Regional gray matter atrophy and neuropsychologcal problems in relapsing-remitting multiple sclerosis

In multiple sclerosis, gray matter atrophy is extensive, and cognitive deficits and mood disorders are frequently encountered. It has been conjectured that focal atrophy is associated with emotional decline. However, conventional MRI has revealed that the pathological characteristics cannot fully account for the mood disorders. Moreover, there is no correlation between cognitive disorders and MRI results in clinically isolated syndromes or in cases of definite multiple sclerosis. In this casecontrol study, voxel-based morphometric analysis was performed on 11 subjects with relapsing-remitting multiple sclerosis, and the results show that these patients exhibit gray matter atrophy. Moreover, the gray matter atrophy in the superior and middle gyri of the right frontal lobe in patients with multiple sclerosis was correlated with scores from the Hamilton Anxiety Rating Scale. The scores obtained with the Repeatable Battery for the Assessment of Neuropsychological Status were associated with gray matter atrophy in the middle gyrus of the left frontal lobe, the superior and middle gyrus of the right frontal lobe, the middle gyrus of the left cingulate, the superior and middle gyri of the left frontal lobe, and the triangular area of the left frontal lobe. However, there was no statistical significance. These findings suggest that the cingulate and frontal cortices of the dominant hemisphere are the most severely atrophic regions of the brain, and this atrophy is correlated with cognitive decline and emotional abnormalities.

Correlations between hippocampal functional connectivity,structural changes,and clinical data in patients with relapsing-remitting multiple sclerosis:a case-control study using multimodal magnetic resonance imaging

Multiple sclerosis is associated with structural and functional brain alterations leading to cognitive impairments across multiple domains including attention,memory,and the speed of information processing.The hippocampus,which is a brain important structure involved in memory,undergoes microstructural changes in the early stage of multiple sclerosis.In this study,we analyzed hippocampal function and structure in patients with relapsing-remitting multiple sclerosis and explored correlations between the functional connectivity of the hippocampus to the whole brain,changes in local brain function and microstructure,and cognitive function at rest.We retrospectively analyzed data from 20 relapsing-remitting multiple sclerosis patients admitted to the Department of Neurology at the China-Japan Union Hospital of Jilin University,China,from April 2015 to November 2019.Sixteen healthy volunteers were recruited as the healthy control group.All participants were evaluated using a scale of extended disability status and the Montreal cognitive assessment within 1 week before and after head diffusion tensor imaging and functional magnetic resonance imaging.Compared with the healthy control group,the patients with relapsing-remitting multiple sclerosis had lower Montreal cognitive assessment scores and regions of simultaneously enhanced and attenuated whole-brain functional connectivity and local functional connectivity in the bilateral hippocampus.Hippocampal diffusion tensor imaging data showed that,compared with the healthy control group,patients with relapsing-remitting multiple sclerosis had lower hippocampal fractional anisotropy values and higher mean diffusivity values,suggesting abnormal hippocampal structure.The left hippocampus whole-brain functional connectivity was negatively correlated with the Montreal cognitive assessment score(r=-0.698,P=0.025),and whole-brain functional connectivity of the right hippocampus was negatively correlated with extended disability status scale score(r=-0.649,P=0.042).The mean diffusivity value of the left hippocampus was negatively correlated with the Montreal cognitive assessment score(r=-0.729,P=0.017)and positively correlated with the extended disability status scale score(r=0.653,P=0.041).The right hippocampal mean diffusivity value was positively correlated with the extended disability status scale score(r=0.684,P=0.029).These data suggest that the functional connectivity and presence of structural abnormalities in the hippocampus in patients with relapse-remission multiple sclerosis are correlated with the degree of cognitive function and extent of disability.This study was approved by the Ethics Committee of China-Japan Union Hospital of Jilin University,China(approval No.201702202)on February 22,2017.

A network-based cognitive training induces cognitive improvements and neuroplastic changes in patients with relapsing-remitting multiple sclerosis:an exploratory case-control study

Cognitive impairments are commonly observed in patients with multiple sclerosis and are associated with lower levels of quality of life.No consensus has been reached on how to tackle effectively cognitive decline in this clinical population non-pharmacologically.This exploratory case-control study aims to investigate the effectiveness of a hypothesis-based cognitive training designed to target multiple domains by promoting the synchronous co-activation of different brain areas and thereby improve cognition and induce changes in functional connectivity in patients with relapsing-remitting multiple sclerosis.Forty-five patients(36 females and 9 males,mean age 44.62±8.80 years)with clinically stable relapsing-remitting multiple sclerosis were assigned to either a standard cognitive training or to control groups(sham training and nonactive control).The standard training included twenty sessions of computerized exercises involving various cognitive functions supported by distinct brain networks.The sham training was a modified version of the standard training that comprised the same exercises and number of sessions but with increased processing speed load.The non-active control group received no cognitive training.All patients underwent comprehensive neuropsychological and magnetic resonance imaging assessments at baseline and after 5 weeks.Cognitive and resting-state magnetic resonance imaging data were analyzed using repeated measures models.At reassessment,the standard training group showed significant cognitive improvements compared to both control groups in memory tasks not specifically targeted by the training:the Buschke Selective Reminding Test and the Semantic Fluency test.The standard training group showed reductions in functional connectivity of the salience network,in the anterior cingulate cortex,associated with improvements on the Buschke Selective Reminding Test.No changes were observed in the sham training group.These findings suggest that multi-domain training that stimulates multiple brain areas synchronously may improve cognition in people with relapsing-remitting multiple sclerosis if sufficient time to process training material is allowed.The associated reduction in functional connectivity of the salience network suggests that training-induced neuroplastic functional reorganization may be the mechanism supporting performance gains.This study was approved by the Regional Ethics Committee of Yorkshire and Humber(approval No.12/YH/0474)on November 20,2013.

Association between rs1800795 (-174 G/C) Polymorphism in the Promoter of <i>IL</i>6 Gene and Risk of Relapsing-Remitting Multiple Sclerosis (RRMS) in Isfahan Population

Multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system (CNS) that mostly affects young adults. The etiology of MS includes both genetic and environmental factors. A single nucleotide polymorphism (SNP) linked with autoimmune disorders predisposition, identified by Genome-Wide Association Study (GWAS) among genes which immunologically related are considerably over signified. The goal of the current study is investigation of the association between rs1800795 (-174 G/C) polymorphism in the promoter of IL6 gene variant with the risk of RRMS in a subset of Iranian population. In this case-control study, 110 healthy subjects and 110 patients with RRMS were included. DNA was extracted from blood samples and polymerase chain reaction (PCR) was used to amplify the fragment of interest contain rs1800795 SNP, restriction fragment length polymorphism (RFLP) method was performed for genotyping of the DNA samples with a specific restriction enzyme (NlaIII). SPSS for Windows software (version 18.0;SPSS, Chicago, IL) was used for statistical analysis. No significant differences were found between RRMS patients and healthy controls with respect to the distribution of the cytokine gene polymorphism investigated. Odds ratio adjusted for age, sex, and blood groups (except A blood group) has displayed similar outcomes. These results indicate that the rs1800795 SNP is not a susceptibility gene variant for development of RRMS in the Isfahan population. Further studies using new data on complex transcriptional interactions between IL-6 polymorphic sites are necessary to determine IL-6 haplotype influence on susceptibility to RRMS.

Intrathecal IgG synthesis in relapsing-remitting multiple sclerosis (MS) is decreased by natural human alpha interferon

Intrathecal IgG synthesis (IT IgG Syn) is an established biomarker used for the diagnosis of multiple sclerosis (MS). Earlier studies used this biomarker to assess the impact of 2 different synthetic forms of interferon alpha (IFN-α) in chronic progressive MS. Unexpectedly, IT IgG synthesis was increased by this treatment. For the first time, we have assessed this parameter in relapsing-remitting patients to measure the impact of natural IFN-α treatment in a doseranging study in six dosage groups (5, 10, 15, 20, 25, & 30 MIU). We have found that IFN-α normalized IT IgG Synthesis at 12 weeks treatment for all dosage groups. Two weeks after stopping IFN-α results rose slightly. At 52 weeks, 28 weeks after stopping IFN-a results revealed cessation of IT IgG Synthesis in half of the patients (15, 20, 25 MIU weekly). These results reflect different outcomes for relapsing-remitting patients vs. chronic progressive patients. They may, however, reflect differences in the biological properties of the interferon products used. An optimal range of dosage with natural human IFN-α dosage for MS is suggested by the results.

Gut flora in multiple sclerosis:implications for pathogenesis and treatment

Multiple sclerosis is an inflammatory disorder chara cterized by inflammation,demyelination,and neurodegeneration in the central nervous system.Although current first-line therapies can help manage symptoms and slow down disease progression,there is no cure for multiple sclerosis.The gut-brain axis refers to complex communications between the gut flo ra and the immune,nervous,and endocrine systems,which bridges the functions of the gut and the brain.Disruptions in the gut flora,termed dys biosis,can lead to systemic inflammation,leaky gut syndrome,and increased susceptibility to infections.The pathogenesis of multiple sclerosis involves a combination of genetic and environmental factors,and gut flora may play a pivotal role in regulating immune responses related to multiple scle rosis.To develop more effective therapies for multiple scle rosis,we should further uncover the disease processes involved in multiple sclerosis and gain a better understanding of the gut-brain axis.This review provides an overview of the role of the gut flora in multiple scle rosis.

Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

Infiltration by monocytes of the central nervous system and its role in multiple sclerosis: reflections on therapeutic strategies

Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood–brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.

Examination of the Effective Factors on the Multiple Sclerosis Diseases

This study was an attempt to examine the effective factors of the Multiple Sclerosis diseases. The participants of the study were selected from among a total number of 45 men and women who were treated in a health center in Azarbayegan and Damavand in Iran. In order to study, the researchers applied various procedures to collect the data of the study. The participants were interviewed and filled out the questionnaires. After categorizing and classifying the collected information and data, it was processed and analyzed and the results are found. To test the research questions, a one-sample T-test was used to analyze the data. The role of hypo vitamin D as a possible risk factor for multiple sclerosis was reviewed. First, it was emphasized that hypo vitamin could be only one of the risk factors for multiple sclerosis and that numerous other environmental and genetic risk factors appear to interact and combine to trigger the disease. The main aim of this study was to examine the effective factors of Multiple Sclerosis diseases. The methodology of this research was to test the research questions;one-sample T-test was used to analyze the data. The findings of this study revealed that the factors of gender, cold weather, vitamin D deficiency, and age (between 30 - 59) were effective on the Multiple Sclerosis diseases.

Microglia depletion as a therapeutic strategy:friend or foe in multiple sclerosis models?

M ultiple sclerosis is a chro nic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation,genetic predisposition,and environmental fa ctors.The activation of microglia and astrocytes is a key player in multiple sclerosis immunopathology,playing specific roles associated with anatomical location and phase of the disease and controlling demyelination and neurodegeneration.Even though reactive mic roglia can damage tissue and heighten deleterious effects and neurodegeneration,activated microglia also perform neuroprotective functions such as debris phagocytosis and growth fa ctor secretion.Astrocytes can be activated into pro-inflammato ry phenotype A1 through a mechanism mediated by activated neuroinflammatory microglia,which could also mediate neurodegeneration.This A1 phenotype inhibits oligodendrocyte prolife ration and differe ntiation and is toxic to both oligodendrocytes and neurons.Howeve r,astroglial activation into phenotype A2 may also take place in response to neurodegeneration and as a protective mechanism.A variety of animal models mimicking specific multiple sclerosis features and the associated pathophysiological processes have helped establish the cascades of events that lead to the initiation,progression,and resolution of the disease.The colonystimulating facto r-1 receptor is expressed by myeloid lineage cells such as peripheral monocytes and macrophages and central nervous system microglia.Importantly,as microglia development and survival critically rely on colony-stimulating factor-1 receptor signaling,colony-stimulating factor-1 receptor inhibition can almost completely eliminate microglia from the brain.In this context,the present review discusses the impact of microglial depletion through colo ny-stimulating factor-1 receptor inhibition on demyelination,neurodegeneration,astroglial activation,and behavior in different multiple sclerosis models,highlighting the diversity of microglial effects on the progression of demyelinating diseases and the strengths and weaknesses of microglial modulation in therapy design.

CDP-choline to promote remyelination in multiple sclerosis:the need for a clinical trial

Multiple sclerosis is a multifactorial chronic inflammatory disease of the central nervous system that leads to demyelination and neuronal cell death,resulting in functional disability.Remyelination is the natural repair process of demyelination,but it is often incomplete or fails in multiple sclerosis.Available therapies reduce the inflammatory state and prevent clinical relapses.However,therapeutic approaches to increase myelin repair in humans are not yet available.The substance cytidine-5′-diphosphocholine,CDP-choline,is ubiquitously present in eukaryotic cells and plays a crucial role in the synthesis of cellular phospholipids.Regenerative properties have been shown in various animal models of diseases of the central nervous system.We have already shown that the compound CDPcholine improves myelin regeneration in two animal models of multiple sclerosis.However,the results from the animal models have not yet been studied in patients with multiple sclerosis.In this review,we summarise the beneficial effects of CDP-choline on biolipid metabolism and turnover with regard to inflammatory and regenerative processes.We also explain changes in phospholipid and sphingolipid homeostasis in multiple sclerosis and suggest a possible therapeutic link to CDP-choline.

The role of fibronectin in multiple sclerosis and the effect of drug delivery across the blood-brain barrier

Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression.Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis.Fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis,thus inhibiting remyelination.Although many advances have been made in the mechanisms and treatment of multiple sclerosis,it remains very difficult for drugs to reach pathological brain tissues;this is due to the complexity of brain structure and function,especially the existence of the blood-brain barrier.Therefore,herein,we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease.

Safety,immunogenicity,efficacy,and acceptability of COVID-19 vaccination in people with multiple sclerosis:a narrative review

In the last two years,a new seve re acute res piratory syndrome coronavirus(SARS-CoV)infection has spread worldwide leading to the death of millions.Va ccination represents the key factor in the global strategy against this pandemic,but it also poses several problems,especially for vulnerable people such as patients with multiple scle rosis.In this review,we have briefly summarized the main findings of the safety,efficacy,and acceptability of Coronavirus Disease 2019(COVID-19)vaccination fo r multiple sclerosis patients.Although the acceptability of COVID-19 vaccines has progressively increased in the last year,a small but significant part of patients with multiple sclerosis still has relevant concerns about vaccination that make them hesitant about receiving the COVID-19 vaccine.Overall,available data suggest that the COVID-19 vaccination is safe and effective in multiple scle rosis patients,even though some pharmacological treatments such as anti-CD20 therapies or sphingosine I-phosphate receptor modulato rs can reduce the immune response to vaccination.Accordingly,COVID-19 vaccination should be strongly recommended for people with multiple scle rosis and,in patients treated with anti-CD20 therapies and sphingosine I-phosphate receptor modulato rs,and clinicians should evaluate the appropriate timing for vaccine administration.Further studies are necessary to understand the role of cellular immunity in COVID-19 vaccination and the possible usefulness of booster jabs.On the other hand,it is mandatory to learn more about the reasons why people refuse vaccination.This would help to design a more effective communication campaign aimed at increasing vaccination coverage among vulnerable people.

Neuroimmune,clinical and treatment challenges in multiple sclerosis-related psychoses

In recent years,epidemiological and genetic studies have shown an association between autoimmune diseases and psychosis.The question arises whether patients with schizophrenia are more likely to develop multiple sclerosis(MS)later in life.It is well known that the immune system plays an important role in the etiopathogenesis of both disorders.Immune disturbances may be similar or very different in terms of different types of immune responses,disturbed myelination,and/or immunogenetic predispositions.A psychotic symptom may be a consequence of the MS diagnosis itself or a separate entity.In this review article,we discussed the timing of onset of psychotic symptoms and MS and whether the use of corticosteroids as therapy for acute relapses in MS is unfairly neglected in patients with psychiatric comorbidities.In addition,we discussed that the anti-inflammatory potential of antipsychotics could be useful and should be considered,especially in the treatment of psychosis that coexists with MS.Autoimmune disorders could precipitate psychotic symptoms,and in this context,autoimmune psychosis must be considered as a persistent symptomatology that requires continuous and specific treatment.

Exploring the mechanism of Yishen Daluo decoction in the treatment of multiple sclerosis based on network pharmacology and in vitro experiments

Objective:To explore the mechanism and related active components of Yishen Daluo decoction(YSDLD)in treating multiple sclerosis(MS).Methods:Targets of YSDLD were collected through the TCMSP,Chemistry,and TCMID databases.The MS targets were collected through OMIM,DrugBank,Gencards,TTD,and Pharmgkb databases.We built“componentetarget”network diagrams and proteineprotein interaction(PPI)diagrams and performed topological analysis.The targets were subjected to GO and KEGG enrichment analysis.Molecular docking verification was conducted on selected targets and molecules.Finally,in vitro experiments were con-ducted.BV2 cells were induced by lipopolysaccharide for model establishment.CCK8 experiment was conducted to explore the effect of YSDLD and RT-qPCR technology was used to explore the expression of key targets.Results:There were 184 active components in YSDLD and 898 targets of its action.There were 940 MS targets,and 215 targets were shared by YSDLD and MS.According to the“componentetarget”diagram,the top five key components included quercetin,kaempferol,beta-sitosterol,stigmasterol,and nar-ingenin.IL-6,IL-1 b,TNF-α,AKT1,and VEGFA were the important targets identified by PPI network to-pology analysis.A total of 564 functions were identified by GO enrichment analysis(P<0.01),mainly involving inflammatory response,hypoxia response,plasma membrane,neuronal cell body,protein phosphatase binding,and cytokine activity.KEGG enrichment analysis enriched 98 pathways(P<.01).YSDLD at the concentration of 20 m g/mL had no effect on BV2 cells.RT-qPCR indicated that YSDLD at the concentrations of 15 m g/mL and 20 m g/mL alleviated LPS-induced inflammatory injury and lowered the content of inflammatory factors(P<0.05).Conclusion:In this paper,the network pharmacology and in vitro experiments were used to explore the potential mechanism of YSDLD in treating MS.The research provides a good basis for the development of YSDLD and drugs for MS in future.

Abnormalcortical thickness in relapsing-remitting multiple sclerosis,correlations with cognition impairment,and effect of modified Bushenyisui decoction(补肾益髓汤)on cognitive function of multiple sclerosis

OBJECTIVE:To investigate the changes of subcortical gray matter volume and cortical thickness,andexplorethe correlations between regional abnormalities of cortical thickness and cognitive impairment and the effect of modified Bushenyisui decoction(补肾益髓汤,BSYSD)on the cognitive function of multiple sclerosis(MS).METHODS:This prospective study was approved by the institutional review board.92 subjects were recruited,including 46 relapsing-remitting multiple sclerosis(RRMS)patients and 46 healthy controls(HC).Of the 46 patients,22 patients experienced the treatment of BSYSD for half a year.A conventional three-dimensional T1-weighted sequence were acquired for all participants on a 3.0 tesla magnetic resonance system.Basic information,detailed cognitive scales Montreal Cognitive Assessment(MoCA),symbol digit modalities test(SDMT),immediate memory,delayed recall,and long-term recognition were evaluated.Subcortical gray matter volume and cortical thickness weremeasured by FreeSurfer.The correlations between cortical thickness which MS patients showed reduced with respect to HC and cognitive scales wereanalyzed by Pearson correlation in RRMS patients.The influence of modified BSYSD on MS patients'cognition was analyzed by paired T Test.RESULTS:MoCA,immediate memory,delayed recall,and long-term delayed recognition in RRMS were significantly decreased than those of HC.Gray matter atrophy measured by FreeSurfer showed mainly in thalamus and hippocampus of RRMS patients.Compared with HC,the cortical thickness of several regions in frontal lobe,parietal lobe,temporal lobe,hippocampal,cingulate gyrus,and fusiform gyrus of RRMS patients were decreased with significant difference.The regions of cortical thickness thinning related to MoCA,immediate memory,delayed recall,and long-term delayed recognition were temporal lobe and fusiform gyrus.Modified BSYSD could improve MoCA,SDMT,immediate memory,delayed recall,and long-term delayed recognition of MS patients,and it could promote the recovery of cognitive function in MS patients.CONCLUSIONS:Gray matter atrophy and cortical thickness thinning were validated in RRMS.Cortical thickness thinning of temporal lobe and fusiform gyrus strongly related to cognitive deficits in RRMS.The modified BSYSD could promote the recovery of cognitive function in MS.

Multiple Sclerosis:A Mast Cell Mediated Psycho-Somatic Disease?

This paper reviews evidence that the presence of mast cells in specific sites of central nervous system, suggesting inflammatory processes, may explain all the symptoms observed in multiple sclerosis. This hypothesis would be relatively easy to test.

Mast Cells:The Key to Multiple Sclerosis?

Mast cells are present in high numbers in the border-zones of the multiple sclerosis-plaques. They are located in small clusters along capillaries and venules, and they are more abundant in females than in men. Mast cells can be stimulated to release specific mediators such as histamine, resulting in oedema formation, as well as proteases that may cause demyelination, by several different activation mechanisms. We hypothesize that a putative mast cell activation may be induced by diet factor(s) as well as long lasting mental stress that may lead to the release of catestatin, as well as ACTH released from the pituitary gland. Given a natural flux of mast cell recovery and activation, a putative phenomenon of massive release of mediators and “silent” reload periods may explain the relapsing-remitting phases of multiple sclerosis.

Role of nuclear factor κB in multiple sclerosis and experimental autoimmune encephalomyelitis

The transcription factor nuclear factor κB（NF-κB） plays major roles in inflammatory diseases through regulation of inflammation and cell viability.Multiple sclerosis（MS） is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system（CNS）.It has been shown that NF-κB is activated in multiple cell types in the CNS of MS patients,including T cells,microglia/macrophages,astrocytes,oligodendrocytes,and neurons.Interestingly,data from animal model studies,particularly studies of experimental autoimmune encephalomyelitis,have suggested that NF-κB activation in these individual cell types has distinct effects on the development of MS.In this review,we will cover the current literature on NF-κB and the evidence for its role in the development of MS and its animal model experimental autoimmune encephalomyelitis.

MicroRNAs as disease progression biomarkers and therapeutic targets in experimental autoimmune encephalomyelitis model of multiple sclerosis

Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination.Focal demyelination is associated with relapsing-remitting multiple sclerosis,while progressive forms of the disease show axonal degeneration and neuronal loss.The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity.MicroRNAs(miRNAs)are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases.A review of recent studies with the experimental autoimmune encephalomyelitis animal model(mostly female mice 6–12 weeks of age)has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset(asymptomatic)stage when assessed in blood plasma and urine exosomes,and spinal cord tissue.The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes,brain and spinal cord tissue,and at the post-peak(chronic)stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue.Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease.Interestingly,experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a,miR-23b,miR-497,miR-26a,and miR-20b,or by suppression of miR-182,miR-181c,miR-223,miR-155,and miR-873.Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course.Additionally,studies should be performed with male mice of a similar age,and with aged male and female mice.