Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results: In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.Bernhard T Baune, Carsten Konrad, Dominik Grotegerd, Thomas Suslow, Eva Birosova, Patricia Ohrmann, Jochen Bauer, Volker Arolt, Walter Heindel, Katharina Domschke, Sonja Schöning, Astrid V Rauch, Christina Uhlmann, Harald Kugel and Udo Dannlowsk

Neuropsychiatric Symptoms in Patients with Aortic Aneurysms

BACKGROUND: Emerging evidence suggests that vascular disease confers vulnerability to a late-onset of depressive illness and the impairment of specific cognitive functions, most notably in the domains of memory storage and retrieval. Lower limb athero-thrombosis and abdominal aortic aneurysm (AAA) have both been previously associated with neuropsychiatric symptoms possibly due to associated intracerebral vascular disease or systemic inflammation, hence suggesting that these illnesses may be regarded as models to investigate the vascular genesis of neuropsychiatric symptoms. The aim of this study was to compare neuropsychiatric symptoms such as depression, anxiety and a variety of cognitive domains in patients who had symptoms of peripheral athero-thrombosis (intermittent claudication) and those who had an asymptomatic abdominal aortic aneurysm AAA. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-sectional study, 26 participants with either intermittent claudication or AAA were assessed using a detailed neuropsychiatric assessment battery for various cognitive domains and depression and anxiety symptoms (Hamilton Depression and Anxiety Scales). Student t test and linear regression analyses were applied to compare neuropsychiatric symptoms between patient groups. AAA participants showed greater levels of cognitive impairment in the domains of immediate and delayed memory as compared to patients who had intermittent claudication. Cognitive dysfunction was best predicted by increasing aortic diameter. CRP was positively related to AAA diameter, but not to cognitive function. AAA and aortic diameter in particular were associated with cognitive dysfunction in this study. CONCLUSIONS/SIGNIFICANCE: AAA patients are at a higher risk for cognitive impairment than intermittent claudication patients. Validation of this finding is required in a larger study, but if confirmed could suggest that systemic factors peculiar to AAA may impact on cognitive function.Bernhard T. Baune, Steven J. Unwin, Frances Quirk and Jonathan Golledg

Interleukin-6 promoter polymorphism interacts with pain and life stress influencing depression phenotypes

Interleukin-6 (IL-6) has emerged as a potent biomarker for depression as its elevated plasma levels in patients with clinical depression have been confirmed by meta-analyses. Increased plasma IL-6 concentration was associated with various psychological stress factors and physical disorders accompanied by pain. Another modulator of the IL-6 level is rs1800795, a promoter polymorphism in the IL-6 gene which is able to influence its expression rate. Therefore, we examined in a Hungarian population sample of 1053 volunteers with European origins if rs1800795 polymorphism can affect depression symptoms measured by Zung Self-rating Depression Scale (ZSDS), and Brief Symptom Inventory (BSI). We also investigated the interactions of the polymorphism with reported painful physical conditions and Recent Negative Life Events (RLE) measured by the List of Life Threatening Experiences. Rs1800795 significantly interacted with both RLE and painful condition on depressive symptoms measured by ZSDS and BSI using different heritability models, while no main effects of the polymorphism were identified. After correction for multiple testing only the rs1800795 x RLE interaction effect (recessive model) remained significant on the BSI score, while both RLE and painful conditions significantly interacted on the ZSDS. In conclusion, the functional IL-6 rs1800795 polymorphism in interaction with various stress factors increases the risk of depression and has a greater impact on symptoms measured by the ZSDS. Thus, IL-6 and other cytokines may be more relevant in the development of somatic symptoms compared to affective signs of depression, delineating a specific genotype-phenotype relationship in this heterogeneous disorder

Acquisition vs. Memorization Trade-Offs Are Modulated by Walking Distance and Pattern Complexity in a Large-Scale Copying Paradigm

In a “block-copying paradigm”, subjects were required to copy a configuration of colored blocks from a model area to a distant work area, using additional blocks provided at an equally distant resource area. Experimental conditions varied between the inter-area separation (walking distance) and the complexity of the block patterns to be copied. Two major behavioral strategies were identified: in the memory-intensive strategy, subjects memorize large parts of the pattern and rebuild them without intermediate visits at the model area. In the acquisition-intensive strategy, subjects memorize one block at a time and return to the model after having placed this block. Results show that the frequency of the memory-intensive strategy is increased for larger inter-area separations (larger walking distances) and for simpler block patterns. This strategy-shift can be interpreted as the result of an optimization process or trade-off, minimizing combined, condition-dependent costs of the two strategies. Combined costs correlate with overall response time. We present evidence that for the memory-intensive strategy, costs correlate with model visit duration, while for the acquisition-intensive strategy, costs correlate with inter-area transition (i.e., walking) times

Anemia of Inflammation Is Related to Cognitive Impairment among Children in Leyte, The Philippines

Past studies have demonstrated that iron deficiency anemia is related to deficits in cognitive fucntioning in children, and treating iron deficiency anemia with iron supplementation can improve cognition. Anemia of inflammation is another type of anemia caused by many diseases of lesser-developed countries including bacterial and parasitic infections. Anemia of inflammation is characterized by disordered iron metabolism, such that iron is sequestered in storage forms, preventing its use from tissues that require it. We hypothesized that decreased iron delivery to the brain in the context of anemia of inflammation might lead to decreased cognitive performance. This study found that children with anemia of inflammation had decreased cognitive performance in specific domains, compared to subjects with no anemia. True total body iron deficiency anemia was related to lower performance in the same domains. The only treatment option for anemia of inflammation is treatment of the underlying disease. Iron supplementation will not prevent cognitive deficits in children with anemia of inflammation. Interventions aimed towards maximizing the cognitive development of children in lesser-developed countries will need to focus on the prevention and treatment of bacterial and parasitic infections

Cytokines as mediators of chemotherapy-associated cognitive changes: Current evidence, limitations and directions for future research

10.1371/journal.pone.0081234PLoS ONE812-POLN

Dose-Dependent Effects of Endotoxin on Neurobehavioral Functions in Humans

Clinical and experimental evidence document that inflammation and increased peripheral cytokine levels are associated with depression-like symptoms and neuropsychological disturbances in humans. However, it remains unclear whether and to what extent cognitive functions like memory and attention are affected by and related to the dose of the inflammatory stimulus. Thus, in a cross-over, double-blind, experimental approach, healthy male volunteers were administered with either placebo or bacterial lipopolysaccharide (LPS) at doses of 0.4 (n = 18) or 0.8 ng/kg of body weight (n = 16). Pro- and anti-inflammatory cytokines, norephinephrine and cortisol concentrations were analyzed before and 1, 1.75, 3, 4, 6, and 24 h after injection. In addition, changes in mood and anxiety levels were determined together with working memory (n-back task) and long term memory performance (recall of emotional and neutral pictures of the International Affective Picture System). Endotoxin administration caused a profound transient physiological response with dose-related elevations in body temperature and heart rate, increases in plasma interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α and IL-1 receptor antagonist (IL-1ra), salivary and plasma cortisol, and plasma norepinephrine. These changes were accompanied by dose-related decreased mood and increased anxiety levels. LPS administration did not affect accuracy in working memory performance but improved reaction time in the high-dose LPS condition compared to the control conditon. In contrast, long-term memory performance was impaired selectively for emotional stimuli after administration of the lower but not of the higher dose of LPS. These data suggest the existence of at least two counter-acting mechanisms, one promoting and one inhibiting cognitive performance during acute systemic inflammation

Response to peripheral immune stimulation within the brain: magnetic resonance imaging perspective of treatment success

Chronic peripheral inflammation in diseases such as rheumatoid arthritis leads to alterations in central pain processing and consequently to mood disorders resulting from sensitization within the central nervous system and enhanced vulnerability of the medial pain pathway. Proinflammatory cytokines such as tumor necrosis factor (TNF) alpha play an important role herein, and therapies targeting their signaling (i.e., anti-TNF therapies) have been proven to achieve good results. However, the phenomenon of rapid improvement in the patients’ subjective feeling after the start of TNFα neutralization remained confusing, because it was observed long before any detectable signs of inflammation decline. Functional magnetic resonance imaging (fMRI), enabling visualization of brain activity upon peripheral immune stimulation with anti-TNF, has helped to clarify this discrepancy. Moreover, fMRI appeared to work as a reliable tool for predicting prospective success of anti-TNF therapy, which is valuable considering the side effects of the drugs and the high therapy costs. This review, which is mainly guided by neuroimaging studies of the brain, summarizes the state-of-the-art knowledge about communication between the immune system and the brain and its impact on subjective well-being, addresses in more detail the outcome of the abovementioned anti-TNF fMRI studies (rapid response to TNFα blockade within the brain pain matrix and differences in brain activation patterns between prospective therapy responders and nonresponders), and discusses possible mechanisms for the latter phenomena and the predictive power of fMRI