Browsing by Author "Dujmovic, Irena (6701590899)"

Antibodies against myelin oligodendrocyte glycoprotein (MOG) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) in different animal species and are implicated in the immunopathogenesis of multiple sclerosis (MS). In order to evaluate the anti-MOG response, we have analyzed the cerebrospinal fluids (CSFs) from 44 MS patients and 51 controls, 11 with other inflammatory neurological disorders (OIND) and 40 with non-inflammatory neurological disorders (NIND). The frequency of anti-MOG antibodies positive patients in the MS group (30%) was significantly higher compared to the NIND (8%, p=0.02), but not compared to the OIND group (55%, p=0.228). Interestingly, all six patients with neurosarcoidosis had MOG-specific antibodies in their CSF. Frequency of anti-MOG antibodies was similar in patients with clinically active and stable MS (32% and 26%, respectively; p=0.921). However, in clinically active MS patients, antibody titers were higher in comparison with patients with stable disease, although the difference did not reach the level of statistical significance (p=0.06). These results further support the potential role of anti-MOG antibodies in the immunopathology of MS in the subset of patients with this disease. Furthermore, our findings suggest for the first time that anti-MOG antibodies could be an accessory diagnostic tool in neurosarcoidosis. © 2003 Elsevier Science B.V. All rights reserved.

Antibodies against myelin oligodendrocyte glycoprotein (MOG) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) in different animal species and are implicated in the immunopathogenesis of multiple sclerosis (MS). In order to evaluate the anti-MOG response, we have analyzed the cerebrospinal fluids (CSFs) from 44 MS patients and 51 controls, 11 with other inflammatory neurological disorders (OIND) and 40 with non-inflammatory neurological disorders (NIND). The frequency of anti-MOG antibodies positive patients in the MS group (30%) was significantly higher compared to the NIND (8%, p=0.02), but not compared to the OIND group (55%, p=0.228). Interestingly, all six patients with neurosarcoidosis had MOG-specific antibodies in their CSF. Frequency of anti-MOG antibodies was similar in patients with clinically active and stable MS (32% and 26%, respectively; p=0.921). However, in clinically active MS patients, antibody titers were higher in comparison with patients with stable disease, although the difference did not reach the level of statistical significance (p=0.06). These results further support the potential role of anti-MOG antibodies in the immunopathology of MS in the subset of patients with this disease. Furthermore, our findings suggest for the first time that anti-MOG antibodies could be an accessory diagnostic tool in neurosarcoidosis. © 2003 Elsevier Science B.V. All rights reserved.

Autophagy, a process of controlled self-digestion which regulates cell homeostasis, is involved in innate and adaptive immunity. We investigated the expression of autophagy genes and autophagic activity in distinct lymphocyte populations in treatment-naive MS patients. The mRNA and protein levels of autophagy-related (ATG)5, required for autophagosome formation, were increased in CD4+ and CD4− T cells, but not B cells of MS patients compared to control subjects. The expression of other investigated autophagy genes, as well as the autophagic activity, did not significantly differ between the two groups. ATG5 mRNA levels in CD4+ T cells from MS patients were positively correlated with those of the proinflammatory cytokine tumor necrosis factor. These data suggest that autophagy-independent increase in ATG5 expression might be associated with the proinflammatory capacity of T cells in multiple sclerosis. © 2018 Elsevier B.V.

Autophagy, a process of controlled self-digestion which regulates cell homeostasis, is involved in innate and adaptive immunity. We investigated the expression of autophagy genes and autophagic activity in distinct lymphocyte populations in treatment-naive MS patients. The mRNA and protein levels of autophagy-related (ATG)5, required for autophagosome formation, were increased in CD4+ and CD4− T cells, but not B cells of MS patients compared to control subjects. The expression of other investigated autophagy genes, as well as the autophagic activity, did not significantly differ between the two groups. ATG5 mRNA levels in CD4+ T cells from MS patients were positively correlated with those of the proinflammatory cytokine tumor necrosis factor. These data suggest that autophagy-independent increase in ATG5 expression might be associated with the proinflammatory capacity of T cells in multiple sclerosis. © 2018 Elsevier B.V.

Background: Peroxynitrite was hypothesized to be involved in the pathogenesis of multiple sclerosis (MS) through its various neurotoxic effects. Uric acid (UA) was shown to be a strong peroxynitrite scavenger. Methods: We analyzed cerebrospinal fluid (CSF) and serum UA concentrations in 30 MS patients and 20 controls with non-inflammatory neurological diseases (NIND) and correlated these findings with demographic and clinical characteristics of MS patients. Disease activity was assessed by brain magnetic resonance imaging (MRI) and the CSF/serum albumin quotient as an indicator of the state of blood-brain-barrier (BBB). Results: Serum UA concentrations were found to be significantly lower in MS patients compared with controls (p=0.019). CSF UA concentrations were lower in MS patients as compared to controls, as well as in patients with active MS (clinical and/or MRI activity) in comparison to patients with inactive MS or controls, but these differences were not statistically significant. Significant correlation was found between CSF and serum UA concentrations (p=0.016) in MS patients, but not in controls; and between CSF UA concentrations and the CSF/serum albumin quotient in MS patients (p=0.043), but not in controls. Conclusions: Our results support the significance of UA in the pathogenesis of MS. Decreased serum UA concentrations in MS patients might be due to both intrinsically reduced antioxidant capacity and increased UA consumption in MS. CSF UA concentrations may not be a reliable marker of disease activity in MS since its concentration is dependent on leakage of UA molecules from serum through the damaged BBB and the balance between consumption/ production within the central nervous system (CNS). © 2009 by Walter de Gruyter Berlin New York.

Background: Peroxynitrite was hypothesized to be involved in the pathogenesis of multiple sclerosis (MS) through its various neurotoxic effects. Uric acid (UA) was shown to be a strong peroxynitrite scavenger. Methods: We analyzed cerebrospinal fluid (CSF) and serum UA concentrations in 30 MS patients and 20 controls with non-inflammatory neurological diseases (NIND) and correlated these findings with demographic and clinical characteristics of MS patients. Disease activity was assessed by brain magnetic resonance imaging (MRI) and the CSF/serum albumin quotient as an indicator of the state of blood-brain-barrier (BBB). Results: Serum UA concentrations were found to be significantly lower in MS patients compared with controls (p=0.019). CSF UA concentrations were lower in MS patients as compared to controls, as well as in patients with active MS (clinical and/or MRI activity) in comparison to patients with inactive MS or controls, but these differences were not statistically significant. Significant correlation was found between CSF and serum UA concentrations (p=0.016) in MS patients, but not in controls; and between CSF UA concentrations and the CSF/serum albumin quotient in MS patients (p=0.043), but not in controls. Conclusions: Our results support the significance of UA in the pathogenesis of MS. Decreased serum UA concentrations in MS patients might be due to both intrinsically reduced antioxidant capacity and increased UA consumption in MS. CSF UA concentrations may not be a reliable marker of disease activity in MS since its concentration is dependent on leakage of UA molecules from serum through the damaged BBB and the balance between consumption/ production within the central nervous system (CNS). © 2009 by Walter de Gruyter Berlin New York.

The role of cerebrospinal fluid (CSF) mitochondrial DNA (mtDNA) levels as biomarker in multiple sclerosis (MS) is unknown. We determined CSF mtDNA levels in a cohort of 237 individuals, including patients with MS and clinically isolated syndrome (CIS), inflammatory and non-inflammatory neurological controls, and cognitively healthy controls (HC). mtDNA concentration was measured by droplet digital polymerase chain reaction. CSF mtDNA levels were increased in all pathological conditions compared with HC, though no differences were observed between relapse-onset and progressive MS clinical forms, CIS patients and neurological controls. These findings do not support the determination of CSF mtDNA levels as a useful biomarker in MS clinical practice. © The Author(s), 2018.

The role of cerebrospinal fluid (CSF) mitochondrial DNA (mtDNA) levels as biomarker in multiple sclerosis (MS) is unknown. We determined CSF mtDNA levels in a cohort of 237 individuals, including patients with MS and clinically isolated syndrome (CIS), inflammatory and non-inflammatory neurological controls, and cognitively healthy controls (HC). mtDNA concentration was measured by droplet digital polymerase chain reaction. CSF mtDNA levels were increased in all pathological conditions compared with HC, though no differences were observed between relapse-onset and progressive MS clinical forms, CIS patients and neurological controls. These findings do not support the determination of CSF mtDNA levels as a useful biomarker in MS clinical practice. © The Author(s), 2018.

Introduction Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain. Methods We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III). Results Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications. Discussion When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate. © 2017 The Authors

The authors of the above paper would like to point out that the first names and surnames of the original, published version were the wrong way around. The correct presentation of the authors' names is as above. The authors apologise for this error. © 2016

The authors of the above paper would like to point out that the first names and surnames of the original, published version were the wrong way around. The correct presentation of the authors' names is as above. The authors apologise for this error. © 2016

ObjectiveTo identify biomarkers associated with progressive phases of MS and with neuroprotective potential.MethodsCombined analysis of the transcriptional and proteomic profiles obtained in CNS tissue during chronic progressive phases of experimental autoimmune encephalomyelitis (EAE) with the transcriptional profile obtained during the differentiation of murine neural stem cells into neurons. Candidate biomarkers were measured by ELISA in the CSF of 65 patients with MS (29 with relapsing-remitting MS [RRMS], 20 with secondary progressive MS, and 16 with primary progressive MS [PPMS]) and 30 noninflammatory neurologic controls (NINCs).ResultsIntegrative analysis of gene and protein expression data identified 2 biomarkers, the serine protease inhibitor Serpina3n and the calcium-binding protein S100A4, which were upregulated in chronic progressive EAE and whose expression was induced during neuronal differentiation. Immunofluorescence studies revealed a primarily neuronal expression of S100A4 and Serpina3n during EAE. CSF levels of SERPINA3, the human ortholog of murine Serpina3n, and S100A4 were increased in patients with MS compared with NINCs (SERPINA3: 1,320 vs 838.6 ng/mL, p = 0.0001; S100A4: 1.6 vs 0.8 ng/mL, p = 0.02). Within the MS group, CSF SERPINA3 levels were significantly elevated in patients with progressive forms, mainly patients with PPMS compared with patients with RRMS (1,617 vs 1,129 ng/mL, p = 0.02) and NINCs (1,617 vs 838.6 ng/mL, p = 0.0001). Of interest, CSF SERPINA3 levels significantly correlated with CSF neurofilament light chain levels only in the PPMS group (r = 0.62, p = 0.01).ConclusionThese results point to a role of SERPINA3 as a biomarker associated with the progressive forms of MS, particularly PPMS. © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

ObjectiveTo identify biomarkers associated with progressive phases of MS and with neuroprotective potential.MethodsCombined analysis of the transcriptional and proteomic profiles obtained in CNS tissue during chronic progressive phases of experimental autoimmune encephalomyelitis (EAE) with the transcriptional profile obtained during the differentiation of murine neural stem cells into neurons. Candidate biomarkers were measured by ELISA in the CSF of 65 patients with MS (29 with relapsing-remitting MS [RRMS], 20 with secondary progressive MS, and 16 with primary progressive MS [PPMS]) and 30 noninflammatory neurologic controls (NINCs).ResultsIntegrative analysis of gene and protein expression data identified 2 biomarkers, the serine protease inhibitor Serpina3n and the calcium-binding protein S100A4, which were upregulated in chronic progressive EAE and whose expression was induced during neuronal differentiation. Immunofluorescence studies revealed a primarily neuronal expression of S100A4 and Serpina3n during EAE. CSF levels of SERPINA3, the human ortholog of murine Serpina3n, and S100A4 were increased in patients with MS compared with NINCs (SERPINA3: 1,320 vs 838.6 ng/mL, p = 0.0001; S100A4: 1.6 vs 0.8 ng/mL, p = 0.02). Within the MS group, CSF SERPINA3 levels were significantly elevated in patients with progressive forms, mainly patients with PPMS compared with patients with RRMS (1,617 vs 1,129 ng/mL, p = 0.02) and NINCs (1,617 vs 838.6 ng/mL, p = 0.0001). Of interest, CSF SERPINA3 levels significantly correlated with CSF neurofilament light chain levels only in the PPMS group (r = 0.62, p = 0.01).ConclusionThese results point to a role of SERPINA3 as a biomarker associated with the progressive forms of MS, particularly PPMS. © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Background Gait pattern is frequently impaired in multiple sclerosis (MS), however gait characteristics in patients with different MS phenotypes have not been fully elucidated. Methods We analyzed spatio-temporal gait pattern characteristics in patients with relapsing-remitting (RR, n=52) and primary-progressive (PP, n=18) MS in comparison with age-matched healthy controls (HC, n=40). All subjects performed a standardized simple walking task, a dual motor- motor task, a dual motor-mental task, and a triple combined motor-mental task at a GAITRite electronic walkway of 5.5 m active area. We measured: cycle time (CT), stride length (SL), swing time (ST), double support time (DST), gait velocity (GV) and calculated symmetry index (SI) for CT, SL and ST. Results With each task performed, CT and DST in the total MS group were significantly longer while SL was significantly shorter and GV significantly lower than in HC. ST was similar in the total MS patient group and HC. In both MS patients and HC, CT and DST increased and SL and GV decreased over repeated assessments. Dual and triple tasks while walking influenced walking performance in both MS patients and HC. Although patients with PPMS differed significantly from those with RRMS in the majority of gait parameters, the subgroup analysis in patients matched for age and disability (Expanded Disability Status Scale Score -EDSS, 3.0–5.0) showed similar gait performance in RRMS and PPMS patients having the same level of disability, except for CT and ST- symmetry parameters that were more impaired in the PPMS group. The EDSS score correlated significantly with CT, DST, SL and GV, but no significant correlation was found with ST except at the triple combined motor-mental task. Conclusion A disturbed gait pattern in MS patients with different MS phenotypes depends on disability and reflects a cognitive-motor interference. © 2017 Elsevier B.V.

Background Gait pattern is frequently impaired in multiple sclerosis (MS), however gait characteristics in patients with different MS phenotypes have not been fully elucidated. Methods We analyzed spatio-temporal gait pattern characteristics in patients with relapsing-remitting (RR, n=52) and primary-progressive (PP, n=18) MS in comparison with age-matched healthy controls (HC, n=40). All subjects performed a standardized simple walking task, a dual motor- motor task, a dual motor-mental task, and a triple combined motor-mental task at a GAITRite electronic walkway of 5.5 m active area. We measured: cycle time (CT), stride length (SL), swing time (ST), double support time (DST), gait velocity (GV) and calculated symmetry index (SI) for CT, SL and ST. Results With each task performed, CT and DST in the total MS group were significantly longer while SL was significantly shorter and GV significantly lower than in HC. ST was similar in the total MS patient group and HC. In both MS patients and HC, CT and DST increased and SL and GV decreased over repeated assessments. Dual and triple tasks while walking influenced walking performance in both MS patients and HC. Although patients with PPMS differed significantly from those with RRMS in the majority of gait parameters, the subgroup analysis in patients matched for age and disability (Expanded Disability Status Scale Score -EDSS, 3.0–5.0) showed similar gait performance in RRMS and PPMS patients having the same level of disability, except for CT and ST- symmetry parameters that were more impaired in the PPMS group. The EDSS score correlated significantly with CT, DST, SL and GV, but no significant correlation was found with ST except at the triple combined motor-mental task. Conclusion A disturbed gait pattern in MS patients with different MS phenotypes depends on disability and reflects a cognitive-motor interference. © 2017 Elsevier B.V.

Objective: The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development. Methods: BioMS-eu consortium, a collaborative network working toward improving the quality of biomarker research in neurologic disorders, discussed the merits of standardizing the reporting of body fluid biomarker research. A checklist of items integrating the results of other published guidances, literature, conferences, regulatory opinion, and personal expertise was created to ultimately form a structured summary guidance incorporating the key features. Results: The summary guidance is comprised of a 10-point uniform reporting format ranging from introduction, materials and methods, through to results and discussion. Each item is discussed in detail in the guidance report. Conclusions: To enhance the future development of body fluid biomarkers, it will be important to standardize the reporting of studies. This guideline by the BioMS-eu consortium is aimed at setting a standard for the reporting of future body fluid biomarker research studies in neurologic disorders. We anticipate that following these guidelines will help to accelerate the selection of biomarkers for clinical development. © 2014 American Academy of Neurology.

[No abstract available]

Cytokines produced by helper T (Th)1 cells, Th17 and regulatory T cells (Treg) are involved in multiple sclerosis (MS) immunopathogenesis. Interferon (IFN)-β alters the numerous genes' expression, but how this alteration affects the treatment response is still elusive. We assessed relative gene expression of nineteen Th1/Th17/Treg-associated mediators in peripheral blood mononuclear cells and plasma levels of GM-CSF, IL-17A and IL-17F, in relapsing-remitting MS (RRMS) patients before IFN-β1b treatment initiation and at 6, 12, 24 and 36. months of therapy. All mRNA levels changed significantly during the IFN-β1b therapy. Higher IL-12Rβ2 mRNA levels were associated with lower risk of relapse. Despite recent reports regarding role of GM-CSF in MS, our study failed to demonstrate its significance as therapy response biomarker, both on the mRNA and protein level. © 2015 Elsevier B.V.

Cytokines produced by helper T (Th)1 cells, Th17 and regulatory T cells (Treg) are involved in multiple sclerosis (MS) immunopathogenesis. Interferon (IFN)-β alters the numerous genes' expression, but how this alteration affects the treatment response is still elusive. We assessed relative gene expression of nineteen Th1/Th17/Treg-associated mediators in peripheral blood mononuclear cells and plasma levels of GM-CSF, IL-17A and IL-17F, in relapsing-remitting MS (RRMS) patients before IFN-β1b treatment initiation and at 6, 12, 24 and 36. months of therapy. All mRNA levels changed significantly during the IFN-β1b therapy. Higher IL-12Rβ2 mRNA levels were associated with lower risk of relapse. Despite recent reports regarding role of GM-CSF in MS, our study failed to demonstrate its significance as therapy response biomarker, both on the mRNA and protein level. © 2015 Elsevier B.V.

Objective: The aim of this study is to assess the impact of interferon (IFN) beta treatment on the development of worsening disability in relapsing-remitting (RR) multiple sclerosis (MS) patients in the single-center observation cohort. Method: This is a prospective study of 236 IFN-beta-treated and 183 untreated RRMS patients recruited consecutively at the Clinic of Neurology in Belgrade (Serbia). Out of this original cohort, 10-year follow-up data were available for 233 IFN-beta-treated and 131 untreated subjects. The median time since recruitment was 9.7 years. Results: IFN-beta treatment significantly delayed (p < 0.001) the time to reach each of the clinical outcomes (secondary progression-SP, EDSS scores 4 and 6) since recruitment. Time from the first visit to SP was reached after 9.7 years for IFN-beta-treated vs. 7.8 years for untreated patients. The delay for the development of EDSS score ≥ 4 from the first visit was 1.6 years (8.7 years for IFN-beta-treated vs. 7.1 years for untreated patients). Time from the first visit to EDSS score of 6 was reached after 9.8 years for IFN-beta-treated vs. 8.8 years for untreated patients. The IFN-beta-treated group showed significant reduction (p < 0.001) in the risk of conversion to SP when compared with untreated patients (HR = 0.22). There was also a significant difference in reaching EDSS scores 4 and 6 (p < 0.001), in favor of the IFN-beta-treated group (HR = 0.40 and HR = 0.27, respectively). Conclusion: Comparison of outcomes in our IFN-beta-treated vs. untreated RRMS patients suggests that this treatment may delay development of long-term disability in MS. © 2019, Fondazione Società Italiana di Neurologia.