Association of peripheral inflammatory markers with chronic fatigue in a population-based sample

Alterations in the innate immune response may contribute to the pathogenesis of chronic fatigue syndrome (CFS). However, studies have been limited by small sample sizes, use of patients from tertiary care settings, inappropriate selection of controls, and failure to control for confounding demographic, medical and behavioral factors independently associated with immune activity. It is also not known whether specific symptoms account for observed associations between CFS and the innate immune response. To address these limitations, the current study examined plasma concentrations of high-sensitivity c-reactive protein (hs-CRP), white blood cell count (WBC) and a combined inflammation factor in a large population-based sample. Log-transformed mean plasma concentrations of hs-CRP were increased in subjects with CFS (n = 102) and in subjects with unwellness symptoms that did not meet diagnostic criteria for CFS (defined as “insufficient fatigue” [ISF]) (n = 240) when compared to subjects who were well (n = 115). Log transformed WBC was increased in ISF and was increased at a trend level in CFS. The combined inflammation factor was increased in both CFS and ISF. Subjects with CFS and ISF did not differ on any of the inflammation measures. In the entire subject population, the physical component summary score (PCS), but not the mental component summary score (MCS), from the Medical Outcomes Study Short Form-36 (SF-36) was negatively associated with each of the inflammation measures. Depressive symptoms were also associated with increased log hs-CRP. After adjustment for age, sex, race, location of residence, BMI, depressive status and immune-modulating medications, subjects classified as ISF continued to demonstrate increased log hs-CRP, WBC and elevations on the inflammation factor when compared to well controls; however, associations between CFS and log hs-CRP and the inflammation factor were no longer statistically significant. After adjustment, PCS score also remained independently associated with each of the inflammation measures. These findings support a role for innate immune activation in unexplained fatigue and unwellness, but do not suggest that immune activation is specific to CFS.     

Differential effects of childhood trauma subtypes on fatigue and physical functioning in chronic fatigue syndrome

ObjectiveThere is wide consensus that childhood trauma plays an important role in the aetiology of chronic fatigue syndrome (CFS). The current study examines the differential effects of childhood trauma subtypes on fatigue and physical functioning in individuals suffering from CFS.MethodsParticipants were 155 well-documented adult, predominantly female CFS patients receiving treatment at the outpatient treatment centre for CFS of the Antwerp University Hospital in Belgium. Stepwise regression analyses were conducted with outcomes of the total score of the Checklist Individual Strength (CIS) measuring fatigue and the scores on the physical functioning subscale of the Medical Outcomes Short Form 36 Health Status Survey (SF-36) as the dependent variables, and the scores on the five subscales of the Traumatic Experiences Checklist (TEC) as the independent variables.ResultsThe patients' fatigue (β = 1.38; p = 0.025) and physical functioning scores (β = − 1.79; p = 0.034) were significantly predicted by childhood sexual harassment. There were no significant effects of emotional neglect, emotional abuse, bodily threat, or sexual abuse during childhood.ConclusionOf the childhood trauma subtypes investigated, sexual harassment emerged as the most important predictor of fatigue and poor physical functioning in the CFS patients assessed. These findings have to be taken into account in further clinical research and in the assessment and treatment of individuals coping with chronic fatigue syndrome.     

Acute phase protein and cytokine levels in serum and saliva: A comparison of detectable levels and correlations in a depressed and healthy adolescent sample

Recent research has examined associations between inflammation and mental health, and has increasingly focused on utilising younger samples to characterise the temporal relationship between inflammatory responses and the emergence of other symptoms. These studies have typically used blood to measure inflammation, although rates of detection for many inflammatory markers appear to be low. Saliva is a safe and low-cost alternative, and adult research has shown that levels of some salivary markers correlate well with those in serum. However, no research has examined this association in young people. This study examined 16 inflammatory markers in serum and saliva in 17 depressed adolescents and 18 healthy controls, aged 13–18 years. In general, detection rates were higher in saliva compared to in serum. When non-detectable levels were excluded, serum levels of C-reactive protein (CRP) correlated with salivary CRP (r = 0.424, p = 0.015), and this correlation appeared to only exist for those individuals with high levels of serum CRP (r = 0.599, p = 0.014). However, when non-detectable levels were included as zero, salivary levels of CRP, interleukin (IL)-2, IL-12p70, and interferon (IFN)-γ correlated with their serum counterparts. No significant clinical group differences in any acute phase proteins or cytokines were present. This study suggests that saliva can be used to measure inflammation in studies with adolescent participants, especially CRP, as it appears to correlate with systemic inflammation for those individuals who are expected to have high levels of inflammation. Implications for future directions in research on salivary inflammatory markers are discussed.     

A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality

BackgroundPatients with depression and suicidality suffer from low-grade neuroinflammation. Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-d-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF).MethodsWe measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over 2 years (total patient samples n = 143, individuals n = 30) and healthy controls (n = 36). The association between the markers and psychiatric symptoms was assessed using the Montgomery Åsberg Depression Rating Scale and the Suicide Assessment Scale.ResultsQuinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms.ConclusionsWe demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression.     

Depressive symptoms are associated with reduced neutrophil function in hip fracture patients

Hip fracture is a common trauma in older adults with a high incidence of depression, which relates to poorer prognosis including increased risk of infection. Ageing is accompanied by reduced immunity, termed immunesenescence, resulting in increased susceptibility to infection. We examined whether physical trauma (hip fracture) and psychological distress (depressive symptoms) had additive effects upon the aged immune system that might contribute to poor outcomes after injury. Neutrophil function was assessed in 101 hip fracture patients (81 female) 6 weeks and 6 months after injury and 43 healthy age-matched controls (28 female). Thirty eight fracture patients had depressive symptoms at 6 weeks. No difference in neutrophil phagocytosis of Escherichia coli was observed between controls and hip fracture patients, but superoxide production was significantly reduced in hip fracture patients with depressive symptoms compared with patients without symptoms (p = .001) or controls (p = .004) at 6 weeks. Superoxide production improved 6 months following fracture to the level seen in controls. We detected elevated serum cortisol, reduced dehydroepiandrosterone sulphate (DHEAS) and an increased cortisol:DHEAS ratio in fracture patients with depressive symptoms compared with patients without depressive symptoms or controls at 6 weeks and 6 months after injury. Serum IL6, TNFα and IL10 were higher among patients with depressive symptoms at 6 weeks. The cortisol:DHEAS ratio and IL6 levels related to depressive symptom scores but not to neutrophil function. In conclusion, depressive symptoms related to poorer neutrophil function after hip fracture, but this was not driven by changes in stress hormone or cytokine levels.     

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.     

Preoperative inflammatory biomarkers and neurovegetative symptoms in peritoneal carcinomatosis patients

BackgroundInflammation plays a central role in peritoneal carcinomatosis (PC) etiology and progression, and circulating levels of inflammatory biomarkers prior to surgery predict progression-free and overall survival in PC patients. Depression and fatigue are prevalent among PC patients, and experimental research shows that these symptoms may be mediated by proinflammatory cytokines. As yet unstudied is the possibility that the heightened levels of inflammatory markers in PC patients may contribute to their experience of common neurovegetative symptoms.MethodsValidated self-report measures of fatigue, depressive symptoms, and quality of life were administered to 64 patients scheduled to undergo aggressive surgical treatment for PC. Serum samples were collected the morning of surgery, and ELISAs were conducted to quantify circulating IL-6, CRP, and TNF-α levels.ResultsConsistent with hypotheses, higher IL-6 levels were associated with more severe fatigue (β = −.39, p < .01) and neurovegetative symptoms of depression (β = .30, p < .05). IL-6 was also related to poorer physical quality of life (β = −.28, p < .05). CRP showed similar significant relationships with fatigue and physical quality of life. Inflammatory biomarkers were not significantly related to emotional symptoms of depression or to emotional or social functioning aspects of quality of life, and TNF-α levels were not related to patient-reported measures.ConclusionPreoperative inflammatory activity may contribute to patients’ experiences of fatigue and neurovegetative depressive symptoms as well as impaired quality of life. These biological mechanisms warrant consideration in the clinical management of neurovegetative symptoms in PC patients.     

Influence of repeated maximal exercise testing on biomarkers and fatigue in sarcoidosis

Fatigue in the immune mediated inflammatory disease sarcoidosis is thought to be associated with impaired exercise tolerance. This prospective study assessed fatigue and recuperative capacity after repeated exercise, and examined whether changing concentrations in biomarkers upon exercise are associated with fatigue.Twenty sarcoidosis patients and 10 healthy volunteers performed maximal cardiopulmonary exercise tests on two successive days. Concentrations of cytokines, stress hormones, ACE and CK were assessed before and after the two exercise tests, and 3 days thereafter. All participants completed a sleep diary.Severely fatigued patients showed significant lower VO₂ max (p = 0.038, p = 0.022) and maximal workload (p = 0.034, p = 0.028) on both exercise tests compared to healthy controls. No impairment of maximal exercise testing was demonstrated during the second cycling test in any group. Fatigue was not correlated with changes in concentrations of biomarkers upon exercise. Severely fatigued patients rated both tests as significantly more fatiguing, and reported significant lower mean subjective night sleeping time during the testing period.Fatigue in sarcoidosis patients cannot be objectified by reduction of exercise capacity after repeated maximal exercise testing, and is not correlated with significant changes in biomarkers. Severe fatigue is only and consistently featured by patient reported outcomes.     

Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms

Some Lyme disease patients report debilitating chronic symptoms of pain, fatigue, and cognitive deficits despite recommended courses of antibiotic treatment. The mechanisms responsible for these symptoms, collectively referred to as post-Lyme disease syndrome (PLS) or chronic Lyme disease, remain unclear. We investigated the presence of immune system abnormalities in PLS by assessing the levels of antibodies to neural proteins in patients and controls. Serum samples from PLS patients, post-Lyme disease healthy individuals, patients with systemic lupus erythematosus, and normal healthy individuals were analyzed for anti-neural antibodies by immunoblotting and immunohistochemistry. Anti-neural antibody reactivity was found to be significantly higher in the PLS group than in the post-Lyme healthy (p < 0.01) and normal healthy (p < 0.01) groups. The observed heightened antibody reactivity in PLS patients could not be attributed solely to the presence of cross-reactive anti-borrelia antibodies, as the borrelial seronegative patients also exhibited elevated anti-neural antibody levels. Immunohistochemical analysis of PLS serum antibody activity demonstrated binding to cells in the central and peripheral nervous systems. The results provide evidence for the existence of a differential immune system response in PLS, offering new clues about the etiopathogenesis of the disease that may prove useful in devising more effective treatment strategies.     

Altered immune pathway activity under exercise challenge in Gulf War Illness: An exploratory analysis

Though potentially linked to the basic physiology of stress response we still have no clear understanding of Gulf War Illness (GWI), a debilitating illness presenting with a complex constellation of immune, endocrine and neurological symptoms. Here we compared male GWI (n = 20) with healthy veterans (n = 22) and subjects with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) (n = 7). Blood was drawn during a Graded eXercise Test (GXT) prior to exercise, at peak effort (VO2 max) and 4-h post exercise. Affymetrix HG U133 plus 2.0 microarray gene expression profiling in peripheral blood mononuclear cells (PBMCs) was used to estimate activation of over 500 documented pathways. This was cast against ELISA-based measurement of 16 cytokines in plasma and flow cytometric assessment of lymphocyte populations and cytotoxicity. A 2-way ANOVA corrected for multiple comparisons (q statistic <0.05) indicated significant increases in neuroendocrine-immune signaling and inflammatory activity in GWI, with decreased apoptotic signaling. Conversely, cell cycle progression and immune signaling were broadly subdued in CFS. Partial correlation networks linking pathways with symptom severity via changes in immune cell abundance, function and signaling were constructed. Central to these were changes in IL-10 and CD2+ cell abundance and their link to two pathway clusters. The first consisted of pathways supporting neuronal development and migration whereas the second was related to androgen-mediated activation of NF-κB. These exploratory results suggest an over-expression of known exercise response mechanisms as well as illness-specific changes that may involve an overlapping stress-potentiated neuro-inflammatory response.     

Cerebrospinal fluid inflammatory markers in Parkinson’s disease – Associations with depression,fatigue, and cognitive impairment

Neuroinflammation may be involved in the pathophysiology of Parkinson’s disease (PD) and specifically in non-motor symptoms such as depression, fatigue and cognitive impairment. The aim of this study was to measure inflammatory markers in cerebrospinal fluid (CSF) samples from PD patients and a reference group, and to investigate correlations between non-motor symptoms and inflammation.We quantified C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, eotaxin, interferon gamma-induced protein-10, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein 1-β in CSF samples from PD patients (N = 87) and the reference group (N = 33). Sixteen of the PD patients had a dementia diagnosis (PDD). We assessed symptoms of fatigue, depression, anxiety and cognitive function using the Functional Assessment of Chronic Illness Therapy-Fatigue, the Hospital Anxiety and Depression Scale, and the Mini Mental State Examination, respectively.There were no significant differences in mean levels of inflammatory markers between PD patients and the reference group. After controlling for age, gender and somatic illness, patients with PDD had significantly higher levels of CRP compared to non-demented PD patients (p = 0.032) and the reference group (p = 0.026). Increased levels of inflammatory markers in CSF were significantly associated with more severe symptoms of depression, anxiety, fatigue, and cognition in the entire PD group. After controlling for PD duration, age, gender, somatic illness and dementia diagnosis, high CRP levels were significantly associated with more severe symptoms of depression (p = 0.010) and fatigue (p = 0.008), and high MCP-1 levels were significantly associated with more severe symptoms of depression (p = 0.032).Our results indicate that non-motor features of PD such as depression, fatigue, and cognitive impairment are associated with higher CSF levels of inflammatory markers.     

Increased soluble interleukin-2 receptor levels are related to somatic but not to cognitive-affective features in major depression

Cell-mediated immune activation may play a role in the pathogenesis of depression as indicated by findings of increased soluble tumor necrosis factor receptor (sTNF-R) levels and meta-analytic evidence for elevated soluble interleukin-2 receptor (sIL-2R) concentrations. However, little research has been done on how these soluble cytokine receptors are differently related to specific features in patients with depression. We measured levels of the soluble cytokine receptors sIL-2R, sTNF-R1 and sTNF-R2 in 25 non-medicated patients with major depression (DSM-IV) and 22 healthy controls. Psychometric measures included cognitive-affective depressive symptoms, somatoform symptoms, somatic and cognitive dimensions of anxiety and current mood states. While patients with depression showed increased levels of sIL-2R (p < 0.01), differences in sTNF-R1 (p = 0.09) and sTNF-R2 (p = 0.08) marginally failed to reach significance. Increased concentrations of sIL-2R were related to somatic measures such as the severity of somatoform symptoms and somatic anxiety symptoms but not to cognitive-affective measures or current mood states. Our findings may suggest some specificity in the relationship between sIL-2R and symptom dimensions and highlight potential pathways by which T cell mediated immune activation may underpin somatic symptoms in depression.     

Modèle en réseau et troubles mentaux : application et intérêts dans la dépression post-AVC

In contrast to the classic models in psychopathology, the network model considers that the temporal interactions between symptoms are the causes of their occurrence. This model could also be particularly suitable for understanding the processes involved in post-stroke depression. The aim of this paper is to perform a network analysis in order to describe the temporal dynamic of the links existing between depression symptoms during the acute phase after stroke. Twenty-five patients (64% male, mean age 58.1 ± 14.9 years old) hospitalized for a minor stroke (no neurocognitive or motor impairment) were involved in an Ecological Momentary Assessment methodology-based study. They used a smartphone application in order to complete four brief questionnaires each day during the week after hospital discharge. The questionnaire included 7-point Likert scales to measure the severity of the following depressive symptoms: sadness, anhedonia, fatigue, diminished concentration ability, negative thoughts on oneself, pessimism. We used Multilevel Vector Autoregressive analysis to describe the temporal links between those symptoms. We used the software R 3.6.0 with the mlVAR package. The p-value was set at .05. The results show two independent symptoms networks. The first one involves the anhedonia, fatigue, negative thoughts on oneself and sadness. It shows that: anhedonia predicts the activation of later fatigue (β = 0.135, P = 0.037) and later negative thoughts (β = 0.152, P = 0.019); negative thoughts predict later negative thoughts (β = 0.143, P = 0.028) and later sadness (β = 0.171, P = 0.021); fatigue predicts later fatigue (β = 0.261, P < 0.000). Pessimism and diminished concentration ability compose the second network, and the results show that pessimism predicts later pessimism (β = 0.215, P = 0.012) and later diminished concentration ability (β = 0.178, P = 0.045). On the one hand, anhedonia thus plays an important role in the initial and progressive activation of the other symptoms of its network. On the other hand, the cognitive symptoms (negative thoughts and pessimism) cause the deterioration of the mood and the deficit of attentional abilities. Using behavioral and cognitive strategies to support patients after hospital discharge would reduce the risk of depressive complications after a stroke. This study provides convincing empirical elements for the interest of the network model for research in psychopathology and the clinical implications and perspectives allowed by network analysis.     

Increased irritability,anxiety, and immune reactivity in transgenic Huntington’s disease monkeys

Although the most notable clinical symptoms of Huntington’s disease (HD) are motor disturbances and brain atrophy, other symptoms include cognitive dysfunction, emotional and hormonal dysregulation. Emotional dysregulation (irritability, anger/aggression, and anxiety) and increased inflammation are early emerging symptoms which can be detected decades before the onset of motor symptoms in HD patients. Despite the advances in understanding the genetic causes of HD there is still no cure or preventative treatment. Thus, to better understand the pathogenesis of HD and develop effective treatments, a holistic understanding of HD is needed, as well as animal models that replicate the full spectrum of HD symptoms. The current study examined the emotional, hormonal, and gene expression responses to an acute stressor of adult male transgenic HD rhesus monkeys (n = 2) as compared to wild-type controls (n = 2). Results revealed that HD monkeys expressed increased anxiety and irritability/aggression as compared to controls. Reactive cortisol response to the stressor was similar between groups. However, HD monkeys exhibited increased pro-inflammatory cytokines and higher induction of immune pathway genes as compared to controls. Overall, results reveal that HD monkeys exhibit these early emerging symptoms of HD and may be an effective animal model to facilitate the development of new therapeutics for HD patients.     

Sex differences in the relationship between obesity,C-reactive protein,physical activity,depression, sleep quality and fatigue in older adults

Fatigue is a serious health concern in the elderly. Sex differences exist in adiposity, systemic inflammation, physical activity/fitness and fatigue; however, the relations among these variables remain inadequately characterized impeding the development of fatigue prevention strategies. Measures of adiposity, C-reactive protein, physical activity, aerobic fitness, fatigue, sleep quality and depression were obtained from 127 community-dwelling older adults. Although similar in age (70 y) and BMI (28.0 kg/m²) women (n = 80) reported 63% greater fatigue than men (p = 0.04). Adiposity (r = 0.44), CRP (r = 0.29), physical activity (r = ?0.26) and fitness (r = ?0.41) were related to fatigue in women (all p < 0.05), but not in men. Depression was also related to fatigue in women (r = 0.37), and was the only variable related to fatigue in men (r = 0.42). In women, fatigue was independently explained (all p < 0.05) by CRP (6.6%), depression (6.3%), physical activity (5.8%), and adiposity (3.9%); however, in men, only depression explained variance in fatigue (12.0%). CRP was 40% higher and adiposity 12% higher in women reporting fatigue compared to those with no fatigue; no such differences existed in men. Obese women perceived a greater degree of fatigue than non-obese women, but this was not the case in men. Women report more fatigue than men which was independently associated with inflammation, depression, physical activity and adiposity, whereas in men the only independent predictor was depression. Strategies to prevent fatigue may differ in older women and men, especially with regard to inflammation, physical activity and adiposity.     

Tyrosine metabolism during interferon-alpha administration: Association with fatigue and CSF dopamine concentrations

Chronic exposure to interferon (IFN)-alpha, an innate immune cytokine, produces high rates of behavioral disturbances, including depression and fatigue. These effects may be mediated by the actions of IFN-alpha on dopamine (DA) metabolism in the basal ganglia. Diminished conversion of phenylalanine (Phen) to tyrosine (Tyr), the primary amino acid precursor of DA, has been associated with inflammation, and may reflect decreased activity of the enzyme phenylalanine-hydroxylase (PAH). This study investigated the peripheral Phen/Tyr ratio in relation to cerebrospinal fluid (CSF) concentrations of DA and its metabolites in subjects treated with IFN-alpha plus ribavirin for hepatitis C and controls awaiting IFN-alpha therapy. Plasma Phen/Tyr ratios were significantly increased in IFN-alpha-treated subjects (n = 25) compared to controls (n = 9), and were negatively correlated with CSF DA (r = −0.59, df = 15, p < 0.05) and its metabolite, homovanillic acid (r = −0.67, df = 15, p < 0.01), and positively correlated with fatigue (r = 0.44, df = 23, p < .05) in IFN-alpha-treated patients but not controls. Given the role of tetrahydrobiopterin (BH4) in the PAH conversion of Phen to Tyr, CSF concentrations of BH4 and its inactive oxidized form, dihydrobiopterin (BH2), were examined along with CSF interleukin (IL)-6 in a subset of patients. BH2 concentrations were significantly increased in IFN-alpha-treated patients (n = 12) compared to controls (n = 7), and decreased CSF BH4 concentrations correlated with increased CSF IL-6 (r = −0.57, df = 12, p < 0.05). These results indicate that IFN-alpha is associated with decreased peripheral conversion of Phen to Tyr, which in turn is associated with reduced DA in the brain as well as fatigue. These alterations may be related to oxidation of BH4 secondary to IFN-alpha-induced activation of a CNS inflammatory response.     

Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy

Elevations in cancer treatment-induced circulating inflammatory cytokines may be partially responsible for the development of significant symptom burden (e.g., pain, fatigue, distress, disturbed sleep) during concurrent chemoradiation therapy (CXRT). Sixty-two patients undergoing CXRT for locally advanced non-small cell lung cancer (NSCLC) reported symptoms weekly for 15 weeks via the M. D. Anderson Symptom Inventory (MDASI). Serum inflammatory cytokines were assessed weekly during therapy via enzyme-linked immunosorbent assay. Dynamic changes in cytokines and associated symptom profiles were estimated using mixed-effect models. MDASI symptom severity increased gradually as CXRT dose accumulated and peaked at week 8. Serum concentrations of interleukin (IL)-6, IL-10, and serum soluble receptor 1 for tumor necrosis factor (sTNF-R1) increased significantly by week 8 (all p < .05). During CXRT, controlled for age, sex, race, body mass index, cancer recurrence, previous treatment status, total radiotherapy dose, and CXRT delivery technique, an increase in sTNF-R1 was significantly related to an increase in the mean score for all 15 MDASI symptoms (estimate, 1.74; SE, 0.69; p < .05) and to a larger radiation dose to normal lung volume (estimate, 1.77; SE, 0.71; p < .01); an increase in serum IL-6 was significantly related to increased mean severity for the five most severe symptoms (pain, fatigue, disturbed sleep, lack of appetite, sore throat) (estimate, 0.32; SE, 0.16; p < .05). These results suggest a role for over-expressed pro-inflammatory cytokines in significant worsening of symptoms in NSCLC patients undergoing CXRT, and warrant further study to identify biological targets for ameliorating treatment-related symptom burden.     

Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans

Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho = 0.6; p = 0.03) determined by [¹²³I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho = 0.76; p = 0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6–8 weeks was associated with a significant reduction in 5-HTT availability (Z = 2.09; p = 0.03; r = 0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression.     

Depression and markers of inflammation as predictors of all-cause mortality in heart failure

BackgroundIn patients with heart failure (HF) depressive symptoms have been associated with mortality, as well as biological risk factors, including inflammation, nitric oxide (NO) regulation, and oxidative stress. We investigated the joint predictive value of depressive symptoms, inflammation and NO regulation on all-cause mortality in patients with HF, adjusted for covariates.MethodsSerum levels of inflammation (TNFα, sTNFr1, sTNFr2, IL-6, hsCRP, NGAL), NO regulation (l-arginine, ADMA, and SDMA), and oxidative stress (isoprostane 8-Epi Prostaglandin F2 Alpha) were measured in 104 patients with HF (mean age 65.7 ± SD 8.4 years, 28% women). Depressive symptoms (Beck Depression Inventory, BDI) were measured as continuous total, cognitive, and somatic symptoms, as well as categorized presence of mild/moderate depression (cut-off BDI ⩾10). In Cox proportional hazard models we adjusted for age, sex, poor exercise tolerance and comorbidity.ResultsAfter on average 6.1 years follow-up (SD = 2.9, range 0.4–9.2), 49 patients died. Total and somatic depressive symptoms, mild/moderate depression, higher NGAL, sTNFr2, IL-6, hsCRP and SDMA serum levels were significantly associated with a higher all-cause mortality rate, adjusted for covariates. The findings were most consistent for CRP level and somatic depressive symptoms. When combined, both depressive symptoms and markers of inflammation and NO regulation remained significantly associated with all-cause mortality. These associations were not confounded by age, sex, poor exercise tolerance and comorbidity.ConclusionDepressive symptoms and markers of inflammation and NO regulation are codominant risk factors for all-cause mortality in heart failure.     

Association between FSP,CVHI, inflammatory cytokines and the incidence of primary stroke

This case-control study was designed to establish a new risk-prediction model for primary stroke using Framingham stroke profile (FSP), cerebral vascular hemodynamic indexes (CVHI) and plasma inflammatory cytokines including hs-CRP, IL-6, TNF-α and Lp-PLA2. A total of 101 primary stroke patients admitted to Dongguan Houjie Hospital between August 2014 and June 2015 were assigned into the case group, and 156 age- and gender-matched healthy subjects from the Houjie Community were allocated into the control group. The prognostic values of FSP, CVHI and inflammatory cytokines including high sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were assessed by multivariate logistic regression analysis. Seven risk-prediction models (FSP, CVHI, inflammatory cytokine, FSP + CVHI, FSP + inflammatory cytokine, CVHI + inflammatory cytokine, CVHI + FSP + inflammatory cytokine) were successfully established and the prognostic values were statistically compared by ROC curve and Z test. For FSP, the stroke risk was significantly elevated by 2.85 times when the FSP score was increased by 1 level (P = 0.043), increased by 3.25 times for CVHI (P = 0.036), 6.53 times for IL-6 (P = 0.003), and 7.75 times for Lp-PLA2 (P = 0.000). The sensitivity of FSP + CVHI + inflammatory cytokine and CVHI + inflammatory cytokine models was higher than 90%. For model specificity, the specificity of FSP + CVHI + inflammatory cytokine model alone exceeded 90%. FSP, CVHI, IL-6 and Lp-PLA2 are independent risk factors of stroke. Integrating IL-6 and Lp-PLA2 into the models can significantly enhance the risk prediction accuracy of primary stroke. Combined application of FSP + CVHI + inflammatory cytokine is of potential for risk prediction of primary stroke.