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Progression of Multiple Sclerosis: Environmental Factors, Genetics, Therapeutics and Immunopathogenesis
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Progression of Multiple Sclerosis: Environmental Factors, Genetics, Therapeutics and Immunopathogenesis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 20 February 2026 | Viewed by 3276

Special Issue Editor

Dr. Alberto Gajofatto

E-Mail Website
Guest Editor
Section of Clinical Neurology, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy
Interests: neurological disorders; neurological diseases; multiple sclerosis; demyelinating diseases; immunomodulators
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue aims to explore the multifaceted aspects of multiple sclerosis (MS), focusing on the interplay of environmental factors, genetic predispositions, therapeutic advancements, and the underlying mechanisms of immunopathogenesis. We are setting out to present cutting-edge research and reviews that illuminate how lifestyle, geographical considerations, and genetic markers influence MS progression. Additionally, we hope that this Special Issue will highlight innovative therapeutic strategies aimed at altering disease outcomes and emphasize advancements in our understanding of the immune system's role in MS pathology. Together, these contributions provide a comprehensive overview of current knowledge and future directions in the management and study of this complex neurological disorder.

In this Special Issue, original research articles and reviews are welcome to be submitted. Research areas may include, but are not limited to, the following:

  1. Progressive multiple sclerosis;
  2. MS progression environmental risk factors;
  3. Genetics insights into MS progression;
  4. Therapeutic challenges of progressive MS;
  5. Immunopathogenesis of progressive MS.

We look forward to receiving your contributions.

Dr. Alberto Gajofatto
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • multiple sclerosis
  • disability progression
  • neurodegeneration
  • pathogenesis
  • immunology
  • risk factor
  • environment
  • genetics
  • treatment

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Published Papers (4 papers)

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Research

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15 pages, 1834 KB  
Article
Serum Levels of miR-34a-5p, miR-30b-5p, and miR-140-5p Are Associated with Disease Activity and Brain Atrophy in Early Multiple Sclerosis
by Riccardo Orlandi, Leopoldo Torresan, Francesca Gobbin, Elisa Orlandi, Macarena Gomez Lira and Alberto Gajofatto
Int. J. Mol. Sci. 2025, 26(17), 8597; https://doi.org/10.3390/ijms26178597 - 4 Sep 2025
Viewed by 530
Abstract
In recent years, research has focused on biomarkers as key tools to predict clinical outcomes and guide therapeutic decisions in Multiple Sclerosis (MS). MicroRNAs (miRs)—small non-coding RNA molecules that regulate gene expression at the post-transcriptional level—have emerged as promising biomarkers in MS due [...] Read more.
In recent years, research has focused on biomarkers as key tools to predict clinical outcomes and guide therapeutic decisions in Multiple Sclerosis (MS). MicroRNAs (miRs)—small non-coding RNA molecules that regulate gene expression at the post-transcriptional level—have emerged as promising biomarkers in MS due to their accessibility in biological fluids. This study investigates the role of specific serum miRs mainly involved in immune response regulation as potential prognostic biomarkers in MS, focusing on young patients with recent diagnosis. The study had a prospective design, involving a cohort of patients followed in the Hub and Spoke MS network of Verona province. Fifty-one patients (33F) aged 18–40 years with recent MS diagnosis (≤2 years; 45 relapsing-remitting, 6 primary progressive) were consecutively enrolled. At baseline, serum samples were collected for miR analysis alongside clinical-demographic and MRI data, including T2 lesion volume, normalized brain volume (NBV), gray matter volume, white matter volume (WMV) calculated at baseline and annual percentage brain volume change (PBVC) and occurrence of new T2 or gadolinium-enhancing (Gd+) lesions on follow-up scans. Candidate miRs were chosen based on their potential biological role in MS pathogenesis reported in the literature. miRs assays were done using real-time PCR and expressed as a ratio relative to a normalizer (i.e., miR-425-5p). Levels of miR-34a-5p were significantly higher in patients with Gd+ lesions (p < 0.001) and correlated to lower NBV (rho = −0.454, p = 0.001) and WMV (rho = −0.494, p < 0.001). Conversely, miR-140-5p exhibited a protective effect against occurrence of new T2 or Gd+ lesions over time (HR 0.43; IC 95% 0.19–0.99; p = 0.048). Additionally, miR-30b-5p correlated directly with PBVC (adjusted rho = −0.646; p < 0.001). These findings support the potential of serum miR-34a-5p, miR-140-5p, and miR-30b-5p as markers of disease activity and progression in patients with recently diagnosed MS. Full article
(This article belongs to the Special Issue Progression of Multiple Sclerosis: Environmental Factors, Genetics, Therapeutics and Immunopathogenesis)
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24 pages, 843 KB  
Article
Brain Atrophy and Cognitive Impairment in Primary and Secondary Progressive Multiple Sclerosis Cohort—Similar Progressive MS Phenotype
by Bartosz Gajewski, Małgorzata Siger, Iwona Karlińska, Igor A. Bednarski, Mariola Świderek-Matysiak and Mariusz Stasiołek
Int. J. Mol. Sci. 2025, 26(17), 8523; https://doi.org/10.3390/ijms26178523 - 2 Sep 2025
Viewed by 500
Abstract
The diagnosis and monitoring of progressive multiple sclerosis (PMS) require further development of fast and effective clinical tools. Relations between MRI-based brain atrophy measures and cognitive impairment in people with primary progressive and secondary progressive MS (PwPPMS, n = 20 and PwSPMS, n [...] Read more.
The diagnosis and monitoring of progressive multiple sclerosis (PMS) require further development of fast and effective clinical tools. Relations between MRI-based brain atrophy measures and cognitive impairment in people with primary progressive and secondary progressive MS (PwPPMS, n = 20 and PwSPMS, n = 19, respectively) were investigated in a prospective study with follow-up after a mean 14.97 ± 4.67 months. MRI analysis showed that at baseline and follow-up in PwSPMS, the left thalamic fraction and corpus callosum fraction were significantly lower than in PwPPMS (baseline: 0.39 ± 0.04 vs. 0.44 ± 0.06, p = 0.0203 and 0.26 ± 0.05 vs. 0.30 ± 0.05, p = 0.0097; respectively and follow-up: 0.40 ± 0.04 vs. 0.44 ± 0.07, p = 0.0443 and 0.25 ± 0.06 vs. 0.30 ± 0.05, p = 0.0103, respectively). In contrast, only at baseline, PwPPMS had a significantly lower cerebellar white matter fraction (CWMF) than PwSPMS (1.83 ± 0.20 vs. 2.01 ± 0.24, p = 0.0132). No other significant differences were observed in the MRI fractions at either study time point or in the changes of the MRI fractions between the PwPPMS and PwSPMS. However, a significant decline in the right putaminal fraction was found during observation in PwSPMS (0.332% ± 0.05% vs. 0.328% ± 0.05%, p = 0.0479). Cognitive test scores and their changes did not differ significantly between the subgroups. Declines in the Brief Visuospatial Memory Test Revised in the whole PMS group (18.74 ± 7.43 vs. 17.03 ± 7.61, p = 0.0209) and in PwPPMS (19.50 ± 8.29 vs. 17.20 ± 7.72, p = 0.0338), as well as in the Brief International Cognitive Assessment for Multiple Sclerosis in PwPPMS (1.05 ± 0.89 vs. 1.25 ± 1.02, p = 0.0421), were observed. In both PwPMS and PwPPMS, a worsening on the Symbol Digit Modalities Test (SDMT) was associated with the reduction of fractions of white matter, cerebellum and right thalamus. SDMT performance also correlated with both gray matter fraction (GMF) and CWMF in the whole group, and with cerebellar gray matter fraction (CGMF) in PwPPMS. In PwSPMS, only Stroop Color and Word Test scores correlated with GMF and CGMF. In conclusion, subtle differences between PwPPMS and PwSPMS were detected both in MRI and neuropsychological parameters. Thus, our results indicate the need for a multicomponent attempt in characterizing progression in different clinical courses of MS. Full article
(This article belongs to the Special Issue Progression of Multiple Sclerosis: Environmental Factors, Genetics, Therapeutics and Immunopathogenesis)
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23 pages, 2805 KB  
Article
Systematic Analysis of Alternative Splicing in Transcriptomes of Multiple Sclerosis Patient Brain Samples
by Müge Sak, Julia H. Chariker and Eric C. Rouchka
Int. J. Mol. Sci. 2025, 26(17), 8195; https://doi.org/10.3390/ijms26178195 - 23 Aug 2025
Viewed by 722
Abstract
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease affecting approximately 1 million people in the United States. Despite extensive research into the mechanisms of disease development, many aspects of the biological changes during MS progression and the varying symptoms among patients remain [...] Read more.
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease affecting approximately 1 million people in the United States. Despite extensive research into the mechanisms of disease development, many aspects of the biological changes during MS progression and the varying symptoms among patients remain unclear. In the era of high-throughput sequencing, transcriptome databases are flooded with data. However, bulk RNA sequencing (RNA-seq) data are typically used only for differential gene expression analysis. Alternative splicing, a key process that alters the transcriptome, can also be identified from bulk data. Here, we accessed 11 studies with bulk RNA-seq data of postmortem MS patients’ brain samples via NCBI’s Gene Expression Omnibus (GEO). We extracted additional information from these data by identifying exclusively alternatively spliced genes via replicate multivariate analysis of transcript splicing (rMATS) analysis. Our analyses revealed that changes in RNA splicing mediate distinct biological signals compared to those driven by differential gene expression. Gene ontology and protein do-main analyses of genes exclusively regulated by alternative splicing revealed distinct molecular differences between progressive and relapsing–remitting MS as well as among lesions from different brain regions and between white and gray matter. These findings highlight the critical role of alternative splicing and its associated pathways in MS disease development and progression. Full article
(This article belongs to the Special Issue Progression of Multiple Sclerosis: Environmental Factors, Genetics, Therapeutics and Immunopathogenesis)
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Review

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51 pages, 1004 KB  
Review
Refining Prognostic Factors in Adult-Onset Multiple Sclerosis: A Narrative Review of Current Insights
by Tommaso Guerra, Massimiliano Copetti, Mariaclara Achille, Caterina Ferri, Marta Simone, Sandra D’Alfonso, Maura Pugliatti and Pietro Iaffaldano
Int. J. Mol. Sci. 2025, 26(16), 7756; https://doi.org/10.3390/ijms26167756 - 11 Aug 2025
Viewed by 1240
Abstract
Multiple sclerosis (MS) is characterized by a continuum of diverse neuroinflammatory and neurodegenerative processes that contribute to disease progression from the earliest stages. This leads to a highly heterogeneous clinical course, requiring early and accurate prognostic assessment: the identification of reliable prognostic biomarkers [...] Read more.
Multiple sclerosis (MS) is characterized by a continuum of diverse neuroinflammatory and neurodegenerative processes that contribute to disease progression from the earliest stages. This leads to a highly heterogeneous clinical course, requiring early and accurate prognostic assessment: the identification of reliable prognostic biomarkers is crucial to support therapeutic decision-making and guide personalized disease management. In this narrative review, we critically examined the current MS literature, investigating prognostic factors associated with disease progression and irreversible disability in adult-onset MS, with a focus on different clinical, radiological, and molecular biomarkers. Particular attention is directed toward the prognostic value of baseline clinical and neuroimaging factors, emerging biomarkers of smoldering disease, and progression independent of relapse activity (PIRA) events. Additionally, we discussed the role of integrated prognostic tools and risk scores, as well as their potential impact on clinical practice. We aim to provide a comprehensive and clinically oriented synthesis of available evidence in the MS biomarkers field, supporting multifaceted prognostication strategies to improve long-term outcomes in people with MS. Full article
(This article belongs to the Special Issue Progression of Multiple Sclerosis: Environmental Factors, Genetics, Therapeutics and Immunopathogenesis)
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