A Role of Cytokine Gene Polymorphisms in Cognitive Functioning.

The changes in cognitive functions that occur with aging and in various pathological conditions are a subject of growing interest. Experimental and clinical data justify the hypothesis about the influence the immune system exerts on cognitive processes. The balance between pro-inflammatory and anti-inflammatory cytokines has been established as a necessary factor for normal cognitive functioning. Cytokine production is under strong genetic control and various single nucleotide polymorphisms (SNPs) in cytokine genes have been described. As cytokine SNPs have been demonstrated to affect the gene expression or the functional activity of the immune protein this logically led to the suggestion about the role of these polymorphisms in cognitive functioning. Studies exploring the association between different genetic variants of cytokine gene polymorphisms and cognitive abilities in healthy subjects and in demented patients show divergent results. The review of relevant literature suggests that SNPs implement their effect on cognition in large interactions with each other, as well as with many other factors, some of which still remain to be identified. This article summarizes the contemporary knowledge about the correlations between SNPs in cytokine genes and cognitive status in humans. Further research is needed to determine the precise role and the molecular mechanisms of action of the SNPs in cognitive processes.

Patient satisfaction with ExtaviPro™ 30G, a new auto-injector for administering interferon ß-1b in multiple sclerosis: results from a real-world, observational EXCHANGE study.

BACKGROUND: Patients with multiple sclerosis (MS) receiving long-term, subcutaneous interferon ß-1b (IFN ß-1b; Extavia®) often experience injection-site reactions and injection-site pain, which together with other side-effects (such as flu-like symptoms) result in suboptimal treatment compliance/adherence. The EXCHANGE study evaluated patient satisfaction with IFN ß-1b treatment, administered using ExtaviPro™ 30G, a new auto-injector, in a real-world setting. METHODS: This 26-week, open-label, prospective, non-interventional, observational, multi-country multi-centre study enrolled patients with MS who had been treated with IFN ß-1b or other disease-modifying therapies with a self-administered auto-injector for ≥3 months and who were planned to switch to IFN ß-1b treatment administered using ExtaviPro™ 30G as part of routine clinical care. Patient-reported outcomes included overall patient satisfaction (primary outcome) and satisfaction associated with treatment effectiveness, convenience and side-effects, assessed using Treatment Satisfaction Questionnaire for Medication (TSQM)-14. The changes in TSQM scores from baseline to Week 26 were reported. All data were analysed using SAS statistical software (version 9.4). RESULTS: Of the 336 patients enrolled, 324 were included in the analysis. At baseline, mean ± standard deviation (SD) age of patients was 41.8 ± 11.3 years and 68.2% were women. The mean ± SD of MS disease duration was 6.9 ± 6.6 years, and the majority of patients (94.1%) had relapsing-remitting MS. The mean ± SD of TSQM score for overall patient satisfaction at Week 26 was 75.6 ± 16.46 (baseline, 73.0 ± 17.14; p = 0.0342). The mean ± SD of TSQM subscale scores for patient satisfaction with effectiveness, side-effects and convenience were 75.0 ± 18.65 (baseline, 71.6 ± 19.45; p = 0.0356), 88.5 ± 18.98 (baseline, 82.7 ± 22.93; p = 0.0002) and 77.6 ± 16.72 (baseline, 71.1 ± 17.53; p < 0.0001), respectively. CONCLUSION: The results from this real-world study suggest that administering IFN ß-1b with the new ExtaviPro™ auto-injector significantly improves overall patient satisfaction, including satisfaction associated with effectiveness, side-effects and convenience in MS patients.

Alterations in serum levels of IL-17 in contrast to TNF-alpha correspond to disease-modifying treatment in relapsing-remitting multiple sclerosis.

Cytokines of different types play an important role in multiple sclerosis (MS) pathogenesis as mediators and regulators of the immune processes in the central nervous system. The aim of the study was to determine the effect of interferon-beta and glatiramer acetate on serum concentrations of TNF-alpha and IL-17 A and their correlation with the degree of disability in clinically stable patients with relapsing-remitting MS. A cross-sectional, case-control study of 220 patients (68 treatment naïve; 152 treated with interferon-beta or glatiramer acetate) and 99 clinically healthy age-gender-body mass index-matched subjects were performed. Serum cytokine concentrations were measured during remission of the disease by means of ELISA. Treatment naïve patients showed significantly higher levels of IL-17 A than the treated individuals (p = .000109) and controls (p = .000044). Within the treated group, only patients with interferon-beta had significantly higher serum IL-17 than the controls (p = .023). TNF-alpha concentrations were significantly higher in the treated patients compared to the healthy controls (p = .000013), regardless of the type of the therapy. Treatment naïve individuals did not differ from the controls according to their serum TNF-alpha (p = .922). No correlation was found between the serum cytokine concentrations and Expanded Disability Status Scale (EDSS) score (p > .05). Serum concentrations of these cytokines could not be regarded as reliable predictors for the severity of the residual neurological deficit during disease-modifying treatment. Our data suggest that suppression of IL-17 A production as one of the mechanisms underlying the beneficial effect of first-line disease-modifying treatments is stronger in glatiramer acetate than in interferon-beta.

Cognitive Impairment in Multiple Sclerosis.

Multiple sclerosis (MS) is a socially significant immune-mediated disease, characterized by demyelination, axonal transection and oligodendropathy in the central nervous system. Inflammatory demyelination and neurodegeneration lead to brain atrophy and cognitive deficit in up to 75% of the patients. Cognitive dysfunctions impact significantly patients' quality of life, independently from the course and phase of the disease. The relationship between pathological brain findings and cognitive impairment is a subject of intensive research. Summarizing recent data about prevalence, clinical specificity and treatment of cognitive disorders in MS, this review aims to motivate the necessity of early diagnosis and complex therapeutic approach to these disturbances in order to reduce the social burden of the disease.

Vitamin D immunomodulatory potential in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of unknown etiology whose treatment is of limited efficiency and therefore has a high social burden. As it has been suggested that myelin destruction model, the clinical manifestation and the potential of therapeutic response in MS are correlated, it is quite justifiable that we study various factors (genetic, hormonal, environmental) that take part in the autoimmune process in order to improve the control over the disrupted immune regulation. Results from epidemiological and clinical studies clearly suggest that changes in vitamin D serum concentrations are correlated with the magnitude of the risk of developing MS, the phases of relapse and remittance and with gender differences in vitamin D metabolism. Experimental and clinical studies also have established that 25-hydroxy vitamin D (25(OH)D) and 1,25-dihydroxy vitamin D (1,25(OH)2D) exert an immunomodulatory effect in the central nervous system and peripheral organs of the immune system. The standard reference range of vitamin D concentration in serum is 50-80 nmol/l--it provides normal calcium metabolism. Issues that are discussed include the vitamin D serum concentration needed to suppress the aberrant immune response in MS patients; a subgroup of MS patients suitable for vitamin D treatment, the vitamin D being applied in optimally effective and safe dosage. MS prevalence rate in Bulgaria has increased two-fold in 17 years but this is a rather short interval to be able to assume that the gene pool of the population changes. Thus further studies on possible interactions between different environmental factors and these factors' role in the disease pathogenesis are justified and necessary.

Clinical and laboratory study of pro-inflammatory and antiinflammatory cytokines in women with multiple sclerosis.

UNLABELLED: Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system characterised with a complex system of interactions between proinflammatory and anti-inflammatory cytokines in its course. AIM: The aim of the present study was to investigate the serum levels of cytokines TNF-a, IFN-gamma, IL-4 and IL-10 in female patients with MS and healthy individuals, the changes occurring in the relapse and remission phases of the disease and their correlation with the severity of the neurological deficit. PATIENTS AND METHODS: Thirty-five women with relapsing-remitting MS were examined. The patients' age ranged between 18 and 50 years and MS was verified clinically and by magnetic resonance imaging according to the McDonald criteria. Thirteen of the patients were treated with interferon-beta-1b. The serum concentrations of TNF-a, IFN-y, IL-4 and IL-10 were determined twice - in relapse and in remission - using an enzyme-linked immunosorbent assay (ELISA). The control group consisted of 35 age-matched healthy females. RESULTS: The comparison of cytokine serum concentrations during the two phases of the disease showed significant elevation of the TNF-alpha serum levels in the relapse phase and of IL-4 - in the remission phase. The comparison between the patients and the healthy control subjects demonstrated statistically significant lower concentrations of TNF-a in remission patients and higher concentrations of IL-10 in relapse patients. The patients with interferon-beta-lb treatment showed different profile of cytokine secretion from the patients without interferon-beta-1b treatment. Interferon-beta-1b-treated patients showed significantly lower serum levels of TNF-a and IFN-gamma during the relapse phase and higher TNF-a and IL-10 serum levels during the remission phase compared with the untreated patients. CONCLUSIONS: Serum levels of TNF-a and IL-4 objectively reflect the immune response during relapse and remission of the disease. The severity of neurological deficit as estimated with the expanded disability status scale (EDSS) does not depend on the serum levels of TNF-a, IL-10 and IFN-gamma in the two phases of MS.

Association of polymorphism -308G/A in tumor necrosis factor-alpha gene (TNF-α) and TNF-α serum levels in patients with relapsing-remitting multiple sclerosis.

TNF-α is an important cytokine of the inflammatory response involved in the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). The aim of this study is to explore the association between the promoter polymorphism -308G/A in the TNF-α gene (rs1800629) with genetic susceptibility to RRMS.Methods: A group of 183 RRMS patients and 169 age and gender-matched healthy controls were enrolled in the study. Genotyping of the polymorphism was performed by PCR-restriction fragment length polymorphism and quantification of TNF-α serum levels was conducted by ELISA.Results: The genotype distribution in female patients showed a significantly elevated frequency of heterozygotes (AG) (23.5% vs. 12.8%, OR = 2.072, p = 0.029) in comparison with the healthy women. Substantially higher TNF-α serum levels were observed in females compared to males, in both patients and healthy controls (p < 0.05). According to the genotype, TNF-α levels in the RRMS group were calculated in the following order: for GA/AA genotypes (5.67pg/ml vs. 3.48pg/ml, p = 0.0031) and for GG genotypes (4.58pg/ml vs. 3.52pg/ml, p = 0.00043). Moreover, the carriers of at least one A-allele of -308G/A TNF-α polymorphism (GA+AA) are significantly associated with two fold increased risk for RRMS development (OR = 1.950; p = 0.042) in women in contrast to men as well as associated with early onset of the disease (OR = 2.400; p = 0.021).Conclusion: Our study showed that the level of TNF-α in the serum of patients with RRMS showed a significant association with the -308G/A TNF-α polymorphism and gender dependency.

A link between promoter polymorphisms of the transforming growth factor ß1 (TGFB1) and TGF-ß1 receptor II (TGFBR2) genes and relapsing-remitting multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic progressive autoimmune disease characterised by nerve demyelination, mediated by myelin-specific Th1 autoreactive cells. Transforming growth factor ï¢1 (TGF-1) is a regulatory cytokine involved in MS aetiology by maintaining CD4+ cell differentiation and preventing autoimmune responses. Because of the important role of the TGF-1 signalling pathway in MS aetiopathogenesis, we aimed to investigate the association of two DNA polymorphisms: TGFB1C[-509]T and TGFBR2G[-875]A and their combined genotypes with the risk of MS development in a cohort of Bulgarian patients. The effect of the two promoter polymorphisms on the disease onset was also assessed. MATERIAL AND METHODS: In the study, a cohort of 183 patients with relapsing-remitting multiple sclerosis (RRMS) and 307 sex- and age-matched healthy subjects were recruited. Genotyping of the TGFB1C[-509]T (rs1800469) and TGFBR2G[-875]A (rs3087465) polymorphisms was performed by PCR-RFLP and PIRA-PCR approaches. RESULTS: Frequencies of the TGFB1T[-509]T genotype and TGFB1[-509]*T-allele were lower in RRMS men than in control healthy men (15.7% vs. 26.9%, 37.3% vs. 50.7%, respectively). Among males, the TGFB1T[-509]T genotype was related to a significantly reduced risk of RRMS (OR = 0.360, 95% CI: 0.126-1.028, p = 0.05) in comparison to the TGFB1C[-509]C genotype. Also, TGFB1[-509]*T-allele was more common in men with RRMS than in healthy men relative to the TGFB1[-509]*C-allele and was associated with a statistically significant protective effect (OR = 0.576, 95% CI: 0.341-0.974, p = 0.039). The combination of TGFB1T[-509]T/TGFB1T[-509]C and TGFBR2G[-875]A genotypes among men was associated with a significant protective effect compared to the wild-type homozygous TGFB1C[-509]C and TGFBR2G[-875]G genotypes (OR = 0.268, 95% CI: 0.088-0.818, p = 0.018). No significant association between rs1800469 and rs3087465 was observed among females with and without (controls) RRMS. CONCLUSIONS: In summary, we suggest that in males, a higher TGF-1 level determined by TGFB1T[-509]T genotype in combination with the TGFBR2G[-875]A genotype might be a protective factor against RRMS development.

Association between TNFA, IL10 and IL18 promoter gene variants and cognitive functions in patients with relapsing-remitting multiple sclerosis.

OBJECTIVES: To investigate the relationship between TNFA-308G > A, IL10-1082A > G, IL18-607C > A, and cognitive functioning in relapsing-remitting multiple sclerosis (RRMS). RESULTS: In the patients' group: AG genotype of TNFA-308G > A was associated with higher serum tumor necrosis factor-alpha (TNF-alpha) than GG genotype, and higher TNF-alpha levels correlated with poorer results on Symbol Digit Modalities Test; CC genotype of IL18-607C > A was related to lower score on Isaacs test, compared to AC variant; AA genotype of IL10-1082A > G was associated with abnormally low results on Paced Auditory Series Addition Test. CONCLUSIONS: TNFA-308G > A, IL10-1082A > G and IL18-607C > A gene variants may be associated with impaired cognitive functions in RRMS patients.

IL12B gene polymorphisms have sex-specific effects in relapsing-remitting multiple sclerosis.

IL-12-family cytokines play a pivotal role in neuroinflammation and neurodegeneration in relapsing-remitting multiple sclerosis (RRMS). The aim of the study was to evaluate whether two polymorphisms in IL12B gene, rs17860508 and rs3212227, are associated with RRMS, and to define their function effect on serum level of IL-12p40 and IL-23 and degree of disability in RRMS cases. In total 156 Bulgarian patients with Expanded Disability Status Scale score ranging from 1.0 to 3.5 in remission of the disease and 379 controls were genotyped by polymerase chain reaction-based methods. The IL-12p40 and IL-23 serum levels were determined by enzyme-linked immunosorbent assay. We have found substantially higher IL-12p40 and IL-23 serum levels in cases than in controls (p < 0.01) in a sex-dependent manner. Women with RRMS had significantly higher IL-12р40 and IL-23 than men. Gender-stratified association analyses showed a significant impact of rs3212227 polymorphism on RRMS susceptibility in men. The carriers of rs3212227*CC-genotype (OR 3.390, 95% CI 1.007-11.545, p = 0.023) and haplotype rs17860508*2-allele/rs3212227*C-allele (OR 3.740; 95% CI 1.36-10.32, p = 0.007), showed higher risk of RRMS in men, in contrast to women. In women, both IL12B polymorphisms influencing the course, rather than genetic predisposition of RRMS. The rs17860508*22-genotype was associated with significantly lower disability (OR 0.208; 95% CI 0.055-0.725; pc = 0.01) and lower IL-23 serum levels (p = 0.0345), while rs3212227*AA-genotype was associated with early onset of the disease (OR 2.368; 95% CI 1.007-5.608; p = 0.03). Our results suggest that sex-specific effects of IL12B polymorphisms, rs17860508 and rs3212227, on genetic predisposition and disease course of RRMS, is probably mediated by their gender-dependent functional effect on IL-12p40-containing cytokines.

Structural and Functional MRI Techniques in Multiple Sclerosis Related Cognitive Dysfunction.

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system that is prevalent in young adults and therefore with significant social impact. Cognitive impairment occurs in 40% to 70% of patients with MS and has a weak correlation with disease duration. Neuropsycho-logical assessment is a standard method in the detection of cognitive dysfunction. However, in order to understand the etiology and evolution of cognitive dysfunction, several elaborate magnetic resonance techniques have been developed. Their aim is to measure structural changes in the CNS that are considered main substrates in cognitive function such as whole brain and gray matter atrophy, cortical lesions and changes in subcortical gray matter. Evidence shows that the clinical manifestations of multiple sclerosis are complex interactions between tissue damage, tissue repair and cortical reorganization. In order to study this heterogeneity, structural magnetic resonance analysis of brain morphology and functional magnetic resonance imaging are essential. This review summarizes current techniques in structural MRI and the value of functional MRI in understanding the link between cognitive deficit and cortical activation and reorganization.

Translational validity of PASAT and the effect of fatigue and mood in patients with relapsing remitting MS: A functional MRI study.

RATIONALE, AIMS, AND OBJECTIVES: Paced Auditory Serial Addition Test (PASAT) is used for assessment of information processing speed, attention, and working memory, which are the most frequently affected cognitive domains in multiple sclerosis (MS) patients, and may be significantly affected by fatigue. However, the effect of fatigue and mood on the PASAT performance in MS patients translationally validated by fMRI has not been studied yet. The aim of this study is to investigate the translational validity of the PASAT, using fMRI during a paced visual serial addition test (PVSAT) paradigm in patients with relapsing remitting MS (RRMS) and to assess the impact of fatigue and mood on test performance. METHODS: Fourteen patients with RRMS in remission and 14 healthy controls, matched by sex, age, and educational status, were enrolled in the study. The subjects underwent a standard neurological examination, neuropsychological evaluation with the PASAT 3', fMRI scanning with a PVSAT paradigm, and Beck Depression Inventory. All patients were assessed by the Modified Fatigue Impact Scale. RESULTS: Paced Auditory Serial Addition Test score was lower in patients (41.4 ± 15.5 vs 51.6 ± 7.5, P = .035). A moderate negative correlation (P = -0.563, P = 0.036) was found between PASAT and MIFS scores. The fMRI scanning showed significant activations in several clusters that differed between patients and controls. The patient group presented wider cluster activation; Brodmann area (BA) 6-bilaterally; left BA7, 8, and 9; and right BA40, while controls presented with activations in left BA6 and BA44. Significant negative correlations between PASAT score and cortical activations in left BA23, right BA32, and left BA7 were observed in patients only. CONCLUSION: Our results show that poorer performance on the PASAT is associated with higher activation in areas connected with working memory, attention, and emotional processes during the fMRI assessment with PVSAT paradigm, which provides evidence for the translational validity of the PASAT in patients with RRMS.

Circulating levels of interleukin-17A, tumor necrosis factor-alpha, interleukin-18, interleukin-10, and cognitive performance of patients with relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is associated with cytokine imbalance and high rate (40-70%) of cognitive impairment. The objective of this study is to investigate the relationship between serum concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-17A, IL-18, IL-10, and cognitive performance in patients with relapsing-remitting MS (RRMS). Methods The study comprised 159 patients with RRMS (mean age 40.08 ± 8.48 years) in remission phase and 86 age-, gender-, and education-matched healthy controls. Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities test (SDMT), and Isaacs test were used for assessment of working memory, attention, visuo-perceptual abilities, information processing speed, and executive functions. Serum cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Results Patients had significantly increased serum concentrations of TNF-alpha and IL-17A and decreased levels of IL-10 compared to the controls (p < 0.05). Negative correlation was found between serum TNF-alpha and SDMT score in patients with disease evolution longer than 10 years (rxy = -0.258 p = 0.033); PASAT and SDMT scores were in negative correlation with concentration of IL-17A (rxy = -0.229 p = 0.004; rxy = -0.166 p = 0.041). Cognitive impairment was established in 46.5% (n = 74) of the patients. Cognitively impaired patients had significantly higher serum IL-17A than cognitively preserved individuals (p = 0.007). Multiple linear regression analysis revealed IL-17A as a significant predictor of cognitive performance in RRMS patients. Conclusion The results from this study suggest that pro-inflammatory cytokines IL-17A and TNF-alpha simultaneously with decreased IL-10 are involved in cognitive deterioration in RRMS.

Cytokines and disability in interferon-ß-1b treated and untreated women with multiple sclerosis.

BACKGROUND AND AIMS: T-helper (Th) cells involved in the pathogenesis of multiple sclerosis (MS) represent a functionally heterogeneous population defined by their cytokine secretion profile. The effects of immunotherapeutic drugs on the cytokine network are still not fully clarified. This study aimed to investigate serum levels of IFN-γ, TNF-α, IL-4, IL-10 in interferon-ß-1b-treated and untreated women with relapsing-remitting MS (RRMS) in comparison with healthy controls and the relationship between cytokine concentrations and the degree of disability. METHODS: The study included 35 women with RRMS and 35 age-matched healthy controls. The patients were divided in two groups: Group A-without disease modifying treatment; Group B-treated with interferon-ß-1b. Degree of disability was assessed by the Expanded Disability Status Scale (EDSS). Serum cytokine concentrations were measured by ELISA during relapse and remission. RESULTS: Group A showed higher IFN-γ in remission (p = 0.0239) than the controls; Group B had lower IFN-γ during relapse (p = 0.0226) than controls. EDSS in relapse correlated with the levels of IL-10 for Group A (p = 0.015) and with the concentration of IFN-γ for Group B (p = 0.039). Nontreated patients showed higher EDSS in relapse compared to the interferon-ß-1b-treated group (p = 0.005). CONCLUSIONS: We found an imbalance in the patients' cytokine profile, which may be seen as supportive of the hypothesis that demyelination in the central nervous system is mediated by Th1 lymphocytes. IFN-γ is probably one of the important indicators for intensity of the immune reaction and shows promise as a potential biomarker for the therapeutic effect of interferon-ß-1b. The role of IL-10 in the autoimmune process needs further investigation.

Female sex hormones and cytokine secretion in women with multiple sclerosis.

UNLABELLED: Data from experimental and clinical research suggest that sex hormones may influence the autoimmune process in multiple sclerosis (MS). Studies on the hormonal profile of patients with MS and its relation to the disease activity provide heterogeneous results. OBJECTIVES: The aim of this study is to investigate the changes in serum levels of estradiol and progesterone and their correlations with the cytokine profile and the degree of disability in women with relapsing-remitting MS (RRMS). METHODS: The serum concentrations of estradiol, progesterone, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukine-4 (IL-4) and interleukine-10 (IL-10) were measured and the degree of disability was determined in 35 women with RRMS, during relapse and remission. Serum levels of hormones were measured by micro-particle enzyme immunoassay and ELISA was used for the cytokines concentrations. The degree of disability was assessed by the Expanded Disability Status Scale and the Scripps Neurological Rating Scale. RESULTS: Sixty per cent of patients had serum concentrations of estradiol and/or progesterone below the lower limit of normal in one or both phases of MS. Hormonal levels increased significantly during remission in these patients. Women with and without hormonal abnormalities differed in terms of cytokine profile during relapse and remission. Significantly higher TNF-alpha in both phases and IFN-gamma in remission was found for the patients with hormonal disturbances compared to these with normal hormonal status. CONCLUSIONS: Our study finds high frequency of hormonal disturbances among female patients with RRMS. Abnormally low concentrations of sex hormones are associated with higher serum levels of TNF-alpha and IFN-gamma, which could suggest suppressive effect of estradiol and progesterone on pro-inflammatory cytokine secretion.