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.

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.

25 Hydroxyvitamin D and Cytokines in Multiple Sclerosis.

INTRODUCTION: Clinical trials of patients with multiple sclerosis (MS) have produced inconsistent results for the profile of cytokine secretion in serum and cerebrospinal fluid in patients with multiple sclerosis during periods of relapse and remission. Epidemiological and clinical observations data reveal an association of the changes in vitamin D serum concentration with the risk of developing MS. AIM: To evaluate changes in serum concentrations of 25(OH)D, IL17, IFN-gamma, TGFß1, IL4, IL10 in relapse and remission and their correlation with the severity of disability. PATIENTS AND METHODS: Fifty-three persons (30 clinically healthy controls and 23 patients with relapsing-remitting multiple sclerosis) living between 41° and 42° northern latitude were registered during the astronomical winter period (October 2012- May 2013). -Patients were diagnosed according to Mc Donald 2010 criteria. The degree of neurological deficit was assessed by EDSS. Serum concentrations of 25(OH)D (nmol/l) and cytokines (pg/ml) were tested by ELISA - once for controls and twice for patients (during relapse and remission). RESULTS: In the studied population average levels of 25(OH)D were close to insufficiency, most pronounced in patients in relapse, as differences were not statistically significant. A reverse correlation was found between the levels of 25(OH)D and the deficit in relapse and remission. Concentrations of TGFß1 significantly increased in remission compared with exacerbation and controls. Serum level of IL4 was significantly lower in relapse compared with controls. In remission there was a marked tendency of increase compared with exacerbation. During clinical improvement IL17 and IFN-gamma tended to decrease compared to the average levels in relapse. In both periods, the average concentrations of IFN-gamma in patients were significantly lower compared with controls. No statistically significant differences were found comparing cytokine changes with those of 25(OH)D and deficit. CONCLUSION: Persistent cytokine imbalance in patients compared with controls is a marker for Th1-mediated CNS demyelination. Anti-inflammatory TGFß1, IL4 are indicators of immune response intensity. The deficit severity does not depend on changes of the tested cytokines, but correlates with 25(OH)D levels during periods of relapse and remission.

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.

Adverse drug reactions after 24-month treatment with two-dosage regimens of betaferon in patients with multiple sclerosis.

UNLABELLED: An open, prospective randomized trial in patients with multiple sclerosis was conducted to investigate the adverse drug reactions after a 24-month Betaferon treatment. AIM: To assess adverse drug reactions after treatment with two-dosage regimens of Betaferon. PATIENTS AND METHODS: Fifty-five patients were included in the study. They were divided into two groups according to the dosage regimen Betaferon was administered. In group A, Betaferon 8MIU was given subcutaneously every other day. In group B, the treatment was carried out using the following dosage regimen: week 1-3 times per week, every other day in the morning, subcutaneously Betaferon in doses of 2 MIU, 4 MIU and 8 MIU, respectively; weeks 2 to 4 inclusive--3 times per week, every other day in the morning, subcutaneously Betaferon in a dose of 8 MIU; week 5 to month 24 inclusive--subcutaneously every other day in the morning Betaferon in a dose of 8 MIU. Paracetamol, ibuprofen, pentoxifylline and prednisolone were used to cope the ADR according to their type and duration. RESULTS: There were significant changes in group B compared with group A: reduction of the flu-like symptoms and local reactions at the end of the first month of treatment, together with lower relative percentage of patients treated for ADR. CONCLUSION: The reduced dosage regimen and corrective treatment reduce the adverse drug reactions and improve drug tolerability.

A clinical study of multiple sclerosis patients treated with betaferon.

UNLABELLED: We conducted an open prospective randomized study of 58 multiple sclerosis patients who received Betaferon in a dose of 8 MIU every other day for 2 years. AIM: To assess the effect of Betaferon treatment depending on the number of relapses in the previous 2 years and the stage of neurological deficit at baseline. INCLUSION CRITERIA: clinically definite and MRI-confirmed multiple sclerosis (MS), relapsing-remitting course, at least one relapse 2 years before the study; age 18-50 years; neurological deficit scoring--between 1.0-5.0 steps. According to initial EDSS stage, two groups were formed: group A (32 patients with EDSS score < 2.5 steps) and group B (26 patients with EDSS score > or = 3.0 steps). According to the number of relapses in the last 2 years patients were assigned to group C (29 persons with 1 relapse) and group D (29 persons with > or = 2 relapses). RESULTS: Betaferon therapy effectively reduced relapse frequency in all groups. The severity of disability was significantly reduced in younger patients and in patients with milder neurological deficit at baseline. Regression analysis showed strong correlation between therapeutic improvement and baseline severity of disability. CONCLUSIONS: The obtained results suggest that Betaferon can be used to treat patients with low score of neurological deficit, in an early stage of the disease.