Clinical Manifestations Of Multiple Sclerosis Research Articles

Expression levels of GSDMB and ORMDL3 are associated with relapsing-remitting multiple sclerosis and IKZF3 rs12946510 variant

Multiple sclerosis (MS), a noncurable autoimmune neurodegenerative disease, requires constant research that could improve understanding of both environmental and genetic factors that lead to its occurrence and/or progression. Recognition of the genetic basis of MS further leads to an investigation of the regulatory role of genetic variants on gene expression. Among risk variants for MS, Ikaros zinc finger 3 (IKZF3) gene variant rs12946510 was identified as one of the top-ranked and the expression quantitative trait loci (eQTL) for genes residing in chromosomal locus 17q12-21. The study aimed to investigate the association of gene expression of the immunologically relevant genes, which map to indicated locus, ORMDL3, GSDMB, and IKZF3, with MS and rs12946510 genotype, taking into account disease phase, clinical parameters of disease progression, and severity and immunomodulatory therapy. We used TaqMan® technology for both allelic discrimination and gene expression determination in 67 relapsing MS patients and 50 healthy controls. Decreased ORMDL3 and GSDMB mRNA levels had significant associations with MS and rs12946510 TT rare homozygote among patients. Significant positive correlations between ORMDL3 and GSDMB mRNA expression were observed in both patients and controls. We detected the significant between-effect of sex and rs12946510 on the expression of ORMDL3 in the patient group and interferon β therapy and rs12946510 on GSDMB expression.Our results show the association of ORMDL3 and GSDMB mRNA expression with the clinical manifestation of MS and confirm that IKZF3 rs12946510 exerts the eQTL effect on both genes in multiple sclerosis. Besides providing novel insight related to MS phases and interferon β therapy, the study results confirm previous studies on regulatory genetic variants, autoimmunity, and MS.

Cytotoxic T cell subsets in peripheral blood and cerebrospinal fluid from patients with multiple sclerosis

Using multicolor flow cytometry, the main cytotoxic T lymphocytes (Tcyt) subsets were identified, based on the expression of CD45RA and CD62L in paired samples of peripheral blood and cerebrospinal fluid from the patients during the relapse (n = 32) and remission (n = 20) of multiple sclerosis (MS), as well as in the peripheral blood samples of healthy volunteers (n = 51). During the relapse of MS, we have observed a decreased relative number of CD3+CD4+ cells and CD4/CD8 ratio in cerebrospinal liquor. In peripheral blood taken from the relapsed MS patients, we have found significant correlations between EDSS score and absolute counts (r = -0,430, p = 0.014), and with relative numbers of CD45RA+CD62L+Tcyt (r = -0,502, p = 0.003). In remission state of MS, the relative numbers of blood CD45RA-CD62L-Tcyt cells exhibited a significant decrease (p = 0.005) to 8.70% (6.51-11.63) against control group with 12.18% (10.38-15.24), although it did not significantly differ (p = 0.114) from the relapsed patients with 11.31% (8.28-13.90). Studies of liquor samples have shown that, during MS relapse, the percentage of CD45RA-CD62L-Tcyt was increased (p = 0.027) up to 8.16% (6.40-11.40), while in remission state these cells comprised only 6.49% (4.51-8.39) from the total CD3+ cell number. During relapse of MS, some positive correlations were revealed between the relative number of nave, CM, EM and TEMRA Tcyt from liquor, and the percentages, as well as contents of similar T cell subsets in peripheral blood samples. The inverse relationship between the level of EM Tcyt from liquor and peripheral blood naive cells showed the close relationship between these two Tcyt subsets and clinical manifestations of MS (i.e., scores of EDSS scale). During the remission period, most of these correlations are disrupted. Further investigations of cytotoxic T cells dynamics in peripheral blood and cerebrospinal fluid will help to approach the understanding of MS pathogenesis by revealing novel markers for the clinical prognosis in this disorder.

Common pathogenetic mechanisms in affective disorders and multiple sclerosis: role of interleukin imbalance in the progression of comorbid pathology

Relevance. Among many comorbid pathologies, it is of considerable interest to study and compare the pathogenetic mechanisms of neurological and mental disorders that combine the clinical manifestations of multiple sclerosis (MS) and affective disorders. The high MS prevalence, economic and social significance of the disease, heterogeneity of clinical symptoms, an unfavorable progressive course, as well as the frequent combination of this pathology with various forms of hypothymic disorders determine the relevance of studying the common pathogenetic mechanisms for the development of this comorbid pathology, which is necessary for the development of effective and safe preventive medical activities. The purpose of the review is to determine the common immunopathological mechanisms of affective disorders and multiple sclerosis, to analyze the role of cytokine status imbalance in the mutual increase in the severity of clinical symptoms in comorbid pathology, and to identify prognostic markers of disease progression. Materials and methods. On the basis of electronic Russian and foreign databases for the period 2017–2022, a theoretical analysis of the pathophysiological mechanisms of autoimmune CNS damage in MS and affective disorders was carried out. In order to search for literary sources, the following resources were used: https://elibrary.ru/, https://www.ncbi.nlm.nih.gov/pubmed/, https://cyberleninka.ru/. 10 Russian and 25 foreign sources were cited. Results. The mechanisms of development of mental affective disorders and multiple sclerosis have common pathogenetic features and are characterized by a violation of pro-inflammatory cytokine reactions and autoimmune nature of changes in the structures of the central nervous system (CNS). The similarity of immunological disorders underlying the pathogenesis of various forms of multiple sclerosis and affective disorders is of undoubted interest in terms of developing common approaches to the prevention and treatment of detectable interleukin status imbalance in neurological and mental diseases. Conclusion. Identification of mutually reinforcing changes in interleukin status and determination of the features of the course of immune imbalance in multiple sclerosis and hypothymic disorders in various pathologies of the mental sphere are necessary for a deeper understanding of neuroimmune interactions.

Recent progress in epidemiology, clinical features, and therapy of multiple sclerosis in China.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by inflammation, demyelination, and neurodegeneration. It mainly affects young adults, imposing a heavy burden on families and society. The epidemiology, clinical features, and management of MS are distinct among different countries. Although MS is a rare disease in China, there are 1.4 billion people in China, so the total number of MS patients is not small. Because of the lack of specific diagnostic biomarkers for MS, there is a high misdiagnosis rate in China, as in other regions. Due to different genetic backgrounds, the clinical manifestations of MS in Chinese are different from those in the West. Herein, this review aims to summarize the disease comprehensively, including clinical profile and the status of disease-modifying therapies in China based on published population-based observation and cohort studies, and also to compare with data from other countries and regions, thus providing help to develop diagnostic guideline and the novel therapeutic drugs. Meanwhile, we also discuss the problems and challenges we face, specifically for the diagnosis and treatment of MS in the middle- and low-income countries.

STRUCTURAL AND FUNCTIONAL FEATURES OF PERIPHERAL BLOOD ERYTHROCYTES AND ANTIOXIDANT PROTECTION ENZYMES IN PATIENTS WITH MULTIPLE SCLEROSIS.

The aim: The aim of this work is to study the structural and functional features of peripheral blood erythrocytes and antioxidant defense enzymes in patients with multiple sclerosis, depending on its clinical forms and the stage of development of the pathological process. Materials and methods: The state of the processes of lipid peroxidation and the antioxidant defense system in 62 patients with multiple sclerosis was studied. The influence of these processes on the clinical manifestations of multiple sclerosis is shown. Results: It has been shown that in multiple sclerosis, the erythrocyte superoxide dismutase / catalase enzyme system is characterized by the phenomenon of cross-regulation of activity, which is reflected in a negative correlation between enzyme activities and is associated with the appearance of irreversibly altered forms of erythrocytes in the general bloodstream. Conclusions: Based on the analysis of the dynamics of laboratory parameters, the pathogenetic significance of membrane-destabilizing processes in peripheral blood erythrocytes of patients with multiple sclerosis was proved.

Axonal Demyelination Leading to Neurologic Impairment: A Review Study of Multiple Sclerosis (MS)

Introduction: Multiple Sclerosis (MS) is a central nervous system auto-immune condition signaled and marked by inflammatory action which leads primarily to demyelination resulting in neurologic impairments. This condition is more common in genetically-disposed individuals and individuals who have had a history of Epstein–Barr virus (EBV) infection
 Aim: The study's aim is to examine recent knowledge on the etiology and clinical manifestations of multiple sclerosis, as well as diagnostic testing and recent management options that are being explored to improve the living conditions of people living with Multiple Sclerosis.
 Method: This review article focuses on research studies that have relevant, up-to-date and current therapies employed in the management of individuals living with Multiple Sclerosis. It also includes research studies that take a look at Multiple Sclerosis from the viewpoint of the caretaker
 Results: In this review, it can be seen that the most common clinical manifestation include cognitive impairment, fatigue, psychiatric impairments. The prevalence of Multiple Sclerosis is closely associated with a history of Epstein–Barr virus (EBV) infection as well as genetic predisposition. Pharmacological therapy has been proven to reduce the incidents of a major relapse but hasn’t been advised for patients with a mild relapse. Physical therapy has been proven to be effective when individualized but this is not cost-effective. It has been advised for patients with a mild relapse and for patients undergoing pharmacological therapy, however there is a drawback – physical of therapy can only be administered by very qualified professionals and there is a scarcity of these professionals.
 Conclusion: Physical Therapy in conjunction with pharmacological therapy, with further improvements, can drastically improve the quality of lives for people living with Multiple Sclerosis.

Neuroprotective Effects of Fingolimod in a Cellular Model of Optic Neuritis.

Visual dysfunction resulting from optic neuritis (ON) is one of the most common clinical manifestations of multiple sclerosis (MS), characterized by loss of retinal ganglion cells, thinning of the nerve fiber layer, and inflammation to the optic nerve. Current treatments available for ON or MS are only partially effective, specifically target the inflammatory phase, and have limited effects on long-term disability. Fingolimod (FTY) is an FDA-approved immunomodulatory agent for MS therapy. The objective of the current study was to evaluate the neuroprotective properties of FTY in the cellular model of ON-associated neuronal damage. R28 retinal neuronal cell damage was induced through treatment with tumor necrosis factor-α (TNFα). In our cell viability analysis, FTY treatment showed significantly reduced TNFα-induced neuronal death. Treatment with FTY attenuated the TNFα-induced changes in cell survival and cell stress signaling molecules. Furthermore, immunofluorescence studies performed using various markers indicated that FTY treatment protects the R28 cells against the TNFα-induced neurodegenerative changes by suppressing reactive oxygen species generation and promoting the expression of neuronal markers. In conclusion, our study suggests neuroprotective effects of FTY in an in vitro model of optic neuritis.

Initial clinical manifestation of multiple sclerosis after immunization with the Pfizer-BioNTech COVID-19 vaccine

Vaccine administration may be involved in the development of some central nervous system demyelinating diseases. The COVID-19 vaccine is being administered to the entire population, but to date, little association between vaccination and the risk of developing multiple sclerosis (MS) has been suggested, and only a few case reports have been published. Here, we present a 40-year-old woman who developed cervical myelitis after receiving the COVID-19 vaccine. Myelitis was considered the initial clinical manifestation of MS. Our case suggests a possible link between the vaccination and the clinical MS attack.

Neuronal NMNAT2 Overexpression Does Not Achieve Significant Neuroprotection in Experimental Autoimmune Encephalomyelitis/Optic Neuritis.

Optic neuritis, inflammation, and demyelination of the optic nerve (ON), is one of the most common clinical manifestations of multiple sclerosis; affected patients suffer persistent visual symptoms due to ON degeneration and secondary retinal ganglion cell (RGC) death. The mouse experimental autoimmune encephalomyelitis (EAE) model replicates optic neuritis and significant RGC soma and axon loss. Nicotinamide mononucleotide adenylyltransferases (NMNATs) are NAD+-synthetic enzymes that have been shown to be essential for axon integrity, activation of which significantly delays axonal Wallerian degeneration. NMNAT2, which is enriched in axons, has been proposed as a promising therapeutic target for axon injury-induced neurodegeneration. We therefore investigated whether activation of NMNAT2 can be used as a gene therapy strategy for neuroprotection in EAE/optic neuritis. To avoid the confounding effects in inflammatory cells, which play important roles in EAE initiation and progression, we used an RGC-specific promoter to drive the expression of the long half-life NMNAT2 mutant in mouse RGCs in vivo. However, optical coherence tomography in vivo retina imaging did not reveal significant protection of the ganglion cell complex, and visual function assays, pattern electroretinography, and optokinetic response also showed no improvement in mice with NMNAT2 overexpression. Postmortem histological analysis of retina wholemounts and semithin sections of ON confirmed the in vivo results: NMNAT2 activation in RGCs does not provide significant neuroprotection of RGCs in EAE/optic neuritis. Our studies suggest that a different degenerative mechanism than Wallerian degeneration is involved in autoimmune inflammatory axonopathy and that NMNAT2 may not be a major contributor to this mechanism.

Autonomic failure in multiple sclerosis, complication or precursor?

Autonomic nervous system abnormalities are being increasingly recognized as an important aspect of multiple sclerosis (MS) on a clinical, neurophysiological and molecular level. Autonomic dysfunction in MS shows a distinctive pattern: the disease activity (manifested with relapses and MRI activity) is associated with sympathetic nervous system dysfunction, while the disease progression (manifested by increasing neurological disability) is associated with parasympathetic nervous system dysfunction, with highest percentages of involvement seen in advanced progressive MS. Furthermore, in MS, not only that autonomic symptoms are present, but may influence the disease course. A recent study has shown that presence of autonomic symptoms increase the risk of the second relapse after the diagnosis of clinically isolated syndrome by 2.7 folds. On the other hand, there is evidence suggesting that multiple sclerosis (MS) starts years before the first clinical presentation, and this period has become known as the MS prodrome. This period can span for more than a decade and the most well characterized symptom of it lies in the spectrum of autonomic nervous system abnormalities. Autonomic symptoms before the diagnosis increase the risk for the first clinical manifestation of MS, and if they are present at the diagnosis of MS, they increase the likelihood of the second relapse. All this data, emphasize the importance of studying ANS involvement in MS.

Neurocognitive performance in relapsing-remitting multiple sclerosis patients is associated with metabolic abnormalities of the thalamus but not the hippocampus– GABA-edited 1H MRS study

ABSTRACT Objectives Multiple sclerosis (MS) is an inflammatory demyelinating disease that may cause physical disabling as well as cognitive dysfunction. The presented study investigated how the neuropsychological status depends on the thalamus and hippocampus’s metabolic processes, using γ-aminobutyric acid-edited magnetic resonance spectroscopy (GABA-edited 1H MRS) in patients with early MS, and how the results differ from healthy volunteers. Methods We recruited 36 relapsing-remitting (RRMS) MS patients and 22 controls (CON). In addition to common 1H MRS metabolites, such as N-acetyl-aspartate (tNAA), myoinositol (mIns), total choline and creatine (tCr, tCho), we also evaluated GABA and glutamate/glutamine (Glx). Metabolite ratios were correlated with the results of Single-Digit Modality Test (SDMT) and Expanded Disability Status Score (EDSS). Results In the thalamus, GABA ratios (GABA/tCr, GABA/tNAA) were significantly lower in RRMS patients than in CON. Both tCho- and mIns-ratios correlated with lower scores of SDMT but not with EDSS. Metabolic ratios in the hippocampus did not differ between RRMS and CON and did not correlate with any of performed tests. Discussion This study is the first to provide GABA-edited 1H MRS evidence for MS-related metabolic changes of the thalamus and hippocampus. The findings underline the importance of evaluating subcortical grey matter in MS patients to improve understanding of the clinical manifestations of MS and as a potential future target for treatment.

Speech Pathology-Specific Questionnaire for Persons with Multiple Sclerosis (SMS): adaptation, validation and preliminary assessment of the diagnostic potential.

IntroductionSpeech and voice disorders are among the least well-described clinical manifestations of Multiple Sclerosis (MS) although their estimated prevalence reaches 40–50%. The aim of the present study was adaptation and validation of the Speech Pathology-Specific Questionnaire for Persons with Multiple Sclerosis (SMS) into the Polish language to be used as part of the diagnostic procedure to quantify important speech-related changes and to improve individual tailoring of therapeutic activities. Material and MethodsThe study included a total number of 178 participants. The study group consisted of 107 patients diagnosed with Multiple Sclerosis, mean age 42.8±11.6 years and the Control Group were 71 healthy sex and age matched normophonic subjects, mean age 44.2±12.5 years with no neurological symptoms. Translated version of SMS was administered to all participants of the study. Voice Handicap Index (VHI) questionnaire was used for comparison purposes. Test-retest reproducibility, internal consistency, floor and ceiling effects, discriminant validity and construct validity of the Polish SMS were investigated. Preliminary assessment of diagnostic value of SMS was conducted on the basis of the results recorded in duration-related quartiles of the Study Group. ResultsHigh value of Intraclass Correlation Coefficient (ICC= 0 .930) obtained for the test-retest indicates a good level of reproducibility of the Polish SMS. High Cronbach's alpha (α=0.94) proves the test's good internal consistency. There were no floor and ceiling effects for the SMS test score in the Study Group and they were negligible in the Control Group. A significant difference in mean SMS total scores between patients and controls (14.22 points vs. 6.06 points) shows discriminant validity of SMS. Similar differences were observed for all the subscales of the test (in t test: p<0.001). A statistically significant correlation was found for the SMS score and its all subscales, as well as between all the subscales of the test proving good construct validity of the test. Similarly, statistically significant correlations were observed for the total score of SMS and VHI (r=.817, p <0.001) as well as between the particular subscales of SMS test and the subscales of VHI. There was a statistically significant difference in the mean total score of SMS in the distinguished quartiles of the Study Group with the highest values (20 points) recorded in the group of patients suffering from MS for over 15 years. Conclusion: The psychometric properties of the Polish version of Speech Pathology-Specific Questionnaire indicate that it is a valid patient-reported outcome measure suitable for the assessment of speech-language pathology aspects on the population of Multiple Sclerosis patients and can be used as an complementary diagnostic tool in clinical practice.

Resveratrol nanoparticles are neuroprotective in a model of multiple sclerosis

AbstractPurposeOptic neuritis is the most common clinical manifestation of multiple sclerosis. Axonal damage and neuronal loss lead to permanent neurological disability in patients and its animal model, experimental autoimmune encephalomyelitis (EAE). Presently, treatments of this condition aim to reduce inflammation without showing any neuroprotection. Resveratrol is a natural polyphenol found in red wine with neuroprotective effects but poor solubility in water. Thus, a novel nanoparticle formulation of resveratrol was developed and assessed in a mouse model of EAE.MethodsResveratrol nanoparticles (RNs) were formulated using a thin rehydration technique and assessed for stability with spectrophotometric techniques. C57/BL6 mice were immunized with the myelin oligodendroglial glycoprotein peptide. From EAE induction, mice were treated daily for 30 days by oral gavage of RNs (n = 6), vehicle (n = 5) or unconjugated resveratrol (UnRSV); n = 6). Mice were assessed for EAE signs daily and for visual function weekly by optokinetic responses (OKR). Optic nerve and spinal cord inflammation were assessed by hematoxylin and eosin (H&amp;E). Retinal ganglion cells were immunostained with Brn3a.ResultsResveratrol nanoparticles (RNs) containing &gt;10 mg/ml resveratrol were stable over 3 months with an encapsulation efficiency &gt;70%. 16.9 mg/kg RNs reduced the EAE clinical score at day 30 compared to 16.9 mg/kg vehicle (1.4 ± 0.4 versus 3.0 ± 0.4, p &lt; 0.05) whereas up to 100 mg/kg UnRSV did not lead to reduction of EAE scores. OKR, optic nerve inflammation and spinal cord inflammation were not significantly modified by oral administration of RNs. 16.9 mg/kg RNs reduced RGC loss compared to 16.9 mg/kg vehicle (347 ± 12 versus 172 ± 12 cells/standardized field, p &lt; 0.0001). Importantly, to get a similar reduction, at least 100 mg/kg of UnRSV were needed suggesting that RNs increase resveratrol bioavailability.ConclusionsResveratrol nanoparticles (RNs) increase resveratrol solubility and bioavailability. They show neuroprotection by reducing RGC loss. However, as previously reported for resveratrol, these nanoparticles do not have any anti‐inflammatory effect.

CD8+ T Cell-Mediated Mechanisms Contribute to the Progression of Neurocognitive Impairment in Both Multiple Sclerosis and Alzheimer's Disease?

Neurocognitive impairment (NCI) is one of the most relevant clinical manifestations of multiple sclerosis (MS). The profile of NCI and the structural and functional changes in the brain structures relevant for cognition in MS share some similarities to those in Alzheimer's disease (AD), the most common cause of neurocognitive disorders. Additionally, despite clear etiopathological differences between MS and AD, an accumulation of effector/memory CD8+ T cells and CD8+ tissue-resident memory T (Trm) cells in cognitively relevant brain structures of MS/AD patients, and higher frequency of effector/memory CD8+ T cells re-expressing CD45RA (TEMRA) with high capacity to secrete cytotoxic molecules and proinflammatory cytokines in their blood, were found. Thus, an active pathogenetic role of CD8+ T cells in the progression of MS and AD may be assumed. In this mini-review, findings supporting the putative role of CD8+ T cells in the pathogenesis of MS and AD are displayed, and putative mechanisms underlying their pathogenetic action are discussed. A special effort was made to identify the gaps in the current knowledge about the role of CD8+ T cells in the development of NCI to “catalyze” translational research leading to new feasible therapeutic interventions.

Demyelinating or hereditary optic neuropathy? Comparison of selected disease entities

The paper discusses retrobulbar optic neuritis secondary to multiple sclerosis, Leber’s hereditary optic neuropathy, and Leber’s hereditary optic neuropathy with multiple sclerosis-like disease – Harding’s syndrome. Retrobulbar optic neuritis secondary to multiple sclerosis is the most common disease (neuropathy) of the optic nerve in young adults and often the first clinical manifestation of multiple sclerosis. Despite a characteristic triad of symptoms and evident focal demyelination in brain magnetic resonance, misdiagnoses still occur. Leber’s hereditary optic neuropathy (atrophy) is a genetic mitochondrial disease, which manifests as a subacute painless loss of vision, and thus can be mistaken for retrobulbar optic neuritis. The coexistence of hereditary optic neuropathy and Harding’s syndrome is another diagnostic difficulty. All these three conditions, the peak of incidence of which occurs in the second to third decade of life, initially manifest only with visual symptoms due to uni- or bilateral optic neuropathy. Magnetic resonance imaging of the brain may show demyelination, while optical coherence tomography of the fundus may detect thinning of the retinal nerve fibre layers in all these neuropathies. We present clinical differences, as well as variances in retinal optical coherence tomography and magnetic resonance imaging between retrobulbar optic neuritis secondary to multiple sclerosis, Leber’s hereditary optic neuropathy, and Leber’s hereditary optic neuropathy with multiple sclerosis-like disease.

Cognitive impairment in multiple sclerosis: lessons from cerebrospinal fluid biomarkers.

Cognitive impairment is a common clinical manifestation of multiple sclerosis, but its pathophysiology is not completely understood. White and grey matter injury together with synaptic dysfunction do play a role. The measurement of biomarkers in the cerebrospinal fluid and the study of their association with cognitive impairment may provide interesting in vivo evidence of the biological mechanisms underlying multiple sclerosis-related cognitive impairment. So far, only a few studies on this topic have been published, giving interesting results that deserve further investigation. Cerebrospinal fluid biomarkers of different pathophysiological mechanisms seem to reflect different neuropsychological patterns of cognitive deficits in multiple sclerosis. The aim of this review is to discuss the studies that have correlated cerebrospinal fluid markers of immune, glial and neuronal pathology with cognitive impairment in multiple sclerosis. Although preliminary, these findings suggest that cerebrospinal fluid biomarkers show some correlation with cognitive performance in multiple sclerosis, thus providing interesting insights into the mechanisms underlying the involvement of specific cognitive domains.

Depression, lower urinary tract symptoms and quality of life in women with multiple sclerosis: A descriptive and correlational study

Background: Among the most ordinary clinical manifestations of Multiple Sclerosis (MS) are depression and the presence of Lower Urinary Tract Symptoms (LUTS). Both can compromise a person’s quality of life. Objective: The objective of this research was to identify the major urinary symptoms and correlate them with quality of life and with depressive symptoms in women with MS. Methodology: This was an observatory, descriptive and correlational study, with non-probabilistic sampling by convenience. This research included women over 18 years old who displayed LUT symptoms and who had been diagnosed with Relapsing-Remitting MS. Assessment consisted of an anamnesis card, the Kurtzke Expanded Disability Status Scale (EDSS), the Incontinence Impact Questionnaire-7 (IIQ-7-BR), the Urogenital Distress Inventory-6 (UDI-6-BR), the Beck Depression Inventory-2 (BDI-II) and the Multiple Sclerosis Quality of Life Questionnaire - Portuguese version (MSQOL-54). Results: 41 women participated in the study, with average age of 50.1 (± 9.45) and average of 4.11 in the EDSS. The most common urinary symptom was urinary urgency (78%). There was no correlation between the severity of the urinary symptom and quality of life. Moderate and significant negative correlation (r = -0.561 p<0.001) was found between depression and the physical component of quality of life and strong negative correlation (r = -0.729 p<0.001) was found between depression and the mental component. Conclusions: The most prevalent urinary symptom was urinary urgency. A strong correlation was found between symptoms of depression and quality of life and there was no correlation between urinary symptoms and quality of life. Keywords: Multiple sclerosis; urinary incontinence; quality of life; depression

INFLUENCE OF SINGLE NUCLEOTIDE POLYMORPHISMS OF “ZINC FINGERS” PROTEINS GENES ON MULTIPLE SCLEROSIS

The genes ZFAT and ZFHX4 encoding the zinc finger proteins were previously identified as predisposing to autoimmune pathology and various cancer diseases, as well as influencing on therapeutic effect of interferonbeta in patients with multiple sclerosis. The aim of the study is to determine the associations of single nucleotide polymorphisms rs11787532 ZFHX4 and rs733254 ZFAT and development and severity of clinical manifestations of multiple sclerosis in Perm krai. A significant predominance of the C/A genotype of rs733254 ZFAT gene, and GC and CC haplotypes in people with multiple sclerosis was found. The association of single nucleotide polymorphisms with the severity of clinical manifestations of multiple sclerosis was not detected.

Association of Polymorphic Variants of Brain-Derived Neurotrophic Factor Gene (Bdnf Rs6265) and Glutamate Transporter Gene of the Second Type (Slc1a2 Rs4354668) with the Course of Multiple Sclerosis in Patients Living in Tomsk Region

Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that affects people of working age and ultimately leads to disability. This disease is of polygenic origin. The role of factors related to the pathogenesis of the disease and affecting both neuroinflammation and remyelination is studied. Aims: Our goal was to investigate the association of single nucleotide polymorphisms BDNF rs6265 and SLC1A2 rs4354668 with the risk of occurrence, clinical manifestations and the course of MS.Materials and methods: The study included 302 patients with MS, 268 healthy volunteers were enrolled in a control group. The obtained blood was used for DNA extraction by standard phenol-chloroform method. The identification of allelic variants of genes SLC1A2 (rs4354668) and BDNF (rs6265) was performed by polymerase chain reaction.Results: When comparing the frequencies of genotypes and alleles of polymorphic variants of BDNF and SLC1A2 genes between the groups of MS patients and the control group, no statistically significant differences were revealed. Comparison of genotype and allele frequencies of patients depending on sex, age of onset of the disease also did not reveal statistically significant differences. The study of the association of polymorphic variant of the gene BDNF (rs6265) with clinical manifestations of the disease revealed the association of genotype CC with oculomotor and trigeminal disorders at the onset of the disease (F=7, p=0.017). The study of the polymorphic variant rs4354668 of the glutamate transporter gene SLC1A2 revealed the association of allele G with an earlier (within 5 years from the moment of debut) transition of the disease to the stage of secondary progression, despite the therapy with DMT (χ2=5.940; p=0.010; OR 1.58; 95% CI 1.09−2.29). Homozygous genotype of TT (χ2=6.393; p=0.041; OR 0.50; 95% CI 0.28−0.88) and allele T (χ2=5.940; p=0.010; OR 0.63; 95% CI 0.44−0.92) of the polymorphism rs4354668 of the glutamate transporter gene SLC1A2 are significantly more common in the group of patients with late transition (15 years or more from the moment of debut) to the secondary progressive course.Conclusions: In our study we revealed the relationship of the studied polymorphic variants of genes with clinical signs at the onset of the disease and with the clinical manifestations of MS in patients living in the Tomsk region.

Immunomodulatory properties of MSC-derived exosomes armed with high affinity aptamer toward mylein as a platform for reducing multiple sclerosis clinical score

Mesenchymal stem cell-derived exosome is a safe and effective delivery platform with a potential capacity to exert immunomodulation effect and peripheral tolerance toward auto-reactive cells via bearing regulatory and tolerogenic molecules. Inflammation and neurodegeneration are the clinical manifestation of multiple sclerosis (MS). In order to fight against MS, the efficient choices are the ones, which prevent inflammation and induce remyelination.In this regard, the previously reported LJM-3064 aptamer which showed considerable affinity toward myelin and demonstrated remyelination induction was employed as both targeting ligand and therapeutic agent. Thus, in the current study, the carboxylic acid-functionalized LJM-3064 aptamer was covalently conjugated to the amine groups on the exosome surface through EDC/NHS chemistry.The obtained results showed that the aptamer-exosome bioconjugate could promote the proliferation of oligodendroglia cell line (OLN93) in vitro. Moreover, in vivo administration of the prepared aptamer-exosome bioconjugate in female C57BL/6 mice as a prophylactic measure produced a robust suppression of inflammatory response as well as lowered demyelination lesion region in CNS, resulting in reduced in vivo severity of the disease.The prepared platform employing exosome-based nanomedicine as a novel approach for managing MS would hopefully pave the way to introduce a versatile approach toward an effective clinical reality.