT-α) and TNF-α were measured in the plasma of 40 female CFS and 59 case-matched controls. Cytokine co-expression networks were constructed from the pair-wise mutual information (MI) patterns found within each subject group. These networks differed in topology significantly more than expected by chance with the CFS network being more hub-like in design. Analysis of local modularity isolated statistically distinct cytokine communities recognizable as pre-programmed immune functional components. These showed highly attenuated Th1 and Th17 immune responses in CFS. High Th2 marker expression but weak interaction patterns pointed to an established Th2 inflammatory milieu. Similarly, altered associations in CFS provided indirect evidence of diminished NK cell responsiveness to IL-12 and LT-α stimulus. These observations are consistent with several processes active in latent viral infection and would not have been uncovered by assessing marker expression alone. Furthermore this analysis identifies key sub-networks such as IL-2:IFN-γ:TNF-α that might be targeted in restoring normal immune function.     

Plasma immune markers in an idiopathic REM sleep behavior disorder cohort

IntroductionIncreasing evidence shows a strong association between idiopathic REM sleep behavior disorder (iRBD) and α-synucleinopathies. Recent studies have indicated an inflammatory mechanism in the pathogenesis of α-synucleinopathies. Whether peripheral inflammatory cytokines are altered in iRBD and can be biomarkers for predicting phenoconversion remains unclear.MethodsWe collected baseline plasma samples from 77 consecutive iRBD patients and 64 age- and sex-matched healthy controls. Ten cytokines were measured: Interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-α. All iRBD patients underwent clinical assessment tests at baseline, and 75 were prospectively followed and received assessments for parkinsonism or dementia. Cox regression analyses were used to evaluate the predictive value of plasma cytokines in a follow-up period of 6.0 years.ResultsTNF-α and IL-10 were significantly elevated in iRBD compared with controls (both p < 0.001). IL-6/IL-10 and IL-8/IL-10 were significantly reduced in iRBD than in controls (p = 0.001, p < 0.001, respectively). After a median follow-up of 3.7 years, 16 iRBD patients developed neurodegenerative synucleinopathies. iRBD patients with higher TNF-α/IL-10 levels were more likely to develop neurodegenerative diseases (adjusted HR 1.07, 95% CI 1.01–1.14). The coexistence of elevated TNF-α/IL-10 and possible mild cognitive impairment predicted an early conversion of iRBD to neurodegenerative synucleinopathies (adjusted HR 4.17, 95% CI 1.47–11.81).ConclusionsOur study supported the early involvement of peripheral inflammation in prodromal α-synucleinopathy. Plasma cytokines may be predictive of disease conversion in iRBD, while large-scale longitudinal studies are warranted to validate the assumption.     

Comorbid psychiatric symptoms in temporal lobe epilepsy: association with chronicity of epilepsy and impact on quality of life

Purpose. The goals of this work were to determine: (1) the nature and extent of differences in self-reported psychiatric symptoms between patients with temporal lobe epilepsy and matched healthy controls, (2) the relationship between chronicity (duration) of temporal lobe epilepsy and comorbid interictal psychiatric symptoms, and (3) the impact of comorbid psychiatric symptoms on self-reported health-related quality of life. Methods. Patients with temporal lobe epilepsy (n = 54) and healthy controls (n = 38) were administered the Symptom Checklist-90-Revised (SCL-90-R) to assess the nature and severity of psychiatric symptomatology and epilepsy patients completed the Quality of Life in Epilepsy-89 (QOLIE-89) to define health-related quality of life. Among epilepsy patients the SCL-90-R scales were examined in relation to chronicity of temporal lobe epilepsy as well as the impact of comorbid emotional-behavioral distress on health-related quality of life. Results. Compared with healthy controls, patients with epilepsy exhibited significantly higher (worse) scores across all but one of the 12 SCL-90-R scales. Among patients with epilepsy, increasing chronicity was associated with significantly higher (worse) scores across all SCL-90-R scales and increased emotional-behavioral distress was associated with lower (worse) scores across all 17 QOLIE-89 scales. Conclusion. Comorbid interictal psychiatric symptoms are elevated among patients with temporal lobe epilepsy compared with healthy controls and appear to be modestly associated with increasing chronicity (duration) of epilepsy. This comorbid emotional-behavioral distress is specifically associated with a significantly poorer health-related quality of life, and suggests that quality-of-life research should devote greater attention to the potential impact of comorbid psychiatric distress.     

Peripheral levels of C-reactive protein,tumor necrosis factor-α, interleukin-6, and interleukin-1β across the mood spectrum in bipolar disorder: A meta-analysis of mean differences and variability

ImportanceIt is unclear whether differences exist in the magnitude and variability of pro-inflammatory mediators in the different phases of bipolar disorder (BD) and among subjects with BD, as compared to healthy controls.ObjectiveTo run a comparative meta-analysis of C-Reactive Protein (CRP), IL-1, IL-6, TNF-α in BD vs healthy controls, measuring mean and variability effects on all subjects. Sensitivity analyses include disease activity.Data sourcesSystematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020.Study selectionCase-control studies reporting inflammatory mediators' levels in BD and controls.Data extraction and synthesisSummary distribution measures of circulating CRP, IL-1β, IL-6, TNF-α in participants with BD and control groups were extracted. Random-effects multivariate meta-analyses were conducted based on individual study/mediator effect sizes (Hedge’s g).Main outcomes and measuresCo-primary outcomes were inflammatory mediators' levels (Hedge’s g) and variability (coefficient of variance ratio (CVR)) differences between participants with BD across the mood spectrum and controls.ResultsOut of the initial 729 papers, 72 were assessed and then excluded after full-text review, and ultimately 53 studies were included in the systematic review, while 49 were included in the meta-analysis. The mean age was 36.96 (SD: 9.29) years, and the mean female percentage was 56.31 (SD: 16.61). CRP (g = 0.70, 95% CI 0.31–1.09, k = 37, BD = 2,215 vs HC = 3,750), IL-6 (g = 0.81, 95% CI 0.46–1.16, k = 45, BD = 1,956 vs HC = 4,106), TNF-α (g = 0.49, 95% CI 0.19–0.78, k = 49, BD = 2,231 vs HC = 3,017) were elevated in subjects with BD vs HC, but not IL-1β (g = -0.28, 95% CI −0.68–0.12, k = 4, BD = 87 vs HC = 66). When considering euthymic, depressive, and manic episodes separately, CRP and TNF-α were elevated in both depressive and manic episodes, but not in euthymia, while IL-6 remained elevated regardless of the disease state. No difference in CVR emerged for CRP, IL-1β, and TNF-α, while a lower CVR was observed for IL-6. When considering disease phases, CVR was higher in BD than in HCs for CRP during depressive episodes, lower for IL-6 during euthymia, and higher during manic episodes for CRP, IL-6, and TNF-α. Sensitivity analyses after excluding outliers identified with funnel plot visual inspection, low-quality studies, and considering only studies matched per body mass index confirmed the main results. Meta-regression showed that age (IL-6, TNF-α), gender (CRP), duration of illness (CRP) moderated elevated individual inflammatory levels.Conclusions and relevancePeripheral pro-inflammatory marker elevations were confirmed in BD. CRP and TNF-α could represent state markers, as they were only elevated during mood episodes, while IL-6 appeared to be a trait marker for BD. Increased variability of specific inflammatory mediators in specific disease active states suggests that a subset of subjects with BD may exhibit elevated inflammation as part of a manic or depressive episode.