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.

The correlation between fatigue and cognitive performance in multiple sclerosis (MS) is well reported, but the intimate mechanisms of the fatigue impact on cognition are not fully defined yet. The aim of this study is to investigate blood oxygen level–dependent (BOLD) activations in relapsing remitting MS (RRMS) patients with and without cognitive dysfunction and the impact of fatigue on cortical activations. Forty-two patients with RRMS were enrolled in the study. Cognitive functioning was assessed by the Symbol Digit Modalities Test (SDMT) and Paced Serial Addition Test (PASAT). A cutoff point of a total score of 55 on the SDMT was used to divide the patients into two groups: cognitively impaired (CI), SDMT score equal to or below 55 points, and cognitively preserved (CP), SMDT score above 55 points. Fatigue was assessed by the Modified Fatigue Impact Scale (MFIS). Participants were assessed with the Beck Depression Inventory (BDI) prior to inclusion in order to exclude major depressive episode. Functional Magnetic Resonance Imaging (fMRI) scanning was performed on a 3T MRI. The PVSAT (Paced Visual Serial Addition Test) paradigm was applied as a cognitive task. All functional data were analyzed with SPM12 and statistical analysis with SPSS 19.0. No statistically significant differences between CI and CP patients were found (p=0.953, p=0.322) in the MFIS and BDI score. Performance on the PASAT in CI patients was 34.07±13.721, for CP patients 46.42±11.453, and the SDMT performance in the CI patient group was 42.40±9.179, in the CP group 57.83±2.552. Between-group analysis revealed increased activations in left Brodmann area (BA) 40 in CP patients with several clusters located in the left supramarginal gyrus. Regression analysis showed increased BOLD signal in left BA 40, right BA 40, and left BA 6, associated with a higher score on MFIS. Stronger BOLD signal in left BA 31 was associated with a lower score on MFIS. Significance level was set to p<0.05, FWE (family-wise error) corrected. The differences in BOLD activations suggest the presence of cortical reorganization in our CP patients. The impact of fatigue on cortical activation during a cognitive task is demonstrated by inconformity of activated areas depending on the MFIS score. Our results suggest that activation in BA 40 may represent a mechanism for diminishing fatigue impact on cognitive functioning in CP patients.

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 (r = -0.258 p = 0.033); PASAT and SDMT scores were in negative correlation with concentration of IL-17A (r = -0.229 p = 0.004; r = -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.

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-α, IFN- γ, 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-β-1b. The serum concentrations of TNF-α, IFN- γ, IL- 4 and IL- 10 were determined twice - in relapse and in remission - using an enzyme-linked immunosorbent assay (EL ISA). 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-α 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-α in remission patients and higher concentrations of IL- 10 in relapse patients. The patients with interferon-β-1b treatment showed different profile of cytokine secretion from the patients without interferon-β-1b treatment. Interferon-β-1b-treated patients showed significantly lower serum levels of TNF-α and IFN- γ during the relapse phase and higher TNF-α and IL- 10 serum levels during the remission phase compared with the untreated patients. Conclusions: Serum levels of TNF-α 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-α, IL- 10 and IFN- γ in the two phases of MS.

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.

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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.