Multiple Sclerosis Research Research Articles

Investigating the Potential Influence of TAS2R16 Genetic Variants and Protein Levels on Multiple Sclerosis Development.

The study aimed to investigate the association between the TAS2R16 gene (rs860170, rs978739, rs1357949), TAS2R16 serum levels, and multiple sclerosis (MS). A total of 265 healthy control subjects and 218 MS patients were included in the study. Single nucleotide polymorphisms (SNPs) were tested by real-time polymerase chain reaction (RT-PCR). The serum concentration of TAS2R16 was measured using the ELISA method. Analyses revealed that the TAS2R16 rs860170 TT genotype was statistically significantly less frequent in the MS group than in the control group (p = 0.041), and the CC genotype was statistically significantly more frequent in the MS group than in the control group (p < 0.001). In the most robust (codominant) model, the CC genotype was found to increase the odds of MS by ~27-fold (p = 0.002), and each C allele increased the odds of MS by 1.8-fold (p < 0.001). Haplotype analysis of the rs860170, rs978739, and rs1357949 polymorphisms showed that the C-C-A haplotype was associated with a ~12-fold increased odds of MS occurrence (p = 0.02). Serum TAS2R16 levels were elevated in the MS group compared to control subjects (p = 0.014). Conclusions: The rs860170, rs978739, and rs1357949 polymorphisms demonstrated that the C-C-A haplotype and elevated TAS2R16 serum levels can promote the development of MS. These preliminary findings underscore the importance of specific genetic variants, such as rs860170, rs978739, and rs1357949, in MS risk. Additionally, elevated TAS2R16 serum levels in MS patients suggest a potential role in MS pathogenesis. These findings provide insights into the genetic and molecular mechanisms underlying MS and pave the way for personalized diagnostic and therapeutic strategies. Integrating genetic and serum biomarker data in MS research offers promising avenues for improving clinical outcomes and advancing precision medicine approaches in the future.

Understanding multiple sclerosis as a disease spectrum: above and below the clinical threshold.

Research in multiple sclerosis (MS) has long been predicated on clinical groupings that do not reflect the underlying biologic heterogeneity apparent within patient populations. This review explicates the various levels of explanation through which the spectrum of disease is described and investigated both above and below the clinical threshold of detection, as framed by the topographical model of MS, to help advance a cogent mechanistic framework. Contemporary evidence has amended the view of MS as consisting of sequential disease phases in favor of a spectrum of disease with an admixture of interdependent and dynamic pathobiological axes driving tissue injury and progression. Recent studies have shown the presence of acute and compartmentalized inflammation and mechanisms of neurodegeneration beginning early and evolving throughout the disease continuum. Still, the gap between the understanding of immunopathologic processes in MS and the tools used to measure relevant molecular, laboratory, radiologic, and clinical metrics needs attention to enable better prognostication of disease and monitoring for changes along specific pathologic axes and variable treatment outcomes. Aligning on a consistently-applied mechanistic framework at distinct levels of explanation will enable greater precision across bench and clinical research, and inform discourse on drivers of disability progression and delivery of care for individuals with MS.

The Economic Impact of Multiple Sclerosis: A Preliminary Look at the North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) (P11-6.002)

The Economic Impact of Multiple Sclerosis: A Preliminary Look at the North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) (P11-6.002)

MS Research: Empowering Contributors and Fostering Engagement (P2-6.012)

MS Research: Empowering Contributors and Fostering Engagement (P2-6.012)

Twin study dissects CXCR3+ memory B cells as non-heritable feature in multiple sclerosis

In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets. In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals. The frequencies of CXCR3+ memory B cells were reduced in the blood of genetically identical twins with MS compared to their unaffected twin siblings. Natalizumab (anti-VLA-4 antibody) was the only treatment regimen under which these frequencies were reversed. The CNS-homing features of CXCR3+ memory B cells were supported by elevated CXCL10 levels in MS cerebrospinal fluid and their invitro propensity to develop into antibody-secreting cells. Circulating CXCR3+ memory B cells are affected by non-heritable cues in people who develop MS. This underlines the requirement of environmental risk factors such as Epstein-Barr virus in triggering these B cells. We propose that after CXCL10-mediated entry into the CNS, CXCR3+ memory B cells mature into antibody-secreting cells to drive MS. This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement no.882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478).

Torben Fog – A Danish pioneer in a multi-faceted spectrum of multiple sclerosis research

Torben Fog was committed to multiple sclerosis (MS) research for more than four decades, starting before the defence of his thesis in 1948 and lasting until his death in 1987. His research was multi-facetted, making him one of the great pioneers in the study of essential parts of the pathology, immunology and treatment of MS. He has contributed with meticulous studies of the MS plaques, documenting the perivenous distribution of plaques in the spinal cord. He constructed a scoring system for the disability in MS and used a computer programme to calculate a total neurological deficit. Together with his co-workers, Fog in 1972 was the first to report the association between MS and the human leukocyte antigen system. Fog can be considered as the father of immunomodulatory therapy in MS, treating MS patients with the first transfer factor, and as early as 1980, he was the first to treat MS with intramuscular natural interferon.

Brain inflammation in experimental autoimmune encephalomyelitis induced in Dark Agouti rats with spinal cord homogenate

We have recently characterized experimental autoimmune encephalomyelitis (EAE) induced in DA rats with spinal cord homogenate without complete Freund's adjuvant (CFA). The main advantage of this multiple sclerosis model is the lack of CFA-related confounding effects which represent the major obstacles in translating findings from EAE to multiple sclerosis. Here, antigen specificity of the cellular and humoral immune response directed against the central nervous system was explored. The reactivity of T and B cells to myelin basic protein, myelin oligodendrocyte glycoprotein, and β-synuclein was detected. Having in mind that reactivity against β-synuclein was previously associated with autoimmunity against the brain, the infiltration of immune cells into different brain compartments, i.e. pons, cerebellum, hippocampus, and cortex was determined. T cell infiltration was observed in all structures examined. This finding stimulated investigation of the effects of immunization on DA rat behavior using the elevated plus maze and the open field test. Rats recovered from EAE displayed increased anxiety-like behavior. These data support CFA-free EAE in DA rats as a useful model for multiple sclerosis research.

Impact of calcitriol and PGD2-G-loaded lipid nanocapsules on oligodendrocyte progenitor cell differentiation and remyelination.

Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system (CNS) in need of a curative treatment. MS research has recently focused on the development of pro-remyelinating treatments and neuroprotective therapies. Here, we aimed at favoring remyelination and reducing neuro-inflammation in a cuprizone mouse model of brain demyelination using nanomedicines. We have selected lipid nanocapsules (LNC) coated with the cell-penetrating peptide transactivator of translation (TAT), loaded with either a pro-remyelinating compound, calcitriol (Cal-LNC TAT), or an anti-inflammatory bioactive lipid, prostaglandin D2-glycerol ester (PGD2-G) (PGD2-G-LNC TAT). Following the characterization of these formulations, we showed that Cal-LNC TAT in combination with PGD2-G-LNC TAT increased the mRNA expression of oligodendrocyte differentiation markers both in the CG-4 cell line and in primary mixed glial cell (MGC) cultures. However, while the combination of Cal-LNC TAT and PGD2-G-LNC TAT showed promising results in vitro, no significant impact, in terms of remyelination, astrogliosis, and microgliosis, was observed in vivo in the corpus callosum of cuprizone-treated mice following intranasal administration. Thus, although calcitriol's beneficial effects have been abundantly described in the literature in the context of MS, here, we show that the different doses of calcitriol tested had a negative impact on the mice well-being and showed no beneficial effect in the cuprizone model in terms of remyelination and neuro-inflammation, alone and when combined with PGD2-G-LNC TAT.

Complete Freund's adjuvant as a confounding factor in multiple sclerosis research.

Complete Freund's adjuvant (CFA) is used as a standard adjuvant for the induction of experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model in multiple sclerosis studies. Still, CFA induces glial activation and neuroinflammation on its own and provokes pain. In addition, as CFA contains Mycobacteria, an immune response against bacterial antigens is induced in parallel to the response against central nervous system antigens. Thus, CFA can be considered as a confounding factor in multiple sclerosis-related studies performed on EAE. Here, we discuss the effects of CFA in EAE in detail and present EAE variants induced in experimental animals without the use of CFA. We put forward CFA-free EAE variants as valuable tools for studying multiple sclerosis pathogenesis and therapeutic approaches.

Visuo-Cognitive Phenotypes in Early Multiple Sclerosis: A Multisystem Model of Visual Processing

Background: Cognitive impairment can emerge in the earliest stages of multiple sclerosis (MS), with heterogeneity in cognitive deficits often hindering symptom identification and management. Sensory–motor dysfunction, such as visual processing impairment, is also common in early disease and can impact neuropsychological task performance in MS. However, cognitive phenotype research in MS does not currently consider the relationship between early cognitive changes and visual processing impairment. Objectives: This study explored the relationship between cognition and visual processing in early MS by adopting a three-system model of afferent sensory, central cognitive and efferent ocular motor visual processing to identify distinct visuo-cognitive phenotypes. Methods: Patients with clinically isolated syndrome and relapsing–remitting MS underwent neuro-ophthalmic, ocular motor and neuropsychological evaluation to assess each visual processing system. The factor structure of ocular motor variables was examined using exploratory factor analysis, and phenotypes were identified using latent profile analysis. Results: Analyses revealed three ocular-motor constructs (cognitive control, cognitive processing speed and basic visual processing) and four visuo-cognitive phenotypes (early visual changes, efferent-cognitive, cognitive control and afferent-processing speed). While the efferent-cognitive phenotype was present in significantly older patients than was the early visual changes phenotype, there were no other demographic differences between phenotypes. The efferent-cognitive and cognitive control phenotypes had poorer performance on the Symbol Digit Modalities Test compared to that of other phenotypes; however, no other differences in performance were detected. Conclusion: Our findings suggest that distinct visual processing deficits in early MS may differentially impact cognition, which is not captured using standard neuropsychological evaluation. Further research may facilitate improved symptom identification and intervention in early disease.

Mechanisms Governing Oligodendrocyte Viability in Multiple Sclerosis and Its Animal Models.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS), which is triggered by an autoimmune assault targeting oligodendrocytes and myelin. Recent research indicates that the demise of oligodendrocytes due to an autoimmune attack contributes significantly to the pathogenesis of MS and its animal model experimental autoimmune encephalomyelitis (EAE). A key challenge in MS research lies in comprehending the mechanisms governing oligodendrocyte viability and devising therapeutic approaches to enhance oligodendrocyte survival. Here, we provide an overview of recent findings that highlight the contributions of oligodendrocyte death to the development of MS and EAE and summarize the current literature on the mechanisms governing oligodendrocyte viability in these diseases.

LST-AI: A deep learning ensemble for accurate MS lesion segmentation

Automated segmentation of brain white matter lesions is crucial for both clinical assessment and scientific research in multiple sclerosis (MS). Over a decade ago, we introduced an engineered lesion segmentation tool, LST. While recent lesion segmentation approaches have leveraged artificial intelligence (AI), they often remain proprietary and difficult to adopt. As an open-source tool, we present LST-AI, an advanced deep learning-based extension of LST that consists of an ensemble of three 3D U-Nets.LST-AI explicitly addresses the imbalance between white matter (WM) lesions and non-lesioned WM. It employs a composite loss function incorporating binary cross-entropy and Tversky loss to improve segmentation of the highly heterogeneous MS lesions. We train the network ensemble on 491 MS pairs of T1-weighted and FLAIR images, collected in-house from a 3T MRI scanner, and expert neuroradiologists manually segmented the utilized lesion maps for training. LST-AI also includes a lesion location annotation tool, labeling lesions as periventricular, infratentorial, and juxtacortical according to the 2017 McDonald criteria, and, additionally, as subcortical. We conduct evaluations on 103 test cases consisting of publicly available data using the Anima segmentation validation tools and compare LST-AI with several publicly available lesion segmentation models.Our empirical analysis shows that LST-AI achieves superior performance compared to existing methods. Its Dice and F1 scores exceeded 0.62, outperforming LST, SAMSEG (Sequence Adaptive Multimodal SEGmentation), and the popular nnUNet framework, which all scored below 0.56. Notably, LST-AI demonstrated exceptional performance on the MSSEG-1 challenge dataset, an international WM lesion segmentation challenge, with a Dice score of 0.65 and an F1 score of 0.63—surpassing all other competing models at the time of the challenge. With increasing lesion volume, the lesion detection rate rapidly increased with a detection rate of >75% for lesions with a volume between 10 mm3 and 100 mm3. Given its higher segmentation performance, we recommend that research groups currently using LST transition to LST-AI. To facilitate broad adoption, we are releasing LST-AI as an open-source model, available as a command-line tool, dockerized container, or Python script, enabling diverse applications across multiple platforms.

Key Components of Qigong for People With Multiple Sclerosis: A Survey of Clinicians, Researchers, and Instructors

Background Preliminary evidence suggests that Qigong (QG), a mind-body therapy, may help address symptoms of multiple sclerosis (MS), but the heterogeneity of QG content and delivery may affect its feasibility, acceptability, and efficacy. Objective To survey researchers, clinicians, and QG instructors with experience working with people with MS to identify key components of MS-specific QG guidelines and protocols. Methods We conducted an online survey to identify QG forms and movements considered helpful for MS, reasons for selection, characteristics of effective learning environments, and recommended dosage and frequency of practice. Quantitative data were analyzed using summary statistics. Qualitative data were analyzed using reflexive thematic analysis. Results Forty-seven experts, including QG instructors, clinicians, and QG and MS researchers, completed the survey. Respondents had a mean (SD) of 20 (11) years of QG teaching experience, 26 (12) years of clinical practice, 24 (9) years of QG research experience, 13 (5) years of MS research experience, and worked with at least 3 (2) people with MS. Approximately 125 QG forms/movements were recommended. Some forms were specifically recommended to address MS symptoms (e.g., emotional regulation, balance and coordination, muscle strength and flexibility, immune regulation, and circulation). Some respondents felt that any QG form could be beneficial if basic principles were met (e.g., intentional movement, posture, focused awareness, rhythmic breathing/movement, and a relaxed mind and body). Instructor qualities included the ability to convey information clearly, being caring and compassionate, proficient in QG, and having basic knowledge of MS. To promote confidence in learning QG, recommendations included having simple, easy-to-learn movements with modifications based on physical ability. We provide a sample protocol based on these recommendations. Conclusions This study provides expert guidance for developing a QG protocol for an MS population, including content and delivery recommendations.

Biobanking in clinical trials involving multiple sclerosis patients

Investigation of multiple sclerosis (MS) pathogenesis requires sophisticated analytical tools of precision medicine, such as omics research, which include genomics, microbiomics and metabolomics (proteomics, lipidomics and glycomics). Such sensitive methods are based on careful preanalytical work with biomaterials to maintain quality and obtain objective results. Implementation of biobanking as a universal method for working with biomaterials will help to standardize the stages of research, compare different scientific team's results. Collaboration of MS researchers with large biobanks can also help to conduct multicenter and long-term prospective studies, to include a wide number of patients. In this article, we analyze the experience of biobanking practice technologies in studies of MS patients and share the experience of partnership between the Center for MS of the Tomsk Region and the Bank of Biological Material of the Siberian State Medical University.

The role of ocrelizumab in recommendations and in the Polish therapeutic programme

Multiple sclerosis is a heterogeneous and chronic disease, and the primary goal of treatment is to prevent relapses and slow the progression of disability. Ocrelizumab is a generally well-tolerated disease-modifying therapy for multiple sclerosis, with high efficacy in the treatment of active relapsing forms, and a valuable treatment method for delaying the progression of the disease in patients with the primary progressive form. The activity of relapsing multiple sclerosis is defined on the basis of the clinical course of the disease or radiological findings assessed over a year. The occurrence of clinical relapses and/or activity on magnetic resonance imaging is taken into account. In line with the recommendations of the European Committee for Treatment and Research in Multiple Sclerosis and the European Academy of Neurology, as well as in accordance with the guidelines of the American Academy of Neurology, updated in 2021, depending on the disease activity in the early stage of multiple sclerosis, the choice of a disease-modifying drug should be motivated by higher efficacy. Recommendations for the treatment of multiple sclerosis in most countries in Europe and around the world are based on the above-mentioned guidelines. In Poland, recommendations for treatment modifying the course of multiple sclerosis were developed in 2023 by experts from the Multiple Sclerosis and Neuroimmunology Section of the Polish Neurological Society. Treatment based on the B.29 drug programme of the National Health Fund in Poland allows, from 1 July 2023, in addition to escalation, using the induction model based on highly effective therapies as first-line treatment.

Evaluation of obsessive-compulsive disorder prevalence in Iranian patients with multiple sclerosis and its relationship with demographic characteristics.

Background: The present study examined the prevalence of obsessive-compulsive disorder (OCD) among Iranian patients with multiple sclerosis (MS) and the relationship between OCD and the patient's demographic characteristics. Methods: The present study used a cluster sampling method to randomly select 297 patients with MS from the patients referred to the MS Clinic and Research Center of Sina University Hospital, Tehran, Iran, during 2018-2019. To gather the required data, a questionnaire consisting of demographic characteristics and disease information sections was used. Moreover, Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Obsessive-Compulsive Inventory-Revised (OCI-R), and Hospital Anxiety and Depression Scale (HADS) were employed in the present study. The comparison of qualitative and quantitative values between OCD-positive and negative groups was examined with chi-square test and independent samples t-test, respectively. Binary logistic regression was used as multivariate modeling to adjust the effects of potential confounders that could distort the relation of OCD with intended variables. Data were analyzed using SPSS software. The significance level was considered lower than 0.05. Results: Of the total of 297 patients, 77.8% were women. Moreover, analysis of the data obtained from the HADS questionnaire revealed that 11.44% (n = 34) and 15.15% (n = 45) of patients had severe depression and severe anxiety, respectively. The results of Y-BOCS indicated that the prevalence of severe OCD among patients was 19.9%. The OCI-R questionnaire revealed that the prevalence of OCD was 47.8%, which was consistent with the total of moderate, severe, and extreme values of Y-BOCS (47.9%). Furthermore, the subscales of ordering-arranging with 69 patients (22.9%) and obsessing with 46 patients (15.5%) indicated the highest frequencies as compared to other subscales. Moreover, OCD had a significant relationship with depression, anxiety, and type of MS in this regard. Conclusion: In this study, the prevalence rate of OCD among patients with MS was higher than its rate among the general population.

Introducing a core dataset for real-world data in multiple sclerosis registries and cohorts: Recommendations from a global task force

Background: As of September 2022, there was no globally recommended set of core data elements for use in multiple sclerosis (MS) healthcare and research. As a result, data harmonisation across observational data sources and scientific collaboration is limited. Objectives: To define and agree upon a core dataset for real-world data (RWD) in MS from observational registries and cohorts. Methods: A three-phase process approach was conducted combining a landscaping exercise with dedicated discussions within a global multi-stakeholder task force consisting of 20 experts in the field of MS and its RWD to define the Core Dataset. Results: A core dataset for MS consisting of 44 variables in eight categories was translated into a data dictionary that has been published and disseminated for emerging and existing registries and cohorts to use. Categories include variables on demographics and comorbidities (patient-specific data), disease history, disease status, relapses, magnetic resonance imaging (MRI) and treatment data (disease-specific data). Conclusion: The MS Data Alliance Core Dataset guides emerging registries in their dataset definitions and speeds up and supports harmonisation across registries and initiatives. The straight-forward, time-efficient process using a dedicated global multi-stakeholder task force has proven to be effective to define a concise core dataset.

Revolutionizing MS Care and Research: Inside Iran's Nationwide Multiple Sclerosis Registry

Revolutionizing MS Care and Research: Inside Iran's Nationwide Multiple Sclerosis Registry

The Journey of Data Within a Global Data Sharing Initiative: A Federated 3-Layer Data Analysis Pipeline to Scale Up Multiple Sclerosis Research.

Investigating low-prevalence diseases such as multiple sclerosis is challenging because of the rather small number of individuals affected by this disease and the scattering of real-world data across numerous data sources. These obstacles impair data integration, standardization, and analysis, which negatively impact the generation of significant meaningful clinical evidence. This study aims to present a comprehensive, research question-agnostic, multistakeholder-driven end-to-end data analysis pipeline that accommodates 3 prevalent data-sharing streams: individual data sharing, core data set sharing, and federated model sharing. A demand-driven methodology is employed for standardization, followed by 3 streams of data acquisition, a data quality enhancement process, a data integration procedure, and a concluding analysis stage to fulfill real-world data-sharing requirements. This pipeline's effectiveness was demonstrated through its successful implementation in the COVID-19 and multiple sclerosis global data sharing initiative. The global data sharing initiative yielded multiple scientific publications and provided extensive worldwide guidance for the community with multiple sclerosis. The pipeline facilitated gathering pertinent data from various sources, accommodating distinct sharing streams and assimilating them into a unified data set for subsequent statistical analysis or secure data examination. This pipeline contributed to the assembly of the largest data set of people with multiple sclerosis infected with COVID-19. The proposed data analysis pipeline exemplifies the potential of global stakeholder collaboration and underlines the significance of evidence-based decision-making. It serves as a paradigm for how data sharing initiatives can propel advancements in health care, emphasizing its adaptability and capacity to address diverse research inquiries.

Early life stress aggravates disease pathogenesis in mice with experimental autoimmune encephalomyelitis: Support for a two-hit hypothesis of multiple sclerosis etiology

Vision problems are one of the earliest diagnosed symptoms of multiple sclerosis (MS). The onset and progression of vision loss and the underlying pathogenesis in MS may be influenced by cumulative psychophysiological stress. Here, we used a two-hit model of stress in female mice to determine if early life stress (ELS, the first hit) influences the response to an immunization that induces experimental autoimmune encephalomyelitis (EAE, the second hit) later in life. We hypothesized that ELS caused by animal transportation from a vendor during early postnatal development represents a co-factor which can exacerbate the clinical severity of EAE. Indeed, adult EAE mice with a history of ELS displayed more severe clinical signs and delayed recovery compared to non-stressed EAE mice. ELS also diminished visual acuity measured by optokinetic responses, as well as locomotion and exploratory behaviours in EAE mice. Notably, ELS accelerated vision loss and caused earlier onset of visual impairments in EAE. Exacerbated functional impairments in stressed EAE mice were highly correlated with circulating corticosterone levels. The findings show that the progression of induced EAE in adulthood can be significantly impacted by adverse early life experiences. These observations emphasize the importance of comprehensive behavioural testing, including non-motor functions, to enhance the translational value of preclinical animal models of MS. Moreover, shipment stress of laboratory animals should be considered a necessary variable in preclinical MS research. The consideration of cumulative lifetime stresses provides a new perspective of MS pathogenesis within a personalized medicine framework.